Sample records for diffuse ssc patients
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Crowell, Michael D; Umar, Sarah B; Griffing, W Leroy; DiBaise, John K; Lacy, Brian E; Vela, Marcelo F
2017-02-01
Systemic scleroderma (SSc) is associated with esophageal aperistalsis and hypotensive esophagogastric junction pressure, although there could be a gradation in esophageal motor dysfunction. We characterized esophageal motor function by high-resolution esophageal manometry (HRM) and assessed associations between SSc severity, health-related quality of life (HRQOL), and HRM findings in patients. We performed a prospective study of 200 patients with SSc and 102 patients without SSc (controls) who underwent HRM at Mayo Clinic Arizona from May 2006 through January 2015. We used data on integrated relaxation pressure, distal contractile integral, and distal latency to classify esophageal motility disorders according to the Chicago Classification v 3.0. A subset of subjects (n = 122) completed SSc-specific gastrointestinal symptom and HRQOL questionnaires. HRM findings, symptoms, and HRQOL data were compared among diffuse SSc, limited SSc, and control subjects. Categorical variables were compared by using the χ 2 or Fisher exact test; continuous variables were compared by using Mann-Whitney or Kruskal-Wallis test. Multivariable logistic regression was used to assess the association between severity of esophageal dysmotility and baseline clinical factors. Among patients with SSc, 83 had diffuse SSc (42%), and 117 had limited SSc (58%). Absent contractility was more frequent in patients with SSc than in controls (56% vs 13%; P < .001). HRM findings varied among the patients; absent contractility (56%) was the most frequent diagnosis, followed by normal motility (26%) and ineffective esophageal motility (10%). Classic scleroderma esophagus (esophagogastric junction pressure with absent contractility) was only observed in 33% of patients (34% with diffuse SSc vs 32% limited SSc) (P = .880). Severe esophageal dysmotility was associated with disease duration, interstitial lung disease, and higher gastrointestinal symptom scores (P < .001). HRQOL was decreased in patients with SSc and severe esophageal dysmotility. Although severe dysmotility is more common in patients with SSc than in controls, we observed the so-called scleroderma esophagus in only one-third of patients with SSc. Esophageal motor function appears to be heterogeneous in SSc. Esophageal dysmotility reduces HRQOL in patients with SSc. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
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Perrot, Serge; Peixoto, Mariana; Dieudé, Philippe; Hachulla, Eric; Avouac, Jerome; Ottaviani, Sebastien; Allanore, Yannick
2017-01-01
Fibromyalgia (FM) may occur with rheumatoid arthritis (RA) and systemic sclerosis (SSc), and debate remains about its diagnosis. We aimed to use three FM tools (a screening tool (FiRST), diagnostic criteria (ACR 1990 and revised 2010), to compare FM prevalence between RA and SSc patients, to describe the phenotypes of patients with comorbid FM, and to analyze links between FM and secondary Sjögren's syndrome (SS). Consecutive adult patients with confirmed RA or SSc from four university hospitals were tested with the three FM tools. FiRST detected FM in 22.6% of the 172 RA patients, with confirmation in 22.1% (ACR1990) and 19.1% (ACR2010). ACR1990FM+ RA patients had more diffuse pain, whereas ACR2010FM+ RA patients had higher BMI and pain intensity, more diffuse pain, active disease, disability, and associated SS. FiRST detected FM in 27.8% of the 122 SSc patients, with confirmation in 30.3% (ACR1990) and 23.7% (ACR2010). ACR1990FM+ SSc patients had greater disability and pain intensity, and more diffuse pain, whereas ACR2010FM+ SSc patients had higher BMI, pain intensity, more disability and diffuse pain, and associated SS. Correlations between FM diagnostic and screening tool results were modest in both conditions. Secondary SS was associated with comorbid FM. The prevalence of FM is high in SSc and RA, whatever the FM diagnostic tool used. Secondary SS is associated with FM in both RA and SSc. The revised ACR 2010 FM criteria and FiRST screening tool reveal specific phenotypes potentially useful for improving disease management.
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Metabolomic profile of systemic sclerosis patients.
Murgia, Federica; Svegliati, Silvia; Poddighe, Simone; Lussu, Milena; Manzin, Aldo; Spadoni, Tatiana; Fischetti, Colomba; Gabrielli, Armando; Atzori, Luigi
2018-05-16
Systemic sclerosis (SSc) is an autoimmune disease of unknown aetiology characterized by vascular lesions, immunological alterations and diffuse fibrosis of the skin and internal organs. Since recent evidence suggests that there is a link between metabolomics and immune mediated disease, serum metabolic profile of SSc patients and healthy controls was investigated by 1 H-NMR and GC-MS techniques. The results indicated a lower level of aspartate, alanine, choline, glutamate, and glutarate in SSc patients compared with healthy controls. Moreover, comparing patients affected by limited SSc (lcSSc) and diffuse SSc (dcSSc), 6 discriminant metabolites were identified. The multivariate analysis performed using all the metabolites significantly different revealed glycolysis, gluconeogenesis, energetic pathways, glutamate metabolism, degradation of ketone bodies and pyruvate metabolism as the most important networks. Aspartate, alanine and citrate yielded a high area under receiver-operating characteristic (ROC) curves (AUC of 0.81; CI 0.726-0.93) for discriminating SSc patients from controls, whereas ROC curve generated with acetate, fructose, glutamate, glutamine, glycerol and glutarate (AUC of 0.84; CI 0.7-0.98) discriminated between lcSSc and dcSSc. These results indicated that serum NMR-based metabolomics profiling method is sensitive and specific enough to distinguish SSc from healthy controls and provided a feasible diagnostic tool for the diagnosis and classification of the disease.
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D-penicillamine in systemic sclerosis? Yes!
Medsger, T A; Lucas, M; Wildy, K S; Baker, C
2001-01-01
The use of D-penicillamine in systemic sclerosis (SSc) has been controversial. We have reviewed the major published studies on this drug in SSc with diffuse cutaneous (dc) involvement and summarized our own recent experience in dcSSc patients treated with and without D-penicillamine. We conclude that D-penicillamine favourably alters the natural history of skin involvement in dcSSc, even when used in low dose. Furthermore, recurrence of diffuse skin change after discontinuation of D-penicillamine and improvement in skin thickening after reinitiation of the drug support its effectiveness. We believe that the rheumatologic community should use D-penicillamine in patients with early dcSSc.
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Significance of palpable tendon friction rubs in early diffuse cutaneous systemic sclerosis.
Doré, Adam; Lucas, Mary; Ivanco, Dana; Medsger, Thomas A; Domsic, Robyn T
2013-08-01
Palpable tendon friction rubs (TFRs) in systemic sclerosis (SSc; scleroderma) have been associated with diffuse skin thickening, increased disability, and poor survival. Our objective was to quantify the prognostic implications of palpable TFRs on the development of disease complications and longer-term mortality in an incident cohort of early diffuse cutaneous SSc (dcSSc) patients. We identified early dcSSc patients (disease duration <2 years from the first SSc symptom) first evaluated at the University of Pittsburgh Scleroderma Center between 1980 and 2006 and found to have palpable TFRs. These patients were matched 1:1 with the next consecutive early dcSSc patient without TFRs as a control. All had ≥2 clinic visits and 5 years of followup from the first visit. A total of 287 early dcSSc patients with TFR were identified and matched to 287 controls. The median disease duration was 0.83 years in TFR patients and 1.04 years in controls. The median followup was 10.1 years in TFR patients and 7.9 years in controls. Over the course of their illness, patients with TFRs had a >2-fold risk of developing renal crisis and cardiac and gastrointestinal disease complications, even after adjustment for other known risk factors. Patients with TFRs had poorer 5- and 10-year survival rates. Patients with early dcSSc having ≥1 TFRs are at an increased risk of developing renal, cardiac, and gastrointestinal involvement before and after their first Scleroderma Center visit and have reduced survival. Patients presenting with TFRs should be carefully monitored for serious internal organ involvement. Copyright © 2013 by the American College of Rheumatology.
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Tolosa-Vilella, Carles; Morera-Morales, Maria Lluisa; Simeón-Aznar, Carmen Pilar; Marí-Alfonso, Begoña; Colunga-Arguelles, Dolores; Callejas Rubio, José Luis; Rubio-Rivas, Manuel; Freire-Dapena, Maika; Guillén-Del Castillo, Alfredo; Iniesta-Arandia, Nerea; Castillo-Palma, Maria Jesús; Egurbide-Arberas, Marivi; Trapiellla-Martínez, Luis; Vargas-Hitos, José A; Todolí-Parra, José Antonio; Rodriguez-Carballeira, Mónica; Marin-Ballvé, Adela; Pla-Salas, Xavier; Rios-Blanco, Juan José; Fonollosa-Pla, Vicent
2016-10-01
Digital ulcers (DU) are the most common vascular complication of systemic sclerosis (SSc). We compared the characteristics between patients with prior or current DU with those never affected and evaluated whether a history of DU may be a predictor of vascular, organ involvement, and/or death in patients with SSc. Data from SSc patients with or without prior or current DU were collected by 19 referral centers in an ongoing registry of Spanish SSc patients, named Registro de ESCLErodermia (RESCLE). Demographics, organ involvement, autoimmunity features, nailfold capillary pattern, survival time, and causes of death were analyzed to identify DU related characteristics and survival of the entire series and according to the following cutaneous subsets-diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and SSc sine scleroderma (ssSSc). Out of 1326, 552 patients enrolled in the RESCLE registry had prior or current DU, 88% were women, the mean age was 50 ± 16 years, and the mean disease duration from first SSc symptom was 7.6 ± 9.6 years. Many significant differences were observed in the univariate analysis between patients with and without prior/current DU. Multivariate analysis identified that history of prior/current DU in patients with SSc was independently associated to younger age at SSc diagnosis, diffuse cutaneous SSc, peripheral vascular manifestations such Raynaud's phenomenon, telangiectasia, and acro-osteolysis but no other vascular features such as pulmonary arterial hypertension or scleroderma renal crisis. DU was also associated to calcinosis cutis, interstitial lung disease, as well as worse survival. Multivariate analysis performed in the cutaneous subsets showed that prior/current DU were independently associated: (1) in dcSSc, to younger age at SSc diagnosis, presence of telangiectasia and calcinosis and rarely a non-SSc pattern on nailfold capillaroscopy; (2) in lcSSc, to younger age at SSc diagnosis, presence of Raynaud's phenomenon as well as calcinosis cutis, interstitial lung disease, and higher incidence of death from all causes; and (3) in ssSSc, to younger age at first SSc symptom and greater incidence of death from all causes. Digital ulcers develop in patients with SSc younger at diagnosis, mainly in patients with dcSSc and lcSSc, and they are associated to other peripheral vascular manifestations such as Raynaud's phenomenon, telangiectasia, and acro-osteolysis but also to calcinosis, and interstitial lung disease. History of DU in SSc leads to worse survival, also noticeable for lcSSc and ssSSc subsets but not for dcSSc patients. Copyright © 2016 Elsevier Inc. All rights reserved.
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Clinical significance of serum decoy receptor 3 levels in patients with systemic sclerosis.
Yamada, Daisuke; Asano, Yoshihide; Takahashi, Takehiro; Masui, Yuri; Aozasa, Naohiko; Akamata, Kaname; Noda, Shinji; Tamaki, Zenshiro; Tada, Yayoi; Sugaya, Makoto; Sato, Shinichi; Kadono, Takafumi
2012-01-01
Decoy receptor 3 (DcR3) is associated with autoimmunity and altered angiogenesis in certain pathological conditions. We herein measured serum DcR3 levels in 51 patients with systemic sclerosis (SSc) and 19 healthy controls and evaluated their clinical significance in this disorder. Serum DcR3 levels were significantly higher in diffuse cutaneous SSc (dcSSc) patients than in limited cutaneous SSc patients and in healthy controls. In dcSSc, serum DcR3 levels were significantly elevated in patients with disease duration of ≤6 years compared with healthy controls, but not in those with disease duration of >6 years. Serum DcR3 levels correlated negatively with the percentage of predicted diffusion lung capacity for carbon monoxide and positively with right ventricular systolic pressure. Furthermore, serum DcR3 levels positively correlated with C-reactive protein, erythrocyte sedimentation rate and immunoglobulin G. Collectively, the elevation of serum DcR3 levels is associated with the development of pulmonary arterial hypertension and systemic inflammation in SSc.
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Sampaio-Barros, Percival D; Bortoluzzo, Adriana B; Marangoni, Roberta G; Rocha, Luiza F; Del Rio, Ana Paula T; Samara, Adil M; Yoshinari, Natalino H; Marques-Neto, João Francisco
2012-10-01
To analyze survival, prognostic factors, and causes of death in a large cohort of patients with systemic sclerosis (SSc). From 1991 to 2010, 947 patients with SSc were treated at 2 referral university centers in Brazil. Causes of death were considered SSc-related and non-SSc-related. Multiple logistic regression analysis was used to identify prognostic factors. Survival at 5 and 10 years was estimated using the Kaplan-Meier method. One hundred sixty-eight patients died during the followup. Among the 110 deaths considered related to SSc, there was predominance of lung (48.1%) and heart (24.5%) involvement. Most of the 58 deaths not related to SSc were caused by infection, cardiovascular or cerebrovascular disease, and cancer. Male sex, modified Rodnan skin score (mRSS) > 20, osteoarticular involvement, lung involvement, and renal crisis were the main prognostic factors associated to death. Overall survival rate was 90% for 5 years and 84% for 10 years. Patients presented worse prognosis if they had diffuse SSc (85% vs 92% at 5 yrs, respectively, and 77% vs 87% at 10 yrs, compared to limited SSc), male sex (77% vs 90% at 5 yrs and 64% vs 86% at 10 yrs, compared to female sex), and mRSS > 20 (83% vs 90% at 5 yrs and 66% vs 86% at 10 yrs, compared to mRSS < 20). Survival was worse in male patients with diffuse SSc, and lung and heart involvement represented the main causes of death in this South American series of patients with SSc.
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High Rhodotorula sequences in skin transcriptome of patients with diffuse systemic sclerosis.
Arron, Sarah T; Dimon, Michelle T; Li, Zhenghui; Johnson, Michael E; Wood, Tammara A; Feeney, Luzviminda; Angeles, Jorge G; Lafyatis, Robert; Whitfield, Michael L
2014-08-01
Previous studies have suggested a role for pathogens as a trigger of systemic sclerosis (SSc), although neither a pathogen nor a mechanism of pathogenesis is known. Here we show enrichment of Rhodotorula sequences in the skin of patients with early, diffuse SSc compared with that in normal controls. RNA-seq was performed on four SSc patients and four controls, to a depth of 200 million reads per patient. Data were analyzed to quantify the nonhuman sequence reads in each sample. We found little difference between bacterial microbiome and viral read counts, but found a significant difference between the read counts for a mycobiome component, R. glutinis. Normal samples contained almost no detected R. glutinis or other Rhodotorula sequence reads (mean score 0.021 for R. glutinis, 0.024 for all Rhodotorula). In contrast, SSc samples had a mean score of 5.039 for R. glutinis (5.232 for Rhodotorula). We were able to assemble the D1-D2 hypervariable region of the 28S ribosomal RNA (rRNA) of R. glutinis from each of the SSc samples. Taken together, these results suggest that R. glutinis may be present in the skin of early SSc patients at higher levels than in normal skin, raising the possibility that it may be triggering the inflammatory response found in SSc.
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CD16-positive circulating monocytes and fibrotic manifestations of systemic sclerosis.
Lescoat, Alain; Lecureur, Valérie; Roussel, Mikael; Sunnaram, Béatrice Ly; Ballerie, Alice; Coiffier, Guillaume; Jouneau, Stéphane; Fardel, Olivier; Fest, Thierry; Jégo, Patrick
2017-07-01
The objective of this study is to assess the association of clinical manifestations of systemic sclerosis (SSc) with the absolute count of circulating blood monocyte subpopulations according to their membrane expression of CD16. Forty-eight consecutive patients fulfilling the 2013 ACR/EULAR classification criteria for SSc were included in this cross-sectional study. CD16+ monocyte absolute count was defined by flow cytometry and confronted to the clinical characteristics of SSc patients. Twenty-three healthy donors (HD) were randomly selected for comparison. SSc patients had an increased number of total circulating blood monocytes compared to HD (p < 0.001). The CD16- subpopulation absolute count was increased in SSc patients compared to HD (p < 0.001) but was similar in limited SSc (lSSc) and diffuse SSc (dSSc). On the contrary, the CD16+ population absolute count was increased in dSSc compared to both HD and lSSc patients (dSSc 0.071 Giga/L (±0.034) vs HD 0.039 Giga/L (±0.030), p < 0.01, and dSSc 0.071 Giga/L (±0.034) vs lSSc 0.048 Giga/L (±0.024), p < 0.05). The CD16+ monocyte subpopulation absolute count was significantly correlated with the severity of skin fibrosis evaluated by the modified Rodnan skin score (p < 0.001). The CD16+ monocyte subpopulation was also associated with pulmonary fibrosis (p < 0.05), with the severity of the restrictive ventilatory defect evaluated by total lung capacity (p < 0.05) and with the pulmonary function impairment reflected by diffusing capacity of the lungs for carbon monoxyde measures (p < 0.01). These results suggest that CD16+ monocytes are associated with the main fibrotic manifestations of SSc and their role in the pathogenesis of fibrosis in this autoimmune disorder should therefore be further considered.
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Denton, Christopher P; Krieg, Thomas; Guillevin, Loic; Schwierin, Barbara; Rosenberg, Daniel; Silkey, Mariabeth; Zultak, Maurice; Matucci-Cerinic, Marco
2012-05-01
The Digital Ulcers Outcome (DUO) Registry was designed to describe the clinical and antibody characteristics, disease course and outcomes of patients with digital ulcers associated with systemic sclerosis (SSc). The DUO Registry is a European, prospective, multicentre, observational, registry of SSc patients with ongoing digital ulcer disease, irrespective of treatment regimen. Data collected included demographics, SSc duration, SSc subset, internal organ manifestations, autoantibodies, previous and ongoing interventions and complications related to digital ulcers. Up to 19 November 2010 a total of 2439 patients had enrolled into the registry. Most were classified as either limited cutaneous SSc (lcSSc; 52.2%) or diffuse cutaneous SSc (dcSSc; 36.9%). Digital ulcers developed earlier in patients with dcSSc compared with lcSSc. Almost all patients (95.7%) tested positive for antinuclear antibodies, 45.2% for anti-scleroderma-70 and 43.6% for anticentromere antibodies (ACA). The first digital ulcer in the anti-scleroderma-70-positive patient cohort occurred approximately 5 years earlier than the ACA-positive patient group. This study provides data from a large cohort of SSc patients with a history of digital ulcers. The early occurrence and high frequency of digital ulcer complications are especially seen in patients with dcSSc and/or anti-scleroderma-70 antibodies.
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Cipriani, Paola; Franca Milia, Anna; Liakouli, Vasiliki; Pacini, Alessandra; Manetti, Mirko; Marrelli, Alessandra; Toscano, Annarita; Pingiotti, Elisa; Fulminis, Antonietta; Guiducci, Serena; Perricone, Roberto; Kahaleh, Bashar; Matucci-Cerinic, Marco; Ibba-Manneschi, Lidia; Giacomelli, Roberto
2006-09-01
Systemic sclerosis (SSc) is characterized by early endothelial damage evolving to vascular desertification. Stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 regulate specific steps in new vessel formation. We undertook this study to determine whether an alteration of the SDF-1/CXCR4 axis might be involved in the pathogenetic mechanisms following ischemic damage during SSc. We enrolled 36 SSc patients and 15 controls. Skin biopsy samples were obtained from each subject, and the expression of SDF-1 and CXCR4 was assessed by immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR), and Western blot analyses. Furthermore, isolated microvascular endothelial cells (MVECs) from 4 patients with diffuse cutaneous SSc (dcSSc) and 3 controls were analyzed for SDF-1 and CXCR4 by confocal laser scanning microscopy, RT-PCR, and Western blotting. SDF-1 and CXCR4 were up-regulated in the skin of patients with early (edematous) SSc, both in the diffuse and limited cutaneous forms, and progressively decreased, with the lowest expression in the latest phases of both SSc subsets. MVECs from patients with dcSSc expressed significantly higher amounts of both isoforms of SDF-1 in the early stage of disease, with a progressive reduction of SDF-1 and CXCR4 in later stages. On the surface of cultured MVECs from patients with dcSSc, SDF-1 and CXCR4 colocalized in polarized areas, suggesting that they are activated in vivo and that they are under strict genetic control to retain capping function. Due to its transient expression, SDF-1 could be considered a future therapeutic target to induce new vessel formation in SSc.
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High Rhodotorula sequences in skin transcriptome of patients with diffuse systemic sclerosis
Arron, Sarah T.; Dimon, Michelle T.; Li, Zhenghui; Johnson, Michael E.; Wood, Tammara; Feeney, Luzviminda; Angeles, Jorge Gil; Lafyatis, Robert; Whitfield, Michael L.
2014-01-01
Previous studies have suggested a role for pathogens as a trigger of systemic sclerosis (SSc), though neither a pathogen nor a mechanism of pathogenesis is known. Here we show enrichment of Rhodotorula sequences in the skin of patients with early, diffuse SSc compared to normal controls. RNA-seq was performed on four SSc and four controls, to a depth of 200 million reads per patient. Data were analyzed to quantify the non-human sequence reads in each sample. We found little difference between bacterial microbiome and viral read counts, but found a significant difference between the read counts for a mycobiome component, R. glutinis. Normal samples contained almost no detected R. glutinis or other Rhodotorula sequence reads (mean score 0.021 for R. glutinis, 0.024 for all Rhodotorula). In contrast, SSc samples had a mean score of 5.039 for R. glutinis (5.232 for Rhodotorula). We were able to assemble the D1–D2 hypervariable region of the 28S rRNA of R. glutinis from each of the SSc samples. Taken together, these results suggest R. glutinis may be present in the skin of early SSc patients at higher levels than normal skin, raising the possibility that it may be triggering the inflammatory response found in SSc. PMID:24608988
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Scolnik, M; Lancioni, E; Saucedo, C; Marin, J; Sabelli, M; Bedran, Z; Soriano, E R; Catoggio, L J
2014-01-01
Prevalence of systemic sclerosis (SSc) and different clinical subsets varies across the world. Few data have been published on SSc patients in Latin America. Our objective was to describe a SSc cohort in Argentina and to compare clinical findings, disease subsets and antibodies with other international SSc populations. Patients with SSc (n=234) seen at the Rheumatology section of the Hospital Italiano de Buenos Aires between 2000-2011 were retrospectively analysed. Data on clinical manifestations, disease subsets and antibodies were obtained. Patients were classified into diffuse cutaneous (dc) and limited cutaneous (lc) subsets. Comparison with other cohorts (France, United States, Germany, Italy, Mexico, EUSTAR and Brazil) was made based on published information. A higher female:male ratio (12:1) and a higher limited subset prevalence (76.1%) was found in this Argentine cohort comparing with others. We also found a lower prevalence of diffuse disease, anti Scl-70 (antitopoisomerase) and nucleolar pattern antinuclear antibodies. Within each subset, clinical findings were similar with other SSc populations except for a very low prevalence in renal crisis (0.02% of dc SS). With slight variations perhaps due to genetic, environmental or referral factors, SSc in this cohort appears to be similar to that described in other parts of the world.
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Semenov, Viktor; Kuryata, Olexandr; Lysunets, Tatiana
2018-01-01
Systemic sclerosis (SSc) is a rare disease of connective tissue, manifestations of which may vary in different geographical areas. We aimed to describe the clinical portrait of patients with SSc in Dnipropetrovsk region and to investigate how initial clinical and laboratory characteristics are connected with the presence of hypertension in SSc onset. Patients were enrolled to this study from the registry of SSc patients, established in the Rheumatology Department, Mechnikov Dnipropetrovsk Regional Clinic, Dnipro. This registry contains histories of new cases of SSc from 1993 to 2014. Patients are followed-up and receive treatment according to EULAR and local standards. Diagnosis of SSc was based on ACR and EULAR Criteria for systemic Sclerosis. Two patients developed scleroderma renal crisis during follow-up. This report is a cross-sectional study. We analysed only data of the first visit to a rheumatologist. In total 148 patients (median age [IQR] - 47 [40; 52] years) fulfilled the inclusion criteria. Male/female ratio was 1 : 20.1. The most frequent clinical signs were Raynaud's phenomenon and arthritis. The prevalence of skin lesion in dcSSc patients was twice as high as in lcSSc patients. Pulmonary fibrosis occurred significantly more commonly in dcSSc patients. Hypertension occurred in 26-33% in both groups. Patients with hypertension at the SSc onset were seven years older than normotensive patients. More hypertensive patients were classified as lcSSc. Mean GFR was dramatically lower in hypertensive patients. The most common clinical form in our study was diffuse cutaneous subset of SSc. Hypertension in patients with SSc may be associated with local cutaneous subset of SSc and renal impairment. The strongest predictors of clinical form of SSc are signs of fibrosis (skin lesion and pulmonary fibrosis) and inflammation (arthritis and elevated CRP).
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Ostojic, Predrag; Zivojinovic, Sladjana; Reza, Tamara; Damjanov, Nemanja
2010-08-01
This study aimed to assess symptoms of depression and anxiety in Serbian patients with systemic sclerosis (SSc) and to estimate the impact of disease severity and socioeconomic factors on development of depression and anxiety in SSc. Thirty-five patients with SSc and 30 age- and gender-matched healthy individuals participated. Symptoms of depression and anxiety were evaluated using the Beck's depression inventory and Zung's anxiety self-assessment scale. We estimated the impact of gender, age, economic status, marital status, disease duration, disease subset (limited or diffuse), and some clinical features on development of depressive symptoms and anxiety in patients with SSc. Symptoms of depression were found in 68.6% of patients (compared with 23.3% in the control group), were more frequent in patients with longer disease duration and in female and older patients, and were more common in unemployed and retired patients than in employed individuals. No differences in anxiety and depressive symptoms was noticed between patients with limited and diffuse SSc or those with or without restrictive lung disease, pulmonary hypertension, finger-tip ulcers, and heart involvement. Symptoms of depression were associated with severe pain. Symptoms of anxiety were found in 80% of patients compared with 13.3% of healthy individuals and were equally as frequent in patients of different gender, age, socioeconomic status, and disease duration and severity. Symptoms of depression and anxiety are common in Serbian patients with SSc. Depressive symptoms depended mostly on socioeconomic factors, disease duration, and pain intensity, whereas disease severity had no significant impact on development of depressive symptoms and anxiety.
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Kundu, Devi; Abraham, David; Black, Carol M; Denton, Christopher P; Bruckdorfer, K Richard
2014-12-01
S-Nitrosothiols (RSNOs) are bioactive forms of nitric oxide which are involved in cell signalling and redox regulation of vascular function. Circulating S-nitrosothiols are predominantly in the form of S-nitrosoalbumin. In this study plasma concentrations of S-nitrosothiols were measured in patients with systemic sclerosis (SSc) where NO metabolism is known to be abnormal. Venous blood was collected from 16 patients with Raynaud's phenomenon (RP), 45 with systemic sclerosis (SSc) (34 patients had limited SSc (IcSSc) and 11 diffuse cutaneous disease (dcSSc)). Twenty six healthy subjects were used as controls. Plasma S-nitrosothiol concentrations were measured by chemiluminescence. The measurements were related to the extent of biological age, capillary/skin scores and disease duration. Plasma RSNO levels in patients with Raynaud's phenomenon (RP) and in those with SSc was significantly lower compared to the concentrations in control subjects. In SSc, plasma S-nitrosothiols were often below the level of detection (1nM). Low S-nitrosothiol concentrations were observed in the blood of patients with SSc and patients with RP indicating a profound disturbance of nitric oxide metabolism. Copyright © 2014 Elsevier Inc. All rights reserved.
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Busquets, Joanna; Del Galdo, Francesco; Kissin, Eugene Y.
2010-01-01
Objectives. To obtain an objective, unbiased assessment of skin fibrosis in patients with SSc for use in clinical trials of SSc disease-modifying therapeutics. Methods. Skin biopsies from the dorsal forearm of six patients with diffuse SSc and six healthy controls, and skin biopsies from the forearm of one patient with diffuse SSc before and following 1 year treatment with mycophenolate mofetil were analysed by confocal laser scanning microscopy (CLSM) with specific antibodies against collagen types I and III or fibronectin. The integrated density of fluorescence (IDF) was calculated employing National Institutes of Health-ImageJ software in at least four different fields per biopsy spanning the full dermal thickness. Results. The intensities of collagen types I and III and fibronectin IDF were 174, 147 and 139% higher in SSc skin than in normal skin, respectively. All differences were statistically significant. The sum of the IDF values obtained for the three proteins yielded a comprehensive fibrosis score. The average fibrosis score for the six SSc samples was 28.3 × 106 compared with 18.6 × 106 for the six normal skin samples (P < 0.0001). Comparison of skin biopsies obtained from the same SSc patient before treatment and after 12 months of treatment with mycophenolate mofetil showed a reduction of 39% in total fibrosis score after treatment. Conclusions. CLSM followed by quantitative image analysis provides an objective and unbiased assessment of skin fibrosis in SSc and could be a useful end-point for clinical trials with disease-modifying agents to monitor the response or progression of the disease. PMID:20202926
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Sujau, Ibrahim; Ng, Chin Teck; Sthaneshwar, Pavai; Sockalingam, Sargunan; Cheah, Tien Eang; Yahya, Fariz; Jasmin, Raja
2015-05-01
To evaluate the clinical and antibody profile of systemic sclerosis (SSc) in a Malaysian cohort. Consecutive patients with SSc in University Malaya Medical Centre from March to November 2012 were included in this study. In addition to clinical characterization, all subjects underwent autoantibody testing using Euroline immunoblot assay. The association between clinical features and autoantibody profile was evaluated. There were 31, predominantly Chinese (45.2%), subjects. Limited cutaneous disease was the most common subtype (71%). Raynaud's phenomenon was the most commonly observed feature (83.9%). Nine (29%) had esophageal dysmotility symptoms and 23 (74.2%), including all patients with diffuse SSc, had symptoms of gastro-esophageal reflux disease (GERD). Restrictive pattern on pulmonary function test and evidence of lung fibrosis were seen in more than 70% of patients. Echocardiographic evidence of pulmonary arterial hypertension was seen in 58.1%. Telangiectasia, calcinosis, digital ulcers, digital pulp loss or pitting were seen more commonly in the diffuse subtype. The two most prevalent autoantibodies were anti-Scl-70 and anti-Ro-52. The presence of anti-Scl-70 was significantly associated with restrictive lung disease (P = 0.05). Anti-Ro-52 was associated with control subjects with other autoimmune diseases (P = 0.043). The presence of anti-PM-Scl-75 was associated with overlap syndrome (P = 0.032). Patients with anticentromere antibodies were more likely to have vasculitic rash (P = 0.012). In Malaysia, SSc most commonly affects the Chinese. Limited cutaneous is more common than diffuse subtype. Features of CREST (calcinosis, Reynaud disease, esophageal dysmotility, sclerodactyly, telangiectasia) are more commonly observed in the diffuse cutaneous subgroup. Anti-Scl-70 and anti-Ro-52 antibodies are promising biomarkers for pulmonary involvement in SSc. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.
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Kuryata, Olexandr; Lysunets, Tatiana
2018-01-01
Objectives Systemic sclerosis (SSc) is a rare disease of connective tissue, manifestations of which may vary in different geographical areas. We aimed to describe the clinical portrait of patients with SSc in Dnipropetrovsk region and to investigate how initial clinical and laboratory characteristics are connected with the presence of hypertension in SSc onset. Material and methods Patients were enrolled to this study from the registry of SSc patients, established in the Rheumatology Department, Mechnikov Dnipropetrovsk Regional Clinic, Dnipro. This registry contains histories of new cases of SSc from 1993 to 2014. Patients are followed-up and receive treatment according to EULAR and local standards. Diagnosis of SSc was based on ACR and EULAR Criteria for systemic Sclerosis. Two patients developed scleroderma renal crisis during follow-up. This report is a cross-sectional study. We analysed only data of the first visit to a rheumatologist. Results In total 148 patients (median age [IQR] – 47 [40; 52] years) fulfilled the inclusion criteria. Male/female ratio was 1 : 20.1. The most frequent clinical signs were Raynaud’s phenomenon and arthritis. The prevalence of skin lesion in dcSSc patients was twice as high as in lcSSc patients. Pulmonary fibrosis occurred significantly more commonly in dcSSc patients. Hypertension occurred in 26–33% in both groups. Patients with hypertension at the SSc onset were seven years older than normotensive patients. More hypertensive patients were classified as lcSSc. Mean GFR was dramatically lower in hypertensive patients. Conclusions The most common clinical form in our study was diffuse cutaneous subset of SSc. Hypertension in patients with SSc may be associated with local cutaneous subset of SSc and renal impairment. The strongest predictors of clinical form of SSc are signs of fibrosis (skin lesion and pulmonary fibrosis) and inflammation (arthritis and elevated CRP). PMID:29686439
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Severity of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension in African Americans
Blanco, Isabel; Mathai, Stephen; Shafiq, Majid; Boyce, Danielle; M. Kolb, Todd; Chami, Hala; K. Hummers, Laura; Housten, Traci; Chaisson, Neal; L. Zaiman, Ari; M. Wigley, Fredrick; J. Tedford, Ryan; A. Kass, David; Damico, Rachel; E. Girgis, Reda; M. Hassoun, Paul
2014-01-01
Abstract African Americans (AA) with systemic sclerosis (SSc) have a worse prognosis compared to Americans of European descent (EA). We conducted the current study to test the hypothesis that AA patients with SSc have more severe disease and poorer outcomes compared to EA patients when afflicted with pulmonary arterial hypertension (PAH). We studied 160 consecutive SSc patients with PAH diagnosed by right heart catheterization, comparing demographics, hemodynamics, and outcomes between AA and EA patients. The cohort included 29 AA and 131 EA patients with similar baseline characteristics except for increased prevalence of diffuse SSc in AA. AA patients had worse functional class (FC) (80% FC III-IV vs 53%; p = 0.02), higher brain natriuretic peptide (NT-pro-BNP) (5729 ± 9730 pg/mL vs 1892 ± 2417 pg/mL; p = 0.02), more depressed right ventricular function, a trend toward lower 6-minute walk distance (263 ± 111 m vs 333 ± 110 m; p = 0.07), and worse hemodynamics (cardiac index 1.95 ± 0.58 L/min/m2 vs 2.62 ± 0.80 L/min/m2; pulmonary vascular resistance 10.3 ± 6.2 WU vs 7.6 ± 5.0 WU; p < 0.05) compared with EA patients. Kaplan-Meier survival estimates for AA and EA patients, respectively, were 62% vs 73% at 2 years and 26% vs 44% at 5 years (p > 0.05). In conclusion, AA patients with SSc-PAH are more likely to have diffuse SSc and to present with significantly more severe PAH compared with EA patients. AA patients also appear to have poorer survival, though larger studies are needed to investigate this association definitively. PMID:25181310
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Iniesta Arandia, Nerea; Simeón-Aznar, Carmen Pilar; Guillén Del Castillo, Alfredo; Colunga Argüelles, Dolores; Rubio-Rivas, Manuel; Trapiella Martínez, Luis; García Hernández, Francisco José; Sáez Comet, Luis; Egurbide Arberas, María Victoria; Ortego-Centeno, Norberto; Freire, Mayka; Marí Alfonso, Begoña; Vargas Hitos, José Antonio; Ríos Blanco, Juan José; Todolí Parra, José Antonio; Rodríguez-Carballeira, Monica; Marín Ballvé, Adela; Chamorro Fernández, Antonio Javier; Pla Salas, Xavier; Madroñero Vuelta, Ana Belen; Ruiz Muñoz, Manuel; Fonollosa Pla, Vicent; Espinosa, Gerard
2017-01-01
To assess the clinical manifestations and prognosis of Spanish patients with systemic sclerosis (SSc) according to their immunological profile. From the Spanish Scleroderma Study Group or RESCLE (Registro de ESCLErodermia as Spanish nomenclature) Registry we selected those patients in which anti-centromere (ACA), anti-topoisomerase I (ATA), and anti-RNA polymerase III (ARA) antibodies had been determined, and a single positivity for each SSc specific antibody was detected. Demographic, clinical, laboratory, and survival data were compared according to the serologic status of these antibodies. Overall, 209 SSc patients were included. In 128 (61%) patients ACA was the only positive antibody, 46 (22%) were only positive for ATA, and 35 (17%) for ARA. Of note, the three groups were mutually exclusive. In univariate analysis, patients with ACA presented more frequently limited cutaneous SSc (lcSSc) (p<0.001), whereas diffuse cutaneous SSc (dcSSc) was the most frequent subtype in patients with ATA (54%) and ARA (62%) (both p<0.001). Positive patients for ARA showed the highest prevalence of joint involvement (p<0.001) and those from ATA group had a higher prevalence of interstitial lung disease (ILD) (p<0.001). Scleroderma renal crisis was more frequent in the ARA group (p<0.001). In multivariate analysis, ACA were associated with female gender and were protective for dcSSc and ILD. ATA were found to be protective for lcSSc and they were independently associated with interstitial reticular pattern. ARA positivity was independently associated with dcSSc. We did not find differences in mortality between the three groups. In Spanish SSc patients, the presence of SSc specific antibodies conferred a distinctive clinical profile.
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Muroi, Eiji; Hara, Toshihide; Yanaba, Koichi; Ogawa, Fumihide; Yoshizaki, Ayumi; Takenaka, Motoi; Shimizu, Kazuhiro; Sato, Shinichi
2011-12-01
Microvascular lesions are a predominant feature in systemic sclerosis (SSc) and seem to play a central pathogenic role. The presence of nailfold capillary abnormalities is useful in diagnosing SSc. Capillaroscopy, however, usually requires special equipment and may be time consuming. Dermatoscope has been presented as a new diagnostic tool for quick and efficient examination of nailfold capillaries for circumstances when standard microscope equipment is not available. To assess the practical utility of dermatoscope for assessment of capillary morphology in patients with SSc, 83 Japanese patients with SSc (68 women, 15 men) and 68 healthy controls were examined in the study. Twenty-one patients (16 women, 5 men) had diffuse cutaneous SSc and 62 (52 women, 10 men) had limited cutaneous SSc. Enlarged capillaries and hemorrhages were evaluated in all 10 fingers with either naked eyes or DermLite(®) DL100 dermatoscope. Enlarged capillaries and hemorrhages were significantly more frequently detected with dermatoscope than without it. These findings were observed most frequently in the fourth finger. The presence of two or more enlarged capillaries in one or more fingers showed 83.1% sensitivity and 100% specificity for SSc. Among patients with SSc with anti-topoisomerase I antibody, the disease duration correlated negatively with the dermatoscopic number of enlarged capillaries and hemorrhages. Dermatoscope allows the easy and rapid identification of capillary nailfold morphological changes in SSc and should be routinely used for diagnosing SSc.
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Pastano, Rocco; Dell'Agnola, Chiara; Bason, Caterina; Gigli, Federica; Rabascio, Cristina; Puccetti, Antonio; Tinazzi, Elisa; Cetto, Gianluigi; Peccatori, Fedro; Martinelli, Giovanni; Lunardi, Claudio
2012-09-01
Human cytomegalovirus (hCMV) infection and its reactivation correlate both with the increased risk and with the worsening of graft-versus-host disease (GVHD). Because scleroderma-like skin lesions can occur in chronic GVHD (cGVHD) in allogeneic stem-cell transplant (HCT) patients and hCMV is relevant in the pathogenesis of systemic sclerosis (SSc), we evaluated the possible pathogenetic link between hCMV and skin cGVHD. Plasma from 18 HCT patients was tested for anti-UL94 and/or anti-NAG-2 antibodies, identified in SSc patients, by direct ELISA assays. Both donors and recipients were anti-hCMV IgG positive, without autoimmune diseases. Patients' purified anti-UL94 and anti-NAG-2 IgG binding to human umbilical endothelial cells (HUVECs) and fibroblasts was performed by FACS analysis and ELISA test. HUVECs apoptosis and fibroblasts proliferation induced by patients' anti-NAG-2 antibodies were measured by DNA fragmentation and cell viability, respectively. About 11/18 patients developed cGVHD and all of them showed skin involvement, ranging from diffuse SSc-like lesions to limited erythema. Eight of eleven cGVHD patients were positive for anti-UL94 and/or anti-NAG-2 antibodies. Remarkably, 4/5 patients who developed diffuse or limited SSc-like lesions had antibodies directed against both UL94 and NAG-2; their anti-NAG-2 IgG-bound HUVECs and fibroblasts induce both endothelial cell apoptosis and fibroblasts proliferation, similar to that induced by purified anti-UL94 and anti-NAG-2 antibodies obtained from SSc patients. In conclusion, our data suggest a pathogenetic link between hCMV infection and scleroderma-like skin cGVHD in HCT patients through a mechanism of molecular mimicry between UL94 viral protein and NAG-2 molecule, as observed in patients with SSc.
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Sacroiliac joint involvement in systemic sclerosis.
Arslan Tas, Didem; Yıldız, Fatih; Sakallı, Hakan; Kelle, Bayram; Ballı, Tuğsan; Erken, Eren
2015-01-01
One of the major problems for systemic sclerosis (SSc) patients is suggested to be articular involvement. Mostly involved joints in SSc were reported as wrist, carpometacarpal-interphalangeal, foot, knee, hip and shoulder; however, there has been little knowledge on the sacroiliac joint. Our aim was to evaluate sacroiliac joint involvement in SSc. Fifty-seven SSc patients, 54 rheumatoid arthritis patients and 64 healthy subjects were included. Anteroposterior pelvic radiographs were obtained and graded twice by three blinded rheumatologists. One competent radiologist has re-evaluated the X-ray results. The ASAS (Assessment of Spondylo Arthritis International Society) scoring method was applied for grading sacroiliac involvement. Inflammatory back pain was also evaluated. Other clinical and laboratory data were collected as proposed by the European Study Group. In the SSc group sacroiliitis was found in 13 patients (23%) and was significantly different from RA patients (two patients, 4%), P = 0.003; and the healthy control group (one participant, 2%), P < 0.001. The frequency of inflammatory back pain in SSc patients with sacroiliitis (8/13 patients, 62%) was significantly higher in SSc patients without sacroiliitis (4/44 patients, 9%), P < 0.001. The SSc patients with sacroiliitis and with inflammatory back pain (8/57 patients, 14%) were regarded as axial spondyloarthritis overlap. Male gender, diffuse subtype, inflammatory back pain and high C-reactive protein levels (odds ratio: 1.069, 1.059, 1.059 and 3.698, respectively) were found to be the significant risk factors for sacroiliitis. We suggest that, sacroiliitis may be a concern to be considered in SSc practice. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.
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Registry of the Spanish Network for Systemic Sclerosis
Simeón-Aznar, C.P.; Fonollosa-Plá, V.; Tolosa-Vilella, Carles; Espinosa-Garriga, G.; Campillo-Grau, M.; Ramos-Casals, M.; García-Hernández, F.J.; Castillo-Palma, M.J.; Sánchez-Román, J.; Callejas-Rubio, J.L.; Ortego-Centeno, N.; Egurbide-Arberas, M.V.; Trapiellla-Martínez, L.; Caminal-Montero, L.; Sáez-Comet, L.; Velilla-Marco, J.; Camps-García, M.T.; de Ramón-Garrido, E.; Esteban-Marcos, E.M.; Pallarés-Ferreres, L.; Navarrete-Navarrete, N.; Vargas-Hitos, J.A.; de la Torre, R. Gómez; Salvador-Cervello, G.; Rios-Blanco, J.J.; Vilardell-Tarrés, M.
2015-01-01
Abstract Systemic sclerosis (SSc) is a rare, multisystem disease showing a large individual variability in disease progression and prognosis. In the present study, we assess survival, causes of death, and risk factors of mortality in a large series of Spanish SSc patients. Consecutive SSc patients fulfilling criteria of the classification by LeRoy were recruited in the survey. Kaplan–Meier and Cox proportional-hazards models were used to analyze survival and to identify predictors of mortality. Among 879 consecutive patients, 138 (15.7%) deaths were registered. Seventy-six out of 138 (55%) deceased patients were due to causes attributed to SSc, and pulmonary hypertension (PH) was the leading cause in 23 (16.6%) patients. Survival rates were 96%, 93%, 83%, and 73% at 5, 10, 20, and 30 years after the first symptom, respectively. Survival rates for diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc were 91%, 86%, 64%, and 39%; and 97%, 95%, 85%, and 81% at 5, 10, 20, and 30 years, respectively (log-rank: 67.63, P < 0.0001). The dcSSc subset, male sex, age at disease onset older than 65 years, digital ulcers, interstitial lung disease (ILD), PH, heart involvement, scleroderma renal crisis (SRC), presence of antitopoisomerase I and absence of anticentromere antibodies, and active capillaroscopic pattern showed reduced survival rate. In a multivariate analysis, older age at disease onset, dcSSc, ILD, PH, and SRC were independent risk factors for mortality. In the present study involving a large cohort of SSc patients, a high prevalence of disease-related causes of death was demonstrated. Older age at disease onset, dcSSc, ILD, PH, and SRC were identified as independent prognostic factors. PMID:26512564
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Knafo, Ruby; Thombs, Brett D; Jewett, Lisa; Hudson, Marie; Wigley, Fred; Haythornthwaite, Jennifer A
2009-10-01
Sexual impairment in women with SSc has received little attention. The objective of this study was to compare levels of sexual impairment in women with SSc with samples of women with medical illnesses for which sexual impairment has been researched more extensively. SSc patients completed the Sexual Relationships subscale of the Psychosocial Adjustment to Illness Scale-Self-Report (PAIS-SR). A systematic review was conducted to select comparison samples. Sexual Relationships subscale scores from SSc patients were compared with scores from comparison samples (breast or gynaecological cancer and HIV) using t-tests and Hedges's g to calculate effect sizes. Samples from 138 female SSc patients were analysed (28.3% diffuse; mean age 52.1 +/- 12.3 years; mean time since diagnosis 9.0 +/- 8.3 years). Women with dcSSc (6.1 +/- 4.2) reported significantly greater sexual impairment (P < 0.05) than those with lcSSc (4.4 +/- 4.2), three breast cancer samples (1.8 +/- 0.1, 3.4 +/- 3.9, 1.6 +/- 0.6) and two samples of HIV-positive female patients (4.4 +/- 3.8, 4.5 +/- 3.9). Scores in dcSSc were similar to one sample of HIV-positive women (5.8 +/- 4.1) and gynaecological cancer patients (7.3 +/- 4.3). Scores in lcSSc were significantly higher than two breast cancer samples, similar to one breast cancer sample and two HIV-positive samples, and significantly lower (P < 0.05) than in one HIV sample and gynaecological cancer. Women with SSc, particularly those with dcSSc, have high levels of sexual impairment compared with women with other chronic diseases, where sexual function has received greater attention. Further research is needed on sexual function among women with SSc.
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2012-01-01
Introduction Potassium voltage-gated channel shaker-related subfamily member 5 (KCNA5) is implicated in vascular tone regulation, and its inhibition during hypoxia produces pulmonary vasoconstriction. Recently, a protective association of the KCNA5 locus with systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) was reported. Hence, the aim of this study was to replicate these findings in an independent multicenter Caucasian SSc cohort. Methods The 2,343 SSc cases (179 PAH positive, confirmed by right-heart catheterization) and 2,690 matched healthy controls from five European countries were included in this study. Rs10744676 single-nucleotide polymorphism (SNP) was genotyped by using a TaqMan SNP genotyping assay. Results Individual population analyses of the selected KCNA5 genetic variant did not show significant association with SSc or any of the defined subsets (for example, limited cutaneous SSc, diffuse cutaneous SSc, anti-centromere autoantibody positive and anti-topoisomerase autoantibody positive). Furthermore, pooled analyses revealed no significant evidence of association with the disease or any of the subsets, not even the PAH-positive group. The comparison of PAH-positive patients with PAH-negative patients showed no significant differences among patients. Conclusions Our data do not support an important role of KCNA5 as an SSc-susceptibility factor or as a PAH-development genetic marker for SSc patients. PMID:23270786
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Brown, Monica; Postlethwaite, Arnold E; Myers, Linda K; Hasty, Karen A
2012-06-01
Systemic sclerosis (SSc) is a chronic fibrosing disease characterized by vasculopathy, autoimmunity, and an accumulation of collagen in tissues. Numerous studies have shown that compared to healthy or diseased controls, the peripheral blood mononuclear cells (PBMC) from patients with SSc produce a variety of cytokines or proliferate when cultured with solubilized type I collagen (CI) or constituent α1(II) and α2(I) polypeptide chains. The purpose of this study was to determine whether PBMC isolated from patients with SSc and cultured in vitro with soluble CI elaborated soluble mediators that inhibit the production of collagenase (i.e., matrix metalloproteinase, MMP-1) by fibroblasts. Supernatants of CI-stimulated PBMC from juvenile and adult diffuse cutaneous (dc)SSc patients significantly reduced MMP-1 production by SSc dermal fibroblasts, while supernatants of CI-stimulated PBMC from patients with localized scleroderma (LS) did not. CI-stimulated PBMC culture supernatants from patients with dcSSc in contrast to patients with LS exhibited increased levels of platelet-derived growth factor (PDGF)-AA, PDGF-BB, TNF-α, IL-13, and EGF. Prolonged culture of SSc dermal fibroblasts with recombinant PDGF-BB or IL-13 inhibited the induction of MMP-1 in response to subsequent TNF-α stimulation. These data suggest that therapies aimed at reducing these cytokines may decrease collagen accumulation in SSc, preventing the development of chronic fibrosis.
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Ruaro, B; Sulli, A; Pizzorni, C; Paolino, S; Smith, V; Cutolo, M
2016-05-01
To correlate blood perfusion (BP) values assessed by laser speckle contrast analysis (LASCA) in selected skin areas of hands and face with nailfold capillary damage scores in systemic sclerosis (SSc) patients. Seventy SSc patients (mean SSc duration 6 ± 5 years) and 70 volunteer healthy subjects were enrolled after informed consent. LASCA was performed at different areas of the face (forehead, tip of nose, zygomas and perioral region) and at dorsal and volar regions of hands. Microvascular damage was assessed and scored by nailfold videocapillaroscopy (NVC) and the microangiopathy evolution score (MES) was calculated. SSc patients showed a significantly lower BP than healthy subjects at fingertips, periungual areas and palm of hands (p<0.0001), but not at the level of face and dorsum of hands. A gradual decrease of BP at fingertips, periungual and palm areas, was found in SSc patients with progressive severity of NVC patterns of microangiopathy ("early", "active", or "late") (p<0.01). A negative correlation was observed between MES and BP values, as well as between loss of capillaries and BP, at the same areas (p<0.001 and p<0.01, respectively). Patients with diffuse cutaneous SSc (dcSSc) showed lower BP than those with limited cutaneous SSc (p<0.04). LASCA detects a significant reduction of BP only in those areas usually affected by Raynaud's phenomenon (fingertips, periungual and palm areas), especially in dcSSc patients, and BP values significantly correlate with the nailfold capillaroscopy scores of microangiopathy. Copyright © 2016. Published by Elsevier Inc.
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[Screening of pulmonary hypertension in a Spanish cohort of patients with systemic sclerosis].
García Hernández, Francisco José; Castillo Palma, María Jesús; Montero Mateos, Enrique; González León, Rocío; López Haldón, José Eduardo; Sánchez Román, Julio
2016-01-01
Pulmonary arterial hypertension (PAH) is an important cause of morbimortality in systemic sclerosis (SSc). Evolution is worse than that of subjects with idiopathic PAH, but prognosis improves when PAH is diagnosed early. The aim of this research is to describe results of a screening program for diagnosis of pulmonary hypertension (PH) carried out in a cohort of Spanish patients with SSc. PH screening was performed by transthoracic doppler echocardiography (TTDE) in 184 patients with SSc. Patients with systolic pulmonary arterial pressure estimated by TTDE>35 mmHg were evaluated per protocol to confirm diagnosis and type of PH. PAH was diagnosed in 25 patients (13.6%). Patients with diffuse and limited SSc developed PAH in a similar degree, 9/60 (15%) vs. 16/100 (16%), with no cases among patients with SSc "sine scleroderma" or "pre-scleroderma" (P<.001). The only clinical or epidemiological data characterizing patients with PAH were older age (mean age 67 years for patients with PAH vs. 56 years for those without PAH, P=.007), limited SSc, a trend toward shorter evolution of the underlying disease (median 8 years for patients with PAH vs. 10 years for those without PAH, P=.73), and a higher frequency of positive anticentromere antibodies (16 patients [64%] with PAH vs. 70 (48,3%) without PAH, P=.19). Prevalence of PAH in SSc was high and supports the implementation of a regular screening program. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.
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Sato, Lucy T; Kayser, Cristiane; Andrade, Luís E C
2009-01-01
The aim of this study was to correlate quantitative and semiquantitative nailfold capillaroscopy (NFC) parameters with the extent of cutaneous and visceral involvement in systemic sclerosis (SSc) patients. The presence of clinical and serological alterations was evaluated retrospectively and correlated with NFC findings (number of capillary loops/mm, vascular deletion score and number of enlarged and giant capillary loops). For evaluation of disease extension five manifestations were analyzed: finger pad lesions, skin involvement, esophageal involvement, interstitial lung disease, and pulmonary hypertension. There were 105 NFC examinations in 92 patients, 13 of whom were evaluated at two different time points. Patients with diffuse cutaneous SSc had a higher vascular deletion score than patients with limited cutaneous SSc, sine scleroderma SSc, and overlap syndrome (1.67+/-0.91 vs 0.99+/-0.82; p=0.0005). Modified Rodnan's skin score correlated positively with capillary deletion, evaluated by the vascular deletion score and the number of capillary loops/mm (p<0.001 and p=0.012; respectively). Patients with three or more involved tracts presented lower number of capillary loops/mm (8.00+/-1.69 vs 9.23+/-1.31 capillary loops/mm; p=0.025) and a higher vascular deletion score (1.41+/-0.95 vs 0.73+/-0.76; p=0.027) when compared to patients with less than three affected tracts. Vascular deletion score was significantly higher in patients with anti-Scl-70 antibodies that in patients without anti-Scl-70 antibodies (p=0.02). NFC abnormalities correlated positively with the diffuse form of SSc, the degree of cutaneous involvement, the number of affected tracts, and the presence of anti-Scl-70 antibodies.
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Bretterklieber, Agnes; Painsi, Clemens; Avian, Alexander; Wutte, Nora; Aberer, Elisabeth
2014-09-02
Systemic sclerosis (SSc) is a rare and potentially life threatening autoimmune disorder. The burden of disease compared to other dermatoses is unknown. The purpose of this study was to assess both the quality of life in patients with SSc and the variables that are associated with poor quality of life. Forty-one patients with systemic sclerosis (29 limited, 2 diffuse, 10 undifferentiated forms) were assessed with respect to their health status and compared to published data for the normal population, SSc patients from other studies, and patients with chronic skin diseases. For the most part, our SSc patients had better outcomes in all 8 dimensions of the SF-36 than SSc patients from other studies, and poorer scores than the healthy population and those with occupational contact dermatitis, ichthyosis, non-melanoma skin cancer, contact dermatitis, atopic eczema, chronic nail disease, vitiligo, health care workers with work-related disease, and those with other chronic skin diseases, but significantly better scores for mental health than those with nail disease, vitiligo, and health-care workers. Patients with atopic dermatitis, psoriasis and pemphigus had significantly poorer mean scores in social function and mental health than SSc patients. Patients with pemphigus were also significantly impaired in their physical and emotional roles. Patients with systemic lupus erythematosus (SLE) had the significantly poorest mean scores for QoL in all 8 domains except bodily pain and emotional role. Besides SLE, SSc is one of the most severe chronic dermatologic diseases in terms of reduced QoL. Since SSc cannot be cured, treatment strategies should include therapeutic interventions such as psychotherapy, social support, physiotherapy, and spiritual care. Their beneficial effects could be studied in future.
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Nguyen, Christelle; Ranque, Brigitte; Baubet, Thierry; Bérezné, Alice; Mestre-Stanislas, Caroline; Rannou, François; Papelard, Agathe; Morell-Dubois, Sandrine; Revel, Michel; Moro, Marie-Rose; Guillevin, Loïc; Poiraudeau, Serge; Mouthon, Luc
2014-01-01
Objectives To identify clinical, functional and health-related quality of life (HRQoL) correlates of clinically significant symptoms of anxiety and depression in patients with systemic sclerosis (SSc). Methods Three-hundred-and-eighty-one patients fulfilling the American College of Rheumatology and/or the Leroy and Medsger criteria for SSc were assessed for visceral involvement, disability and HRQoL (assessed by SF-36). Clinically significant symptoms of anxiety and depression were evaluated with the Hospital Anxiety Depression Scale (HAD) (defined cut-off≥8). Results 9.2% the patients had limited SSc, 50.5% limited cutaneous SSc (lcSSc), and 40.3% diffuse cutaneous SSc (dcSSc). Overall, 40.4% and 58.8% of the patients had clinically significant symptoms of depression and anxiety, respectively. Compared to patients without clinically significant symptoms of depression, patients with clinically significant symptoms of depression had poorer health status, HRQoL mental and physical component, and greater global disability, hand disability and aesthetic impairment. Compared to patients without clinically significant symptoms of anxiety, patients with clinically significant symptoms of anxiety had poorer SF-36 mental and physical component scores. On multivariable analysis, excluding mental component score of SF-36, variables independently associated with clinically significant symptoms of depression and anxiety were global disability and physical component of SF-36, plus female gender for clinically significant symptoms of anxiety only. Remarkably, patients with and without clinically significant psychiatric symptoms were comparable for all disease-related clinical features assessed. Conclusion High levels of clinically significant symptoms of anxiety and depression are observed among SSc patients. Clinically significant psychiatric symptoms are rather associated with increased disability and altered HRQoL, than with disease-specific organ manifestations. PMID:24587375
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Wielosz, Ewa; Majdan, Maria; Koszarny, Arkadiusz; Dryglewska, Magdalena; Tabarkiewicz, Jacek
2017-01-01
The aim of the study was the assessment of changes in the glomerular filtration rate (GFR) during long-term observation in a group of systemic sclerosis (SSc) patients with and without chronic antiphospholipid (aPL) antibody positivity. The observation comprised 50 patients - 23 with diffuse cutaneous SSc - dcSSc and 27 limited cutaneous SSc - lcSSc. After 24 months we assessed 27 patients (9 died, 14 lost follow up); 24 patients (88%) were treated chronically with angiotensin-converting-enzyme inhibitors (ACEIs). Patients were investigated for the presence of aPL: to cardiolipin and to β2 glycoprotein I in IgM and IgG classes. Serum levels of creatinine (S-Cr), cystatin C and creatinine clearance values were determined in all patients. According to the presence of a significant level of at least one of aPL antibodies, pts were divided into groups: group I aPL positive: 14 patients, group II aPL negative - 13 patients. We did not find significant differences in S-Cr, cystatin C levels and creatinine clearance before and after 24 months of observation between both groups. In follow up observations, the presence of anti-centromere antibodies was significantly more frequent in the aPL positive, as compared to the aPL negative group (p = 0.01). In follow up observations, the level of anticardiolipin antibodies in IgG class was significantly higher in dcSSc compared to lcSSc patients (p = 0.02). In long-term observation chronic positivity for aPL antibodies does not significantly decrease the GFR in patients with SSc treated with ACEIs.
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There is a need for new systemic sclerosis subset criteria. A content analytic approach.
Johnson, S R; Soowamber, M L; Fransen, J; Khanna, D; Van Den Hoogen, F; Baron, M; Matucci-Cerinic, M; Denton, C P; Medsger, T A; Carreira, P E; Riemekasten, G; Distler, J; Gabrielli, A; Steen, V; Chung, L; Silver, R; Varga, J; Müller-Ladner, U; Vonk, M C; Walker, U A; Wollheim, F A; Herrick, A; Furst, D E; Czirjak, L; Kowal-Bielecka, O; Del Galdo, F; Cutolo, M; Hunzelmann, N; Murray, C D; Foeldvari, I; Mouthon, L; Damjanov, N; Kahaleh, B; Frech, T; Assassi, S; Saketkoo, L A; Pope, J E
2018-01-01
Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets. We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed. Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly). We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).
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Klein, S; Kretz, C C; Ruland, V; Stumpf, C; Haust, M; Hartschuh, W; Hartmann, M; Enk, A; Suri-Payer, E; Oberle, N; Krammer, P H; Kuhn, A
2011-08-01
To determine the frequency and suppressive capacity of regulatory T cells (T(reg)) and their association with clinical parameters in patients with systemic scleroderma (SSc). Peripheral blood from 25 patients with SSc, 15 patients with localised scleroderma (LS) and 29 healthy controls (HC) was studied. Analysis of CD4(+) forkhead box P3 (Foxp3)(+) and CD4(+)CD25(++)Foxp3(+) T(reg) subpopulations was carried out by flow cytometry and cell proliferation was quantified by (3)H-thymidine incorporation. Quantitative analysis of T(reg) was further performed in skin biopsies from 17 patients with SSc and 21 patients with LS using anti-CD4 and anti-Foxp3 monoclonal antibodies for immunohistochemistry. The frequency of CD4(+)Foxp3(+) and CD4(+)CD25(++)Foxp3(+) T(reg) in peripheral blood from patients with SSc was not significantly different from that of patients with LS or HC. The suppressive capacity of CD4(+)CD25(++) T(reg) in SSc was also found to be similar to that of HC. Phenotypic and functional data revealed no significant difference between the limited or diffuse form of SSc. Moreover, therapy with bosentan showed no significant effect on the frequency of T(reg) during the course of the disease. However, the frequency of T(reg) in skin lesions from patients with SSc or LS, determined as the percentage of CD4(+) cells expressing Foxp3 in the inflammatory infiltrate, was significantly reduced compared with other inflammatory skin diseases. These results indicate that although the authors found no defect in the frequency or function of peripheral T(reg) subpopulations, the reduction of CD4(+)Foxp3(+) T(reg) in the skin of patients with SSc may be important in the pathogenesis of the disease.
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Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis.
Nishijima, C; Hayakawa, I; Matsushita, T; Komura, K; Hasegawa, M; Takehara, K; Sato, S
2004-11-01
Systemic sclerosis (SSc) is characterized by multi-organ fibrosis with an autoimmune background. Although autoantibodies are detected frequently in SSc patients, the role of autoantibody in the development of fibrosis remains unknown. Connective tissue homeostasis is a balance between the synthesis and degradation of the extracellular matrix (ECM); ECM degradation is regulated mainly by matrix metalloproteinases (MMPs). Anti-MMP-1 antibody is suggested to inhibit MMP-1 and be involved in the development of the fibrosis in SSc. However, the accumulation of various ECM components in the tissue of SSc cannot be explained by the anti-MMP-1 antibody alone. In this study, we examined the presence or levels of antibody to MMP-3, a protein which degrades various ECM components relevant to SSc fibrosis. Enzyme-linked immunosorbent assay (ELISA) using human recombinant MMP-3 revealed that IgG anti-MMP-3 autoantibody levels were elevated significantly in the sera from SSc patients, but not in patients with active systemic lupus erythematosus or dermatomyositis. IgG and IgM anti-MMP-3 antibody levels were significantly higher in diffuse cutaneous SSc, a severe form, than those in limited cutaneous SSc. Consistently, IgG anti-MMP-3 antibody levels correlated significantly with fibrosis of the skin, lung and renal blood vessels. The presence of IgG anti-MMP-3 autoantibody in sera from SSc patients was confirmed by immunoblotting analysis. Remarkably, MMP-3 activity was inhibited by IgG anti-MMP-3 antibody. These results suggest that anti-MMP-3 antibody is a serological marker that reflects the severity of SSc and also suggest that it may contribute to the development of fibrosis by inhibiting MMP-3 activity and reducing the ECM turnover.
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The role of nailfold capillary dropout on mortality in systemic sclerosis.
Tieu, Joanna; Hakendorf, Paul; Woodman, Richard J; Patterson, Karen; Walker, Jenny; Roberts-Thomson, Peter
2018-05-01
Semi-quantitative wide-field nailfold capillaroscopy (NFC) is a simple technique with proven utility in the early diagnosis of systemic sclerosis (SSc). Its role in prognosis, however, remains uncertain. To investigate the possible utility of NFC in predicting survival. Patients with SSc listed on the South Australian Scleroderma Register (SASR) with prior NFC performed at Flinders Medical Centre from 1991 to 2015 were included in this study. Baseline demographic data, diagnosis, scleroderma antibody status and mortality status were also collected for each patient. The cohort consisted of 99 patients with limited cutaneous SSc, 30 patients with diffuse cutaneous SSc and 23 with an overlap scleroderma syndrome. Fifty-six patients died during the period of study (censured end June 2015). Patients with diffuse scleroderma had significantly greater capillary dropout compared with limited and overlap scleroderma (P < 0.001). In univariate analysis, both capillary dropout scores (log-rank χ 2 = 8.75, P = 0.003) and antibody status (log-rank χ 2 = 13.94, P = 0.003) were associated with mortality. ANOVA showed a significant association between antibody status and capillary dropout (P < 0.001). In Cox regression, adjustment for capillary dropout attenuated the impact of autoantibody group on survival. Nailfold capillary dropout was significantly associated with mortality and the severity of dropout attenuates survival dictated by antibody status. Together these observations support the hypothesis that capillary dropout is on the causal pathway between induction of scleroderma associated autoantibodies and mortality. © 2018 Royal Australasian College of Physicians.
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Guiducci, Serena; Manetti, Mirko; Romano, Eloisa; Mazzanti, Benedetta; Ceccarelli, Claudia; Dal Pozzo, Simone; Milia, Anna Franca; Bellando-Randone, Silvia; Fiori, Ginevra; Conforti, Maria Letizia; Saccardi, Riccardo; Ibba-Manneschi, Lidia; Matucci-Cerinic, Marco
2011-11-01
To characterise bone marrow-derived mesenchymal stem cells (MSCs) from patients with systemic sclerosis (SSc) for the expression of factors implicated in MSC recruitment at sites of injury, angiogenesis and fibrosis. The study also analysed whether the production/release of bioactive mediators by MSCs were affected by stimulation with cytokines found upregulated in SSc serum and tissues, and whether MSCs could modulate dermal microvascular endothelial cell (MVEC) angiogenesis. MSCs obtained from five patients with early severe diffuse SSc (SSc-MSCs) and five healthy donors (H-MSCs) were stimulated with vascular endothelial growth factor (VEGF), transforming growth factor β (TGFβ) or stromal cell-derived factor-1 (SDF-1). Transcript and protein levels of SDF-1 and its receptor CXCR4, VEGF, TGFβ(1) and receptors TβRI and TβRII were evaluated by quantitative real-time PCR, western blotting and confocal microscopy. VEGF, SDF-1 and TGFβ(1) secretion in culture supernatant was measured by ELISA. MVEC capillary morphogenesis was performed on Matrigel with the addition of MSC-conditioned medium. In SSc-MSCs the basal expression of proangiogenic SDF-1/CXCR4 and VEGF was significantly increased compared with H-MSCs. SSc-MSCs constitutively released higher levels of SDF-1 and VEGF. SDF-1/CXCR4 were upregulated after VEGF stimulation and CXCR4 redistributed from the cytoplasm to the cell surface. VEGF was increased by SDF-1 challenge. VEGF, TGFβ and SDF-1 stimulation upregulated TGFβ(1), TβRI and TβRII in SSc-MSCs. TβRII redistributed from the cytoplasm to focal adhesion contacts. SSc-MSC-conditioned medium showed a greater proangiogenic effect on MVECs than H-MSCs. Experiments with blocking antibodies showed that MSC-derived cytokines were responsible for this potent proangiogenic effect. SSc-MSCs constitutively overexpress and release bioactive mediators/proangiogenic factors and potentiate dermal MVEC angiogenesis.
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Computerized nailfold video capillaroscopy--a new tool for assessment of Raynaud's phenomenon.
Anderson, Marina E; Allen, P Danny; Moore, Tonia; Hillier, Val; Taylor, Christopher J; Herrick, Ariane L
2005-05-01
To develop a computer based nailfold video capillaroscopy system with enhanced image quality and to assess its disease-subgroup resolving power in patients with primary and secondary Raynaud's phenomenon (RP). Using frame registration software, digitized video images from the microscope were combined to form a panoramic mosaic of the nailfold. Capillary dimensions (apex, arterial, venous, and total width) and density were measured onscreen. Significantly, the new system could guarantee analysis of the same set of capillaries by 2 observers. Forty-eight healthy control subjects, 21 patients with primary RP, 40 patients with limited cutaneous systemic sclerosis (lcSSc), and 11 patients with diffuse cutaneous SSc (dcSSc) were studied. Intra- and interobserver variability were calculated in a subset of 30 subjects. The number of loops/mm was significantly lower, and all 4 capillary dimensions significantly greater, in SSc patients versus controls plus primary RP patients (p < 0.001 for all measures). When comparing control (+ primary RP) patients with SSc patients (lcSSc + dcSSc) the most powerful discriminator was found to be the number of loops/mm. Results for intra- and interobserver reproducibility showed that the limits of agreement were closer when both observers measured the same capillaries. The key feature of the newly developed system is that it improves reproducibility of nailfold capillary measurements by allowing reidentification of the same capillaries by different observers. By allowing access to previous measurements, the new system should improve reliability in longitudinal studies, and therefore has the potential of being a valuable outcome measure of microvessel disease/involvement in clinical trials of scleroderma spectrum disorders.
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AGARWAL, SANDEEP K.; GOURH, PRAVITT; SHETE, SANJAY; PAZ, GENE; DIVECHA, DIPAL; REVEILLE, JOHN D.; ASSASSI, SHERVIN; TAN, FILEMON K.; MAYES, MAUREEN D.; ARNETT, FRANK C.
2010-01-01
Objective IL23R has been identified as a susceptibility gene for development of multiple autoimmune diseases. We investigated the possible association of IL23R with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis. Methods We tested 9 single-nucleotide polymorphisms (SNP) in IL23R for association with SSc in a cohort of 1402 SSc cases and 1038 controls. IL23R SNP tested were previously identified as SNP showing associations with inflammatory bowel disease. Results Case-control comparisons revealed no statistically significant differences between patients and healthy controls with any of the IL23R polymorphisms. Analyses of subsets of SSc patients showed that rs11209026 (Arg381Gln variant) was associated with anti-topoisomerase I antibody (ATA)-positive SSc (p = 0.001)) and rs11465804 SNP was associated with diffuse and ATA-positive SSc (p = 0.0001, p = 0.0026, respectively). These associations remained significant after accounting for multiple comparisons using the false discovery rate method. Wild-type genotype at both rs11209026 and rs11465804 showed significant protection against the presence of pulmonary hypertension (PHT). (p = 3×10−5, p = 1×10−5, respectively). Conclusion Polymorphisms in IL23R are associated with susceptibility to ATA-positive SSc and protective against development of PHT in patients with SSc. PMID:19918037
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Lafyatis, Robert; Burkly, Linda C.
2017-01-01
Systemic sclerosis (SSc) is a devastating disease affecting the skin and internal organs. Dermal fibrosis manifests early and Modified Rodnan Skin Scores (MRSS) correlate with disease progression. Transcriptomics of SSc skin biopsies suggest the role of the in vivo microenvironment in maintaining the pathological myofibroblasts. Therefore, defining the structural changes in dermal collagen in SSc patients could inform our understanding of fibrosis pathogenesis. Here, we report a method for quantitative whole-slide image analysis of dermal collagen from SSc patients, and our findings of more aligned dermal collagen bundles in diffuse cutaneous SSc (dcSSc) patients. Using the bleomycin-induced mouse model of SSc, we identified a distinct high dermal collagen bundle alignment gene signature, characterized by a concerted upregulation in cell migration, adhesion, and guidance pathways, and downregulation of spindle, replication, and cytokinesis pathways. Furthermore, increased bundle alignment induced a cell migration gene signature in fibroblasts in vitro, and these cells demonstrated increased directed migration on aligned ECM fibers that is dependent on expression of Arhgdib (Rho GDP-dissociation inhibitor 2). Our results indicate that increased cell migration is a cellular response to the increased collagen bundle alignment featured in fibrotic skin. Moreover, many of the cell migration genes identified in our study are shared with human SSc skin and may be new targets for therapeutic intervention. PMID:28662216
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COUSTET, BAPTISTE; AGARWAL, SANDEEP K.; GOURH, PRAVITT; GUEDJ, MICKAEL; MAYES, MAUREEN D.; DIEUDE, PHILIPPE; WIPFF, JULIEN; AVOUAC, JEROME; HACHULLA, ERIC; DIOT, ELISABETH; CRACOWSKI, JEAN LUC; TIEV, KIET; SIBILIA, JEAN; MOUTHON, LUC; FRANCES, CAMILLE; AMOURA, ZAHIR; CARPENTIER, PATRICK; MEYER, OLIVIER; KAHAN, ANDRE; BOILEAU, CATHERINE; ARNETT, FRANK C.; ALLANORE, YANNICK
2012-01-01
Objective Accumulating evidence shows that shared autoimmunity is critical for the pathogenesis of many autoimmune diseases. Systemic sclerosis (SSc) belongs to the connective tissue disorders, and recent data have highlighted strong associations with autoimmunity genes shared with other autoimmune diseases. To determine whether novel risk loci associated with systemic lupus erythematosus or multiple sclerosis may confer susceptibility to SSc, we tested single-nucleotide polymorphisms (SNP) from ITGAM, ITGAX, and CD58 for associations. Methods SNP harboring associations with autoimmune diseases, ITGAM rs9937837, ITGAX rs11574637, and CD58 rs12044852, were genotyped in 2 independent cohorts of European Caucasian ancestry: 1031 SSc patients and 1014 controls from France and 1038 SSc patients and 691 controls from the USA, providing a combined study population of 3774 individuals. ITGAM rs1143679 was additionally genotyped in the French cohort. Results The 4 polymorphisms were in Hardy-Weinberg equilibrium in the 2 control populations, and allelic frequencies were similar to those expected in European Caucasian populations. Allelic and genotypic frequencies for these 3 SNP were found to be statistically similar in SSc patients and controls. Subphenotype analyses for subgroups having diffuse cutaneous subtype disease, specific autoantibodies, or fibrosing alveolitis did not reveal any difference between SSc patients and controls. Conclusion These results obtained through 2 large cohorts of SSc patients of European Caucasian ancestry do not support the implication of ITGAM, ITGAX, and CD58 genes in the genetic susceptibility of SSc, although they were recently identified as autoimmune disease risk genes. PMID:21362770
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Sampaio-Barros, Marília M; Takayama, Liliam; Sampaio-Barros, Percival D; Bonfá, Eloísa; Pereira, Rosa Maria R
2016-01-01
The aim of this study was to analyze the correlation of vitamin D levels with clinical parameters, bone mineral density (BMD), quality of life (QoL) and nailfold capillaroscopy (NC) in patients with diffuse systemic sclerosis (SSc). Thirty-eight female patients with diffuse SSc were analyzed regarding 25-hydroxyvitamin D (25OHD) serum levels. At inclusion, organ involvement, autoantibodies, modified Rodnan skin score (mRSS), Medsger Disease Severity Index (MDSI), body mass index (BMI), BMD, NC, Short-Form-36 Questionnaire (SF-36), and Health Assessment Questionnaire (HAQ), were performed through a standardized interview, physical examination and electronic chart review. Mean 25OHD serum level was 20.66±8.20ng/mL. Eleven percent of the patients had 25OHD levels ≤10ng/mL, 50% ≤20ng/mL and 87% ≤30ng/mL. Vitamin D serum levels were positively correlated with BMI (r=0.338, p=0.038), BMD-total femur (r=0.340, p=0.037), BMD-femoral neck (r=0.384, p=0.017), SF-36-Vitality (r=0.385, p=0.017), SF-36-Social Function (r=0.320, p=0.050), SF-36-Emotional Role (r=0.321, p=0.049) and SF-36-Mental Health (r=0.531, p=0.0006) and were negatively correlated with HAQ-Reach (r=-0.328, p=0.044) and HAQ-Grip Strength (r=-0.331, p=0.042). A negative correlation with NC-diffuse devascularization (p=0.029) and NC-avascular area (p=0.033) was also observed. The present study provides novel evidence demonstrating that low levels of 25OHD have a negative impact in diffuse SSc QoL and further studies are needed to define whether vitamin D supplementation can improve health related QoL in these patients. The additional observation of a correlation with severe NC alterations suggests a possible role of 25OHD in the underlying SSc vascular involvement. Copyright © 2016 Elsevier Editora Ltda. All rights reserved.
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Thiebaut, Mathilde; Launay, David; Rivière, Sébastien; Mahévas, Thibault; Bellakhal, Syrine; Hachulla, Eric; Fain, Olivier; Mekinian, Arsène
2018-06-01
To describe safety and efficacy of rituximab in patients with systemic sclerosis. We included 13 patients with systemic sclerosis treated with rituximab and pooled with 40 additional patients from the literature. SSc rituximab untreated patients were matched to rituximab treated ones. Thirteen patients who received rituximab and 26 rituximab-untreated patients were included. In comparison to 26 patients who did not received rituximab, FVC changes were not significantly different, whereas DLCO improved in 13 patients who received rituximab (0 [-4; 4] vs loss of -7 [-19; 0]; p=0.05). Considering 7 rituximab treated and 14 untreated diffuse SSc, FVC was improved during the 24 [12; 46] months of follow up in dSSc who received rituximab (gain of 12 [7.5:14] % vs loss of 1.5 [-16.8; 2.5], (p=0.003)). Pooled analysis of 53 patients (40 literature patients and 13 from personal series) showed significant improvement of median mRSS from 18 [8; 32] at baseline to 9 [4; 18] at M6 (p=0.007), 13 [8; 18] at M12 (p=0.008) and 10 [4; 16] at the last follow-up (p=0.0002). FVC increased from 71% [66; 80] at baseline to 84% [75; 90] at M12 (p=0.001). DLCO increased from 58% [39; 65] at M0 to 63% [53; 78] at M12 (p=0.04). Our personal data and pooled literature analysis suggest the efficacy of rituximab in the subset of diffuse SSc in particular in skin and interstitial disease involvements. The safety of rituximab seems to be reasonable and similar to previous data in other autoimmune diseases. Copyright © 2018 Elsevier B.V. All rights reserved.
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Suspended sediment diffusion mechanisms in the Yangtze Estuary influenced by wind fields
NASA Astrophysics Data System (ADS)
Wang, Lihua; Zhou, Yunxuan; Shen, Fang
2018-01-01
The complexity of suspended sediment concentration (SSC) distribution and diffusion has been widely recognized because it is influenced by sediment supply and various hydrodynamic forcing conditions that vary over space and over time. Sediment suspended by waves and transported by currents are the dominant sediment transport mechanisms in estuarine and coastal areas. However, it is unclear to what extent the SSC distribution is impacted by each hydrodynamic factor. Research on the quantitative influence of wind fields on the SSC diffusion range will contribute to a better understanding of the characteristics of sediment transport change and sedimentary geomorphic evolution. This study determined SSC from three Envisat Medium-Resolution Imaging Spectrometer acquisitions, covering the Yangtze Estuary and adjacent water area under the same season and tidal conditions but with varying wind conditions. SSC was examined based on the Semi-Empirical Radiative Transfer model, which has been well validated with the observation data. Integrating the corresponding wind field information from European Centre for Medium-Range Weather Forecasts further facilitated the discussion of wind fields affecting SSC, and in turn the influence of water and suspended sediment transportation and diffusion in the Yangtze estuarine and coastal area. The results demonstrated that the SSC present much more distinctive fluvial features in the inner estuary and wind fields are one of the major factors controlling the range of turbid water diffusion.
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Davies, Christine Ann; Jeziorska, Maria; Freemont, Anthony J; Herrick, Ariane L
2006-02-01
Our aim was to evaluate (a) whether there is differential expression of the endothelial regulator vascular endothelial growth factor (VEGF), its receptor (VEGFR-2), and the hypoxia-associated glucose transporter molecule, GLUT-1, in skin biopsies from different disease subtypes of systemic sclerosis (SSc) and (b) whether they associate with dermal calcinosis, a significant complication of SSc. Skin punch biopsies were taken from the forearms of 66 SSc patients including 18 with limited cutaneous disease without calcinosis (lcSSc), 23 with calcinosis (lcSSc/cal), and 25 with diffuse cutaneous disease (dcSSc) and from 12 healthy control subjects. The histological appearance of the skin was graded as G0 (normal), G1 (dermal edema), or G2 or G3 (increasing fibrotic changes). Immunohistochemistry was performed with antibodies to VEGF, VEGFR-2, and GLUT-1. Staining was assessed in the epidermis, microvessels, and fibroblasts. The Kruskal-Wallis 1-way analysis of variance was used to compare the data between disease groups. VEGF protein was located in the epidermis and in dermal endothelial cells, pericytes, fibroblasts, and inflammatory cells. In dcSSc only, there was a significant increase in VEGF staining intensity in the keratinocytes and pericytes and the lowest percentage of microvessels with VEGF-positive endothelial cells. GLUT-1 protein was located in the epidermis, erythrocytes, and perineurium. In both lcSSc/cal and dcSSC, but not lcSSc, there were significant increases in GLUT-1 staining intensity of keratinocytes. We propose that in patients with dcSSc, there is a net increase in unbound VEGF in skin that may account for the raised levels of VEGF in serum reported by others. Increased GLUT-1 expression in lcSSc/cal and dcSSc indicates that hypoxia is an associated factor.
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Outcome of Patients with Systemic Sclerosis in the Intensive Care Unit.
Pène, Frédéric; Hissem, Tarik; Bérezné, Alice; Allanore, Yannick; Geri, Guillaume; Charpentier, Julien; Avouac, Jérôme; Guillevin, Loïc; Cariou, Alain; Chiche, Jean-Daniel; Mira, Jean-Paul; Mouthon, Luc
2015-08-01
Patients with systemic sclerosis (SSc) are prone to disease-specific or treatment-related life-threatening complications that may warrant intensive care unit (ICU) admission. We assessed the characteristics and current outcome of patients with SSc admitted to the ICU. We performed a single-center retrospective study over 6 years (November 2006-December 2012). All patients with SSc admitted to the ICU were enrolled. Short-term (in-ICU and in-hospital) and longterm (6-mo and 1-yr) mortality rates were studied, and the prognostic factors were analyzed. Forty-one patients with a median age of 50 years [interquartile range (IQR) 40-65] were included. Twenty-nine patients (72.5%) displayed diffuse cutaneous SSc. The time from diagnosis to ICU admission was 78 months (IQR 34-128). Twenty-eight patients (71.7%) previously had pulmonary fibrosis, and 12 (31.5%) had pulmonary hypertension. The main reason for ICU admission was acute respiratory failure in 27 patients (65.8%). Noninvasive ventilation was first attempted in 13 patients (31.7%) and was successful in 8 of them, whereas others required endotracheal intubation within 24 h. Altogether, 13 patients (31.7%) required endotracheal intubation and mechanical ventilation. The overall in-ICU, in-hospital, 6-month, and 1-year mortality rates were 31.8%, 39.0%, 46.4%, and 61.0%, respectively. Invasive mechanical ventilation was the worst prognostic factor, associated with an in-hospital mortality rate of 84.6%. This study provides reliable prognostic data in patients with SSc who required ICU admission. The devastating outcome of invasive mechanical ventilation in patients with SSc requires a reappraisal of indications for ICU admission and early identification of patients likely to benefit from noninvasive ventilation.
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Allanore, Yannick; Distler, Oliver; Jagerschmidt, Alexandre; Illiano, Stephane; Ledein, Laetitia; Boitier, Eric; Agueusop, Inoncent; Denton, Christopher P; Khanna, Dinesh
2018-05-06
Preclinical studies suggest a role for lysophosphatidic acid (LPA) in the pathogenesis of systemic sclerosis (SSc). SAR100842, a potent selective oral antagonist of LPA1 receptor, was assessed for safety, biomarkers and clinical efficacy in patients with diffuse cutaneous SSc (dcSSc). An 8-week double-blind, randomized, placebo-controlled study followed by a 16-week open label extension with SAR100842 was performed in patients with early dcSSc and a baseline Rodnan skin score (mRSS) of at least 15. The primary endpoint was safety during the double-blind phase of the trial. Exploratory endpoints included the identification of a LPA-induced gene signature in patients 'skin. 17 of 32 subjects were randomized to placebo and 15 to SAR100842; 30 patients participated in the extension study. The most frequent adverse events reported for SAR100842 during the blinded phase were headache, diarrhea, nausea and fall and the safety profile was acceptable during the extension part. At Week 8, mean reduction in mRSS was numerically greater in the SAR100842 compared to placebo (mean change [SD]: -3.57 [4.18] versus -2.76 [4.85]; difference [95% CI]: -1.2 [-4.37 to 2.02], p=0.46). A greater reduction of LPA related genes was observed in skin of SAR100842 group at Week 8, indicating LPA 1 target engagement. SAR100842, a selective orally available LPA 1 receptor antagonist, was well tolerated in patients with dcSSc. MRSS improved during the study although not reaching significance, and additional gene signature analysis suggested target engagement. These results need to be confirmed in a larger controlled trial. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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Systemic Sclerosis Disease Modification Clinical Trials Design: Quo Vadis?
Mendoza, Fabian A.; Keyes-Elstein, Lynette L.; Jimenez, Sergio A.
2012-01-01
The purpose of this manuscript is to discuss relevant aspects of clinical trials for Systemic Sclerosis (SSc) and to identify important considerations for the design of SSc disease modification clinical trials. Placebo randomized controlled trials with appropriate identification of SSc patients with diffuse progressive SSc skin involvement of recent onset, along with a rescue strategy for patients with worsening lung and skin involvement are suggested. If change in skin thickening is a major outcome of the study, the selection of patients with recent onset of disease and a predetermined degree of skin involvement are crucial requirements. The trial duration should be of at least 12 months. Sample size calculations should consider differences that exceed the Minimal Important Difference. Other relevant trial designs and potential threats to study validity are also discussed. Previous SSc-disease modifying trials have been beset by high dropout rates. Analyses on the subset of subjects completing the trial or applying the last-observation-carried-forward approach can potentially lead to biased estimates and false conclusions. Strategies for retention of subjects should be included at the design stage and analyses to account for missing data should be performed. PMID:22422541
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Association of the FAM167A-BLK region with systemic sclerosis.
Ito, Ikue; Kawaguchi, Yasushi; Kawasaki, Aya; Hasegawa, Minoru; Ohashi, Jun; Kawamoto, Manabu; Fujimoto, Manabu; Takehara, Kazuhiko; Sato, Shinichi; Hara, Masako; Tsuchiya, Naoyuki
2010-03-01
An association of single-nucleotide polymorphisms (SNPs) in the FAM167A (previously referred to as C8orf13)-BLK region with systemic lupus erythematosus (SLE) has been demonstrated in Caucasians and in Asians. Recent studies have shown that many genes, including IRF5, STAT4, and PTPN22, are shared susceptibility genes in multiple autoimmune diseases. We undertook the current study to examine whether the FAM167A-BLK region is also associated with susceptibility to systemic sclerosis (SSc). Japanese patients with SSc (n = 309) and healthy controls (n = 769) were enrolled in a 2-tiered case-control association study. In tier 1, 124 patients and 412 controls were tested to determine association of 16 tag SNPs encompassing the FAM167A-BLK region with SSc. In tier 2, an additional 185 patients and 357 controls were analyzed for SNP rs13277113. Two haplotype blocks that correspond approximately to FAM167A and BLK were observed. In tier 1 of the study, the rs13277113A allele in the BLK block exhibited the most significant association with SSc after correction for multiple testing (permutated P = 0.024). Two SNP haplotypes formed by rs13277113 and the most significant SNP in the FAM167A block did not exhibit stronger association. When samples from tier 1 and tier 2 were combined, the rs13277113A allele was significantly associated with SSc (odds ratio 1.45 [95% confidence interval 1.17-1.79], P = 6.1 x 10(-4)). Association or a tendency toward association of rs13277113A with SSc was observed regardless of a patient's autoantibody profile or whether a patient had diffuse cutaneous or limited cutaneous SSc. Our findings indicate that the rs13277113A allele is associated not only with SLE but also with SSc and that the FAM167A-BLK region is a common genetic risk factor for both SLE and SSc.
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Arat, Seher; Verschueren, Patrick; De Langhe, Ellen; Smith, Vanessa; Vanthuyne, Marie; Diya, Luwis; Van den Heede, Koen; Blockmans, Daniel; De Keyser, Filip; Houssiau, Frédéric A; Westhovens, René
2012-03-01
The aim of the present study was to evaluate the association between illness perceptions and the ability to cope with physical and mental health problems in a large cohort of systemic sclerosis (SSc) patients. This was a cross-sectional study in 217 systemic sclerosis patients from the Belgian Systemic Sclerosis Cohort. Illness perception and coping were measured by the Revised Illness Perception Questionnaire and a coping questionnaire--the Coping Orientation of Problem Experience inventory (COPE). Physical and mental health-related quality of life was measured by the 36-item short-form health survey (SF-36), as were disease activity and several severity parameters. The relationship between illness perceptions and the ability to cope with physical/mental health problems was examined using multiple linear regression analysis. According to LeRoy's classification, 49 patients had limited SSc (lSSc), 129 had limited cutaneous SSc (lcSSc) and 39 had diffuse cutaneous SSc (dcSSc). Median disease duration was five years and the modified Rodnan skin score was 4. Good physical health was significantly associated with the lcSSc subtype and low disease activity (p < 0.01 and p < 0.05, respectively). The perception of 'serious consequences' and strong 'illness identity' correlated with poor physical health (p < 0.001). Good mental health was associated with low illness identity scores and low 'emotional response' scores (p < 0.001). Coping variables were less significantly correlated with physical and mental health compared with the illness perception items. Illness representations contribute more than classical disease characteristics to physical and mental health. Copyright © 2011 John Wiley & Sons, Ltd.
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Borghini, Alice; Poscia, Andrea; Bosello, Silvia; Teleman, Adele Anna; Bocci, Mario; Iodice, Lanfranco; Ferraccioli, Gianfranco; La Milìa, Daniele Ignazio; Moscato, Umberto
2017-10-26
Atmospheric air pollution has been associated with a range of adverse health effects. The environment plays a causative role in the development of Systemic Sclerosis (SSc). The aim of the present study is to explore the association between particulate (PM 10 ) and benzene (B) exposure in Italian patients with systemic sclerosis and their clinical characteristics of the disease. A correlation study was conducted by enrolling 88 patients who suffer from SSc at the Fondazione Policlinico "A. Gemelli" in Rome (Italy) in the period from January 2013 to January 2014. The average mean concentrations of B (in 11 monitoring sites) and PM 10 (in 14 sites) were calculated using data from the Regional Environmental Protection Agency's monitoring stations located throughout the Lazio region (Italy) and then correlated with the clinical characteristics of the SSc patients. Of the study sample, 92.5% were female. The mean age was 55 ± 12.9 years old and the mean disease duration from the onset of Raynaud's phenomenon was 13.0 ± 9.4 years. The Spearman's correlation showed that concentrations of B correlate directly with the skin score (R = 0.3; p ≤ 0.05) and inversely with Diffusing Lung Carbon Monoxide (DLCO) results (R = -0.36; p = 0.04). This study suggests a possible role of B in the development of diffuse skin disease and in a worse progression of the lung manifestations of SSc.
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Disturbed angiogenesis in systemic sclerosis: high levels of soluble endoglin.
Wipff, J; Avouac, J; Borderie, D; Zerkak, D; Lemarechal, H; Kahan, A; Boileau, C; Allanore, Y
2008-07-01
SSc is a CTD characterized by early generalized microangiopathy with disturbed angiogenesis. Soluble endoglin (sENG), a serum anti-angiogenic protein, has recently been described as a major actor in pre-eclampsia, another severe vascular disease with abnormal angiogenesis. The aim of this study was to investigate, in a cross-sectional study, sENG levels together with other serum vascular markers. Serum levels of sENG were assessed by ELISA in consecutive SSc patients and controls matched for age and sex. We also measured by ELISA serum levels of VEGF and asymmetric dimethylarginine (ADMA), as respective markers of angiogenesis and endothelial dysfunction. We included 235 unrelated subjects: 187 SSc patients and 48 controls. Higher concentrations of sENG (P = 0.002) and sVEGF (P < 0.0001) were found in SSc patients compared with controls whereas there was no difference for ADMA. In multivariate analysis, sENG levels were significantly increased in SSc patients with cutaneous ulcerations (P = 0.0003), positive for ACAs (P = 0.009) and with abnormal diffusing capacity for carbon monoxide divided by alveolar volume (P = 0.03). Soluble ENG levels negatively correlated with ADMA, but no relationship was found between sENG and sVEGF. This study shows increased values of sENG in a large SSc cohort and a relevant association with a vascular phenotype. The predictive value of the biomarker sENG and its potential role on cellular endothelial disturbances remain to be determined.
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Gene Profiling in Patients with Systemic Sclerosis Reveals the Presence of Oncogenic Gene Signatures
Dolcino, Marzia; Pelosi, Andrea; Fiore, Piera Filomena; Patuzzo, Giuseppe; Tinazzi, Elisa; Lunardi, Claudio; Puccetti, Antonio
2018-01-01
Systemic sclerosis (SSc) is a rare connective tissue disease characterized by three pathogenetic hallmarks: vasculopathy, dysregulation of the immune system, and fibrosis. A particular feature of SSc is the increased frequency of some types of malignancies, namely breast, lung, and hematological malignancies. Moreover, SSc may also be a paraneoplastic disease, again indicating a strong link between cancer and scleroderma. The reason of this association is still unknown; therefore, we aimed at investigating whether particular genetic or epigenetic factors may play a role in promoting cancer development in patients with SSc and whether some features are shared by the two conditions. We therefore performed a gene expression profiling of peripheral blood mononuclear cells (PBMCs) derived from patients with limited and diffuse SSc, showing that the various classes of genes potentially linked to the pathogenesis of SSc (such as apoptosis, endothelial cell activation, extracellular matrix remodeling, immune response, and inflammation) include genes that directly participate in the development of malignancies or that are involved in pathways known to be associated with carcinogenesis. The transcriptional analysis was then complemented by a complex network analysis of modulated genes which further confirmed the presence of signaling pathways associated with carcinogenesis. Since epigenetic mechanisms, such as microRNAs (miRNAs), are believed to play a central role in the pathogenesis of SSc, we also evaluated whether specific cancer-related miRNAs could be deregulated in the serum of SSc patients. We focused our attention on miRNAs already found upregulated in SSc such as miR-21-5p, miR-92a-3p, and on miR-155-5p, miR 126-3p and miR-16-5p known to be deregulated in malignancies associated to SSc, i.e., breast, lung, and hematological malignancies. miR-21-5p, miR-92a-3p, miR-155-5p, and miR-16-5p expression was significantly higher in SSc sera compared to healthy controls. Our findings indicate the presence of modulated genes and miRNAs that can play a predisposing role in the development of malignancies in SSc and are important for a better risk stratification of patients and for the identification of a better individualized precision medicine strategy. PMID:29559981
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Kahaleh, M B; Fan, P S; Otsuka, T
1999-05-01
In view of the documented perivascular mononuclear cell infiltration in the involved organs in scleroderma (SSc) and the reported accumulation of gammadelta-T cells in SSc skin and lung, we evaluated gammadelta-T cell interaction with endothelial cells (EC) in vitro. gammadelta- and alphabeta-T cells were isolated from BPMN of SSc patients with early diffuse disease and of matched control subjects by an immunomagnetic method after stimulation with mycobacterium lysate and interleukin-2 for 2 weeks. Lymphocyte adhesion, proliferation, and cytotoxicity to EC were investigated. SSc gammadelta-T cells adhered to cultured EC and proliferated at higher rates than control cells. Furthermore, significant EC cytotoxicity by SSc gammadelta was seen. The cytotoxicity was blocked by addition of anti-gammadelta-TCR antibody and by anti-granzyme A antibody but not by anti-MHC class I and II antibodies. Expression of granzyme A mRNA was seen in five/five SSc gammadelta-T cells and in one/five control cells. alphabeta-T cells from both SSc and control subjects were significantly less interactive with EC than gammadelta-T cells. The data demonstrate EC recognition by SSc gammadelta-T cells and propose gammadelta-T cells as a possible effector cell type in the immune pathogenesis of SSc. Copyright 1999 Academic Press.
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Ichimura, Yohei; Asano, Yoshihide; Akamata, Kaname; Noda, Shinji; Taniguchi, Takashi; Takahashi, Takehiro; Toyama, Tetsuo; Tada, Yayoi; Sugaya, Makoto; Sato, Shinichi; Kadono, Takafumi
2015-12-01
Progranulin is a growth factor that is active in wound repair and is an antagonist of tumor necrosis factor (TNF) receptors, regulating fibroblast activation, angiogenesis, and inflammation. Because long-standing activation of gene programs related to wound healing is a hallmark of systemic sclerosis (SSc), we sought to investigate the role of progranulin in SSc. Progranulin expression levels in human and murine skin samples were determined by immunohistochemical analysis and quantitative reverse transcription-polymerase chain reaction. The role of progranulin in fibroblast activation was examined using a gene-silencing technique. Progranulin levels in serum obtained from 60 patients with SSc and 16 healthy control subjects were determined by enzyme-linked immunosorbent assay. Progranulin expression was increased in SSc dermal fibroblasts compared with normal dermal fibroblasts, both in vivo and in vitro. Transcription factor Fli-1, a deficiency of which is involved in the activation of SSc dermal fibroblasts, served as a potent repressor of the progranulin gene, and Fli-1(+/-) mice and bleomycin-treated wild-type mice exhibited up-regulated expression of progranulin in dermal fibroblasts. SSc dermal fibroblasts were resistant to the antifibrotic effect of TNF, but this resistance was reversed by gene silencing of progranulin. Serum progranulin levels were elevated in patients with early diffuse cutaneous SSc (dcSSc), especially in those with inflammatory skin symptoms, and were positively correlated with the C-reactive protein level. Progranulin overproduction due to Fli-1 deficiency may contribute to the constitutive activation of SSc dermal fibroblasts by antagonizing the antifibrotic effect of TNF. Progranulin may also be involved in the inflammatory process associated with progressive skin sclerosis in early dcSSc. © 2015, American College of Rheumatology.
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Pendergrass, Sarah A.; Lemaire, Raphael; Francis, Ian; Mahoney, J. Matthew; Lafyatis, Robert; Whitfield, Michael L.
2012-01-01
Skin biopsy gene expression was analyzed by DNA microarray from 13 dSSc patients enrolled in an open label study of rituximab, 9 dSSc patients not treated with rituximab, and 9 healthy controls. These data recapitulate the patient ‘intrinsic’ gene expression subsets described previously including proliferation, inflammatory, and normal-like groups. Serial skin biopsies showed consistent and non-progressing gene expression over time, and importantly, the patients in the inflammatory subset do not move to the fibroproliferative subset, and vice versa. We were unable to detect significant differences in gene expression before and after rituximab treatment, consistent with an apparent lack of clinical response. Serial biopsies from each patient stayed within the same gene expression subset regardless of treatment regimen or the time point at which they were taken. Collectively, these data emphasize the heterogeneous nature of SSc and demonstrate that the intrinsic subsets are an inherent, reproducible and stable feature of the disease that is independent of disease duration. Moreover, these data have fundamental importance for the future development of personalized therapy for SSc; drugs targeting inflammation are likely to benefit those patients with an inflammatory signature, whereas drugs targeting fibrosis are likely to benefit those with a fibroproliferative signature. PMID:22318389
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Sumpton, Daniel; Thakkar, Vivek; O'Neill, Sean; Singh-Grewal, Davinder; Craig, Jonathan C; Tong, Allison
2017-11-01
Patients with systemic sclerosis (SSc) experience severe physical limitations and psychological morbidity, but their lived experience remains underrepresented and is reflected in the scarcity of evidence-based patient-centered interventions. We aimed to describe patients' perspectives of SSc to inform strategies to improve their care. Face-to-face semistructured interviews were conducted with 30 adult patients with limited cutaneous or diffuse cutaneous SSc in Australia. Transcripts were thematically analyzed using HyperRESEARCH software. Six themes were identified: bodily malfunction (restrictive pain, debilitating physical changes, pervasive exhaustion), deprivation of social function (loss of work and career, social isolation, threat to traditional roles, loss of intimacy), disintegration of identity (stigmatizing physical changes, disassociated self-image, extinguished hopes, alone and powerless, invisibility of illness), insecurity of care (unrecognized disease, ambiguity around diagnosis and cause, information insufficiency, resigning to treatment limitations, seeking reassurance, fear of progression), avoiding the sick role (evading thoughts of sickness, protecting family, favorable comparison), and perseverance and hope (positive stoicism, optimism about treatment and monitoring, taking control of own health, pursuing alternative treatments, transcending illness through support). SSc inflicts major bodily and social restrictions that crush patients' identity and self-image. Uncertainties about the cause, diagnosis, and prognosis can undermine confidence in care, leading to anxiety and therapeutic nihilism. Access to psychosocial care to support the patients' role and functioning capacity, as well as communication and education that explicitly address their concerns regarding management may potentially improve treatment satisfaction, self-efficacy, adherence, and outcomes in patients with SSc. © 2017, American College of Rheumatology.
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Schwab, Kristin; Saggar, Rajeev; Duffy, Erin; Elashoff, David; Tseng, Chi-Hong; Weigt, Sam; Charan, Deepshikha; Abtin, Fereidoun; Johannes, Jimmy; Derhovanessian, Ariss; Conklin, Jeffrey; Ghassemi, Kevin; Khanna, Dinesh; Siddiqui, Osama; Ardehali, Abbas; Hunter, Curtis; Kwon, Murray; Biniwale, Reshma; Lo, Michelle; Volkmann, Elizabeth; Torres Barba, David; Belperio, John A.; Mahrer, Thomas; Furst, Daniel E.; Kafaja, Suzanne; Clements, Philip; Shino, Michael; Gregson, Aric; Kubak, Bernard; Lynch, Joseph P.; Ross, David
2016-01-01
Rationale: Consideration of lung transplantation in patients with systemic sclerosis (SSc) remains guarded, often due to the concern for esophageal dysfunction and the associated potential for allograft injury and suboptimal post–lung transplantation outcomes. Objectives: The purpose of this study was to systematically report our single-center experience regarding lung transplantation in the setting of SSc, with a particular focus on esophageal dysfunction. Methods: We retrospectively reviewed all lung transplants at our center from January 1, 2000 through August 31, 2012 (n = 562), comparing the SSc group (n = 35) to the following lung transplant diagnostic subsets: all non-SSc (n = 527), non-SSc diffuse fibrotic lung disease (n = 264), and a non-SSc matched group (n = 109). We evaluated post–lung transplant outcomes, including survival, primary graft dysfunction, acute rejection, bronchiolitis obliterans syndrome, and microbiology of respiratory isolates. In addition, we defined severe esophageal dysfunction using esophageal manometry and esophageal morphometry criteria on the basis of chest computed tomography images. For patients with SSc referred for lung transplant but subsequently denied (n = 36), we queried the reason(s) for denial with respect to the concern for esophageal dysfunction. Measurements and Main Results: The 1-, 3-, and 5-year post–lung transplant survival for SSc was 94, 77, and 70%, respectively, and similar to the other groups. The remaining post–lung transplant outcomes evaluated were also similar between SSc and the other groups. Approximately 60% of the SSc group had severe esophageal dysfunction. Pre–lung transplant chest computed tomography imaging demonstrated significantly abnormal esophageal morphometry for SSc when compared with the matched group. Importantly, esophageal dysfunction was the sole reason for lung transplant denial in a single case. Conclusions: Relative to other lung transplant indications, our SSc group experienced comparable survival, primary graft dysfunction, acute rejection, bronchiolitis obliterans syndrome, and microbiology of respiratory isolates, despite the high prevalence of severe esophageal dysfunction. Esophageal dysfunction rarely precluded active listing for lung transplantation. PMID:27078625
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Social/economic costs and health-related quality of life in patients with scleroderma in Europe.
López-Bastida, Julio; Linertová, Renata; Oliva-Moreno, Juan; Serrano-Aguilar, Pedro; Posada-de-la-Paz, Manuel; Kanavos, Panos; Taruscio, Domenica; Schieppati, Arrigo; Iskrov, Georgi; Péntek, Márta; Delgado, Claudia; von der Schulenburg, Johann Mathias; Persson, Ulf; Chevreul, Karine; Fattore, Giovanni
2016-04-01
The aim of this study was to determine the economic burden from a societal perspective and the health-related quality of life (HRQOL) of patients with systemic sclerosis (SSc; scleroderma) in Europe. We conducted a cross-sectional study of patients with SSc (involving both localised and systemic sclerosis) from Germany, Italy, Spain, France, the UK, Hungary and Sweden. Data on demographic characteristics, healthcare resource utilisation, informal care, labour productivity losses and HRQOL were collected from the questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ-5D) questionnaire. A total of 589 patients completed the questionnaire. The rate of patients with localised scleroderma, limited cutan and diffuse cutan SSc were 28, 68 and 4 %, respectively. Average annual costs varied from country to country and ranged from € 4607 to € 30,797 (reference year: 2012). Estimated direct healthcare costs ranged from € 1413 to € 17,300; direct non-healthcare costs ranged from € 1875 to € 4684 and labour productivity losses ranged from € 1701 to € 14,444. The mean EQ-5D index score for adult SSc patients varied from 0.49 to 0.75 and the mean EQ-5D visual analogue scale score was between 58.72 and 65.86. The main strengths of this study lie in our bottom-up approach to costing and our evaluation of SSs patients from a broad societal perspective. This type of analysis is very unusual in the international literature on rare diseases in comparison with other illnesses. We concluded that SSc patients incur considerable societal costs and experience substantial deterioration in HRQOL.
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Antoniou, K M; Margaritopoulos, G A; Goh, N S; Karagiannis, K; Desai, S R; Nicholson, A G; Siafakas, N M; Coghlan, J G; Denton, C P; Hansell, D M; Wells, A U
2016-04-01
To assess the prevalence of combined pulmonary fibrosis and emphysema (CPFE) in systemic sclerosis (SSc) patients with interstitial lung disease (ILD) and the effect of CPFE on the pulmonary function tests used to evaluate the severity of SSc-related ILD and the likelihood of pulmonary hypertension (PH). High-resolution computed tomography (HRCT) scans were obtained in 333 patients with SSc-related ILD and were evaluated for the presence of emphysema and the extent of ILD. The effects of emphysema on the associations between pulmonary function variables and the extent of SSc-related ILD as visualized on HRCT and echocardiographic evidence of PH were quantified. Emphysema was present in 41 (12.3%) of the 333 patients with SSc-related ILD, in 26 (19.7%) of 132 smokers, and in 15 (7.5%) of 201 lifelong nonsmokers. When the extent of fibrosis was taken into account, emphysema was associated with significant additional differences from the expected values for diffusing capacity for carbon monoxide (DLco) (average reduction of 24.1%; P < 0.0005), and the forced vital capacity (FVC)/DLco ratio (average increase of 34.8%; P < 0.0005) but not FVC. These effects were identical in smokers and nonsmokers. Multivariate analysis showed that the presence of emphysema had a greater effect than echocardiographically determined PH on the FVC/DLco ratio, regardless of whether it was analyzed as a continuous variable or using a threshold value of 1.6 or 2.0. Among patients with SSc-related ILD, emphysema is sporadically present in nonsmokers and is associated with a low pack-year history in smokers. The confounding effect of CPFE on measures of gas exchange has major implications for the construction of screening algorithms for PH in patients with SSc-related ILD. © 2016, American College of Rheumatology.
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Espinosa, Gerard; Simeón, Carmen Pilar; Plasín, Miguel Ángel; Xaubet, Antoni; Muñoz, Xavier; Fonollosa, Vicent; Cervera, Ricard; Vilardell, Miquel
2011-05-01
Cyclophosphamide (CYC) stabilizes the parameters of lung function tests (LFT) of patients with (SSc) and interstitial lung disease (ILD) treated for 12 months. There is little information about long-term treatment (24 months). The aim of this study is to analyze the effect of intravenous CYC in LFT parameters in patients with SSc and ILD treated for 24 months. Retrospective study of 37 patients with ILD associated with scleroderma treated with intravenous CYC for 24 months and regularly assessed by LFT (at baseline, 6, 12 and 24 months) including forced vital capacity (FVC) and transfer capacity of carbon monoxide (DL(CO)). To evaluate response to treatment the recommendations of the ATS and SEPAR were considered. The difference between FVC and DL(CO) values performed at baseline and those performed at 6, 12, and 24 months were less than 10%, which meant that CYC stabilized LFT. There were no differences in LFT when patients treated for 6 months were evaluated according to the type of skin involvement of the SSc (diffuse or limited) and the duration of the ILD. Although patients with severe restriction (FVC<70%) showed more improvement, it was less than 10% in all cases. In this series of patients with ILD associated with SSc intravenous CYC was effective in stabilizing LFT in long-term treatment. Copyright © 2010 SEPAR. Published by Elsevier Espana. All rights reserved.
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Distler, Oliver; Allanore, Yannick; Denton, Christopher P; Matucci-Cerinic, Marco; Pope, Janet E; Hinzmann, Barbara; Davies, Siobhan; de Oliveira Pena, Janethe; Khanna, Dinesh
2018-05-01
To gain insight into clinical practice regarding referral, early diagnosis and other aspects of the management of patients with dcSSc in Europe and the USA. Semi-structured interviews were conducted with 84 rheumatologists (or internal medicine physicians) and 40 dermatologists in different countries (the UK, France, Germany, Italy, Spain and the USA). Physicians were asked to identify key steps in the patient pathway relating to patient presentation, diagnosis and referral, in addition to other treatment and follow-up processes. The interviewed physicians reported that late presentation with dcSSc was common, with some patients presenting to primary care physicians after symptoms had persisted for up to 1 year. Awareness of dcSSc is reported to vary widely among primary care physicians. Final diagnosis, generally following guideline-based recommendations, was by rheumatologists in most cases (or internal medicine physicians in France) and they remained responsible for global patient management, with lesser involvement in diagnosis and management by dermatologists. Specialist centres were not well defined and did not exist in all countries. Patients and primary healthcare providers can be unaware of the symptoms of dcSSc, therefore presentation and referral to specialist care are often late. Thus, improved awareness among patients and primary care physicians is necessary to facilitate earlier referral and diagnosis. Once referred, more consistent use of the modified Rodnan skin score at diagnosis and follow-up may help to monitor disease progression. Furthermore, establishing specialist centres may help to promote such changes and improve patient care.
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Torok, Kathryn S; Baker, Nancy A; Lucas, Mary; Domsic, Robyn T; Boudreau, Robert; Medsger, Thomas A
2010-01-01
To determine the reliability and validity of a new measure of finger motion in patients with systemic sclerosis (SSc), the 'delta finger-topalm' (delta FTP) and compare its psychometric properties to the traditional measure of finger motion, the finger-topalm (FTP). Phase 1: The reliability of the delta FTP and FTP were examined in 39 patients with SSc. Phase 2: Criterion and convergent construct validity of both measures were examined in 17 patients with SSc by comparing them to other clinical measures: Total Active Range of Motion (TAROM), Hand Mobility in Scleroderma (HAMIS), the Duruoz Hand Index (DHI), Health Assessment Questionnaire (HAQ), and modified Rodnan skin score (mRSS). Phase 3: Sensitivity to change of the delta FTP was investigated in 24 patients with early diffuse cutaneous SSc. Both measures had excellent intra-rater and inter-rater reliability (ICC 0.92 to 0.99). Fair to strong correlations (rs=0.49-0.94) were observed between the delta FTP and TAROM, HAMIS, and DHI. Fair to moderate correlations were observed between delta FTP and HAQ components related to hand function and upper extremity mRSS. Correlations of the traditional FTP with these measures were fair to strong, but most often the delta FTP outperformed the FTP. The effect size and standardised response mean for the mean delta FTP were 0.50 and 1.10 respectively, over a 2-8 month period. The delta FTP is a valid and reliable measure of finger motion in patients with SSc which outperforms the FTP.
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N-terminal pro-brain natriuretic peptide is a strong predictor of mortality in systemic sclerosis.
Allanore, Yannick; Komocsi, Andras; Vettori, Serena; Hachulla, Eric; Hunzelmann, Nicolas; Distler, Jörg; Avouac, Jérôme; Gobeaux, Camille; Launay, David; Czirjak, Laszlo; Kahan, André; Meune, Christophe
2016-11-15
Cardiovascular involvement is a major contributor to mortality in systemic sclerosis (SSc). We examined whether N-terminal pro-brain natriuretic peptide (NT-proBNP) is a reliable predictor of mortality in SSc. This multicentre prospective cohort study included 523 patients presenting with SSc, whose mean age was 54±13years, mean disease duration 8±9years, and diffuse cutaneous form in 168. Plasma NT-proBNP was measured at baseline and the patients were followed yearly. Overall mortality was measured at 3years. At baseline, cardiovascular involvement was present in 37 patients, including 17 with pulmonary artery hypertension (PAH) and 20 with a left ventricular ejection fraction (LVEF) <55%. At 3years, 32 (7%) patients had died. The median [25th-75th percentile] NT-proBNP concentration was 203ng/l [129-514] in patients who died within 3years, versus 88ng/l [47-167] in survivors (P<0.001). NT-proBNP was an independent predictor of 3-years mortality in multivariate analysis (P=0.046). The optimal cut-off derived from the ROC curve was 129ng/l; sensitivity and specificity to predict 3y mortality were 78.1 and 66.7%. Using the previously recommended 125-ng/l concentration as threshold value, NT-proBNP reliably and independently predicted 3year mortality, with a sensitivity of 78.1 and a negative predictive value of 97.6%, respectively (P=0.006). The consideration of SSc patients without PAH or LVEF<55% at baseline yielded similar results. NT-proBNP appears as a reliable and independent predictor of mortality in patients with SSc. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
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Rituximab for the therapy of systemic sclerosis: a series of 10 cases in a single center.
Vilela, Verônica Silva; Maretti, Giselle Baptista; Gama, Lívia Marques da Silva; Costa, Claudia Henrique da; Rufino, Rogério Lopes; Levy, Roger A
Systemic sclerosis (SSc) is a chronic autoimmune disease with a high morbidity and mortality. Although cyclophosphamide is effective for severe and refractory cases, there is demand for new treatments. The biological treatment with B-cell depletion with rituximab (RTX) has demonstrated efficacy for this demand in open-label studies. This study was conducted with the aim to retrospectively evaluate all patients who used RTX for the treatment of SSc in our center. We retrospectively evaluated medical records of all patients with SSc who used RTX to treat this disease from January 2009 to January 2015. Systemic, cutaneous, and pulmonary involvement data and laboratory results before and six months after the first infusion of RTX were collected. Ten patients received treatment during the study period and were included in this series. All patients had a diffuse form of the disease. Five patients suffered from an early (duration of disease shorter or equal to four years), rapidly progressive disease, and another five received RTX at late stages of the disease. In both groups of patients, stabilization of the pulmonary picture was observed, with a fall in the skin score in those patients with early forms of the disease. Similar to findings in previous studies, RTX was effective in treating early and rapidly progressive forms of SSc. We also found that patients with long-term illness may benefit from the treatment. Copyright © 2016. Published by Elsevier Editora Ltda.
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Tashkin, Donald P; Volkmann, Elizabeth R; Tseng, Chi-Hong; Roth, Michael D; Khanna, Dinesh; Furst, Daniel E; Clements, Philip J; Theodore, Arthur; Kafaja, Suzanne; Kim, Grace Hyun; Goldin, Jonathan; Ariolla, Edgar; Elashoff, Robert M
2017-04-01
Cough is a common symptom of scleroderma-related interstitial lung disease (SSc-ILD), but its relationship to other characteristics of SSc-ILD, impact on cough-specific quality of life (QoL), and response to therapy for SSc-ILD have not been well studied. We investigated frequent cough (FC) in patients with SSc-ILD (N = 142) enrolled in the Scleroderma Lung Study II, a randomized controlled trial comparing mycophenolate mofetil (MMF) and oral cyclophosphamide (CYC) as treatments for interstitial lung disease (ILD). We determined the impact of FC on QoL (Leicester Cough Questionnaire [LCQ]), evaluated the change in FC in response to treatment for SSc-ILD, and examined the relationship between gastroesophageal reflux disease (GERD) and cough during the trial. Study participants who reported FC at baseline (61.3%) reported significantly more dyspnea, exhibited more extensive ILD on high-resolution CT, had a lower diffusing capacity for carbon monoxide, and reported more GERD symptoms than did those without FC. Cough-specific QoL was modestly impaired in patients with FC (total LCQ score, 15.4 ± 3.7; normal range, 3-21 [higher scores indicate worse QoL]). The proportion of patients with FC at baseline declined by 44% and 41% over 2 years in the CYC and MMF treatment arms, respectively, and this decline was significantly related to changes in GERD and ILD severity. FC occurs commonly in SSc-ILD, correlates with both the presence and severity of GERD and ILD at baseline, and declines in parallel with improvements in both ILD and GERD over a 2-year course of therapy. Frequent cough might serve as a useful surrogate marker of treatment response in SSc-ILD trials. ClinicalTrials.gov; No.: NCT00883129; URL: www.clinicaltrials.gov. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
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Osteopontin in Systemic Sclerosis and its Role in Dermal Fibrosis
Wu, Minghua; Schneider, Daniel J.; Mayes, Maureen D; Assassi, Shervin; Arnett, Frank C.; Tan, Filemon K.; Blackburn, Michael R.; Agarwal, Sandeep K.
2012-01-01
Osteopontin (OPN) is a matricellular protein with proinflammatory and profibrotic properties. Previous reports demonstrate a role for OPN in wound healing and pulmonary fibrosis. Herein, we determined if OPN levels are increased in a large cohort of systemic sclerosis (SSc) patients and if OPN contributes dermal fibrosis. Plasma OPN levels were increased in SSc patients, including patients with limited and diffuse disease, compared to healthy controls. Immunohistology demonstrated OPN on fibroblast-like and inflammatory cells in SSc skin and lesional skin from mice in the bleomycin-induced dermal fibrosis model. OPN deficient (OPN−/−) mice developed less dermal fibrosis compared to wild-type mice in the bleomycin-induced dermal fibrosis model. Additional in vivo studies demonstrated that lesional skin from OPN−/− mice had fewer Mac-3+ cells, fewer myofibroblasts, decreased TGF-beta (TGFβ) and genes in the TGFβ pathway and decreased numbers of cells expressing phosphorylated SMAD2 (pSMAD) and ERK. In vitro, OPN−/− dermal fibroblasts had decreased migratory capacity but similar phosphorylation of SMAD2 by TGFβ. Finally, TGFβ production by OPN deficient macrophages was reduced compared to wild type. These data demonstrate an important role for OPN in the development of dermal fibrosis and suggest that OPN may be a novel therapeutic target in SSc. PMID:22402440
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GERD questionnaire for diagnosis of gastroesophageal reflux disease in systemic sclerosis.
Chunlertrith, K; Noiprasit, A; Foocharoen, C; Mairiang, P; Sukeepaisarnjaroen, W; Sangchan, A; Sawadpanitch, K
2014-01-01
Gastroesophageal reflux disease (GERD) is clinically-identified in patients with systemic sclerosis (SSc). The GERD-questionnaire (GERD-Q) score is a sensitive, non-invasive, diagnostic screening tool for diagnosis of GERD in general patients, but it has been not investigated for use in SSc. Our aim was to evaluate the proper cut-off GERD-Q score, sensitivity and specificity for a diagnosis of GERD in SSc patients. A cross-sectional study using the GERD-Q was performed during May 2012-January 2013 on patients over 18 with the diffuse SSc subset. Both esophago-gastro-duodenoscopy (EGD) and 24-hr pH-monitoring (24hr-pH) were performed as the gold standard tests for both symptomatic and asymptomatic GERD. A total of 75 SSc patients completed the GERD-Q, EGD and 24hr-pH. We identified 22 males (29.3%), 53 females (70.7%) with a mean age of 54.2 years. The respective number of symptomatic and asymptomatic GERD was 69 and 6 cases. For a GERD diagnosis, a cut-off GERD-Q score of 4 provided the best balance between sensitivity and specificity (96.9% and 50%, respectively). Of 48 participants (69.6%) with symptomatic GERD (i.e. positive for both EGD and 24hr-pH), 65 (94.2%) were positive for either EGD or 24hr-pH, and 4 (5.8%) were negative for both EGD and 24hr-pH. A respective majority (83%) vs. one-third of the asymptomatic group had reflux as detected by 24hr-pH vs. A GERD-Q score of 4 or higher indicates a high sensitivity for a diagnosis of GERD in SSc. It can thus be used as a non-invasive screening tool for diagnosing GERD in cases where EGD and 24hr-pH are unavailable.
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Torok, Kathryn S.; Baker, Nancy A.; Lucas, Mary; Domsic, Robyn T.; Boudreau, Robert; Medsger, Thomas A.
2010-01-01
Objectives To determine the reliability and validity of a new measure of finger motion in patients with systemic sclerosis (SSc), the ‘delta finger-to-palm’ (delta FTP) and compare its psychometric properties to the traditional measure of finger motion, the finger-to-palm (FTP). Methods Phase 1: The reliability of the delta FTP and FTP were examined in 39 patients with SSc. Phase 2: Criterion and convergent construct validity of both measures were examined in 17 patients with SSc by comparing them to other clinical measures: Total Active Range of Motion (TAROM), Hand Mobility in Scleroderma (HAMIS), the Duruoz Hand Index (DHI), Health Assessment Questionnaire (HAQ), and modified Rodnan skin score (mRSS). Phase 3: Sensitivity to change of the delta FTP was investigated in 24 patients with early diffuse cutaneous SSc. Results Both measures had excellent intra-rater and inter-rater reliability (ICC 0.92 to 0.99). Fair to strong correlations (rs=0.49–0.94) were observed between the delta FTP and TAROM, HAMIS, and DHI. Fair to moderate correlations were observed between delta FTP and HAQ components related to hand function and upper extremity mRSS. Correlations of the traditional FTP with these measures were fair to strong, but most often the delta FTP outperformed the FTP. The effect size and standardised response mean for the mean delta FTP were 0.50 and 1.10 respectively, over a 2–8 month period. Conclusion The delta FTP is a valid and reliable measure of finger motion in patients with SSc which outperforms the FTP. PMID:20576211
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2014-01-01
Introduction The crucial role of innate immunity in the pathogenesis of systemic sclerosis (SSc) is well established, and in the past few years the hypothesis that Toll-like receptor 4 (TLR4) activation induced by endogenous ligands is involved in fibrogenesis has been supported by several studies on skin, liver, and kidney fibrosis. These findings suggest that TLR4 activation can enhance transforming growth factor beta (TGF-β) signaling, providing a potential mechanism for TLR4/Myeloid differentiation factor 88 (MyD88)-dependent fibrosis. Methods The expression of TLR4, CD14 and MD2 genes was analyzed by real-time polymerase chain reaction from skin biopsies of 24 patients with diffuse cutaneous SSc. In order to investigate the effects of the chronic skin exposure to endotoxin (Lipopolysaccharide (LPS)) in vivo we examined the expression of inflammation, TGF-β signaling and cellular markers genes by nanostring. We also identified cellular subsets by immunohistochemistry and flow cytometry. Results We found that TLR4 and its co-receptors, MD2 and CD14, are over-expressed in lesional skin from patients with diffuse cutaneous SSc, and correlate significantly with progressive or regressive skin disease as assessed by the Delta Modified Rodnan Skin Score. In vivo, a model of chronic dermal LPS exposure showed overexpression of proinflammatory chemokines, recruitment and activation of macrophages, and upregulation of TGF-β signature genes. Conclusions We delineated the role of MyD88 as necessary for the induction not only for the early phase of inflammation, but also for pro-fibrotic gene expression via activation of macrophages. Chronic LPS exposure might be a model of early stage of SSc when inflammation and macrophage activation are important pathological features of the disease, supporting a role for innate immune activation in SSc skin fibrosis. PMID:24984848
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Stifano, Giuseppina; Affandi, Alsya J; Mathes, Allison L; Rice, Lisa M; Nakerakanti, Sashidhar; Nazari, Banafsheh; Lee, Jungeun; Christmann, Romy B; Lafyatis, Robert
2014-07-01
The crucial role of innate immunity in the pathogenesis of systemic sclerosis (SSc) is well established, and in the past few years the hypothesis that Toll-like receptor 4 (TLR4) activation induced by endogenous ligands is involved in fibrogenesis has been supported by several studies on skin, liver, and kidney fibrosis. These findings suggest that TLR4 activation can enhance transforming growth factor beta (TGF-β) signaling, providing a potential mechanism for TLR4/Myeloid differentiation factor 88 (MyD88)-dependent fibrosis. The expression of TLR4, CD14 and MD2 genes was analyzed by real-time polymerase chain reaction from skin biopsies of 24 patients with diffuse cutaneous SSc. In order to investigate the effects of the chronic skin exposure to endotoxin (Lipopolysaccharide (LPS)) in vivo we examined the expression of inflammation, TGF-β signaling and cellular markers genes by nanostring. We also identified cellular subsets by immunohistochemistry and flow cytometry. We found that TLR4 and its co-receptors, MD2 and CD14, are over-expressed in lesional skin from patients with diffuse cutaneous SSc, and correlate significantly with progressive or regressive skin disease as assessed by the Delta Modified Rodnan Skin Score. In vivo, a model of chronic dermal LPS exposure showed overexpression of proinflammatory chemokines, recruitment and activation of macrophages, and upregulation of TGF-β signature genes. We delineated the role of MyD88 as necessary for the induction not only for the early phase of inflammation, but also for pro-fibrotic gene expression via activation of macrophages. Chronic LPS exposure might be a model of early stage of SSc when inflammation and macrophage activation are important pathological features of the disease, supporting a role for innate immune activation in SSc skin fibrosis.
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All-cause Healthcare Costs and Mortality in Patients with Systemic Sclerosis with Lung Involvement.
Fischer, Aryeh; Kong, Amanda M; Swigris, Jeffrey J; Cole, Ashley L; Raimundo, Karina
2018-02-01
Patients with systemic sclerosis (SSc) often develop interstitial lung disease (ILD) and/or pulmonary arterial hypertension (PAH). The effect of ILD and PAH on healthcare costs among patients with SSc is not well described. The objective of this analysis was to describe healthcare costs in patients with newly diagnosed SSc and SSc patients newly diagnosed with ILD and/or PAH in the United States. This retrospective cohort analysis was conducted in the Truven Health MarketScan Commercial and Medicare Supplemental healthcare claims databases from 2003 to 2014. Based on International Classification of Diseases-9-Clinical Modification diagnosis codes on medical claims, patients were classified into 3 groups: incident SSc, SSc with incident ILD (SSc-ILD), and SSc with incident PAH (SSc-PAH). Patients were required to have continuous enrollment for 5 years to measure all-cause healthcare costs. Costs (adjusted to US$) were reported overall and by service type and year following diagnosis. Because of the overlap between groups, statistical comparisons were not conducted. There were 1957 patients with incident SSc, 219 with incident SSc-ILD, and 108 patients with incident SSc-PAH. Average (mean ± SD) all-cause healthcare costs over followup were higher for patients with incident SSc-ILD ($191,107 ± $322,193) or patients with incident SSc-PAH ($254,425 ± $240,497), compared to patients with incident SSc ($101,839 ± $167,155). Average annual costs over the 5-year period ranged from $18,513 to $23,268 for patients with incident SSc, from $31,285 to $55,446 for patients with incident SSc-ILD, and from $44,454 to $63,320 for patients with incident SSc-PAH. Costs tended to be the highest in the fifth year of followup. Among patients with SSc, ILD and PAH can result in substantial increases in healthcare costs.
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Factors associated with gingival inflammation among adults with systemic sclerosis.
Yuen, H K; Weng, Y; Reed, S G; Summerlin, L M; Silver, R M
2014-02-01
To identify factors associated with increased gingival inflammation in adults with systemic sclerosis (SSc, scleroderma). In this cross-sectional study, forty-eight adults with SSc received assessment of gingival inflammation using Löe and Silness gingival index (LSGI), measurement of oral aperture and evaluation of manual dexterity to perform oral hygiene using the Toothbrushing Ability Test, as well as completion of an oral health-related questionnaire. Three explanatory variables in the final multiple predictor models for the LSGI outcome were statistically significant--manual dexterity to perform oral hygiene, flossing in the evening and SSc subtype, with higher (i.e., worse) LSGI score among those with impaired manual dexterity, not flossing in the evening and diffuse form of SSc. In addition, posterior teeth had higher LSGI scores compared with that of the anterior teeth after adjusting for other variables. Results suggest that dental health professionals take manual dexterity into consideration when educating patients with SSc to improve their oral hygiene and educate them on paying more attention on cleaning their posterior teeth and the importance of flossing in the evening--especially those who only floss once a day or less often. © 2013 John Wiley & Sons A/S.
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Digital ulcers predict a worse disease course in patients with systemic sclerosis.
Mihai, Carina; Landewé, Robert; van der Heijde, Désirée; Walker, Ulrich A; Constantin, Paul I; Gherghe, Ana Maria; Ionescu, Ruxandra; Rednic, Simona; Allanore, Yannick; Avouac, Jérôme; Czirják, László; Hachulla, Eric; Riemekasten, Gabriela; Cozzi, Franco; Airò, Paolo; Cutolo, Maurizio; Mueller-Ladner, Ulf; Matucci-Cerinic, Marco
2016-04-01
Systemic sclerosis (SSc) is a systemic autoimmune disease with high morbidity and significant mortality. There is a great need of predictors that would allow risk stratification of patients with SSc and ultimately initiation of treatment early enough to ensure optimal clinical results. In this study, we evaluated whether a history of digital ulcers (HDU) at presentation may be a predictor of vascular outcomes and of overall clinical worsening and death in patients with SSc. Patients from the EULAR Scleroderma Trials and Research (EUSTAR) database, satisfying at inclusion the 1980 American College of Rheumatology classification criteria for SSc, who had a follow-up of at least 3 years since baseline or who have died, were included in the analysis. HDU at presentation as a predictor of disease worsening or death was evaluated by Cox proportional hazards regression analysis. 3196 patients matched the inclusion criteria (male sex 13.2%, 33.4% diffuse subset). At presentation, 1092/3196 patients had an HDU (34.1%). In multivariable analysis adjusting for age, gender and all parameters considered potentially significant, HDU was predictive for the presence of active digital ulcers (DUs) at prospective visits (HR (95% CI)): 2.41 (1.91 to 3.03), p<0.001, for an elevated systolic pulmonary arterial pressure on heart ultrasound (US-PAPs):1.36 (1.03 to 1.80), p=0.032, for any cardiovascular event (new DUs, elevated US-PAPs or LV failure): 3.56 (2.26 to 5.62), p<0.001, and for death (1.53 (1.16 to 2.02), p=0.003). In patients with SSc, HDU at presentation predicts the occurrence of DUs at follow-up and is associated with cardiovascular worsening and decreased survival. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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Santosa, A; Tan, C S; Teng, G G; Fong, W; Lim, A; Law, W G; Chan, G; Ng, S C; Low, Ahl
2016-11-01
To assess contemporary outcomes and predictors of mortality in the well-characterized multi-ethnic systemic sclerosis cohort Singapore (SCORE). From 2008, patients diagnosed with systemic sclerosis (SSc) fulfilling the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) or Very Early Diagnosis of Systemic Sclerosis (VEDOSS) criteria were recruited from three major tertiary rheumatology centres in Singapore. Mortality was verified with the Singapore National Registry of Deaths and in-hospital cause of death was determined by two independent reviewers, up to 10 December 2013. A Cox proportional hazard (PH) regression analysis was used to examine the association between demographic and clinical indices and mortality, controlling for age and race. Of the 349 patients (86.8% female; 77.7% Chinese), 97.4% fulfilled the ACR/EULAR 2013 criteria. The mean age at diagnosis was 46.2 years. The prevalence of limited (lcSSc), diffuse (dcSSc) cutaneous SSc, and SSc-overlap syndromes was 34.4, 37.1, and 26.8%, respectively. Thirty-five patients died after a mean follow-up of 2.1 years (743.6 person-years). Fifty-seven per cent of deaths were attributed to SSc, with pulmonary arterial hypertension (PAH), interstitial lung disease (ILD), and gastrointestinal (GI) complications as the leading causes of death. Multivariate analysis (n = 275) showed that smoking [hazard ratio (HR) 4.0, 95% confidence interval (CI) 1.5-10.6], SSc-overlap (HR 6.0, 95% CI 1.8-19.1), baseline renal involvement (HR 2.5, 95% CI 1.1-6.0), pulmonary artery systolic pressure (PASP) ≥ 40 mmHg on echocardiography (HR 5.1, 95% CI 2.2-11.7), treatment for peripheral vasculopathy (HR 2.6, 95% CI 1.1-6.5), and parenteral nutrition (HR 8.8, 95% CI 2.2-34.3) were independent predictors of mortality. PAH, ILD, and GI complications were leading causes of death in this cohort. We identified a high-risk group of patients who would benefit from closer monitoring and early intervention.
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[The diagnostic significance of nailfold video-capillaroscopy in systemic sclerosis].
Li, Lin-Guang; Zhang, Jiang-Lin; Liu, Xiu-Hua; Huang, Feng
2012-05-01
To observe nailfold capillary changes in a cohort of connective tissue disease (CTD) with Raynaud's phenomenon (RP) and to explore the diagnostic value of nailfold video-capillaroscopy (NVC) in systemic sclerosis (SSc). Sixty CTD patients with RP divided into SSc group (n = 36) and non-SSc group (n = 24) were referred to an experienced operator for NVC. The patients had decreased capillary loops in SSc group with the capillary diameter more enlarged in SSc group than non-SSc group. The number of patients in SSc group with giant capillaries was 14, while 3 in non-SSc group. There were 23 patients with haemorrhages in SSc group and 9 in non-SSc group. The number of patients with severe effusion was 15 in SSc group, while 2 in non-SSc group. By using the ROC curves, indexes with AUC at least 0.7 of the input capillary diameter, the output capillary diameter, the middle capillary diameter, blood color and effusion for the diagnostic cutoff points were 18.5 µm, 24.5 µm, 19.5µm, deep red and severe effusion. With at least 2 out of the top 3 indexes, the diagnostic sensitivity and specificity of SSc were higher. CTD Patients with RP of SSc have less capillary loops, more enlarged capillaries, more giant capillaries, more severe effusion and more haemorrhages than non-SSc patients. The characteristics of nailfold capillary changes in SSc patients with RP can be helpful for the diagnosis and the differential diagnosis of SSc.
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Pope, Janet; Harding, Sarah; Khimdas, Sarit; Bonner, Ashley; Baron, Murray
2012-03-01
We determined congruence with published guidelines from the European League Against Rheumatism (EULAR)/EULAR Scleroderma Trials and Research group, for systemic sclerosis (SSc) investigations and treatment practices within the Canadian Scleroderma Research Group (CSRG). Investigations and medication use for SSc complications were obtained from records of patients with SSc in the CSRG to determine adherence to guidelines for patients enrolled before and after the guidelines were published. The CSRG database of 1253 patients had 992 patients with SSc enrolled before publication of the guidelines and 261 after. For pulmonary arterial hypertension (PAH) treatment, there were no differences in use before and after the guidelines, yet annual echocardiograms for PAH screening were done in 95% of patients enrolled before the guidelines and in only 86% of those enrolled after (p <0.0001), and fewer followup echocardiograms were done 1 year later in the latter group (88% vs 59%). No differences were found for the frequency of PAH-specific treatment; 60% had ever used calcium channel blockers for Raynaud's phenomenon, with no differences in the groups before and after the guidelines. But the use of phosphodiesterase type 5 inhibitors (which does not have guidelines) was increased in the after-guidelines group. Proton pump inhibitors were used in > 80% with gastroesophageal reflux disease before and after the guidelines. One-quarter with gastrointestinal symptoms were taking prokinetic drugs. For those with past SSc renal crisis, use of angiotensin-converting enzyme inhibitors was not different before and after the guidelines. For early diffuse SSc < 2 years, ever-use of methotrexate was similar (one-quarter of each group); and for symptomatic interstitial lung disease, 19% had ever used cyclophosphamide before the guidelines and 9% after (p = nonsignificant). CSRG practices were generally comparable to recently published guidelines; however, use of iloprost and bosentan was low for digital ulcers because these drugs are not approved for use in Canada. There did not seem to be an increase in adherence to recommendations once the guidelines were published. For many guidelines, 25% to 40% of patients who would qualify received the recommended treatment.
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Vitamin D, parathyroid hormone, and acroosteolysis in systemic sclerosis.
Braun-Moscovici, Yolanda; Furst, Daniel E; Markovits, Doron; Rozin, Alexander; Clements, Philip J; Nahir, Abraham Menahem; Balbir-Gurman, Alexandra
2008-11-01
.Sclerodactyly with acroosteolysis (AO) and calcinosis are prominent features of systemic sclerosis (SSc), but the pathogenesis of these findings is poorly understood. Vitamin D and parathyroid hormone (PTH) have a crucial role in bone metabolism and resorption and may affect AO and calcinosis. We assessed vitamin D and PTH in patients with SSc. Medical records of 134 consecutive patients with SSc (American College of Rheumatology criteria) followed at the rheumatology department during the years 2003-2006 were reviewed for clinical assessment, laboratory evaluation [including 25(OH) vitamin D, calcium, phosphorus, alkaline phosphatase, PTH, creatinine, and albumin]; imaging data confirming AO and/or calcinosis. Patients followed routinely at least once a year were included (81 patients). Of these, 60 patients' medical records were found to have complete, relevant clinical, laboratory, and radiographic imaging. Thirteen patients had diffuse disease and 47 limited disease - 51 women and 9 men, 44 Jews and 16 Arabs; mean age 55 +/- 14 years; disease duration 8 +/- 6 years. AO with or without calcinosis was observed in 42 patients (70%). Vitamin D deficiency was found in 46% of patients (16 out of 44 Jewish patients, 10 out of 16 Arab patients). PTH was elevated in 21.7% of patients. Significant correlations were observed between acroosteolysis and PTH (p = 0.015), calcinosis (p = 0.009), and disease duration (p = 0.008), and between PTH and vitamin D levels (p = 0.01). All patients had normal serum concentrations of calcium, phosphorus, magnesium, and albumin, and liver and kidney functions. In this group of Mediterranean patients with SSc, the incidence of vitamin D deficiency and secondary hyperparathyroidism was surprisingly high. This finding correlated with the occurrence of AO and calcinosis. Low levels of vitamin D may reflect silent malabsorption and might be a risk factor for secondary hyperparathyroidism and bone resorption. Traditional dress habits and low exposure to sun may contribute to vitamin D deficiency in an Arab population but do not explain all the findings. The pathogenesis of these findings needs to be corroborated in other SSc populations.
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Volkmann, Elizabeth R; Tashkin, Donald P; Roth, Michael D; Clements, Philip J; Khanna, Dinesh; Furst, Daniel E; Mayes, Maureen; Charles, Julio; Tseng, Chi-Hong; Elashoff, Robert M; Assassi, Shervin
2016-12-30
Increased circulatory levels of the chemokine CXCL4 have been associated with the presence of interstitial lung disease (ILD) in an observational study of patients with systemic sclerosis (SSc). The purpose of the present study was to evaluate the relationship between baseline CXCL4 level and extent of ILD in the context of a randomized controlled trial and to determine whether changes in CXCL4 levels in response to immunosuppression are associated with future progression of SSc-ILD. A total of 142 SSc-ILD patients from Scleroderma Lung Study (SLS) II were randomized in a double-blind, parallel-arm trial, to receive mycophenolate (MMF) for 2 years or oral cyclophosphamide (CYC) for 1 year followed by 1 year of placebo. Plasma CXCL4 levels were measured at baseline, 12 months, and 24 months in SLS II participants (N = 136) and at a single time point in healthy controls (N = 67). A mixed-effects model evaluated the relationship between change in CXCL4 levels and SSc-ILD progression. The primary outcome was the course of the forced vital capacity. Baseline CXCL4 levels were significantly higher in SSc-ILD patients compared with healthy controls (2699 ± 1489 ng/ml vs 2233 ± 1351 ng/ml (mean ± SD); P = 0.019). However, no significant correlations were identified between CXCL4 levels and extent of ILD at baseline, as measured by the forced vital capacity, diffusing capacity of carbon monoxide, or radiographic extent of ILD. Plasma CXCL4 decreased significantly from baseline to 12 months in all patients (CYC: P < 0.001; MMF: P = 0.006) with no between-treatment differences (CYC vs MMF). Patients with the largest decline in CXCL4 levels during the first 12 months had an improved course of forced vital capacity %-predicted from 12 to 24 months (P = 0.040), even after adjusting for baseline disease severity and treatment arm assignment. Levels of CXCL4 were higher in patients with SSc-ILD compared with controls and decreased in all patients treated with immunosuppressive therapy. While CXCL4 levels were not correlated with extent of ILD at baseline, changes in CXCL4 at 12 months predicted future progression of SSc-ILD from 12 to 24 months. These findings suggest that intermediate-term changes in CXCL4 may have predictive significance for long-term progression of SSc-ILD in patients receiving immunosuppressive therapy. ClinicalTrials.gov NCT00883129 . Registered 16 April 2009.
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Guillen-Del Castillo, Alfredo; Sánchez-Vidaurre, Sara; Simeón-Aznar, Carmen P; Cruz, María J; Fonollosa-Pla, Vicente; Muñoz, Xavier
2017-03-01
Interstitial lung disease (ILD) is one of the major causes of death in systemic sclerosis (SSc). This study investigated exhaled breath (EB) and exhaled breath condensate (EBC) biomarkers in patients with SSc and analyzed their role as a prognostic tool in SSc-related ILD. Fraction exhaled nitric oxide (FeNO) and exhaled carbon monoxide (eCO) measured in EB, together with pH, nitrite, nitrate and interleukin-6 levels measured in EBC were prospectively analyzed in 35 patients with SSc. Twelve patients had established ILD by chest high-resolution computed tomography (HRCT), and 23 patients showed no evidence of ILD. EB and EBC biomarkers were determined at inclusion, and pulmonary function tests were annually performed during 4 years of follow-up. No differences at baseline biomarkers levels were found between groups. In all patients studied, low EBC pH levels were associated with a decreased diffusing capacity for carbon monoxide (DLCO) during follow-up. Low FeNO levels were correlated with lower forced vital capacity (FVC) at baseline, 4years of follow-up and with a decrease in FVC and DLCO during monitoring. Among ILD patients, high eCO levels were correlated with lower baseline FVC. In the global cohort, a worse progression-free survival was identified in patients with EBC pH values lower than 7.88 and FeNO levels lower than 10.75ppb (Log Rank P=.03 and P<.01, respectively). EB and EBC could help to detect patients likely to present a deterioration on lung function during follow up. Copyright © 2016 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.
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Jordan, Suzana; Maurer, Britta; Toniolo, Martin; Michel, Beat; Distler, Oliver
2015-08-01
The preliminary classification criteria for SSc lack sensitivity for mild/early SSc patients, therefore, the new ACR/EULAR classification criteria for SSc were developed. The objective of this study was to evaluate the performance of the new classification criteria for SSc in clinical practice in a cohort of mild/early patients. Consecutive patients with a clinical diagnosis of SSc, based on expert opinion, were prospectively recruited and assessed according to the EULAR Scleroderma Trials and Research group (EUSTAR) and very early diagnosis of SSc (VEDOSS) recommendations. In some patients, missing values were retrieved retrospectively from the patient's records. Patients were grouped into established SSc (fulfilling the old ACR criteria) and mild/early SSc (not fulfilling the old ACR criteria). The new ACR/EULAR criteria were applied to all patients. Of the 304 patients available for the final analysis, 162/304 (53.3%) had established SSc and 142/304 (46.7%) had mild/early SSc. All 162 established SSc patients fulfilled the new ACR/EULAR classification criteria. The remaining 142 patients had mild/early SSc. Eighty of these 142 patients (56.3%) fulfilled the new ACR/EULAR classification criteria. Patients with mild/early SSc not fulfilling the new classification criteria were most often suffering from RP, had SSc-characteristic autoantibodies and had an SSc pattern on nailfold capillaroscopy. Taken together, the sensitivity of the new ACR/EULAR classification criteria for the overall cohort was 242/304 (79.6%) compared with 162/304 (53.3%) for the ACR criteria. In this cohort with a focus on mild/early SSc, the new ACR/EULAR classification criteria showed higher sensitivity and classified more patients as definite SSc patients than the ACR criteria. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Azar, Marleine; Rice, Danielle B; Kwakkenbos, Linda; Carrier, Marie-Eve; Shrier, Ian; Bartlett, Susan J; Hudson, Marie; Mouthon, Luc; Poiraudeau, Serge; van den Ende, Cornelia H M; Johnson, Sindhu R; Rodriguez Reyna, Tatiana Sofia; Schouffoer, Anne A; Welling, Joep; Thombs, Brett D
2018-08-01
Exercise is associated with improved health in many medical conditions. Little is known about the exercise habits of people with systemic sclerosis (SSc, or scleroderma). This study assessed the proportion of individuals with SSc who exercise and associations of demographic and disease variables with exercise. Additionally, the weekly amount of time spent exercising and the types of exercise performed were assessed among patients exercising. The sample consisted of adult participants with SSc enrolled in the Scleroderma Patient-centered Intervention Network (SPIN) Cohort who completed baseline questionnaires from March 2014 through August 2015. Baseline questionnaires included questions on exercise habits, physician-reported medical characteristics, self-report demographic characteristics, the Health Assessment Questionnaire-Disability Index, Patient Health Questionnaire-9, and Patient-Reported Outcomes Measurement Information System-29. Of 752 patients, 389 (51.7%) reported presently engaging in exercise, and these patients exercised on average 4.7 h [standard deviation (SD) = 2.8] per week. Among patients who reported exercising, walking was most commonly reported (n = 295, 75.8%). In bivariate analyses, present exercise was associated with more education, lower body mass index, some (versus no) alcohol consumption, non-smoking, limited/sine disease subtype, absence of skin thickening, lower disability, higher physical function, lower symptoms of anxiety and depression, less fatigue, lower sleep disturbance, higher ability to participate in social roles and activities, and less pain. Approximately half of SSc patients reported that they are currently exercising with walking being the most common form of exercise. Understanding exercise patterns and factors associated with exercise will help better inform intervention programs to support exercise for patients with SSc. Implications for rehabilitation Systemic sclerosis is a rare autoimmune rheumatic disease associated with great morbidity and highly diverse presentation. Approximately half of people with both limited and diffuse systemic sclerosis report exercising. Most exercisers walk, but patients engage in a wide variety of exercise-related activities. Individually designed exercise programs are most likely to support and encourage exercise in patients with diverse disease manifestations.
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Mills, Sarah D; Kwakkenbos, Linda; Carrier, Marie-Eve; Gholizadeh, Shadi; Fox, Rina S; Jewett, Lisa R; Gottesman, Karen; Roesch, Scott C; Thombs, Brett D; Malcarne, Vanessa L
2018-01-17
Systemic sclerosis (SSc) is an autoimmune disease that can cause disfiguring changes in appearance. This study examined the structural validity, internal consistency reliability, convergent validity, and measurement equivalence of the Social Appearance Anxiety Scale (SAAS) across SSc disease subtypes. Patients enrolled in the Scleroderma Patient-centered Intervention Network Cohort completed the SAAS and measures of appearance-related concerns and psychological distress. Confirmatory factor analysis (CFA) was used to examine the structural validity of the SAAS. Multiple-group CFA was used to determine if SAAS scores can be compared across patients with limited and diffuse disease subtypes. Cronbach's alpha was used to examine internal consistency reliability. Correlations of SAAS scores with measures of body image dissatisfaction, fear of negative evaluation, social anxiety, and depression were used to examine convergent validity. SAAS scores were hypothesized to be positively associated with all convergent validity measures, with correlations significant and moderate to large in size. A total of 938 patients with SSc were included. CFA supported a one-factor structure (CFI: .92; SRMR: .04; RMSEA: .08), and multiple-group CFA indicated that the scalar invariance model best fit the data. Internal consistency reliability was good in the total sample (α = .96) and in disease subgroups. Overall, evidence of convergent validity was found with measures of body image dissatisfaction, fear of negative evaluation, social anxiety, and depression. The SAAS can be reliably and validly used to assess fear of appearance evaluation in patients with SSc, and SAAS scores can be meaningfully compared across disease subtypes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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A3 Subscale Diffuser Test Article Design
NASA Technical Reports Server (NTRS)
Saunders, G. P.
2009-01-01
This paper gives a detailed description of the design of the A3 Subscale Diffuser Test (SDT) Article Design. The subscale diffuser is a geometrically accurate scale model of the A3 altitude rocket facility. It was designed and built to support the SDT risk mitigation project located at the E3 facility at Stennis Space Center, MS (SSC) supporting the design and construction of the A3 facility at SSC. The subscale test article is outfitted with a large array of instrumentation to support the design verification of the A3 facility. The mechanical design of the subscale diffuser and test instrumentation are described here
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Nailfold capillaroscopy by digital microscope in an Indian population with systemic sclerosis.
Bhakuni, Darshan S; Vasdev, Vivek; Garg, M K; Narayanan, Krishanan; Jain, Rahul; Mullick, Gautam
2012-02-01
Nailfold capillaroscopy (NFC) is a simple, non-invasive method with exceptional predictive value for the analysis of microvascular abnormalities, especially in systemic sclerosis (SSc) but remains underutilized due to cost factors of the nailfold videocapillaroscope, lack of expertise and availability issues. The aim of this study was to establish the utility of an inexpensive digital microscope to study NFC changes in SSc in correlation with disease subsets and extent of skin involvement. Twenty-two diffuse cutaneous SSc (DSS), 20 limited cutaneous SSc (LSS) patients and 42 controls were evaluated with NFC using a digital microscope at 30× and 100× magnification. Digital micrographs were used to study qualitative and quantitative changes in microvasculature. The capillary density was significantly less in all cases of SSc as compared to controls (5.3 ± 1.4 vs. 8.7 ± 1.2; P < 0.00001). Disorganized architecture was much more prevalent in DSS versus LSS (86.4%vs. 25%). The vascular deletion score (VDS) was significantly higher in DSS as compared to LSS (P < 0.0001). Scleroderma pattern (SP) was seen in 18 (81.9%) and 15 (75%) of patients with DSS and LSS, respectively. Only 4% of normal subjects showed non-specific pattern and none showed SP. The mean modified Rodnan skin score (MRSS) was positively correlated with vascular deletion score (r = 0.572; P < 0.001) and negatively with capillary density (r = -0.8; P < 0.001). Nailfold capillaroscopy changes in SSc are related to disease subset and MRSS. NFC with digital microscope is a simplified, inexpensive, outpatient procedure with results comparable to previous studies. © 2011 The Authors. International Journal of Rheumatic Diseases © 2011 Asia Pacific League of Associations for Rheumatology and Blackwell Publishing Asia Pty Ltd.
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Ponticos, Markella; Papaioannou, Ioannis; Xu, Shiwen; Holmes, Alan M; Khan, Korsa; Denton, Christopher P; Bou-Gharios, George; Abraham, David J
2015-01-01
Objective The excessive deposition of extracellular matrix, including type I collagen, is a key aspect in the pathogenesis of connective tissue diseases such as systemic sclerosis (SSc; scleroderma). To further our understanding of the mechanisms governing the dysregulation of type I collagen production in SSc, we investigated the role of the activator protein 1 (AP-1) family of transcription factors in regulating COL1A2 transcription. Methods The expression and nuclear localization of AP-1 family members (c-Jun, JunB, JunD, Fra-1, Fra-2, and c-Fos) were examined by immunohistochemistry and Western blotting in dermal biopsy specimens and explanted skin fibroblasts from patients with diffuse cutaneous SSc and healthy controls. Gene activation was determined by assessing the interaction of transcription factors with the COL1A2 enhancer using transient transfection of reporter gene constructs, electrophoretic mobility shift assays, chromatin immunoprecipitation analysis, and RNA interference involving knockdown of individual AP-1 family members. Inhibition of fibroblast mammalian target of rapamycin (mTOR), Akt, and glycogen synthase kinase 3β (GSK-3β) signaling pathways was achieved using small-molecule pharmacologic inhibitors. Results Binding of JunB to the COL1A2 enhancer was observed, with its coalescence directed by activation of gene transcription through the proximal promoter. Knockdown of JunB reduced enhancer activation and COL1A2 expression in response to transforming growth factor β. In SSc dermal fibroblasts, increased mTOR/Akt signaling was associated with inactivation of GSK-3β, leading to blockade of JunB degradation and, thus, constitutively high expression of JunB. Conclusion In patients with SSc, the accumulation of JunB resulting from altered mTOR/Akt signaling and a failure of proteolytic degradation underpins the aberrant overexpression of type I collagen. These findings identify JunB as a potential target for antifibrotic therapy in SSc. PMID:25303440
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Yamakawa, Hideaki; Hagiwara, Eri; Kitamura, Hideya; Yamanaka, Yumie; Ikeda, Satoshi; Sekine, Akimasa; Baba, Tomohisa; Iso, Shinichiro; Okudela, Koji; Iwasawa, Tae; Takemura, Tamiko; Kuwano, Kazuyoshi; Ogura, Takashi
2016-01-01
Background Patients with idiopathic interstitial pneumonias sometimes have a few features of connective tissue disease (CTD) and yet do not fulfil the diagnostic criteria for any specific CTD. Objective This study was conducted to elucidate the characteristics, prognosis, and disease behavior in patients with interstitial lung disease (ILD) associated with systemic sclerosis (SSc)-related autoantibodies. Methods We retrospectively analyzed medical records of 72 ILD patients: 40 patients with SSc (SSc-ILD) and 32 patients with SSc-related autoantibody-positive ILD but not with CTD (ScAb-ILD), indicating lung-dominant CTD with SSc-related autoantibody. Results Patients with SSc-ILD were predominantly females and non-smokers, and most had nonspecific interstitial pneumonia confirmed by high-resolution computed tomography (HRCT) and pathological analysis. However, about half of the patients with ScAb-ILD were male and current or ex-smokers. On HRCT analysis, honeycombing was more predominant in patients with ScAb-ILD than with SSc-ILD. Pathological analysis showed the severity of vascular intimal or medial thickening in the SSc-ILD patients to be significantly higher than that in the ScAb-ILD patients. Survival curves showed that the patients with ScAb-ILD had a significantly poorer outcome than those with SSc-ILD. Conclusion Data from this study suggest that lung-dominant CTD with SSc-related autoantibody is a different disease entity from SSc-ILD. PMID:27564852
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From Localized Scleroderma to Systemic Sclerosis: Coexistence or Possible Evolution.
Dilia, Giuggioli; Michele, Colaci; Emanuele, Cocchiara; Amelia, Spinella; Federica, Lumetti; Clodoveo, Ferri
2018-01-01
Systemic sclerosis (SSc) and localized scleroderma (LoS) are two different diseases that may share some features. We evaluated the relationship between SSc and LoS in our case series of SSc patients. We analysed the clinical records of 330 SSc patients, in order to find the eventual occurrence of both the two diseases. Eight (2.4%) female patients presented both the two diagnoses in their clinical histories. Six developed LoS prior to SSc; in 4/6 cases, the presence of autoantibodies was observed before SSc diagnosis. Overall, the median time interval between LoS and SSc diagnosis was 18 (range 0-156) months. LoS and SSc are two distinct clinical entities that may coexist. Moreover, as anecdotally reported in pediatric populations, we suggested the possible development of SSc in adult patients with LoS, particularly in presence of Raynaud's phenomenon or antinuclear antibodies before the SSc onset.
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Clinical and laboratory features of systemic sclerosis complicated with localized scleroderma.
Toki, Sayaka; Motegi, Sei-ichiro; Yamada, Kazuya; Uchiyama, Akihiko; Kanai, Sahori; Yamanaka, Masayoshi; Ishikawa, Osamu
2015-03-01
Localized scleroderma (LSc) primarily affects skin, whereas systemic sclerosis (SSc) affects skin and various internal organs. LSc and SSc are considered to be basically different diseases, and there is no transition between them. However, LSc and SSc have several common characteristics, including endothelial cell dysfunction, immune activation, and excess fibrosis of the skin, and there exist several SSc cases complicated with LSc during the course of SSc. Clinical and laboratory characteristics of SSc patients with LSc remain unclear. We investigated the clinical and laboratory features of 8 SSc patients with LSc among 220 SSc patients (3.6%). The types of LSc included plaque (5/8), guttate (2/8), and linear type (1/8). All cases were diagnosed as having SSc within 5 years before or after the appearance of LSc. In three cases of SSc with LSc (37.5%), LSc skin lesions preceded clinical symptoms of SSc. Young age, negative antinuclear antibody, and positive anti-RNA polymerase III antibody were significantly prevalent in SSc patients with LSc. The positivity of anticentromere antibody tended to be prevalent in SSc patients without LSc. No significant difference in the frequency of complications, such as interstitial lung disease, reflux esophagitis, and pulmonary artery hypertension, was observed. The awareness of these characteristic of SSc with LSc are essential to establish an early diagnosis and treatment. © 2015 Japanese Dermatological Association.
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Haak, Andrew J.; Tsou, Pei-Suen; Amin, Mohammad A.; Ruth, Jeffrey H.; Campbell, Phillip; Fox, David A.; Khanna, Dinesh; Larsen, Scott D.
2014-01-01
Systemic sclerosis (SSc), or scleroderma, similar to many fibrotic disorders, lacks effective therapies. Current trials focus on anti-inflammatory drugs or targeted approaches aimed at one of the many receptor mechanisms initiating fibrosis. In light of evidence that a myocardin-related transcription factor (MRTF)–and serum response factor (SRF)–regulated gene transcriptional program induced by Rho GTPases is essential for myofibroblast activation, we explored the hypothesis that inhibitors of this pathway may represent novel antifibrotics. MRTF/SRF-regulated genes show spontaneously increased expression in primary dermal fibroblasts from patients with diffuse cutaneous SSc. A novel small-molecule inhibitor of MRTF/SRF-regulated transcription (CCG-203971) inhibits expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and collagen 1 (COL1A2) in both SSc fibroblasts and in lysophosphatidic acid (LPA)–and transforming growth factor β (TGFβ)–stimulated fibroblasts. In vivo treatment with CCG-203971 also prevented bleomycin-induced skin thickening and collagen deposition. Thus, targeting the MRTF/SRF gene transcription pathway could provide an efficacious new approach to therapy for SSc and other fibrotic disorders. PMID:24706986
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Tovoli, Francesco; Granito, Alessandro; Giampaolo, Luca; Frisoni, Magda; Volta, Umberto; Fusconi, Marco; Masi, Chiara; Lenzi, Marco
2014-03-01
Primary biliary cirrhosis (PBC) is frequently associated with other autoimmune diseases, including systemic sclerosis (SSc). In the last years many efforts have been dedicated to the research of widely accepted criteria for the early diagnosis of SSc. Since studies on the prevalence of early SSc in PBC patients are lacking, our aim was to investigate its hitherto unknown prevalence in a large cohort of PBC patients. We studied 80 PBC patients and 72 patients with other chronic liver diseases. Diagnostic workup included research into signs of connective tissue disease, determination of autoantibody profile, and examination of capillary abnormalities through nailfold videocapillaroscopy. Ten PBC patients (12.5%) satisfied diagnostic criteria for early SSc and 5 (6.3%) had definite SSc. None of the patients in the control group were diagnosed either with early or definite SSc. No differences were observed in terms of aminotransferases, alkaline phosphatase, and liver function tests between PBC patients with and without associated SSc. Early SSc is significantly frequent in PBC patients. The detection of early SSc in PBC patients may lead to a prompt treatment of its complications, preventing inabilities and preserving the chance of liver transplantation.
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From Localized Scleroderma to Systemic Sclerosis: Coexistence or Possible Evolution
Emanuele, Cocchiara; Amelia, Spinella; Clodoveo, Ferri
2018-01-01
Background Systemic sclerosis (SSc) and localized scleroderma (LoS) are two different diseases that may share some features. We evaluated the relationship between SSc and LoS in our case series of SSc patients. Methods We analysed the clinical records of 330 SSc patients, in order to find the eventual occurrence of both the two diseases. Results Eight (2.4%) female patients presented both the two diagnoses in their clinical histories. Six developed LoS prior to SSc; in 4/6 cases, the presence of autoantibodies was observed before SSc diagnosis. Overall, the median time interval between LoS and SSc diagnosis was 18 (range 0–156) months. Conclusions LoS and SSc are two distinct clinical entities that may coexist. Moreover, as anecdotally reported in pediatric populations, we suggested the possible development of SSc in adult patients with LoS, particularly in presence of Raynaud's phenomenon or antinuclear antibodies before the SSc onset. PMID:29666638
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Valentini, Gabriele; Riccardi, Antonella; Vettori, Serena; Irace, Rosaria; Iudici, Michele; Tolone, Salvatore; Docimo, Ludovico; Bocchino, Marialuisa; Sanduzzi, Alessandro; Cozzolino, Domenico
2017-08-01
The aim of the study was to evaluate CXCL4 levels in undifferentiated connective tissue disease at risk for SSc (UCTD-SSc-risk) and confirm its increase and investigate its prognostic value. Serum CXCL4 levels were measured in 45 patients and 24 controls. CXCL4 was significantly higher in UCTD-SSc-risk patients than in controls. It resulted higher in patients with a shorter disease duration and in those lacking capillaroscopic alterations. We confirm that CXCL4 levels are increased in UCTD-risk-SSc patients. Further studies are needed to investigate the role of CXCL4 assessment in UCTD-risk-SSc.
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Della Rossa, Alessandra; Cazzato, Massimiliano; d'Ascanio, Anna; Tavoni, Antonio; Bencivelli, Walter; Pepe, Pasquale; Mosca, Marta; Baldini, Chiara; Rossi, Marco; Bombardieri, Stefano
2013-01-01
To investigate blood flow and microvascular reactivity by laser speckle perfusion imager (Perimed, Jarfalla) in consecutive patients affected by Raynaud's phenomenon at baseline and following dynamic stimulations. Skin blood flow in the dorsum of the hand was measured at baseline and after cold test and post-occlusive hyperemia test in 56 consecutive subjects affected by Raynaud's phenomenon (RP), 20 primary (PRP) and 36 secondary to systemic sclerosis (SSc). Twenty healthy subjects (HS) were studied as controls. After cold test, SSc had a significant reduction of blood flow (-58%) as compared to HS (-19%) (p=0.01). Recovery time was significantly higher in SSc (58 minutes) as compared to HS (18 minutes) and PRP (19 minutes) (p=0.006 and 0.0016, respectively). Peak flow after ischaemic test was significantly reduced in SSc (+237%) as compared to PRP (+485%) (p=0.0068). Post-ischaemic hyperemic area under the curve (AUC) was blunted in SSc (79U/sec) compared to PRP (167 U/sec) (p=0.0126). Proximal distal gradient was noticed in 74% of HS, 45% of PRP and 36% of SSc (p=0.01). Homogeneous pattern of flux distribution was significantly different between HS (95%), PRP (80%), and SSc (16%) (p<0.0001). Among SSc patients, a significant difference in ischaemic challenge was shown between patients with early-SSc versus patients with definite-SSc. Our preliminary results indicate a clearcut alteration of the dynamic of microcirculation in SSc-RP as compared to PRP and HS. Among SSc patients, early-SSc is a separate entity as compared to established disease.
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Manetti, Mirko; Pratesi, Sara; Romano, Eloisa; Bellando-Randone, Silvia; Rosa, Irene; Guiducci, Serena; Fioretto, Bianca Saveria; Ibba-Manneschi, Lidia; Maggi, Enrico; Matucci-Cerinic, Marco
2017-01-01
The mechanisms underlying endothelial cell injury and defective vascular repair in systemic sclerosis (SSc) remain unclear. Since the recently discovered angiogenic T cells (Tang) may have an important role in the repair of damaged endothelium, this study aimed to analyze the Tang population in relation to disease-related peripheral vascular features in SSc patients. Tang (CD3+CD31+CXCR4+) were quantified by flow cytometry in peripheral blood samples from 39 SSc patients and 18 healthy controls (HC). Circulating levels of the CXCR4 ligand stromal cell-derived factor (SDF)-1α and proangiogenic factors were assessed in paired serum samples by immunoassay. Serial skin sections from SSc patients and HC were subjected to CD3/CD31 and CD3/CXCR4 double immunofluorescence. Circulating Tang were significantly increased in SSc patients with digital ulcers (DU) compared either with SSc patients without DU or with HC. Tang levels were significantly higher in SSc patients with late nailfold videocapillaroscopy (NVC) pattern than in those with early/active NVC patterns and in HC. No difference in circulating Tang was found when comparing either SSc patients without DU or patients with early/active NVC patterns and HC. In SSc peripheral blood, Tang percentage was inversely correlated to levels of SDF-1α and CD34+CD133+VEGFR-2+ endothelial progenitor cells (EPC), and positively correlated to levels of vascular endothelial growth factor and matrix metalloproteinase-9. Tang were frequently detected in SSc dermal perivascular inflammatory infiltrates. In summary, our findings demonstrate for the first time that Tang cells are selectively expanded in the circulation of SSc patients displaying severe peripheral vascular complications like DU. In SSc, Tang may represent a potentially useful biomarker reflecting peripheral vascular damage severity. Tang expansion may be an ineffective attempt to compensate the need for increased angiogenesis and EPC function. Further studies are required to clarify the function of Tang cells and investigate the mechanisms responsible for their change in SSc.
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Systemic sclerosis and infections.
Randone, Silvia Bellando; Guiducci, Serena; Cerinic, Marco Matucci
2008-10-01
Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular obliteration, excessive extracellular matrix deposition and fibrosis of the connective tissues of the skin, lungs, gastrointestinal tract, heart, and kidneys. Numerous infectious agents (bacterial and viral) have been proposed as possible triggering factors (Parvovirus B19, Cytomegalovirus, Epstein-Barr virus, Retroviruses). Homology between viruses and autoantibody targets suggests that molecular mimicry may have a role in initiating antibody response in different disorders characterized by diffuse vascular disease, including SSc. Endothelial cell may be infected bacteria or viruses that play a particular role in inducing vasculitis. The pathogenic hypothesis include: a mechanism of molecular mimicry, the role played by endothelial cell damage, the presence of superantigens and the role of microchimeric cells. Although several studies provide important information linking infectious agents to SSc, a direct casual association between infections and SSc is still missing. In SSc viral products could synergize with other factors in the microenvironment predisposing to SSc development.
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Systemic sclerosis complicated with localized scleroderma-like lesions induced by Köbner phenomenon.
Saigusa, Ryosuke; Asano, Yoshihide; Yamashita, Takashi; Takahashi, Takehiro; Nakamura, Kouki; Miura, Shunsuke; Ichimura, Yohei; Toyama, Tetsuo; Taniguchi, Takashi; Sumida, Hayakazu; Tamaki, Zenshiro; Miyazaki, Miki; Yoshizaki, Ayumi; Sato, Shinichi
2018-03-01
Scleroderma is a chronic disease of unknown etiology characterized by skin fibrosis and is divided into two clinical entities: systemic sclerosis (SSc) and localized scleroderma (LSc). In general, LSc is rarely complicated with SSc, but a certain portion of SSc patients manifests bilateral symmetric LSc-like lesions on the trunk and extremities. We investigated SSc patients with LSc-like lesions to clarify the underlying pathophysiology. Nine SSc cases complicated with LSc-like lesions were clinically and histologically characterized. SSc patients with LSc-like lesions exhibited multiple progressive hyper- and/or hypo-pigmented plaques with mild sclerosis symmetrically distributed on the trunk and extremities, especially abdominal region. In histological assessment, epidermal IL-1α expression was elevated in both forearms and LSc-like lesions of these patients to a greater extent than in forearms of control patients (SSc patients without LSc-like lesions). Of note, the infiltration and degranulation of mast cells were evident throughout the dermis of LSc-like lesions, while detectable to a lesser extent in forearms of SSc patients with LSc-like lesions and control patients. The epidermis of SSc patients with LSc-like lesions seems to possess an inflammatory phenotype, leading to the activation of mast cells in the dermis of mechanically stressed skin. Köbner phenomenon may be involved in the induction of LSc-like lesions in a certain subset of SSc. Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
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Herrick, Ariane L; Pan, Xiaoyan; Peytrignet, Sébastien; Lunt, Mark; Hesselstrand, Roger; Mouthon, Luc; Silman, Alan; Brown, Edith; Czirják, László; Distler, Jörg H W; Distler, Oliver; Fligelstone, Kim; Gregory, William J; Ochiel, Rachel; Vonk, Madelon; Ancuţa, Codrina; Ong, Voon H; Farge, Dominique; Hudson, Marie; Matucci-Cerinic, Marco; Balbir-Gurman, Alexandra; Midtvedt, Øyvind; Jordan, Alison C; Jobanputra, Paresh; Stevens, Wendy; Moinzadeh, Pia; Hall, Frances C; Agard, Christian; Anderson, Marina E; Diot, Elisabeth; Madhok, Rajan; Akil, Mohammed; Buch, Maya H; Chung, Lorinda; Damjanov, Nemanja; Gunawardena, Harsha; Lanyon, Peter; Ahmad, Yasmeen; Chakravarty, Kuntal; Jacobsen, Søren; MacGregor, Alexander J; McHugh, Neil; Müller-Ladner, Ulf; Riemekasten, Gabriela; Becker, Michael; Roddy, Janet; Carreira, Patricia E; Fauchais, Anne Laure; Hachulla, Eric; Hamilton, Jennifer; İnanç, Murat; McLaren, John S; van Laar, Jacob M; Pathare, Sanjay; Proudman, Susannah; Rudin, Anna; Sahhar, Joanne; Coppere, Brigitte; Serratrice, Christine; Sheeran, Tom; Veale, Douglas J; Grange, Claire; Trad, Georges-Selim; Denton, Christopher P
2017-01-01
Objectives The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. Methods This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or ‘no immunosuppressant’. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. Results Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: −4.0 (−5.2 to −2.7) units for methotrexate, −4.1 (−5.3 to −2.9) for MMF, −3.3 (−4.9 to −1.7) for cyclophosphamide and −2.2 (−4.0 to −0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months. Conclusions These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed. Trial registration number NCT02339441. PMID:28188239
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An Overview of Follow-On Testing Activities of the A-3 Subscale Diffuser Test Project
NASA Technical Reports Server (NTRS)
Ryan, James E.
2009-01-01
An overview of NASA Stennis Space Center's (SSC) A-3 Subscale Diffuser Test (SDT) Project is presented. The original scope of the SDT Project, conducted from April 2007 to January 2008, collected data to support mitigation of risk associated with design and procurement activities of the A-3 Test Stand Project, an effort to construct a simulated altitude test facility at SSC in support of NASA's Constellation Program. Follow-on tests were conducted from May 2008 through August 2009, utilizing the SDT test setup as a testbed for additional risk mitigation activities. Included are descriptions of the Subscale Diffuser (SD) test article, the test facility configuration, and test approaches.
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Correlation between bone quality and microvascular damage in systemic sclerosis patients.
Ruaro, Barbara; Casabella, Andrea; Paolino, Sabrina; Pizzorni, Carmen; Alessandri, Elisa; Seriolo, Chiara; Botticella, Giulia; Molfetta, Luigi; Odetti, Patrizio; Smith, Vanessa; Cutolo, Maurizio
2018-05-18
SSc patients are recognized as presenting an increased risk of altered bone mass. The aim of this study was to assess the bone quality, by trabecular bone score (TBS), in SSc patients in correlation with different levels of microvascular damage, as evaluated by nailfold videocapillaroscopy (NVC), and to compare the results regarding bone quality with RA patients and healthy subjects (CNT). Eighty-four SSc patients, 98 RA patients and 60 CNT, were studied. BMD (g/cm2) of the lumbar spine (L1-L4) was analysed by DXA scan. Lumbar spine bone quality was derived from each spine DXA examination using the TBS analysis. NVC patterns were analysed. A total of 56/84 SSc patients (66%) as well as 78/98 RA patients (80%) showed bone loss at DXA and BMD was found to be significantly lower than in the CNT (P < 0.001). Similarly, lumbar spine TBS was found to be significantly lower in SSc and RA patients than in CNT (P < 0.001). TBS values were found to be lower in SSc with a late NVC pattern, compared with the active or early pattern (late vs active and early pattern, P < 0.001). There was no statistically significant difference in the mean lumbar spine TBS between SSc and RA patients (P = 0.238). The data obtained showed significantly lower bone quality (lower TBS and BMD) in SSc and RA patients compared with CNT. The bone quality seemed lower in SSc patients with more altered microvasculature (late NVC pattern).
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Foocharoen, Chingching; Chunlertrith, Kitti; Mairiang, Pisaln; Mahakkanukrauh, Ajanee; Suwannaroj, Siraphop; Namvijit, Suwassa; Wantha, Orathai; Nanagara, Ratanavadee
2017-02-01
Twice-daily dosing of proton pump inhibitor (PPI), the standard therapy for gastro-oesophageal reflux disease (GERD), is an effective therapy for GERD in SSc. The aim of this study was to compare the efficacy of omeprazole in combination with domperidone vs in combination with algycon in reducing the severity and frequency of reflux symptoms of PPI partial response (PPI-PR) GERD in SSc. Adult SSc patients having PPI-PR GERD were randomly assigned to receive domperidone plus algycon placebo or algycon plus domperidone placebo in a 1:1 ratio plus omeprazole for 4 weeks. The assessment included severity of symptom grading by visual analogue scale, frequency of symptoms by frequency scale for symptoms of GERD and quality of life (QoL) by EuroQol five-dimensions questionnaire scoring. One hundred and forty-eight SSc-GERD patients were enrolled, of whom 88 had PPI-PR. Eighty cases were randomized for either domperidone (n = 38) or algycon (n = 37) therapy. The majority in both groups had the diffuse SSc subset. At the end of the study, no significant difference in symptom grading was found between groups. After treatment and compared with baseline, the severity of symptoms, frequency scale for symptoms of GERD and QoL significantly improved in both groups. Five (13.2%) and 8 (21.6%) respective cases in the domperidone and algycon groups did not respond. The prevalence of PPI-PR GERD is common. Domperidone and algycon are equally effective treatments in combination with omeprazole. However, ∼17% of patients were non-responsive, so the effectiveness of domperidone, algycon and PPI combination therapy should be further investigated. https://clinicaltrials.gov (NCT01878526). © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Lobasso, Antonio; Nappi, Liliana; Barbieri, Letizia; Peirce, Carmela; Ippolito, Serena; Arpaia, Debora; Rossi, Francesca Wanda; de Paulis, Amato; Biondi, Bernadette
2017-01-01
Thyroid function abnormalities and thyroid autoantibodies have been frequently described in patients with systemic autoimmune diseases as systemic sclerosis (SSc). Serum TSH levels are higher in SSc patients with more severe skin diseases and a worse modified Rodnan skin score. Asymptomatic esophageal involvement due to SSc has never been described as a cause of severe hypothyroidism due to l-thyroxine (l-T4) malabsorption in patients with Hashimoto's thyroiditis (HT) and SSc. Here, we report a case of a 56-year-old female affected by both SSc and HT who developed severe hypothyroidism due to the loss of therapeutic efficacy of l-T4. Therapeutic failure resulted from the altered l-T4 absorption because of SSc esophageal complications. Clinical findings improved after the administration of oral liquid l-T4. Thyroid function completely normalized with a full clinical recovery, the disappearance of the pericardial effusion and the improvement of the pulmonary pressure. A recognition of a poor absorption is crucial in patients with hypothyroidism and SSc to reduce the risk of the subsequent adverse events. This case suggests the importance of clinical and laboratory surveillance in patients with SSc and HT because the systemic complications of these dysfunctions may worsen the prognosis of hypothyroid SSc/HT patients.
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Fructose Malabsorption in Systemic Sclerosis
Marie, Isabelle; Leroi, Anne-Marie; Gourcerol, Guillaume; Levesque, Hervé; Ménard, Jean-François; Ducrotte, Philippe
2015-01-01
Abstract The deleterious effect of fructose, which is increasingly incorporated in many beverages, dairy products, and processed foods, has been described; fructose malabsorption has thus been reported in up to 2.4% of healthy subjects, leading to digestive clinical symptoms (eg, pain, distension, diarrhea). Because digestive involvement is frequent in patients with systemic sclerosis (SSc), we hypothesized that fructose malabsorption could be responsible for intestinal manifestations in these patients. The aims of this prospective study were to: determine the prevalence of fructose malabsorption, in SSc; predict which SSc patients are at risk of developing fructose malabsorption; and assess the outcome of digestive symptoms in SSc patients after initiation of standardized low-fructose diet. Eighty consecutive patients with SSc underwent fructose breath test. All SSc patients also completed a questionnaire on digestive symptoms, and a global symptom score (GSS) was calculated. The prevalence of fructose malabsorption was as high as 40% in SSc patients. We also observed a marked correlation between the presence of fructose malabsorption and: higher values of GSS score of digestive symptoms (P = 0.000004); and absence of delayed gastric emptying (P = 0.007). Furthermore, in SSc patients with fructose malabsorption, the median value of GSS score of digestive symptoms was lower after initiation of standardized low-fructose diet (4 before vs. 1 after; P = 0.0009). Our study underscores that fructose malabsorption often occurs in SSc patients. Our findings are thus relevant for clinical practice, highlighting that fructose breath test is a helpful, noninvasive method by: demonstrating fructose intolerance in patients with SSc; and identifying the group of SSc patients with fructose intolerance who may benefit from low-fructose diet. Interestingly, because the present series also shows that low-fructose diet resulted in a marked decrease of gastrointestinal clinical manifestations in SSc patients with fructose malabsorption, our findings underscore that fructose malabsorption may play a significant role in the onset of gastrointestinal symptoms in these patients. Finally, we suggest that fructose malabsorption may be due to reduced fructose absorption by enterocytes, impaired enteric microbiome, and decreased intestinal permeability. PMID:26426642
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Zlatanovic, Maja; Tadic, Marijana; Celic, Vera; Ivanovic, Branislava; Stevanovic, Ana; Damjanov, Nemanja
2017-01-01
We aimed to determine left ventricular (LV) and right ventricular (RV) structure, function and mechanics, as well as heart rate variability (HRV), and their relationship, in patients with systemic sclerosis (SSc). The study included 41 SSc patients and 30 age-matched healthy volunteers. All the patients underwent clinical examination, serological tests, pulmonary function testing, 24-h Holter monitoring and complete two-dimensional echocardiography including strain analysis. The parameters of LV structure (interventricular septum thickness and LV mass index) and RV structure (RV wall thickness) were significantly higher in SSc patients. LV and RV diastolic function (estimated by mitral and tricuspid E/e' ratio) was significantly impaired in SSc group comparing with the healthy controls. LV and RV longitudinal function was significantly deteriorated in SSc patients. LV circumferential strain was also significantly lower in SSc group, whereas LV radial strain was similar between the observed groups. All parameters of time and frequency domain of HRV were decreased in SSc patients. LV and RV cardiac remodeling parameters, particularly diastolic function and longitudinal strain, were associated with HRV indices without regard to the main demographic or the clinical and echocardiographic characteristics. Rodnan Skin Score was also independently associated with biventricular cardiac remodeling in SSc patients. LV and RV structure, function and mechanics, as well as autonomic nervous function, were significantly impaired in SSc patients. There is the significant association between biventricular cardiac remodeling and autonomic function in these patients, which could be useful for their everyday clinical assessment.
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Informatics can identify systemic sclerosis (SSc) patients at risk for scleroderma renal crisis.
Redd, Doug; Frech, Tracy M; Murtaugh, Maureen A; Rhiannon, Julia; Zeng, Qing T
2014-10-01
Electronic medical records (EMR) provide an ideal opportunity for the detection, diagnosis, and management of systemic sclerosis (SSc) patients within the Veterans Health Administration (VHA). The objective of this project was to use informatics to identify potential SSc patients in the VHA that were on prednisone, in order to inform an outreach project to prevent scleroderma renal crisis (SRC). The electronic medical data for this study came from Veterans Informatics and Computing Infrastructure (VINCI). For natural language processing (NLP) analysis, a set of retrieval criteria was developed for documents expected to have a high correlation to SSc. The two annotators reviewed the ratings to assemble a single adjudicated set of ratings, from which a support vector machine (SVM) based document classifier was trained. Any patient having at least one document positively classified for SSc was considered positive for SSc and the use of prednisone≥10mg in the clinical document was reviewed to determine whether it was an active medication on the prescription list. In the VHA, there were 4272 patients that have a diagnosis of SSc determined by the presence of an ICD-9 code. From these patients, 1118 patients (21%) had the use of prednisone≥10mg. Of these patients, 26 had a concurrent diagnosis of hypertension, thus these patients should not be on prednisone. By the use of natural language processing (NLP) an additional 16,522 patients were identified as possible SSc, highlighting that cases of SSc in the VHA may exist that are unidentified by ICD-9. A 10-fold cross validation of the classifier resulted in a precision (positive predictive value) of 0.814, recall (sensitivity) of 0.973, and f-measure of 0.873. Our study demonstrated that current clinical practice in the VHA includes the potentially dangerous use of prednisone for veterans with SSc. This present study also suggests there may be many undetected cases of SSc and NLP can successfully identify these patients. Copyright © 2014 Elsevier Ltd. All rights reserved.
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Fenoglio, Daniela; Battaglia, Florinda; Parodi, Alessia; Stringara, Silvia; Negrini, Simone; Panico, Nicoletta; Rizzi, Marta; Kalli, Francesca; Conteduca, Giuseppina; Ghio, Massimo; De Palma, Raffaele; Indiveri, Francesco; Filaci, Gilberto
2011-06-01
Aim of the study has been to understand the relationship between TH17 and Treg cell subsets in patients affected with systemic sclerosis (SSc). Phenotypes and functions of Th17 and Treg cell subsets were analyzed in a series of 36 SSc patients. Th17 cell concentration in the peripheral blood was found to be increased in SSc patients with respect to healthy controls independently from type or stage of disease. After PBMC stimulation with a polyclonal stimulus or Candida albicans antigens the frequency of Th17 T cell clones was significantly higher in SSc patients with respect to controls suggesting the skewing of immune response in SSc patients toward Th17 cell generation/expansion. Concerning the Treg compartment, both CD4+CD25+ and CD8+CD28- Treg subsets showed quantitative and qualitative alteration in the peripheral blood of SSc patients. Collectively, these data highlight the existence of an imbalanced ratio between Th17 and Treg cell subsets in SSc patients. Copyright © 2011 Elsevier Inc. All rights reserved.
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Laique, Sobia; Singh, Tavankit; Dornblaser, David; Gadre, Abhishek; Rangan, Vikram; Fass, Ronnie; Kirby, Donald; Chatterjee, Soumya; Gabbard, Scott
2018-01-19
This study was carried out to assess the clinical characteristics and associated systemic diseases seen in patients diagnosed with absent contractility as per the Chicago Classification version 3.0, allowing us to propose a diagnostic algorithm for their etiologic testing. The Chicago Classification version 3.0 has redefined major and minor esophageal motility disorders using high-resolution esophageal manometry. There is a dearth of publications based on research on absent contractility, which historically has been associated with myopathic processes such as systemic sclerosis (SSc). We conducted a retrospective, multicenter study. Data of patients diagnosed with absent contractility were pooled from Cleveland Clinic, Cleveland, OH (January 2006 to July 2016) and Metrohealth Medical Center, Cleveland, OH (July 2014 to July 2016) and included: age, gender, associated medical conditions, surgical history, medications, and specific antibody testing. A total of 207 patients, including 57 male individuals and 150 female individuals, with mean age of 56.1 and 60.0 years, respectively, were included. Disease distribution was as follows: SSc (diffuse or limited cutaneous) 132, overlap syndromes 7, systemic lupus erythematosus17, Sjögren syndrome 4, polymyositis 3, and dermatomyositis 3. Various other etiologies including gastroesophageal reflux disease, postradiation esophagitis, neuromuscular disorders, and surgical complications were seen in the remaining cohort. Most practitioners use the term "absent contractility" interchangeably with "scleroderma esophagus"; however, only 63% of patients with absent contractility had SSc. Overall, 20% had another systemic autoimmune rheumatologic disease and 16% had a nonrheumatologic etiology for absent contractility. Therefore, alternate diagnosis must be sought in these patients. We propose an algorithm for their etiologic evaluation.
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Costa, Ciliana Cardoso B; Medeiros, Morgana; Watanabe, Karen; Martin, Patricia; Skare, Thelma L
2014-01-01
Recent studies show an association between autoimmune thyroiditis and systemic sclerosis (SSc) and suggest that this condition may interfere with the ES phenotype. However these studies evaluate the autoimmune thyroiditis as a whole and none of them specifically addresses Hashimoto's thyroiditis (HT) in SSc. To investigate the presence of HT in SSc patients and its possible association with disease manifestations. Clinical manifestations of hypothyroidism, TSH and anti-thyroid auto antibodies (anti-TPO. anti TBG and TRAb) were studied in 56 patients with SSc. SSc patients with HT were compared with SSc patients without thyroiditis. HT was observed in 19.64% of patients with SSc. No association was observed between HT and the different forms of disease or profile of autoantibodies. Likewise, there was no difference between the mean modified Rodnan score and presence of Raynaud's phenomenon, scars, digital necrosis, myositis, arthritis, sicca symptoms, esophageal dysmotility and scleroderma renal crisis when the groups were compared. On the other hand, patients with HT had higher frequency of pulmonary hypertension in relation to patients without HT (66.6% vs 22.5%, p=0.016). In the studied sample patients with ES and HT had higher prevalence of pulmonary hypertension. Long-term follow-up studies with a larger number of TH and SSc patients are needed to confirm these data. Copyright © 2014 Elsevier Editora Ltda. All rights reserved.
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[Cognitive function in patients with systemic sclerosis].
Straszecka, J; Jonderko, G; Kucharz, E J; Brzezińska-Wcisło, L; Kotulska, A; Bogdanowski, T
1997-09-01
Central nervous system involvement is seldom reported in patients with systemic sclerosis (SSc). Cognitive functions were determined in 21 patients with definite SSc and 42 healthy controls. Thyroid function was also measured in order to eliminate the effect of hypothyroidism on cognitive functioning. It was found that the SSc patients with normal thyroid function showed defective long-term and recent memory, learning ability, criticism, perception and visuo-perceptual skills, their simple reaction time was prolonged. Similar but less advanced cognitive defects were shown in the SSc patients with overt or latent hypothyroidism. The obtained results indicate that the central nervous system involvement is more common in patients with SSc than it has been reported earlier.
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Joven, Beatriz E; Escribano, Pilar; Andreu, Jose Luis; Loza, Estibaliz; Jimenez, Carmen; de Yebenes, M Jesus Garcia; Ruiz-Cano, M Jose; Carmona, Loreto; Carreira, Patricia E
2018-06-01
To analyze the performance of the 1980 ACR and new 2013 ACR/EULAR criteria for systemic sclerosis (SSc) in cutaneous SSc (lcSSc) patients, especially those affected by lcSSc and pulmonary arterial hypertension (PAH). All patients with a clinical lcSSc diagnosis from a prospective observational SSc cohort were included. Sociodemographic and disease-related variables were collected, and PAH confirmed by right heart catheterization (RHC). Performance of the 2013 and 1980 SSc criteria was analyzed in terms of clinical diagnosis. Descriptive and between-group analyses were performed as to the fulfillment of criterion sets, including comparison of survival. Overall, 321 patients were included, 63% of whom fulfilled the 1980 ACR and 93% the 2013 ACR/EULAR criteria. Agreement between both criteria sets proved poor (κ = 0.23). LcSSC patients fulfilling both criterion sets were significantly younger at diagnosis, whilst presenting organ involvement, calcinosis, fingertip digital ulcers, and pitting scars more frequently than those who met the 2013 criteria only. Patients who fulfilled the 2013 but not the 1980 criteria presented a higher degree of ACA positivity and PAH. Nearly 12% of patients developed PAH. Patients who did not meet the 1980 criteria were affected by a milder disease from but demonstrated higher pulmonary vascular resistance and lower cardiac index than those fulfilling both criterion sets. Whereas patients with PAH met the 2013 criteria, only 47% fulfilled the 1980 criteria. Regardless of criterion set fulfillment, high mortality was observed in PAH patients, with no significant between-patient difference based on criterion set. The new 2013 ARC/EULAR criteria prove more accurate than the former 1980 ACR criteria in identifying and differentiating patients with lcSSc, especially those with associated PAH. Since PAH exhibits a better prognosis if treated early, all SSc patients should undergo PAH screening. Copyright © 2018 Elsevier Inc. All rights reserved.
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van Bon, Lenny; Cossu, Marta; Scharstuhl, Alwin; Pennings, Bas W C; Vonk, Madelon C; Vreman, Hendrik J; Lafyatis, Robert L; van den Berg, Wim; Wagener, Frank A D T G; Radstake, Timothy R D J
2016-11-01
SSc is a disease characterized by inflammation and fibrosis. Heme Oxygenase-1 (HO-1) is a haem-degrading enzyme that mediates resolution of inflammation and is induced upon mediators abundantly present in SSc. We aimed to assess whether HO-1 expression/function is disturbed in SSc patients and could therefore be contributing to the ongoing inflammation. In total, 92 SSc patients and 48 healthy controls were included. By measuring total bilirubin in plasma in vivo, HO-activity was assessed. HO-1 expression levels were determined with western blot in monocytes before and after induction of HO-1 with cobalt protoporphyrin (CoPP) with or without CXCL4. Monocyte-derived dendritic cells (DCs) were stimulated with several Toll-like receptor (TLR) ligands with or without pre-stimulation with CoPP for 24 h. Cytokine levels were measured in the supernatants using the Luminex Bead Array. SSc patients have lower plasma levels of bilirubin, suggestive of an aberrant HO-1 function. We demonstrated low HO-1 expression in immune cells from SSc patients, whereas induction with CoPP was able to restore HO-1 levels in DCs from SSc patients, almost normalizing the increased TLR response observed in SSc. Co-exposure to CXCL4 completely abrogated CoPP-induced HO-1 expression, suggesting that the high CXCL4 levels present in SSc patients block the normal induction of HO-1 and its function. We demonstrate that HO activity in SSc patients is decreased and show its functional consequences. Since CXCL4 blocks the induction of HO-1 expression, neutralization of CXCL4 in SSc patients could have clinical benefits by diminishing overactivation of immune cells and other anti-inflammatory effects of HO-1. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Voigtländer, Torsten; Leuchs, Ensieh; Vonberg, Ralf-Peter; Solbach, Philipp; Manns, Michael P; Suerbaum, Sebastian; Lankisch, Tim O
2015-05-01
Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is an emerging disease entity with unfavourable outcome. Our aim was to analyze the microbial spectrum in bile of patients with SSC-CIP and to evaluate the potential impact on the empiric antibiotic treatment in these patients. 169 patients (72 patients with SSC-CIP and 97 patients with primary sclerosing cholangitis (PSC)) were included in a prospective observational study between 2010 and 2013. Bile was obtained during endoscopic retrograde cholangiography (ERC) and microbiologically analyzed. Patients with SSC displayed a significantly different microbiological profile in bile. Enterococcus faecium, Pseudomonas aeruginosa and non-albicans species of Candida were more frequent in SSC compared to patients with PSC (p < 0.05). Patients with SSC showed a higher incidence of drug or multi-drug resistant organisms in bile (p = 0.001). The antimicrobial therapy was adjusted in 64% of patients due to resistance or presence of microorganisms not covered by the initial therapy regimen. Patients with SSC-CIP have a distinct microbial profile in bile. Difficult to treat organisms are frequent and an ERC with bile fluid collection for microbiological analysis should be considered in case of insufficient antimicrobial treatment. Copyright © 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
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Systemic Sclerosis and Malignancy: A Review of Current Data
Zeineddine, Nabil; Khoury, Lara El; Mosak, Joseph
2016-01-01
Systemic sclerosis (SSc) is associated with increased risk of malignancy. The organ systems most commonly affected are the lungs, the breasts and the hematological system. Risk factors predisposing a SSc patient for development of malignancy are not well defined, and the pathogenic basis of the association is yet to be explained. The incidence of malignancies in SSc patients is variable from one report to another, but most importantly, questions regarding the role of immunosuppressive therapies and the effect of autoantibodies have weak or sometimes contradictory answers in most of the currently available literature and physicians have no available guidelines to screen their SSc patients for malignancies. The lack of a concretely defined high-risk profile and the absence of malignancy screening guidelines tailored for SSc patients raise the importance of the need for more studies on the association of SSc and cancer and should incite rheumatology colleges to develop specific recommendations for the clinician to follow while approaching patients with SSc. PMID:27540435
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Association of anti-RNA polymerase III autoantibodies and cancer in scleroderma
2014-01-01
Introduction We assessed the profile and frequency of malignancy subtypes in a large single-centre UK cohort for patients with scleroderma (systemic sclerosis; SSc). We evaluated the cancer risk among SSc patients with different antibody reactivities and explored the temporal association of cancer with the duration between SSc onset and cancer diagnosis. Methods We conducted a retrospective study of a well-characterised cohort of SSc patients attending a large tertiary referral centre, with clinical data collected from our clinical database and by review of patient records. We evaluated development of all cancers in this cohort, and comparison was assessed with the SSc cohort without cancer. The effect of demographics and clinical details, including antibody reactivities, were explored to find associations relevant to the risk for development of cancer in SSc patients. Results Among 2,177 patients with SSc, 7.1% had a history of cancer, 26% were positive for anticentromere antibodies (ACAs), 18.2% were positive for anti-Scl-70 antibodies and 26.6% were positive for anti-RNA polymerase III (anti-RNAP) antibody. The major malignancy cancer subtypes were breast (42.2%), haematological (12.3%), gastrointestinal (11.0%) and gynaecological (11.0%). The frequency of cancers among patients with RNAP (14.2%) was significantly increased compared with those with anti-Scl-70 antibodies (6.3%) and ACAs (6.8%) (P < 0.0001 and P < 0.001, respectively). Among the patients, who were diagnosed with cancer within 36 months of the clinical onset of SSc, there were more patients with RNAP (55.3%) than those with other autoantibody specificities (ACA = 23.5%, P < 0.008; and anti-Scl-70 antibodies = 13.6%, P < 0.002, respectively). Breast cancers were temporally associated with onset of SSc among patients with anti-RNAP, and SSc patients with anti-RNAP had a twofold increased hazard ratio for cancers compared to patients with ACAs (P < 0.0001). Conclusions Our study independently confirms, in what is to the best of our knowledge the largest population examined to date, that there is an association with cancer among SSc patients with anti-RNAP antibodies in close temporal relationship to onset of SSc, which supports the paraneoplastic phenomenon in this subset of SSc cases. An index of cautious suspicion should be maintained in these cases, and investigations for underlying malignancy should be considered when clinically appropriate. PMID:24524733
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Poormoghim, Hadi; Andalib, Elham; Jalali, Arash; Ghaderi, Afshin; Ghorbannia, Ali; Mojtabavi, Nazanin
2016-07-01
The aims of the study were to determine prognostic factors for survival and causes of death in a cohort of patients with systemic sclerosis (SSc). This was a cohort study of SSc patients in single rheumatologic center from January 1998 to August 2012. They fulfilled the American College of Rheumatology classification criteria for SSc or had calcinosis Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia or sine sclerosis. Causes of death were classified as SSc related and non-SSc related. Kaplan-Meier and Cox proportional hazard regression models were used in univariate and multivariate analysis to analyse survival in subgroups and determine prognostic factors of survival. The study includes 220 patients (192 female, 28 male). Out of thirty-two (14.5 %) who died, seventeen (53.1 %) deaths were SSc related and in nine (28.1 %) non-SSc-related causes, and in six (18.8 %) of patients causes of death were not defined. Overall survival rate was 92.6 % (95 % CI 87.5-95.7 %) after 5 years and 82.3 % (95 % CI 73.4-88.4 %) after 10 years. Pulmonary involvement was a major SSc-related cause of death, occurred in seven (41.1 %) patients. Cardiovascular events were leading cause of in overall death (11) 34.3 % and 6 in non-SSc-related death. Independent risk factors for mortality were age >50 at diagnosis (HR 5.10) advance pulmonary fibrosis (HR 11.5), tendon friction rub at entry (HR 6.39), arthritis (HR 3.56). In this first Middle Eastern series of SSc registry, pulmonary and cardiac involvements were the leading cause of SSc-related death.
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Methyl-CpG-binding protein 2 mediates antifibrotic effects in scleroderma fibroblasts.
He, Ye; Tsou, Pei-Suen; Khanna, Dinesh; Sawalha, Amr H
2018-05-14
Emerging evidence supports a role for epigenetic regulation in the pathogenesis of scleroderma (SSc). We aimed to assess the role of methyl-CpG-binding protein 2 (MeCP2), a key epigenetic regulator, in fibroblast activation and fibrosis in SSc. Dermal fibroblasts were isolated from patients with diffuse cutaneous SSc (dcSSc) and from healthy controls. MeCP2 expression was measured by qPCR and western blot. Myofibroblast differentiation was evaluated by gel contraction assay in vitro. Fibroblast proliferation was analysed by ki67 immunofluorescence staining. A wound healing assay in vitro was used to determine fibroblast migration rates. RNA-seq was performed with and without MeCP2 knockdown in dcSSc to identify MeCP2-regulated genes. The expression of MeCP2 and its targets were modulated by siRNA or plasmid. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) using anti-MeCP2 antibody was performed to assess MeCP2 binding sites within MeCP2-regulated genes. Elevated expression of MeCP2 was detected in dcSSc fibroblasts compared with normal fibroblasts. Overexpressing MeCP2 in normal fibroblasts suppressed myofibroblast differentiation, fibroblast proliferation and fibroblast migration. RNA-seq in MeCP2-deficient dcSSc fibroblasts identified MeCP2-regulated genes involved in fibrosis, including PLAU , NID2 and ADA . Plasminogen activator urokinase (PLAU) overexpression in dcSSc fibroblasts reduced myofibroblast differentiation and fibroblast migration, while nidogen-2 (NID2) knockdown promoted myofibroblast differentiation and fibroblast migration. Adenosine deaminase (ADA) depletion in dcSSc fibroblasts inhibited cell migration rates. Taken together, antifibrotic effects of MeCP2 were mediated, at least partly, through modulating PLAU, NID2 and ADA. ChIP-seq further showed that MeCP2 directly binds regulatory sequences in NID2 and PLAU gene loci. This study demonstrates a novel role for MeCP2 in skin fibrosis and identifies MeCP2-regulated genes associated with fibroblast migration, myofibroblast differentiation and extracellular matrix degradation, which can be potentially targeted for therapy in SSc. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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Informatics can identify systemic sclerosis (SSc) patients at risk for scleroderma renal crisis
Redd, Doug; Frech, Tracy M.; Murtaugh, Maureen A.; Rhiannon, Julia; Zeng, Qing T.
2016-01-01
Background Electronic medical records (EMR) provide an ideal opportunity for the detection, diagnosis, and management of systemic sclerosis (SSc) patients within the Veterans Health Administration (VHA). The objective of this project was to use informatics to identify potential SSc patients in the VHA that were on prednisone, in order to inform an outreach project to prevent scleroderma renal crisis (SRC). Methods The electronic medical data for this study came from Veterans Informatics and Computing Infrastructure (VINCI). For natural language processing (NLP) analysis, a set of retrieval criteria was developed for documents expected to have a high correlation to SSc. The two annotators reviewed the ratings to assemble a single adjudicated set of ratings, from which a support vector machine (SVM) based document classifier was trained. Any patient having at least one document positively classified for SSc was considered positive for SSc and the use of prednisone ≥ 10 mg in the clinical document was reviewed to determine whether it was an active medication on the prescription list. Results In the VHA, there were 4,272 patients that have a diagnosis of SSc determined by the presence of an ICD-9 code. From these patients, 1,118 patients (21%) had the use of prednisone ≥_10 mg. Of these patients, 26 had a concurrent diagnosis of hypertension, thus these patients should not be on prednisone. By the use of natural language processing (NLP) an additional 16,522 patients were identified as possible SSc, highlighting that cases of SSc in the VHA may exist that are unidentified by ICD-9. A 10-fold cross validation of the classifier resulted in a precision (positive predictive value) of 0.814, recall (sensitivity) of 0.973, and f-measure of 0.873. Conclusions Our study demonstrated that current clinical practice in the VHA includes the potentially dangerous use of prednisone for veterans with SSc. This present study also suggests there may be many undetected cases of SSc and NLP can successfully identify these patients. PMID:25168254
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Circulating miR-142-3p levels in patients with systemic sclerosis.
Makino, K; Jinnin, M; Kajihara, I; Honda, N; Sakai, K; Masuguchi, S; Fukushima, S; Inoue, Y; Ihn, H
2012-01-01
Recently, increased evidence has shown that serum micro (mi)RNA levels are a useful biomarker for the diagnosis, prognosis and therapeutic value of various diseases. However, serum miRNA has not been investigated in patients with systemic sclerosis (SSc), to our knowledge. To investigate the possibility that serum levels of Homo sapiens miR-142 stem-loop (hsa-miR-142-3p), one of the miRNAs regulating the expression of integrin αV, could be a specific disease marker for SSc. Serum samples were obtained from 61 patients with SSc and 20 healthy controls. Patients with systemic lupus erythematosus (SLE), dermatomyositis (DM) and scleroderma spectrum disorder (SSD), who did not fulfil American College of Rheumatology criteria for SSc but might develop SSc in the future, were included as disease controls in this study. miRNAs were purified from serum, and miR-142-3p levels were measured with a quantitative real-time PCR assay. Serum miR-142-3p levels in patients with SSc were significantly higher than in patients with SSD, SLE or DM, and healthy control groups. Patients with increased miR-142-3p levels tended to have a short sublingual frenulum. Our data indicate that serum levels of miR-142-3p may be elevated specifically in patients with SSc, correlating with the severity of this disease, and may be useful diagnostic markers for the presence of SSc and for the differentiation of SSc from SSD. © The Author(s). CED © 2011 British Association of Dermatologists.
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Recke, Andreas; Regensburger, Ann-Katrin; Weigold, Florian; Müller, Antje; Heidecke, Harald; Marschner, Gabriele; Hammers, Christoph M; Ludwig, Ralf J; Riemekasten, Gabriela
2018-01-01
Systemic sclerosis (SSc) is a severe chronic autoimmune disease with high morbidity and mortality. Sera of patients with SSc contain a large variety of autoantibody (aab) reactivities. Among these are functionally active aab that bind to G protein-coupled receptors (GPCR) such as C-X-C motif chemokine receptor 3 (CXCR3) and 4 (CXCR4). Aab binding to the N-terminal portion of these two GPCRs have been shown to be associated with slower disease progression in SSc, especially deterioration of lung function. Aabs binding to GPCRs exhibit functional activities by stimulating or inhibiting GPCR signaling. The specific functional activity of aabs crucially depends on the epitopes they bind to. To identify the location of important epitopes on CXCR3 recognized by aabs from SSc patients, we applied an array of 36 overlapping 18-20mer peptides covering the entire CXCR3 sequence, comparing epitope specificity of SSc patient sera ( N = 32, with positive reactivity with CXCR3) to healthy controls ( N = 30). Binding of SSc patient and control sera to these peptides was determined by ELISA. Using a Bayesian model approach, we found increased binding of SSc patient sera to peptides corresponding to intracellular epitopes within CXCR3, while the binding signal to extracellular portions of CXCR3 was found to be reduced. Experimentally determined epitopes showed a good correspondence to those predicted by the ABCpred tool. To verify these results and to translate them into a novel diagnostic ELISA, we combined the peptides that represent SSc-associated epitopes into a single ELISA and evaluated its potential to discriminate SSc patients ( N = 31) from normal healthy controls ( N = 47). This ELISA had a sensitivity of 0.61 and a specificity of 0.85. Our data reveals that SSc sera preferentially bind intracellular epitopes of CXCR3, while an extracellular epitope in the N-terminal domain that appears to be target of aabs in healthy individuals is not bound by SSc sera. Based upon our results, we could devise a novel ELISA concept that may be helpful for monitoring of SSc patients.
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Recke, Andreas; Regensburger, Ann-Katrin; Weigold, Florian; Müller, Antje; Heidecke, Harald; Marschner, Gabriele; Hammers, Christoph M.; Ludwig, Ralf J.; Riemekasten, Gabriela
2018-01-01
Systemic sclerosis (SSc) is a severe chronic autoimmune disease with high morbidity and mortality. Sera of patients with SSc contain a large variety of autoantibody (aab) reactivities. Among these are functionally active aab that bind to G protein-coupled receptors (GPCR) such as C-X-C motif chemokine receptor 3 (CXCR3) and 4 (CXCR4). Aab binding to the N-terminal portion of these two GPCRs have been shown to be associated with slower disease progression in SSc, especially deterioration of lung function. Aabs binding to GPCRs exhibit functional activities by stimulating or inhibiting GPCR signaling. The specific functional activity of aabs crucially depends on the epitopes they bind to. To identify the location of important epitopes on CXCR3 recognized by aabs from SSc patients, we applied an array of 36 overlapping 18-20mer peptides covering the entire CXCR3 sequence, comparing epitope specificity of SSc patient sera (N = 32, with positive reactivity with CXCR3) to healthy controls (N = 30). Binding of SSc patient and control sera to these peptides was determined by ELISA. Using a Bayesian model approach, we found increased binding of SSc patient sera to peptides corresponding to intracellular epitopes within CXCR3, while the binding signal to extracellular portions of CXCR3 was found to be reduced. Experimentally determined epitopes showed a good correspondence to those predicted by the ABCpred tool. To verify these results and to translate them into a novel diagnostic ELISA, we combined the peptides that represent SSc-associated epitopes into a single ELISA and evaluated its potential to discriminate SSc patients (N = 31) from normal healthy controls (N = 47). This ELISA had a sensitivity of 0.61 and a specificity of 0.85. Our data reveals that SSc sera preferentially bind intracellular epitopes of CXCR3, while an extracellular epitope in the N-terminal domain that appears to be target of aabs in healthy individuals is not bound by SSc sera. Based upon our results, we could devise a novel ELISA concept that may be helpful for monitoring of SSc patients. PMID:29623076
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Maddali Bongi, S; Del Rosso, A; Miniati, I; Galluccio, F; Landi, G; Tai, G; Matucci-Cerinic, M
2012-09-01
In systemic sclerosis (SSc), mouth and face involvement leads to problems in oral health-related quality of life (OHRQoL). Mouth Handicap in Systemic Sclerosis scale (MHISS) is a 12-item questionnaire specifically quantifying mouth disability in SSc, organized in 3 subscales. Our aim was to validate Italian version of MHISS, by assessing its test-retest reliability and internal and external consistency in Italian SSc patients. Forty SSc patients (7 dSSc, 33 lSSc; age and disease duration: 57.27 ± 11.41, 9.4 ± 4.4 years; 22 with sicca syndrome) were evaluated with MHISS. MHISS was translated following a forward-backward translation procedure, with independent translations and counter-translation. Test-retest reliability was evaluated, comparing the results of two administrations, with intraclass correlation coefficient (ICC). Internal consistency was assessed by Cronbach's α and external consistency by comparison with mouth opening. MHISS has a good test-retest reliability (ICC: 0.93) and internal consistency (Cronbach's α:0.99). A good external consistency was confirmed by correlation with mouth opening (rho: -0,3869, p: 0.0137). Total MHISS score was 17.65 ± 5.20, with scores of subscale 1 (reduced mouth opening) of 6.60 ± 2.85 and scores of subscales 2 (sicca syndrome) and 3 (aesthetic concerns) of 7.82 ± 2.59 and 3.22 ± 1.14. Total and subscale 2 scores are higher in dSSc than in lSSc. This result may be due to the higher presence of sicca syndrome in dSSc than in lSSc (p = 0.0109). Our results support validity and reliability in Italian SSc patients of MHISS, specifically measuring SSc OHRQoL.
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Work Productivity in Scleroderma – Analysis from the UCLA Scleroderma Quality of Life Study
Singh, Manjit K.; Clements, Philip J.; Furst, Daniel E.; Maranian, Paul; Khanna, Dinesh
2011-01-01
Objective To examine the productivity of patients with scleroderma (SSc) both outside and within the home in a large observational cohort. Methods 162 patients completed the Work Productivity Survey. Patients indicated whether or not they were employed outside of the home, how many days/month they missed work (employment or household work) due to SSc and how many days/month productivity was decreased ≥ 50%. Patients also completed other patient-reported outcome measures. We developed binomial regression models to assess the predictors of days missed from work (paid employment or household activities). The covariates included: type of SSc, education, physician and patient global assessments, HAQ-DI, FACIT-Fatigue, and Center of Epidemiologic Studies Depression Scale – Short Form (CESD). Results The average age of patients was 51.8 years and 51% had limited SSc. Of 37% patients employed outside of the home, patients reported missing 2.6 days/month of work and had 2.5 days per month productivity reduced by half. Of the 102 patients who were not employed, 39.4% were unable to work due to their SSc. When we assessed patients for household activities (N = 162), patients missed an average of 8 days of housework/month and had productivity reduced by average of 6 days/month. In the regression models, patients with lower education and poor assessment of overall health by physician were more likely to miss work outside the home. Patients with limited SSc and high HAQ-DI were more likely to miss work at home. Conclusion SSc has a major impact on productivity at home and at work. Nearly 40% of patients reported disability due to their SSc. PMID:22012885
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Whole-exome Sequencing Identifies Rare Variants in ATP8B4 as a Risk Factor for Systemic Sclerosis
Gao, Li; Emond, Mary J; Louie, Tin; Cheadle, Chris; Berger, Alan E.; Rafaels, Nicholas; Vergara, Candelaria; Kim, Yoonhee; Taub, Margaret A.; Ruczinski, Ingo; Mathai, Stephen C.; Rich, Stephen S; Nickerson, Deborah A; Hummers, Laura K.; Bamshad, Michael J; Hassoun, Paul M.; Mathias, Rasika A; Barnes, Kathleen C.
2015-01-01
Objective To determine the contribution of rare variants as genetic modifiers of the expressivity, penetrance, and severity of systemic sclerosis (SSc). Methods We performed whole-exome sequencing of 78 European American systemic sclerosis patients, including 35 patients without pulmonary arterial hypertension (SSc-PAH−) and 43 patients with PAH (SSc-PAH+). Association testing of case-control probability for rare variants was performed using the aSKAT-O method with small sample adjustment by comparing all SSc patients with a reference population of 3,179 controls from the ESP 5,500 exome dataset. Replication genotyping was performed in an independent sample of 3,263 patients (415 SSc and 2,848 controls). We conducted expression profiling of mRNA from 61 SSc patients (19 SSc-PAH− and 42 SSc-PAH+) and 41 corresponding controls. Results The ATP8B4 gene was associated with a significant increase in the risk of SSc (P = 3.18 × 10−7). Among the 64 ATP8B4 variants tested, a single missense variant, c.1308C>G (F436L, rs55687265), provided the most compelling evidence for association (P = 9.35 × 10−10; OR = 6.11), which was confirmed in the replication cohort (P = 0.012; OR = 1.86) and meta-analysis (P = 1.92 x 10−7; OR = 2.5). Genes involved in E3 ubiquitin-protein ligase complex (ASB10) and cyclic nucleotide gated channelopathies (CNGB3) as well as HLA-DRB5 and HSPB2 (aka heat shock protein 27) provided additional evidence for association (P < 10−5). Differential ATP8B4 expression was observed among the SSc patients compared to the controls (P = 0.0005). Conclusion ATP8B4 may represent a putative genetic risk factor for SSc and pulmonary vascular complications. PMID:26473621
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Christmann, Romy B; Mathes, Allison; Affandi, Alsya J; Padilla, Cristina; Nazari, Banafsheh; Bujor, Andreea M; Stifano, Giuseppina; Lafyatis, Robert
2013-05-01
To explore the expression of thymic stromal lymphopoietin (TSLP) in patients with diffuse cutaneous systemic sclerosis (dcSSc) and compare its effects in vivo and in vitro with those of interleukin-13 (IL-13) and transforming growth factor β (TGFβ). Skin biopsy specimens from patients with dcSSc (n = 14) and healthy controls (n = 13) were analyzed by immunohistochemistry and immunofluorescence for TSLP, TSLP receptor, CD4, CD8, CD31, and CD163 markers. Wild-type, IL-4Rα1-, and TSLP-deficient mice were treated with TGFβ, IL-13, poly(I-C), or TSLP by osmotic pump. Human fibroblasts and peripheral blood mononuclear cells (PBMCs) were stimulated with TGFβ, IL-13, poly(I-C), or TSLP. Microarray analysis and quantitative polymerase chain reaction were performed to determine gene expression, and protein levels of phospho-Smad2 and macrophage marker CD163 were tested. TSLP was highly expressed in the skin of dcSSc patients, more strongly in perivascular areas and in immune cells, and was produced mainly by CD163+ cells. The skin of TSLP-treated mice showed up-regulated clusters of gene expression that overlapped strongly with those in IL-13- and TGFβ-treated mice. TSLP up-regulated specific genes, including CXCL9, proteasome, and interferon (IFN)-regulated genes. TSLP treatment in IL-4Rα1-deficient mice promoted similar cutaneous inflammation as in wild-type mice, though TSLP-induced arginase 1, CCL2, and matrix metalloproteinase 12 messenger RNA levels were blocked. In PBMCs, TSLP up-regulated tumor necrosis factor α, Mx-1, IFNγ, CXCL9, and mannose receptor 1 gene expression. TSLP-deficient mice treated with TGFβ showed less fibrosis and blocked expression of plasminogen activator inhibitor 1 and osteopontin 1. Poly(I-C)-treated mice showed high levels of cutaneous TSLP. TSLP is highly expressed in the skin of dcSSc patients and interacts in a complex manner with 2 other profibrotic cytokines, TGFβ and IL-13, strongly suggesting that it might promote SSc fibrosis directly or indirectly by synergistically stimulating profibrotic genes, or production of these cytokines. Copyright © 2013 by the American College of Rheumatology.
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Rajapakse, C
2016-11-01
Dysfunction of upper pharyngoesophageal region in systemic sclerosis (SSc) is infrequent, poorly recognised and poorly documented in the literature. Yet, it can have very distressing and even fatal consequences that may yet be very responsive to appropriate management. This paper documents the findings and outcome of management of a series of five patients with SSc who had pharyngoesophageal dysphagia to demonstrate the above. Following the documentation of a patient with SSc that had severe pharyngoesophageal dysphagia in 1981, this paper reports the findings in five patients with SSc presenting thereafter, having the same manifestations. Patients 1-4 who had barium swallow and fluoroscopy, demonstrated pharyngoesophageal dysfunction as basis of their symptoms. Patient 1 had fatal outcome from pulmonary haemorrhage following repeated bouts of aspiration pneumonia. Patients 2 and 3 had a long history of SSc and were on appropriate medical treatment. They developed a short history of dysphagia that resolved with additional improvements in swallowing techniques. Patient 4 had a short history of scleroderma, but severe and very distressing dysphagia that failed to respond to improved swallowing techniques alone, but responded well to the addition of medical treatment for SSc, over a 14-24 months period. Patient 5 had a short history of SSc and dysphagia that responded well to medical treatment over 6-12months. We conclude that pharyngoesophageal dysphagia in SSc, is a rare, very distressing and potentially fatal manifestation that can have a very favourable outcome with appropriate management. © 2016 Royal Australasian College of Physicians.
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Secchi, M E; Sulli, A; Pizzorni, C; Cutolo, M
2009-01-01
Systemic sclerosis (SSc) is characterized by altered microvascular structure and function. Nailfold videocapillaroscopy (NVC) is the tool to evaluate capillary morphological structure and laser-Doppler Blood flowmetry (LDF) can be used to estimate cutaneous blood flow of microvessels. The aim of this study was to investigate possible relationships between capillary morphology and blood flow in SSc. Twenty-seven SSc patients and 12 healthy subjects were enrolled. SSc microvascular involvement, as evaluated by NVC, was classified in three different patterns ("Early", "Active", "Late"). LDF analysis was performed at the II, III, IV, V hand fingers in both hands and both at cutaneous temperature and at 36 degrees C. Statistical evaluation was carried out by non-parametric procedures. Blood flow was found significantly lower in SSc patients when compared with healthy subjects (p<0.05). The heating of the probe to 36 degrees C induced a significant increase in peripheral blood flow in all subjects compared to baseline (p <0.05), however, the amount of variation was significantly lower in patients with SSc, compared with healthy controls (p <0.05). The SSc patients with NVC "Late" pattern, showed lower values of peripheral blood flow than patients with NVC "Active" or "Early" patterns (p<0.05). Moreover, a negative correlation between the tissue perfusion score and the progression of the SSc microangiopathy was observed, as well as between the tissue perfusion and the duration of the Raynaud's phenomenon (p <0.03). LDF can be employed to evaluate blood perfusion in the microvascular circulation in SSc patients. The blood flow changes observed with the LDF seem to correlate with the severity of microvascular damage in SSc as detected by NVC.
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Abscisic acid ameliorates the systemic sclerosis fibroblast phenotype in vitro
DOE Office of Scientific and Technical Information (OSTI.GOV)
Bruzzone, Santina, E-mail: santina.bruzzone@unige.it; Centre of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 9, 16132 Genova; Advanced Biotechnology Center, Largo Rosanna Benzi 10, 16132 Genova
Highlights: Black-Right-Pointing-Pointer ABA is an endogenous hormone in humans, regulating different cell responses. Black-Right-Pointing-Pointer ABA reverts some of the functions altered in SSc fibroblasts to a normal phenotype. Black-Right-Pointing-Pointer UV-B irradiation increases ABA content in SSc cultures. Black-Right-Pointing-Pointer SSc fibroblasts could benefit from exposure to ABA and/or to UV-B. -- Abstract: The phytohormone abscisic acid (ABA) has been recently identified as an endogenous hormone in humans, regulating different cell functions, including inflammatory processes, insulin release and glucose uptake. Systemic sclerosis (SSc) is a chronic inflammatory disease resulting in fibrosis of skin and internal organs. In this study, we investigated themore » effect of exogenous ABA on fibroblasts obtained from healthy subjects and from SSc patients. Migration of control fibroblasts induced by ABA was comparable to that induced by transforming growth factor-{beta} (TGF-{beta}). Conversely, migration toward ABA, but not toward TGF-{beta}, was impaired in SSc fibroblasts. In addition, ABA increased cell proliferation in fibroblasts from SSc patients, but not from healthy subjects. Most importantly, presence of ABA significantly decreased collagen deposition by SSc fibroblasts, at the same time increasing matrix metalloproteinase-1 activity and decreasing the expression level of tissue inhibitor of metalloproteinase (TIMP-1). Thus, exogenously added ABA appeared to revert some of the functions altered in SSc fibroblasts to a normal phenotype. Interestingly, ABA levels in plasma from SSc patients were found to be significantly lower than in healthy subjects. UV-B irradiation induced an almost 3-fold increase in ABA content in SSc cultures. Altogether, these results suggest that the fibrotic skin lesions in SSc patients could benefit from exposure to high(er) ABA levels.« less
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Dariel, Anne; Poocharoen, Wannisa; de Silva, Nicole; Pleasants, Hazel; Gerstle, Justin Ted
2015-02-01
Nonsurgical closure after primary silo placement, secondary plastic closure (SPC), has been used as an alternative to secondary surgical closure (SSC) in gastroschisis. The benefits described were closure without formal surgical procedure, cosmetic aspect, and minimization of intra-abdominal pressures. This study compared requirements for mechanical ventilation and general anesthesia, nutritional care, and outcomes between SPC and SSC. We included patients with primary staged-silo reduction with a 1-year minimum follow-up. SPC was performed at bedside with sedation using a nonadherent dressing. SSC was performed in operating room under general anesthesia using standard surgical techniques. This retrospective study included 64 patients, 23 SPC and 41 SSC. The characteristics of the two groups were comparable. Mechanical ventilation was used for 15 SPC and 41 SSC (p=0.0001) with a comparable median duration (5.5 and 6.0 days, not significant [NS]). General anesthesia was required for 9 SPC and 41 SSC (p<0.0001). Complications included one SPC and six SSC with necrotizing enterocolitis, zero SPC and four SSC with intestinal atresia, two SPC and four SSC with small bowel obstruction, zero SPC and one SSC with abdominal compartment syndrome resulting in a short bowel syndrome (NS). Median duration of parenteral nutrition (30 and 27 days), time to first feeds (14 and 14 days), time at or above minimal enteral feeding (22 and 17 days), time to full feeds (31 and 28 days), length of stay (LOS) in neonatal intensive care unit (24 and 23.5 days) and overall hospital LOS (37 and 36 days) were not statistically different between SPC and SSC patients without complications, respectively. These data were comparable for SPC and SSC patients with complications. Five SPC and six SSC developed an umbilical hernia (NS); two patients in each group required a surgical repair (NS). Plastic closure of gastroschisis after primary silo reduction is simple, safe, reproducible, and associated with a significant lower incidence of mechanical ventilation. Nutritional management and length of hospital stay were similar to conventional surgical closure for patients. Plastic closure allows nonoperative management without general anesthesia at patient's bedside, in comparison with surgical closure that must be performed under general anesthesia in the operating room. Plastic closure does not appear to be associated with more umbilical hernias in this retrospective study. Georg Thieme Verlag KG Stuttgart · New York.
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Hegner, Björn; Schaub, Theres; Catar, Rusan; Kusch, Angelika; Wagner, Philine; Essin, Kirill; Lange, Claudia; Riemekasten, Gabriela; Dragun, Duska
2016-01-01
Obliterative vasculopathy and fibrosis are hallmarks of systemic sclerosis (SSc), a severe systemic autoimmune disease. Bone marrow-derived mesenchymal stromal cells (MSCs) from SSc patients may harbor disease-specific abnormalities. We hypothesized disturbed vascular smooth muscle cell (VSMC) differentiation with increased propensity towards myofibroblast differentiation in response to SSc-microenvironment defining growth factors and determined responsible mechanisms. We studied responses of multipotent MSCs from SSc-patients (SSc-MSCs) and healthy controls (H-MSCs) to long-term exposure to CTGF, b-FGF, PDGF-BB or TGF-β1. Differentiation towards VSMC and myofibroblast lineages was analyzed on phenotypic, biochemical, and functional levels. Intracellular signaling studies included analysis of TGF-β receptor regulation, SMAD, AKT, ERK1/2 and autocrine loops. VSMC differentiation towards both, contractile and synthetic VSMC phenotypes in response to CTGF and b-FGF was disturbed in SSc-MSCs. H-MSCs and SSc-MSCs responded equally to PDGF-BB with prototypic fibroblastic differentiation. TGF-β1 initiated myofibroblast differentiation in both cell types, yet with striking phenotypic and functional differences: In relation to H-MSC-derived myofibroblasts induced by TGF-β1, those obtained from SSc-MSCs expressed more contractile proteins, migrated towards TGF-β1, had low proliferative capacity, and secreted higher amounts of collagen paralleled by reduced MMP expression. Higher levels of TGF-β receptor 1 and enhanced canonical and noncanonical TGF-β signaling in SSc-MSCs accompanied aberrant differentiation response of SSc-MSCs in comparison to H-MSCs. Deregulated VSMC differentiation with a shift towards myofibroblast differentiation expands the concept of disturbed endogenous regenerative capacity of MSCs from SSc patients. Disease related intrinsic hyperresponsiveness to TGF-β1 with increased collagen production may represent one responsible mechanism. Better understanding of repair barriers and harnessing beneficial differentiation processes in MSCs could widen options of autologous MSC application in SSc patients.
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Safety and Effectiveness of Mycophenolate in Systemic Sclerosis. A Systematic Review
2015-01-01
Background Mycophenolate is increasingly being used in the rheumatic diseases. Its main adverse effects are gastrointestinal, myelosuppression, and infection. These may limit use in systemic sclerosis (SSc) since gastrointestinal involvement is common. The objective of this study is to evaluate gastrointestinal adverse events of mycophenolate in SSc. Secondarily we evaluated other adverse events, and the effectiveness of mycophenolate in skin and lung disease. Methods A literature search of Medline, Embase, Cochrane Central Register of Controlled Trials, and CINAHL (inception-2013) was performed. Studies reporting use of mycophenolate in SSc patients, adverse events, modified Rodnan skin score (MRSS), forced vital capacity (FVC), or diffusing capacity of carbon monoxide (DLCO) were included. The primary outcome was gastrointestinal events occurring after the initiation of mycophenolate. Secondary safety outcomes included myelosuppression, infection, malignancy, and death after the initiation of mycophenolate. Results 617 citations were identified and 21 studies were included. 487 patients were exposed to mycophenolate. The mean disease duration ranged between 0.8-14.1 years. There were 18 deaths and 90 non-lethal adverse events. The non-lethal adverse events included 43 (47.7%) gastrointestinal events, 34 (26%) infections, 6 (5%) cytopenias and 2 (2%) malignancies. The most common gastrointestinal events included diarrhea (n=18 (14%)), nausea (n=12 (9%)), and abdominal pain (n=3 (2%)). The rate of discontinuation ranged between 8%-40%. Seven observational studies reported improvement or stabilization in FVC, and 5 studies report stabilization or improvement in MRSS. Conclusion Mycophenolate-associated gastrointestinal adverse events are common in SSc, but not severe enough to preclude its use. Observational data suggests mycophenolate may be effective in improving or stabilizing interstitial lung disease, and skin involvement. PMID:25933090
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Is immunosuppressive therapy the anchor treatment to achieve remission in systemic sclerosis?
Cappelli, Susanna; Bellando-Randone, Silvia; Guiducci, Serena; Matucci-Cerinic, Marco
2014-06-01
Since activation of the immune system and a perivascular infiltrate of inflammatory cells are key features of SSc, immunosuppression has long been considered to be an anchor treatment. Non-selective immunosuppression remains central to the treatment of interstitial lung disease (ILD) and skin involvement, with CYC most widely used to obtain remission. The use of MTX as a first-line agent may be considered in the presence of skin involvement without ILD. More recently, MMF has shown encouraging results in observational studies, but still needs more formal evaluation to verify if it can be considered an alternative drug to CYC or a maintenance agent such as AZA. Rituximab has provided promising results in small open-label studies and other novel therapies targeting specific molecular and cellular targets are under evaluation. Patients with rapidly progressing diffuse cutaneous SSc should be evaluated for haematopoietic stem cell transplantation.
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Attitudes and beliefs about the surgical safety checklist: Just another tick box?
Dharampal, Navjit; Cameron, Christopher; Dixon, Elijah; Ghali, William; Quan, May Lynn
2016-08-01
Following a landmark study showing decreased morbidity and mortality after implementation of the surgical safety checklist (SSC), it has been widely adopted into perioperative policy. We explored the impact of attitudes and beliefs surrounding the SSC on its uptake in Calgary. We used qualitative methodology to examine factors influencing SSC use. We performed semistructured interviews based on Rogers' theory of diffusion of innovation. Purposive and snowball sampling were used to identify surgeons, anesthesiologists and operating room nurses from hospitals in Calgary. Data collection and analysis were based on grounded theory. Two individuals jointly analyzed data and achieved consensus on emerging themes. Generated themes included 1) the SSC has brought organization to previous informal perioperative checks, 2) the SSC is most helpful when it is simple, and 3) the 3 current components of the checklist are redundant. The briefing was considered the most important aspect and the debriefing the least important. Initially the SSC was difficult to implement owing to a shift in time management and perioperative culture; however, it has now assimilated into perioperative routine. Finally, though most participants agreed that the SSC might avoid some delays and complications, only a few believe there have been observable improvements to morbidity and mortality. Although the SSC has been integrated into perioperative practice in Calgary, participants believe that previous informal checkpoints were able to circumvent most perioperative issues. Although the SSC may help with flow and equipment, participants believe it fails to show a subjective, clinically important improvement.
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Avouac, Jérôme; Walker, Ulrich A; Hachulla, Eric; Riemekasten, Gabriela; Cuomo, Giovanna; Carreira, Patricia E; Caramaschi, Paola; Ananieva, Lidia P; Matucci-Cerinic, Marco; Czirjak, Laszlo; Denton, Christopher; Ladner, Ulf Müller; Allanore, Yannick
2016-01-01
To determine whether joint synovitis and tendon friction rubs (TFRs) can predict the progression of systemic sclerosis (SSc) over time. We performed a prospective cohort study that included 1301 patients with SSc from the EUSTAR database with disease duration ≤3 years at inclusion and with a follow-up of at least 2 years. Presence or absence at clinical examination of synovitis and TFRs was extracted at baseline. Outcomes were skin, cardiovascular, renal and lung progression. Overall disease progression was defined according to the occurrence of at least one organ progression. Joint synovitis (HR: 1.26, 95% CI 1.01 to 1.59) and TFRs (HR: 1.32, 95% CI 1.03 to 1.70) were independently predictive of overall disease progression, as were also the diffuse cutaneous subset (HR: 1.30, 95% CI 1.05 to 1.61) and positive antitopoisomerase-I antibodies (HR: 1.25, 95% CI 1.02 to 1.53). Regarding skin progression, joint synovitis (HR: 1.67, 95% CI 1.06 to 2.64) and TFRs (HR: 1.69, 95% CI 1.02 to 2.77) were also independently predictive of worsening of the modified Rodnan skin score. For cardiovascular progression, joint synovitis was predictive of the occurrence of new digital ulcer(s) (HR: 1.45, 95% CI 1.08 to 1.96) and decreased left ventricular ejection fraction (HR: 2.20, 95% CI 1.06 to 4.57); TFRs were confirmed to be an independent predictor of scleroderma renal crisis (HR: 2.33, 95% CI 1.03 to 6.19). Joint synovitis and TFRs are independent predictive factors for disease progression in patients with early SSc. These easily detected clinical markers may be useful for the risk stratification of patients with SSc. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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Winsz-Szczotka, Katarzyna; Kuźnik-Trocha, Kornelia; Komosińska-Vassev, Katarzyna; Kucharz, Eugeniusz; Kotulska, Anna; Olczyk, Krystyna
2016-07-01
The relationship between adiponectin, leptin, insulin-like growth factor-1 (IGF-1) and total lipid peroxide (TLP) concentrations, and its possible role in the development of diffuse cutaneous systemic sclerosis (dcSSc), were evaluated in this study. Plasma adipokines and IGF-1 levels were determined using the enzyme-linked immunosorbent assay method, whereas TLP levels were determined using a photometric test, in 36 dcSSc patients and 40 healthy controls matched by age, sex and body mass index (BMI). Plasma levels of adipokines were significantly lowered, while TLP and IGF-1 were increased in dcSSc patients compared to controls. Adiponectin correlated significantly with leptin (r = 0.44), TLP (r = -0.54), CRP (r = -0.47), erythrocyte sedimentation rate (ESR) (r = -0.40) and duration of disease (r = -0.44). A significant relationship was found between leptinemia and IGF-1 (r = -0.40), TLP (r = 0.44), duration of disease (r = -0.38) and BMI (r = 0.65). TLP correlated with IGF-1 (r = -0.43), C-reactive protein (r = 0.47), ESR (r = 0.49) and duration of disease (r = 0.46), while IGF-1 correlated with ESR (r = -0.40). Adipose tissue may play a complex role in the development of dcSSc, affecting both the metabolic state of the organism, as well as free radical-induced connective tissue degradation. Although, leptin seems to exert a pro-oxidative effect and both adiponectin and IGF-1 appear to prevent free radical damage, confirmation of the above effects requires further research. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.
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Longitudinal Evaluation of Central Corneal Thickness in Patients With Systemic Sclerosis.
Gomes, Beatriz F; Santhiago, Marcony R; Gomes, Silvia Fiuza; Kara-Junior, Newton; Moraes, Haroldo V
2016-12-01
To investigate the longitudinal change of central corneal thickness (CCT) in patients with systemic sclerosis (SSc) and to elucidate whether it contributes to misinterpretation of intraocular pressure (IOP) in this group of patients. Twenty patients with SSc and 20 sex- and age-matched controls were examined at 2 visits 5 years apart. Age, sex, race, subtype of SSc, disease duration, autoantibody profile, use of disease-modifying antirheumatic drugs (DMARDs), best-corrected visual acuity, spherical equivalent refraction, IOP, and CCT were recorded. IOP was assessed by applanation tonometry and CCT by ultrasonic pachymetry. CCT decreased by 7.2 μm [95% confidence interval (CI), -2.1 to -12.2 μm] between the first and second measurements (P = 0.008) in patients with SSc and by 2.4 μm (P = 0.39, 95% CI, -8.0 to 3.3 μm) in the control group. Considering patients with SSc, CCT decreased by a mean of 11.6 μm [95% CI, -4.3 to -19.0 μm (P = 0.007)] among those taking DMARDs at the second visit and by 4.2 μm [95% CI, -3.0 to -11.5 μm (P = 0.2)] in patients not taking any DMARDs. There was no statistically significant change in IOP between the 2 visits for either the SSc group (P = 0.84) or the control group (P = 0.29). Mean change in CCT was not associated with either IOP at first visit or with change in IOP in SSc patients. CCT decreased with time in SSc. However, the slight rates of thinning observed are unlikely to considerably influence applanation tonometry or clinical decision-making over the short to intermediate term.
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Odaka, M; Hasegawa, M; Hamaguchi, Y; Ishiura, N; Kumada, S; Matsushita, T; Komura, K; Sato, S; Takehara, K; Fujimoto, M
2010-02-01
Studies have demonstrated that B cells play important roles in systemic sclerosis (SSc), especially through the CD19/CD22 autoimmune loop. CD22 is a B cell-specific inhibitory receptor that dampens B cell antigen receptor (BCR) signalling via tyrosine phosphorylation-dependent mechanism. In this study, we examined the presence and functional property of circulating autoantibodies reacting with CD22 in systemic sclerosis. Serum samples from 10 tight skin (TSK/+) mice and 50 SSc patients were assessed for anti-CD22 autoantibodies by enzyme-linked immunosorbent assays using recombinant mouse or human CD22. The association between anti-CD22 antibodies and clinical features was also investigated in SSc patients. Furthermore, the influence of SSc serum including anti-CD22 autoantibodies for CD22 tyrosine phosphorylation was examined by Western blotting using phosphotyrosine-specific antibodies reacting with four major tyrosine motifs of CD22 cytoplasmic domain. Anti-CD22 autoantibodies were positive in 80% of TSK/+ mice and in 22% of SSc patients. Patients positive for anti-CD22 antibodies showed significantly higher modified Rodnan skin thickness score compared with patients negative for anti-CD22 antibodies. Furthermore, anti-CD22 antibodies from patients' sera were capable of reducing phosphorylation of all four CD22 tyrosine motifs, while sera negative for anti-CD22 antibodies did not affect CD22 phosphorylation. Thus, a subset of SSc patients possessed autoantibodies reacting with a major inhibitory B cell response regulator, CD22. Because these antibodies can interfere CD22-mediated suppression onto B cell activation in vitro, SSc B cells produce functional autoantibodies that can enhance their own activation. This unique regulation may contribute to the autoimmune aspect of SSc.
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2014-10-01
fibrosis, interstitial lung diseases 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON...cadherin-11 in scleroderma patients with interstitial lung disease . We have been working with our collaborators at UTHSC to identify and sera that...83% female, avg age 49, avg disease duration 2.5 years, 59% with diffuse SSc, 28% with ILD and avg skin score of 16 at enrollment). Since there is
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Potential use of TNF-α inhibitors in systemic sclerosis.
Murdaca, Giuseppe; Spanò, Francesca; Contatore, Miriam; Guastalla, Andrea; Puppo, Francesco
2014-01-01
Systemic sclerosis (SSc) is a rare connective tissue disease characterized by chronic inflammation and fibrosis of the skin, vascular abnormalities and variable involvement of organs. TNF-α has a central role in initial host response to infections and in the pathogenesis of various systemic immune-mediated diseases. Serum levels of TNF-α are elevated in patients with SSc and favor the development of pulmonary fibrosis and pulmonary arterial hypertension. Inflammatory arthritis can occur in patients with SSc. Infliximab and etanercept may improve the inflammatory arthritis and disability in SSc. TNF-α inhibitors reduce the systemic inflammation, improve the endothelial function decreasing the risk of pulmonary arterial hypertension progression and of acute cardiovascular and/or cerebrovascular events. Physicians need to be aware of the potential risks of tuberculosis reactivation and opportunistic infections. Randomized controlled trials with TNF-α inhibitors in patients with SSc are needed to confirm the potential role of these agents in the treatment of SSc.
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2010-01-01
Introduction Laser Doppler imaging (LDI) is a relatively new method for assessing the functional aspect of superficial skin blood flow in systemic sclerosis (SSc) and Raynaud's phenomenon. The present study investigated the dynamic behavior of digital skin microvascular blood flow before and after cold stimulus (CS) in SSc patients and in healthy controls by means of a comprehensive approach of the functional (LDI), morphological (nailfold capillaroscopy (NFC)), and biochemical (fingertip lacticemy (FTL)) microcirculation components. Methods Forty-four SSc patients and 40 healthy controls were included. After acclimatization, all subjects underwent NFC followed by LDI and FTL measurement. NFC was performed with a stereomicroscope under 10× to 20× magnification in the 10 digits of the hands. Skin blood flow of the dorsum of four fingertips (excluding the thumb) of the left hand was measured using LDI at baseline and for 30 minutes after CS. The mean finger blood flow (FBF) of the four fingertips was expressed as arbitrary perfusion units. FTL was determined on the fourth left finger before (pre-CS-FTL) and 10 minutes after CS. Results LDI showed significantly lower mean baseline FBF in SSc patients as compared with controls (296.9 ± 208.8 vs. 503.6 ± 146.4 perfusion units; P < 0.001) and also at all time points after CS (P < 0.001). There was a significant decrease in mean FBF after CS as compared with baseline in SSc patients and in controls, followed by recovery of the blood flow 27 minutes after CS in healthy controls, but not in SSc patients. FBF tended to be lower in patients with digital scars and previous ulceration/amputation (P = 0.06). There was no correlation between mean baseline FBF and NFC parameters. Interestingly, there was a negative correlation between FTL and FBF measured by LDI in basal conditions and 10 minutes after CS in SSc patients. Conclusions LDI showed lower digital blood flow in SSc patients when compared with healthy controls and correlated well with FTL both at baseline and after CS, allowing objective measurement of blood perfusion in SSc patients. The lack of correlation between functional and morphological microvascular abnormalities, measured by LDI and NFC, suggests they are complementary tools for evaluation of independent microangiopathy aspects in SSc patients. PMID:20696074
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Correa, Marcelo Ju; Andrade, Luis Ec; Kayser, Cristiane
2010-01-01
Laser Doppler imaging (LDI) is a relatively new method for assessing the functional aspect of superficial skin blood flow in systemic sclerosis (SSc) and Raynaud's phenomenon. The present study investigated the dynamic behavior of digital skin microvascular blood flow before and after cold stimulus (CS) in SSc patients and in healthy controls by means of a comprehensive approach of the functional (LDI), morphological (nailfold capillaroscopy (NFC)), and biochemical (fingertip lacticemy (FTL)) microcirculation components. Forty-four SSc patients and 40 healthy controls were included. After acclimatization, all subjects underwent NFC followed by LDI and FTL measurement. NFC was performed with a stereomicroscope under 10× to 20× magnification in the 10 digits of the hands. Skin blood flow of the dorsum of four fingertips (excluding the thumb) of the left hand was measured using LDI at baseline and for 30 minutes after CS. The mean finger blood flow (FBF) of the four fingertips was expressed as arbitrary perfusion units. FTL was determined on the fourth left finger before (pre-CS-FTL) and 10 minutes after CS. LDI showed significantly lower mean baseline FBF in SSc patients as compared with controls (296.9 ± 208.8 vs. 503.6 ± 146.4 perfusion units; P < 0.001) and also at all time points after CS (P < 0.001). There was a significant decrease in mean FBF after CS as compared with baseline in SSc patients and in controls, followed by recovery of the blood flow 27 minutes after CS in healthy controls, but not in SSc patients. FBF tended to be lower in patients with digital scars and previous ulceration/amputation (P = 0.06). There was no correlation between mean baseline FBF and NFC parameters. Interestingly, there was a negative correlation between FTL and FBF measured by LDI in basal conditions and 10 minutes after CS in SSc patients. LDI showed lower digital blood flow in SSc patients when compared with healthy controls and correlated well with FTL both at baseline and after CS, allowing objective measurement of blood perfusion in SSc patients. The lack of correlation between functional and morphological microvascular abnormalities, measured by LDI and NFC, suggests they are complementary tools for evaluation of independent microangiopathy aspects in SSc patients.
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Gonzalez-Lopez, Laura; Rocha-Muñoz, Alberto D; Olivas-Flores, Eva M; Garcia-Gonzalez, Araceli; Peguero-Gómez, Ana R; Flores-Navarro, Juan; Villa-Manzano, Alberto I; Zavaleta-Muñiz, Soraya A; Salazar-Paramo, Mario; Mejía, Mayra; Juárez-Contreras, Pablo; Vazquez-Del Mercado, Monica; Cardona-Muñoz, Ernesto G; Trujillo-Hernández, Benjamin; Nava-Zavala, Arnulfo H; Gamez-Nava, Jorge I
2015-09-01
Interstitial lung disease (ILD) is a frequent complication in progressive systemic sclerosis (SSc), being present in 25% to 90% of cases. To evaluate whether serum levels of procollagen typei and iii aminoterminal propeptide (PINP and PIIINP) correlate with severity and patterns of ILD in Mexican women with SSc. Thirty three SSc patients were assessed for disease characteristics and anti-topoisomerase antibodies (topoi), and also underwent pulmonary function tests and high-resolution computed tomography (HRCT). Nineteen patients had ILD+SSc, and 14 had no lung involvement (no ILD-SSc); data were compared with those from 45 healthy controls. PINP and PIIINP were assessed in all 3 groups. Patients with SSc had higher PINP and PIIINP vs controls (P=.001, P<.001, respectively). Compared to no ILD-SSc patients, those with ILD+SSc had longer disease duration in years (P=.005), higher modified Rodnan skin score (P<.001), higher Health Assessment Questionnaire-Disability-Index scores (P<.001), higher topoi U/mL (P<.001), PINP (49.28±28.63 vs. 32.12±18.58μg/L, P=.05), and PIIINP (4.33±1.03 vs. 2.67±1.26μg/L, P<.001) levels. ILD severity based on total HRCT correlated with PINP (r=.388, P=.03) and PIIINP (P=.594, P<.001). On adjusted analysis, ILD severity was associated with disease duration (P=.037), PIIINP (P=.038), and topoi (P=.045). PINP and PIIINP are useful markers for severe ILD+SSc, suggesting they could play a role in the follow-up of this complication in SSc. Copyright © 2014 SEPAR. Published by Elsevier Espana. All rights reserved.
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Alhajeri, Hebah; Hudson, Marie; Fritzler, Marvin; Pope, Janet; Tatibouet, Solène; Markland, Janet; Robinson, David; Jones, Niall; Khalidi, Nader; Docherty, Peter; Kaminska, Elzbieta; Masetto, Ariel; Sutton, Evelyn; Mathieu, Jean-Pierre; Ligier, Sophie; Grodzicky, Tamara; LeClercq, Sharon; Thorne, Carter; Gyger, Geneviève; Smith, Douglas; Fortin, Paul R; Larché, Maggie; Baron, Murray
2015-04-01
The goal of this study was to determine the sensitivity of the new 2013 classification criteria for systemic sclerosis (SSc; scleroderma) in an independent cohort of SSc subjects and to assess the contribution of individual items of the criteria to the overall sensitivity. SSc subjects from the Canadian Scleroderma Research Group cohort were assessed. Sensitivity was determined in several subgroups of patients. In patients without the criterion of skin thickening proximal to the metacarpophalangeal (MCP) joints, we recalculated sensitivity after removing the individual criterion. A total of 724 SSc patients were included. Most were women (86%), mean age was 55.8 years, mean disease duration was 10.9 years, and 59% had limited cutaneous SSc (lcSSc). Overall, the sensitivity of the 2013 criteria was 98.3% compared to 88.3% for the 1980 criteria. This pattern was consistent among those with lcSSc (98.8% versus 85.6%), anticentromere antibodies (98.9% versus 79.8%), disease duration ≤3 years (98.7% versus 84.7%), and no skin involvement proximal to the MCP joints (97% versus 60%). In the latter subgroup, removing Raynaud's phenomenon and sclerodactyly from the criteria reduced the sensitivity to 77% and 79%, respectively. Removing both sclerodactyly and puffy fingers reduced the sensitivity to 62%. The 2013 SSc classification criteria classify more SSc patients than the 1980 criteria. The improvement in sensitivity is most striking in those with lcSSc, especially those without skin involvement proximal to the MCP joints. The addition of Raynaud's phenomenon and puffy fingers to the 2013 criteria accounts for important gains in sensitivity. Copyright © 2015 by the American College of Rheumatology.
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Thombs, Brett D; Kwakkenbos, Linda; Riehm, Kira E; Saadat, Nazanin; Fedoruk, Claire
2017-02-01
The complexity and burden of systemic sclerosis (SSc) pose challenges to developing and sustaining disease management self-efficacy. The objective of this systematic review was to compare scores on a commonly used self-efficacy measure, the Self-Efficacy for Managing Chronic Disease (SEMCD) Scale, between SSc and other diseases. Data sources included the CINAHL, EMBASE, MEDLINE, and Scopus databases, searched through January 25, 2016, and reference lists of included articles and relevant reviews. Studies in any language that reported total SEMCD scores or individual item scores in adult non-psychiatric medical patients were eligible. We identified one eligible non-intervention study of SSc patients (n = 553), 13 other non-intervention studies, and 21 studies with pre-intervention data for patients enrolled in a self-management program or a trial of a program. Of 13 non-intervention studies with published total score means in cancer, cardiovascular disease, Parkinson's disease, spinal cord injuries, organ transplant candidates and recipients, dialysis, and lupus, SEMCD scores were statistically significantly lower (poorer self-efficacy) in SSc than 6 other disease samples, not significantly different from 6, and significantly higher than lupus patients. Compared to 18 studies of patients in self-management programs or trials with published total score means, SSc patients were similar or lower than 9 samples and significantly higher than 9 samples. Compared to patients with other diseases not enrolled in programs to improve self-efficacy, SSc patients report lower self-efficacy scores than most patient groups. Rigorously tested self-care interventions designed to meet the unique needs of patients with SSc are needed.
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Systemic sclerosis with normal or nonspecific nailfold capillaroscopy.
Fichel, Fanny; Baudot, Nathalie; Gaitz, Jean-Pierre; Trad, Salim; Barbe, Coralie; Francès, Camille; Senet, Patricia
2014-01-01
In systemic sclerosis (SSc), a specific nailfold videocapillaroscopy (NVC) pattern is observed in 90% of cases and seems to be associated with severity and progression of the disease. To describe the characteristics of SSc patients with normal or nonspecific (normal/nonspecific) NVC. In a retrospective cohort study, clinical features and visceral involvements of 25 SSc cases with normal/nonspecific NVC were compared to 63 SSc controls with the SSc-specific NVC pattern. Normal/nonspecific NVC versus SSc-specific NVC pattern was significantly associated with absence of skin sclerosis (32 vs. 6.3%, p = 0.004), absence of telangiectasia (47.8 vs. 17.3%, p = 0.006) and absence of sclerodactyly (60 vs. 25.4%, p = 0.002), and less frequent severe pulmonary involvement (26.3 vs. 58.2%, p = 0.017). Normal/nonspecific NVC in SSc patients appears to be associated with less severe skin involvement and less frequent severe pulmonary involvement. © 2014 S. Karger AG, Basel.
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Evaluation and management of esophageal manifestations in systemic sclerosis.
Denaxas, Konstantinos; Ladas, Spyros D; Karamanolis, George P
2018-01-01
Systemic sclerosis (SSc) is a multisystemic autoimmune connective tissue disorder; in the gastrointestinal tract, the esophagus is the most commonly affected organ. Symptoms of esophageal disease are due to gastroesophageal reflux disease (GERD) and esophageal motor dysfunction. Since the development of high-resolution manometry (HRM), this method has been preferred for the study of SSc patients with esophageal involvement. Using HRM, classic scleroderma esophagus, defined as absent or ineffective peristalsis of the distal esophagus in combination with a hypotensive lower esophageal sphincter, was found in as many as 55% of SSc patients. Endoscopy is the appropriate test for evaluating dysphagia and identifying evidence and possible complications of GERD. In the therapeutic area, treatment ranges from general supportive measures to the administration of drugs such as proton pump inhibitors and/or prokinetics. However, as many SSc patients do not respond to existing therapies, there is an urgent need for new therapeutic modalities. Buspirone, a 5-hydroxytryptamine 1A receptor agonist, could be a putative therapeutic option, as it was found to exert a significant beneficial effect in SSc patients with esophageal involvement. This review summarizes our knowledge concerning the evaluation and management of esophageal manifestations in SSc patients, including emerging therapeutic modalities.
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Evaluation and management of esophageal manifestations in systemic sclerosis
Denaxas, Konstantinos; Ladas, Spyros D.; Karamanolis, George P.
2018-01-01
Systemic sclerosis (SSc) is a multisystemic autoimmune connective tissue disorder; in the gastrointestinal tract, the esophagus is the most commonly affected organ. Symptoms of esophageal disease are due to gastroesophageal reflux disease (GERD) and esophageal motor dysfunction. Since the development of high-resolution manometry (HRM), this method has been preferred for the study of SSc patients with esophageal involvement. Using HRM, classic scleroderma esophagus, defined as absent or ineffective peristalsis of the distal esophagus in combination with a hypotensive lower esophageal sphincter, was found in as many as 55% of SSc patients. Endoscopy is the appropriate test for evaluating dysphagia and identifying evidence and possible complications of GERD. In the therapeutic area, treatment ranges from general supportive measures to the administration of drugs such as proton pump inhibitors and/or prokinetics. However, as many SSc patients do not respond to existing therapies, there is an urgent need for new therapeutic modalities. Buspirone, a 5-hydroxytryptamine 1A receptor agonist, could be a putative therapeutic option, as it was found to exert a significant beneficial effect in SSc patients with esophageal involvement. This review summarizes our knowledge concerning the evaluation and management of esophageal manifestations in SSc patients, including emerging therapeutic modalities. PMID:29507463
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Levis, Brooke; Kwakkenbos, Linda; Hudson, Marie; Baron, Murray; Thombs, Brett D
2017-02-01
Fatigue is prevalent among patients with systemic sclerosis (SSc). To date, studies investigating fatigue in SSc have been hampered by the instruments used to measure fatigue in SSc and have included patient-reported rather than objectively-rated measures of disease. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale is a validated measure for assessing fatigue in SSc that, compared to other instruments, provides good coverage of the full range of the fatigue spectrum. The objective of this study was to assess sociodemographic and objectively-rated disease-related associates of fatigue, as measured by the FACIT-F, in a large sample of patients with SSc. Fatigue was assessed using the FACIT-F scale. Disease severity was assessed using Medsger's severity scale. Multivariable linear regression was performed to assess the independent associations between sociodemographic and medical variables and fatigue. Among 785 patients, the mean FACIT-F score was 32.2 (SD = 12.1). Being age 40-49 (reference = 60+; standardized regression coefficient (β) = -0.11), less than post-secondary education (β = 0.07), having more medical comorbidities (β = -0.11) and more severe muscle (β = -0.10), gastrointestinal (β = -0.15), lung (β = -0.13), and general system disease severity (β = -0.13) were independently associated with more fatigue (p < 0.05). Fatigue in SSc was independently associated with more severe disease. These data contribute to a better understanding of fatigue in SSc and help inform patient-centered research in SSc.
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Kennedy, Barry; Branagan, Peter; Moloney, Fiachra; Haroon, Muhammad; O'Connell, Oisin J; O'Connor, Terence M; O'Regan, Kevin; Harney, Sinead; Henry, Michael T
2015-09-14
SSc-ILD and IPF demonstrate significant morbidity and mortality. Predicting disease progression is challenging in both diseases. We sought a serum biomarker that could identify patients with SSc-ILD or IPF and prospectively predict short-term decline in lung function in these patients. 10 healthy controls, 5 SSc w/o ILD, 6 SSc-ILD and 13 IPF patients underwent venesection. An array of cytokines including KL-6, SP-D and MMP7 were measured. PFTs were obtained at baseline and six months. Cytokine measurements were correlated with PFTs. KL-6 in IPF patients (633 ng/ml, IQR 492-1675) was significantly elevated compared to controls (198 ng/ml, IQR 52-360, p<0.01) and SSc w/o ILD patients (192 ng/ml, IQR 0-524, p<0.05); KL-6 in SSc-ILD patients (836 ng/ml, IQR 431-1303) was significantly higher than in controls (p<0.05). SP-D was significantly higher in IPF patients (542 ng/ml, IQR 305-577) compared to controls (137 ng/ml, IQR 97-284, p<0.01) or to SSc w/o ILD patients (169 ng/ml, IQR 137-219, p<0.05). In comparison with controls (0.0 ng/ml, IQR 0.0-0.6), MMP7 was significantly higher in both IPF patients (2.85 ng/ml, IQR 1.5-3.6, p<0.05) and SSc-ILD patients (5.41 ng/ml, IQR 2.6-7.2, p<0.001). Using a cut-off level of 459ng/ml for KL-6 and of 1.28 ng/ml for MMP7, 18 out of 19 patients with ILD had a serum value of either KL-6 or MMP7 above these thresholds. For all ILD patients, baseline serum SP-D correlated with ΔFVC %pred over six months (r=-0.63, p=0.005, 95% CI -0.85 to -0.24). Combining KL-6 with MMP7 may be a useful screening tool for patients at risk of ILD. SP-D may predict short-term decline in lung function.
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Wipff, J; Kahan, A; Hachulla, E; Sibilia, J; Cabane, J; Meyer, O; Mouthon, L; Guillevin, L; Junien, C; Boileau, C; Allanore, Y
2007-04-01
Systemic sclerosis (SSc) is a connective tissue disorder characterized by early generalized microangiopathy with disturbed angiogenesis. Endoglin gene (ENG) encodes a transmembrane glycoprotein which acts as an accessory receptor for the transforming growth factor-beta (TGF-beta) superfamily, and is crucial for maintaining vascular integrity. A 6-base insertion in intron 7 (6bINS) of ENG has been reported to be associated with microvascular disturbance. Our objective was to investigate the relationship between 6bINS and the vascular complication pulmonary arterial hypertension (PAH) in SSc in a French Caucasian population. Two hundred eighty SSc cases containing 29/280 having PAH diagnosed by catheterism were compared with 140 patients with osteoarthritis. Genotyping was performed by polymerase-chain-reaction-based fluorescence and direct sequencing of genomic DNA. The polymorphism was in Hardy-Weinberg equilibrium. We observed a significant lower frequency of 6bINS allele in SSc patients with associated PAH compared with controls [10.3 vs 23.9%, P = 0.01; odds ratio (OR) 0.37, 95% confidence interval (CI) 0.15-0.89], and a trend in comparison with SSc patients without PAH (10.3 vs 20.3%, P = 0.05; OR: 0.45, 95% CI: 0.19-1.08). Genotypes carrying allele 6bINS were also less frequent in SSc patients with PAH than in controls (20.7 vs 42.9%, P = 0.02). Thus the frequency of 6bINS differs between SSc patients with or without PAH, suggesting the implication of ENG in this devastating vascular complication of SSc.
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Serum osteopontin and vitronectin levels in systemic sclerosis.
Gundogdu, Baris; Yolbas, Servet; Yilmaz, Musa; Aydin, Suleyman; Koca, Sulayman Serdar
2017-11-01
Osteopontin a matricellular protein has pro-fibrotic effects and binds integrin such as αvβ1 and αvβ3. Vitronectin is one of the integrin αvβ3 ligands and is a multifunctional glycoprotein. The aim of the present study was to evaluate serum osteopontin and vitronectin levels in a cohort of patients with systemic sclerosis (SSc). Eighty-six patients with SSc, 46 patients with systemic lupus erythematosus (SLE), and 38 healthy controls (HC) were enrolled in the study. Serum osteopontin, vitronectin, IL-6, and TGF-β levels were analyzed. Serum osteopontin levels were higher in the SSc and SLE groups compared to the HC group (p < 0.01 and p < 0.001, respectively). However, it was not correlated with disease activity and severity scores in the SSc group. On the other hand, serum vitronectin levels were lower in the SSc group than in the SLE and HC groups (p < 0.001 for both). These results may suggest that osteopontin levels may be increased due to the inflammatory process and osteopontin has not a specific role on fibrosis in SSc. On the other hand, serum vitronectin levels decrease in SSc in contrast to SLE. It may be concluded that the one cause of decreased serum vitronectin levels in SSc may be its accumulation in fibrotic area.
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Camiciottoli, G; Diciotti, S; Bartolucci, M; Orlandi, I; Bigazzi, F; Matucci-Cerinic, M; Pistolesi, M; Mascalchi, M
2013-03-01
Spiral low-dose computed tomography (LDCT) permits to measure whole-lung volume and density in a single breath-hold. To evaluate the agreement between static lung volumes measured with LDCT and pulmonary function test (PFT) and the correlation between the LDCT volumes and lung density in restrictive lung disease. Patients with Systemic Sclerosis (SSc) with (n = 24) and without (n = 16) pulmonary involvement on sequential thin-section CT and patients with chronic obstructive pulmonary disease (COPD)(n = 29) underwent spirometrically-gated LDCT at 90% and 10% of vital capacity to measure inspiratory and expiratory lung volumes and mean lung attenuation (MLA). Total lung capacity and residual volume were measured the same day of CT. Inspiratory [95% limits of agreement (95% LoA)--43.8% and 39.2%] and expiratory (95% LoA -45.8% and 37.1%) lung volumes measured on LDCT and PFT showed poor agreement in SSc patients with pulmonary involvement, whereas they were in substantial agreement (inspiratory 95% LoA -14.1% and 16.1%; expiratory 95% LoA -13.5% and 23%) in SSc patients without pulmonary involvement and in inspiratory scans only (95% LoA -23.1% and 20.9%) of COPD patients. Inspiratory and expiratory LDCT volumes, MLA and their deltas differentiated both SSc patients with or without pulmonary involvement from COPD patients. LDCT lung volumes and density were not correlated in SSc patients with pulmonary involvement, whereas they did correlate in SSc without pulmonary involvement and in COPD patients. In restrictive lung disease due to SSc there is poor agreement between static lung volumes measured using LDCT and PFT and the relationship between volume and density values on CT is altered.
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Mahler, Michael; Satoh, Minoru; Hudson, Marie; Baron, Murray; Chan, Jason Y F; Chan, Edward K L; Wick, James; Fritzler, Marvin J
2014-07-01
Antinuclear antibodies (ANA) occur in up to 95% of patients with systemic sclerosis (SSc). In most, SSc-associated antibodies are detected (i.e., centromere, topoisomerase I, RNA polymerase III, PM/Scl, Ro52/TRIM21, and U1RNP). Ribonuclease P protein subunit p25, (Rpp25) is an autoantigenic component of the Th/To complex. The contribution of anti-Th/To and anti-Rpp25 antibodies to ANA positivity in patients with SSc remains unknown. Sera from 873 patients with SSc were tested for ANA, and SSc-associated antibodies were measured. Samples without antibodies to extractable nuclear antigens (ENA; n = 53, ANA+/ENA-), were analyzed by immunoprecipitation (IP) and metabolically labeled proteins and for anti-Rpp25 antibodies (n = 50) by a chemiluminescent immunoassay (CLIA) and Rpp25 ELISA. Anti-Th/To antibodies occurred in 19/53 (36%), as determined by IP, and were the most common autoantibody in ANA+/ENA- SSc. Of those samples, 50/53 were available for additional testing by CLIA and ELISA. Anti-Rpp25 antibodies were detected in 12 (24% CLIA) or 10 (20% ELISA) of 50 patients. Receiver-operating characteristic curve analysis showed similar discrimination between Th/To IP-positive (n = 19) and -negative samples (n = 31) by CLIA and ELISA (area under the curve 0.90 vs 0.87; p = 0.6691). The positive percent agreement between IP and CLIA or ELISA was 12/19 (63.2%, 95% CI 38.4-83.7%) or 10/19 (52.6%, 95% CI 73.3-94.2%), respectively. Negative percent agreement was 100% for both assays. Autoantibodies to the Th/To autoantigen are important in patients with SSc who have been considered negative for SSc-specific or SSc-associated antibodies by widely available commercial assays. Rpp25 can be considered a major target of anti-Th/To antibodies. Assays detecting anti-Th/To and anti-Rpp25 antibodies may be important in SSc.
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Castellví, Ivan; Simeón-Aznar, Carmen Pilar; Sarmiento, Mónica; Fortuna, Ana; Mayos, Mercedes; Geli, Carme; Diaz-Torné, César; Moya, Patricia; De Llobet, Josep Maria; Casademont, Jordi
2015-02-01
To determine whether there is an association between different capillaroscopic findings and pulmonary function tests in systemic sclerosis (SSc). We did a retrospective observational study in a cohort of patients with SSc and early SSc. Patients with at least 1 nailfold videocapillaroscopy (NVC) magnified 120× were included. Pathological findings were giant capillaries, angiogenesis, and density loss. Findings were compared with lung function values: percent expected value of forced vital capacity (FVC), DLCO, and FVC/DLCO ratio. Other variables collected were sex and SSc type, and the presence of digital ulcers (DU), interstitial lung disease (ILD), scleroderma renal crisis, and/or pulmonary hypertension (PH). Of 136 patients with SSc, 85 had undergone an NVC. The frequency of ILD, DU, and PH was 24.1%, 28.7%, and 17.2%, respectively. Data analysis showed that patients with density loss had worse FVC% (86.91 ± 19.42 vs 101.13 ± 16.06, p < 0.01) and DLCO% (71.43 ± 21.19 vs 85.9 ± 19.81, p < 0.01) compared to those without. Patients with loss of density present worse FVC and DLCO values. Prospective studies are warranted to determine whether NVC is useful for studying pulmonary function in SSc.
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Management of Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD)
Silver, Katherine Culp
2015-01-01
Although scleroderma-associated interstitial lung disease (SSc-ILD) is a significant contributor to both morbidity and mortality, its pathogenesis is largely unclear. Pulmonary function tests (PFTs) and high resolution CT (HRCT) scanning continue to be the most effective tools to screen for lung involvement and to monitor for disease progression. More research and better biomarkers are needed to identify patients most at risk for developing SSc-ILD as well as to recognize which of these patients will progress to more severe disease. While immunosuppression remains the mainstay of treatment, anti-fibrotic agents may offer new avenues of treatment for patients with SSc-ILD in the future. PMID:26210128
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Wiese, Alexandra B; Berrocal, Veronica J; Furst, Daniel E; Seibold, James R; Merkel, Peter A; Mayes, Maureen D; Khanna, Dinesh
2014-11-01
Skin and musculoskeletal involvement are frequently present early in diffuse cutaneous systemic sclerosis (dcSSc). The current study examined the correlates for skin and musculoskeletal measures in a 1-year longitudinal observational study. Patients with dcSSc were recruited at 4 US centers and enrolled in a 1-year study. Prespecified and standardized measures included physician and patient assessments of skin involvement, modified Rodnan skin score (MRSS), durometer score, Health Assessment Questionnaire disability index, serum creatine phosphokinase, tender joint counts, and presence/absence of tendon friction rubs, small joint contractures, and large joint contractures. Additionally, physician and patient global health assessments and health-related quality of life assessments were recorded. Correlations were computed among the baseline global assessments, skin variables, and musculoskeletal variables. Using the followup physician and patient anchors, effect sizes were calculated. A total of 200 patients were studied: 75% were women, mean ± SD age was 50.0 ± 11.9 years, and mean ± SD disease duration from first non-Raynaud's phenomenon symptom was 1.6 ± 1.4 years. Physician global health assessment had large correlations with MRSS (r = 0.60) and physician-reported skin involvement visual analog scale in the last month (r = 0.74), whereas patient global assessment had large correlations with MRSS, the Short Form 36 health survey physical component scale, skin interference, and skin involvement in the last month (r = 0.37-0.72). Four of 9 skin variables had moderate to large effect sizes (0.51-1.09). Physician and patient global assessments have larger correlations with skin measures compared to musculoskeletal measures. From a clinical trial perspective, skin variables were more responsive to change than musculoskeletal variables over a 1-year period, although both provide complementary information. Copyright © 2014 by the American College of Rheumatology.
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Wiese, Alexandra B.; Berrocal, Veronica J.; Furst, Daniel E.; Seibold, James R.; Merkel, Peter A.; Mayes, Maureen D.; Khanna, Dinesh
2015-01-01
Objective Skin and musculoskeletal involvement are frequently present early in diffuse cutaneous systemic sclerosis (dcSSc). The current study examined the correlates for skin and musculoskeletal measures in a 1-year longitudinal observational study. Methods Patients with dcSSc were recruited at 4 US centers and enrolled in a 1-year study. Prespecified and standardized measures included physician and patient assessments of skin involvement, modified Rodnan skin score (MRSS), durometer score, Health Assessment Questionnaire disability index, serum creatine phosphokinase, tender joint counts, and presence/absence of tendon friction rubs, small joint contractures, and large joint contractures. Additionally, physician and patient global health assessments and health-related quality of life assessments were recorded. Correlations were computed among the baseline global assessments, skin variables, and musculoskeletal variables. Using the followup physician and patient anchors, effect sizes were calculated. Results A total of 200 patients were studied: 75% were women, mean ± SD age was 50.0 ± 11.9 years, and mean ± SD disease duration from first non–Raynaud’s phenomenon symptom was 1.6 ± 1.4 years. Physician global health assessment had large correlations with MRSS (r = 0.60) and physician-reported skin involvement visual analog scale in the last month (r = 0.74), whereas patient global assessment had large correlations with MRSS, the Short Form 36 health survey physical component scale, skin interference, and skin involvement in the last month (r = 0.37–0.72). Four of 9 skin variables had moderate to large effect sizes (0.51–1.09). Conclusion Physician and patient global assessments have larger correlations with skin measures compared to musculoskeletal measures. From a clinical trial perspective, skin variables were more responsive to change than musculoskeletal variables over a 1-year period, although both provide complementary information. PMID:24692361
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Unique Abnormalities in Right Ventricular Longitudinal Strain in Systemic Sclerosis Patients.
Mukherjee, Monica; Chung, Shang-En; Ton, Von Khue; Tedford, Ryan J; Hummers, Laura K; Wigley, Fredrick M; Abraham, Theodore P; Shah, Ami A
2016-06-01
Cardiac involvement in systemic sclerosis (scleroderma [SSc]) adversely affects long-term prognosis, often remaining undetectable despite close clinical examination and 2-dimensional echocardiographic monitoring. Speckle-derived strain of the right ventricle (RV) was utilized to detect occult abnormalities in regional and global contractility in SSc patients. A total of 138 SSc patients with technically adequate echocardiograms was studied and compared with 40 age- and sex-matched healthy non-SSc controls. Standard assessment of RV chamber function included tricuspid annular plane systolic excursion and fractional area change. RV longitudinal systolic speckle-derived strain was assessed in the basal, mid, and apical free wall. Tricuspid annular plane systolic excursion was not different between groups (P=0.307). Although fractional area change was lower in SSc patients than in controls (mean, 48.9 versus 55; P=0.002), the mean fractional area change was still within the normal range (>35). In contrast, RV longitudinal systolic speckle-derived strain measures were significantly different between groups, both globally (-20.4% versus -17.7%; P=0.005) and regionally: they were decreased in the apex (-8.5% versus -17.1%; P<0.0001) and mid segments (-12.4% versus -20.9%; P<0.0001), and increased in the base (-32.2% versus -23.3%; P=0.0001) for the SSc group. The regional difference in the base compared with the apex was significantly greater for SSc than for controls (P<0.0001 for interaction). The differences observed in regional strain between SSc and control were unchanged after adjusting for RV systolic pressure. Speckle-derived strain reveals a heterogenous pattern of regional heart strain in SSc that is not detected by conventional measures of function, suggestive of occult RV myocardial disease. © 2016 American Heart Association, Inc.
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Neuropathic pain in Systemic Sclerosis patients: A cross-sectional study.
Sousa-Neves, Joana; Cerqueira, Marcos; Santos-Faria, Daniela; Afonso, Carmo; Teixeira, Filipa
2018-01-31
To investigate if patients with Systemic Sclerosis (SSc) show a higher prevalence of neuropathic pain (NP) in comparison with controls. To study the relationship between clinical variables of the disease and NP among SSc patients. 48 patients and 45 controls were included. Presence of NP was assessed applying the DN4 "Douleur Neuropathique en 4 Questions" questionnaire. Different clinical variables were also assessed in patients. Statistical analysis included parametric, nonparametric tests and multivariate logistic regression. NP was significantly higher in SSc patients (56.2% vs 13.3%, p<0.001). Mean Modified Rodnan Skin Score was independently associated with the presence of NP (p<0.05, OR 1.90). Peripheral nervous system involvement in SSc is not well studied and, as far as the authors are aware, this is the first study published evaluating NP in SSc patients and controls. These findings should raise the awareness of the clinician to recognize and address the presence of NP in these patients, especially in those with severe skin involvement. Copyright © 2018 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.
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2011-01-01
Introduction Systemic sclerosis (SSc) is characterized by fibrosis and microvascular abnormalities including dysregulated angiogenesis. Chemokines, in addition to their chemoattractant properties, have the ability to modulate angiogenesis. Chemokines lacking the enzyme-linked receptor (ELR) motif, such as monokine induced by interferon-γ (IFN-γ) (MIG/CXCL9) and IFN-inducible protein 10 (IP-10/CXCL10), inhibit angiogenesis by binding CXCR3. In addition, CXCL16 promotes angiogenesis by binding its unique receptor CXCR6. In this study, we determined the expression of these chemokines and receptors in SSc skin and serum. Methods Immunohistology and enzyme-linked immunosorbent assays (ELISAs) were used to determine chemokine and chemokine receptor expression in the skin and serum, respectively, of SSc and normal patients. Endothelial cells (ECs) were isolated from SSc skin biopsies and chemokine and chemokine receptor expression was determined by quantitative PCR and immunofluorescence staining. Results Antiangiogenic IP-10/CXCL10 and MIG/CXCL9 were elevated in SSc serum and highly expressed in SSc skin. However, CXCR3, the receptor for these chemokines, was decreased on ECs in SSc vs. normal skin. CXCL16 was elevated in SSc serum and increased in SSc patients with early disease, pulmonary arterial hypertension, and those that died during the 36 months of the study. In addition, its receptor CXCR6 was overexpressed on ECs in SSc skin. At the mRNA and protein levels, CXCR3 was decreased while CXCR6 was increased on SSc ECs vs. human microvascular endothelial cells (HMVECs). Conclusions These results show that while the expression of MIG/CXCL9 and IP-10/CXCL10 are elevated in SSc serum, the expression of CXCR3 is downregulated on SSc dermal ECs. In contrast, CXCL16 and CXCR6 are elevated in SSc serum and on SSc dermal ECs, respectively. In all, these findings suggest angiogenic chemokine receptor expression is likely regulated in an effort to promote angiogenesis in SSc skin. PMID:21303517
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Solvent oriented hobbies and the risk of systemic sclerosis.
Nietert, P J; Sutherland, S E; Silver, R M; Pandey, J P; Dosemeci, M
1999-11-01
To examine whether those participating in solvent oriented hobbies (SOH) are at greater risk of developing systemic sclerosis (SSc), and if the association is modified by the presence of the anti-Scl70 antibody. Patients with SSc and controls were recruited from a university hospital rheumatology clinic. Recreational hobby and occupational histories were obtained along with blood samples. Cumulative scores were created for participation in SOH. Logistic regression was used to calculate odds ratios associated with SOH exposure after adjustment for sex, age at diagnosis, and occupational solvent exposure, and to examine the association between SOH exposure and the presence of anti-Scl70. Solvent exposure based on hobbies and occupations was determined for 178 cases (141 women, 37 men) and 200 controls (138 women, 62 men). Overall participation in SOH was not associated with SSc. However, odds of high cumulative SOH exposure was 3 times greater in those patients with SSc testing positive for the anti-Scl70 antibody compared to patients testing negative (OR 2.9, 95% CI 1.1, 7.9), and twice as great as controls (OR 2.5, 95% CI 1.1, 5.9). While patients with SSc did not participate more often in SOH than controls over all, odds of high cumulative SOH exposure was greater among patients with SSc testing positive for anti-Scl70 compared to those testing negative and compared to controls. These results provide further evidence that environmental agents may play a role in the development of Ssc.
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Marí-Alfonso, Begoña; Amengual-Guedan, María José; Vergara-Gómez, Mercè; Simeón-Aznar, Carmen Pilar; Fonollosa-Plà, Vicente; Jove-Buxeda, Esther; Oliva-Morera, Juan; Tolosa-Vilella, Carles
2016-01-01
Primary biliary cirrhosis (PBC) is associated to any systemic autoimmune disease (SAD), in particular systemic sclerosis (SSc). To investigate the prevalence of SAD in a cohort of patients with PBC, specifically the prevalence of SSc and its clinical subtypes, and determining the clinical and biological profile of patients with associated PBC and SSc. Observational study of 62 patients with PBC following a protocol that included an anamnesis and physical examination to detect the presence of SAD as well as a nailfold capillaroscopy and an immunological study with specific SSc autoantibodies. A comparative analysis was conducted between patients with isolated PBC and patients with PBC and an associated SAD. SAD was associated to PBC in 22 patients (35,4%), and SSc was the most frequent illness, identified in 13 cases (21%). Five patients (8%) without previous diagnosis of SAD fulfilled pre-scleroderma criteria, according to LeRoy and Medsger criteria. The presence of anticentromere antibodies (54,5% vs. 5%, P<.001) was the unique immunological determination identified more frequently in patients with PBC-SAD. The SSc suggestive capillary pattern was visualized in 11 patients (20,4%), mainly the slow pattern. No factors associated with greater morbi-mortality were identified in the PBC-SAD group. It does exist a subgroup of patients with PBC and clinical-biological features suggestive of an SAD, which advise a protocolized study to detect early the association to an SAD. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.
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Sun, Huanxing; Zhu, Yangyang; Pan, Hongyi; Chen, Xiaosong; Balestrini, Jenna L; Lam, TuKiet T; Kanyo, Jean E; Eichmann, Anne; Gulati, Mridu; Fares, Wassim H; Bai, Hanwen; Feghali-Bostwick, Carol A; Gan, Ye; Peng, Xueyan; Moore, Meagan W; White, Eric S; Sava, Parid; Gonzalez, Anjelica L; Cheng, Yuwei; Niklason, Laura E; Herzog, Erica L
2016-05-01
Fibrocytes are collagen-producing leukocytes that accumulate in patients with systemic sclerosis (SSc; scleroderma)-related interstitial lung disease (ILD) via unknown mechanisms that have been associated with altered expression of neuroimmune proteins. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in SSc has not been explored. The aim of this study was to use a novel translational platform based on decellularized human lungs to determine whether the lung ECM of patients with scleroderma controls the development of fibrocytes from peripheral blood mononuclear cells. We performed biomechanical evaluation of decellularized scaffolds prepared from lung explants from healthy control subjects and patients with scleroderma, using tensile testing and biochemical and proteomic analysis. Cells obtained from healthy controls and patients with SSc-related ILD were cultured on these scaffolds, and CD45+pro-ColIα1+ cells meeting the criteria for fibrocytes were quantified. The contribution of the neuromolecule netrin-1 to fibrosis was assessed using neutralizing antibodies in this system and by administering bleomycin via inhalation to netrin-1(+/-) mice. Compared with control lung scaffolds, lung scaffolds from patients with SSc-related ILD showed aberrant anatomy, enhanced stiffness, and abnormal ECM composition. Culture of control cells in lung scaffolds from patients with SSc-related ILD increased production of pro-ColIα1+ cells, which was stimulated by enhanced stiffness and abnormal ECM composition. Cells from patients with SSc-related ILD demonstrated increased pro-ColIα1 responsiveness to lung scaffolds from scleroderma patients but not enhanced stiffness. Enhanced detection of netrin-1-expressing CD14(low) cells in patients with SSc-related ILD was observed, and antibody-mediated netrin-1 neutralization attenuated detection of CD45+pro-ColIα1+ cells in all settings. Netrin-1(+/-) mice were protected against bleomycin-induced lung fibrosis and fibrocyte accumulation. Factors present in the lung matrices of patients with scleroderma regulate fibrocyte accumulation via a netrin-1-dependent pathway. Netrin-1 regulates bleomycin-induced pulmonary fibrosis in mice. Netrin-1 might be a novel therapeutic target in SSc-related ILD. © 2016, American College of Rheumatology.
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Irritable bowel syndrome and organic diseases: A comparative analysis of esophageal motility
Thomaidis, Thomas; Goetz, Martin; Gregor, Sebastian Paul; Hoffman, Arthur; Kouroumalis, Elias; Moehler, Markus; Galle, Peter Robert; Schwarting, Andreas; Kiesslich, Ralf
2013-01-01
AIM: To assess the esophageal motility in patients with irritable bowel syndrome (IBS) and to compare those with patients with autoimmune disorders. METHODS: 15 patients with IBS, 22 with systemic lupus erythematosus (SLE) and 19 with systemic sclerosis (SSc) were prospectively selected from a total of 115 patients at a single university centre and esophageal motility was analysed using standard manometry (Mui Scientific PIP-4-8SS). All patients underwent esophago-gastro-duodenoscopy before entering the study so that only patients with normal endoscopic findings were included in the current study. All patients underwent a complete physical, blood biochemistry and urinary examination. The grade of dysphagia was determined for each patient in accordance to the intensity and frequency of the presented esophageal symptoms. Furthermore, disease activity scores (SLEDAI and modified Rodnan score) were obtained for patients with autoimmune diseases. Outcome parameter: A correlation coefficient was calculated between amplitudes, velocity and duration of the peristaltic waves throughout esophagus and patients’ dysphagia for all three groups. RESULTS: There was no statistical difference in the standard blood biochemistry and urinary analysis in all three groups. Patients with IBS showed similar pathologic dysphagia scores compared to patients with SLE and SSc. The mean value of dysphagia score was in IBS group 7.3, in SLE group 6.73 and in SSc group 7.56 with a P-value > 0.05. However, the manometric patterns were different. IBS patients showed during esophageal manometry peristaltic amplitudes at the proximal part of esophagus greater than 60 mmHg in 46% of the patients, which was significant higher in comparison to the SLE (11.8%) and SSc-Group (0%, P = 0.003). Furthermore, IBS patients showed lower mean resting pressure of the distal esophagus sphincter (Lower esophageal sphincter, 22 mmHg) when compared with SLE (28 mmHg, P = 0.037) and SSc (26 mmHg, P = 0.052). 23.5% of patients with SLE showed amplitudes greater as 160 mmHg in the distal esophagus (IBS and SSc: 0%) whereas 29.4% amplitudes greater as 100 mmHg in the middle one (IBS: 16.7%, SSc: 5.9% respectively, P = 0.006). Patients with SSc demonstrated, as expected, in almost half of the cases reduced peristalsis or even aperistalsis in the lower two thirds of the esophagus. SSc patients demonstrated a negative correlation coefficient between dysphagia score, amplitude and velocity of peristaltic activity at middle and lower esophagus [r = -0.6, P < 0.05]. CONCLUSION: IBS patients have comparable dysphagia-scores as patients with autoimmune disorders. The different manometric patterns might allow differentiating esophageal symptoms based on IBS from other organic diseases. PMID:24151359
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Reese, Charles; Perry, Beth; Heywood, Jonathan; Bonner, Michael; Visconti, Richard P; Lee, Rebecca; Hatfield, Corey M; Silver, Richard M; Hoffman, Stanley; Tourkina, Elena
2014-07-01
Interstitial lung disease (ILD) is the leading cause of death in patients with systemic sclerosis (SSc; scleroderma). Although SSc-related ILD is more common and severe in African Americans than in Caucasians, little is known about factors underlying this significant health disparity. The aim of this study was to examine the role that low expression of caveolin-1 might play in susceptibility to ILD among African Americans. Assays of monocyte migration toward stromal cell-derived factor 1 (SDF-1) were performed using monocytes from Caucasian and African American healthy donors and patients with SSc. For fibrocyte differentiation studies, total peripheral blood mononuclear cells were incubated on fibronectin-coated plates. Protein expression was evaluated by immunohistochemistry and Western blotting. Monocytes from healthy African American donors and those from patients with SSc had low caveolin-1 levels, enhanced migration toward the CXCR4 ligand SDF-1, and enhanced differentiation to fibrocytes. Enhanced migration and differentiation of monocytes from African Americans and patients with SSc appeared to be attributable to the lack of caveolin-1, because restoring caveolin-1 function using a caveolin-1 scaffolding domain peptide inhibited these processes. Although they differed from monocytes from Caucasians, monocytes from both African Americans and patients with SSc were not identical, because SSc monocytes showed major increases from baseline in ERK, JNK, p38, and Smad2/3 activation, while monocytes from African Americans showed only limited ERK activation and no activation of JNK, p38, or Smad2/3. In contrast, SDF-1 exposure caused no additional ERK activation in SSc monocytes but did cause significant additional activation in monocytes from African Americans. African Americans may be predisposed to SSc-related ILD due to low baseline caveolin-1 levels in their monocytes, potentially affecting signaling, migration, and fibrocyte differentiation. The monocytes of African Americans may lack caveolin-1 due to high levels of transforming growth factor β in their blood. Copyright © 2014 by the American College of Rheumatology.
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Reese, Charles; Perry, Beth; Heywood, Jonathan; Bonner, Michael; Visconti, Richard P.; Lee, Rebecca; Hatfield, Corey M.; Silver, Richard M.; Hoffman, Stanley; Tourkina, Elena
2014-01-01
Objective Interstitial lung disease (ILD) is the leading cause of death in patients with systemic sclerosis (SSc; scleroderma). Although SSc-related ILD is more common and severe in African Americans than in Caucasians, little is known about factors underlying this significant health disparity. The aim of this study was to examine the role that low expression of caveolin-1 might play in susceptibility to ILD among African Americans. Methods Assays of monocyte migration toward stromal cell–derived factor 1 (SDF-1) were performed using monocytes from Caucasian and African American healthy donors and patients with SSc. For fibrocyte differentiation studies, total peripheral blood mono-nuclear cells were incubated on fibronectin-coated plates. Protein expression was evaluated by immuno-histochemistry and Western blotting. Results Monocytes from healthy African American donors and those from patients with SSc had low caveolin-1 levels, enhanced migration toward the CXCR4 ligand SDF-1, and enhanced differentiation to fibrocytes. Enhanced migration and differentiation of monocytes from African Americans and patients with SSc appeared to be attributable to the lack of caveolin-1, because restoring caveolin-1 function using a caveolin-1 scaffolding domain peptide inhibited these processes. Although they differed from monocytes from Caucasians, monocytes from both African Americans and patients with SSc were not identical, because SSc monocytes showed major increases from baseline in ERK, JNK, p38, and Smad2/3 activation, while monocytes from African Americans showed only limited ERK activation and no activation of JNK, p38, or Smad2/3. In contrast, SDF-1 exposure caused no additional ERK activation in SSc monocytes but did cause significant additional activation in monocytes from African Americans. Conclusion African Americans may be predisposed to SSc-related ILD due to low baseline caveolin-1 levels in their monocytes, potentially affecting signaling, migration, and fibrocyte differentiation. The monocytes of African Americans may lack caveolin-1 due to high levels of transforming growth factor β in their blood. PMID:24578173
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Gitelis, Matthew E; Kaczynski, Adelaide; Shear, Torin; Deshur, Mark; Beig, Mohammad; Sefa, Meredith; Silverstein, Jonathan; Ujiki, Michael
2017-07-01
In 2009, NorthShore University HealthSystem adapted the World Health Organization Surgical Safety Checklist (SSC) at each of its 4 hospitals. Despite evidence that SSC reduces intraoperative mistakes and increase patient safety, compliance was found to be low with the paper form. In November 2013, NorthShore integrated the SSC into the electronic health record (EHR). The aim was to increase communication between operating room (OR) personnel and to encourage best practices during the natural workflow of surgeons, anesthesiologists, and nurses. The purpose of this study was to examine the impact of an electronic SSC on compliance and patient safety. An anonymous OR observer selected cases at random and evaluated the compliance rate before the rollout of the electronic SSC. In June 2014, an electronic audit was performed to assess the compliance rate. Random OR observations were also performed throughout the summer in 2014. Perioperative risk events, such as consent issues, incorrect counts, wrong site, and wrong procedure were compared before and after the electronic SSC rollout. A perception survey was also administered to NorthShore OR personnel. Compliance increased from 48% (n = 167) to 92% (n = 1,037; P < .001) after the SSC was integrated into the electronic health record. Surgeons (91% vs 97%; P < .001), anesthesiologists (89% vs 100%; P < .001), and nurses (55% vs 93%; P < .001) demonstrated an increase in compliance. A comparison between risk events in the pre- and post-rollout period showed a 32% decrease (P < .01). Hospital-wide indicators including length of stay and 30-day readmissions were lower. In a survey to assess the OR personnel's perceptions of the new checklist, 76% of surgeons, 86% of anesthesiologists, and 88% of nurses believed the electronic SSC will have a positive impact on patient safety. The World Health Organization SSC is a validated tool to increase patient safety and reduce intraoperative complications. The electronic SSC has demonstrated an increased compliance rate, a reduced number of risk events, and most OR personnel believe it will have a positive impact on patient safety. Copyright © 2016 Elsevier Inc. All rights reserved.
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Parra, Edwin Roger; Lin, Flavia; Martins, Vanessa; Rangel, Maristela Peres; Capelozzi, Vera Luiza
2013-01-01
OBJECTIVE: To study the expression of COX-1 and COX-2 in the remodeled lung in systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF) patients, correlating that expression with patient survival. METHODS: We examined open lung biopsy specimens from 24 SSc patients and 30 IPF patients, using normal lung tissue as a control. The histological patterns included fibrotic nonspecific interstitial pneumonia (NSIP) in SSc patients and usual interstitial pneumonia (UIP) in IPF patients. We used immunohistochemistry and histomorphometry to evaluate the expression of COX-1 and COX-2 in alveolar septa, vessels, and bronchioles. We then correlated that expression with pulmonary function test results and evaluated its impact on patient survival. RESULTS: The expression of COX-1 and COX-2 in alveolar septa was significantly higher in IPF-UIP and SSc-NSIP lung tissue than in the control tissue. No difference was found between IPF-UIP and SSc-NSIP tissue regarding COX-1 and COX-2 expression. Multivariate analysis based on the Cox regression model showed that the factors associated with a low risk of death were younger age, high DLCO/alveolar volume, IPF, and high COX-1 expression in alveolar septa, whereas those associated with a high risk of death were advanced age, low DLCO/alveolar volume, SSc (with NSIP), and low COX-1 expression in alveolar septa. CONCLUSIONS: Our findings suggest that strategies aimed at preventing low COX-1 synthesis will have a greater impact on SSc, whereas those aimed at preventing high COX-2 synthesis will have a greater impact on IPF. However, prospective randomized clinical trials are needed in order to confirm that. PMID:24473763
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A system out of breath: how hypoxia possibly contributes to the pathogenesis of systemic sclerosis.
van Hal, T W; van Bon, L; Radstake, T R D J
2011-01-01
Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular alterations and immunological disturbances and fibrosis, the order of which remains to be fully determined. Clinically, patients show clear signs of hypoxia in skin and internal organs. The low oxygen tension is potentially caused by a yet to be indentified circuitry involving the three features that typify SSc. In addition, once present, the hypoxia creates a vicious circle of ongoing pathology. In this paper, we provide an overview of the evidence that points towards the mechanisms causing hypoxia in SSc. In addition, data that suggest how hypoxia itself may orchestrate worsening of symptoms is presented. Altogether, it is clear that hypoxia is an important hallmark in SSc patients. By providing an overview of the mechanisms at play and the possible therapeutic avenues that have emerged, we hope to stimulate researchers to provide novel clues into the conundrum in SSc patients.
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Kabasakal, Y; Elvins, D M; Ring, E F; McHugh, N J
1996-01-01
OBJECTIVE: To describe and quantify the morphological characteristics of nailfold capillaries that distinguish different forms of connective tissue disease from healthy controls. METHODS: A CCD video microscope with fibreoptic illumination and PC based image processing was used to visualise nailfold capillaries and to quantify findings in 23 patients with systemic sclerosis (SSc), 22 patients with systemic lupus erythematosus (SLE), 21 patients with undifferentiated connective tissue disease (UCTD), and 38 healthy controls. RESULTS: Capillary density was reduced in SSc (5.2 (SD 1.3) capillaries/mm) compared with other patient groups and controls. The average number of enlarged capillaries/finger was high in all disease groups (5.5-6.6) compared with controls (2). However, giant capillaries were most frequent in SSc (43%) and were not present in controls. Mild and moderate avascular areas were present in all groups (35%-68%), but severe avascularity was most frequent in SSc (44%) compared with other patients (18%-19%) and controls (0%). The greatest frequency of extensive haemorrhage was in SSc (35%). CONCLUSIONS: There is a range of abnormal capillary findings in patients with connective tissue disease and healthy controls. However, certain abnormalities such as a reduced number of capillaries, severe avascularity, giant capillaries, and haemorrhage are most commonly associated with SSc. Videomicroscopy with image processing offers many technical advantages that can be exploited in further studies of nailfold capillaries. Images PMID:8774177
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Ingegnoli, Francesca; Boracchi, Patrizia; Gualtierotti, Roberta; Smith, Vanessa; Cutolo, Maurizio; Foeldvari, Ivan
2015-11-01
Qualitative capillaroscopy patterns in juvenile- and adult-onset systemic sclerosis (SSc) were studied in adulthood using data from the EULAR Scleroderma Trials and Research (EUSTAR) database. Data collected between June 2004 and April 2013 were examined with focus on capillaroscopy. In this retrospective exploratory study, series of patients with juvenile-onset SSc were matched with series of adult-onset SSc having the same gender and autoantibody profile. 30 of 123 patients with juvenile-onset and 2108 of 7133 with adult-onset SSc had data on capillaroscopy. Juvenile-onset SSc showed scleroderma pattern more frequently than adult-onset SSc (93.3% and 88%). The OR was 2.44 and 95% CI 0.57-10.41. An active scleroderma pattern was present in 58% of juvenile- and 61% of adult-onset SSc. The OR was 0.91 and 95% CI 0.28-2.93. The late scleroderma pattern was present in 61% of juvenile- and 55.5% of adult-onset SSc. The OR was 1.06 and 95% CI 0.34-3.56. This is the first exploratory study on the comparison of capillaroscopy between juvenile- and adult-onset SSc in adulthood. Juvenile-onset SSc had an increase prevalence of scleroderma pattern, but a similar distribution of the three patterns was suggested. Further studies are needed to define this issue. Copyright © 2015 Elsevier Inc. All rights reserved.
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Herrick, Ariane L; Peytrignet, Sebastien; Lunt, Mark; Pan, Xiaoyan; Hesselstrand, Roger; Mouthon, Luc; Silman, Alan J; Dinsdale, Graham; Brown, Edith; Czirják, László; Distler, Jörg H W; Distler, Oliver; Fligelstone, Kim; Gregory, William J; Ochiel, Rachel; Vonk, Madelon C; Ancuţa, Codrina; Ong, Voon H; Farge, Dominique; Hudson, Marie; Matucci-Cerinic, Marco; Balbir-Gurman, Alexandra; Midtvedt, Øyvind; Jobanputra, Paresh; Jordan, Alison C; Stevens, Wendy; Moinzadeh, Pia; Hall, Frances C; Agard, Christian; Anderson, Marina E; Diot, Elisabeth; Madhok, Rajan; Akil, Mohammed; Buch, Maya H; Chung, Lorinda; Damjanov, Nemanja S; Gunawardena, Harsha; Lanyon, Peter; Ahmad, Yasmeen; Chakravarty, Kuntal; Jacobsen, Søren; MacGregor, Alexander J; McHugh, Neil; Müller-Ladner, Ulf; Riemekasten, Gabriela; Becker, Michael; Roddy, Janet; Carreira, Patricia E; Fauchais, Anne Laure; Hachulla, Eric; Hamilton, Jennifer; İnanç, Murat; McLaren, John S; van Laar, Jacob M; Pathare, Sanjay; Proudman, Susanna M; Rudin, Anna; Sahhar, Joanne; Coppere, Brigitte; Serratrice, Christine; Sheeran, Tom; Veale, Douglas J; Grange, Claire; Trad, Georges-Selim; Denton, Christopher P
2018-01-01
Objectives Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). Methods The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. ‘Progressors’ were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). Results 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. Conclusions Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. Trial registration number NCT02339441. PMID:29306872
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Arif, Tasleem; Masood, Qazi; Singh, Jaswinder; Hassan, Iffat
2015-02-15
Systemic sclerosis (SSc) is a generalized disorder of unknown etiology affecting the connective tissue of the body. It affects the skin and various internal organs. Gastrointestinal tract involvement is seen in almost 90% of the patients. Esophagus is the most frequently affected part of the gastrointestinal tract. Esophageal motility disturbance classically manifests as a reduced lower esophageal sphincter pressure (LESP) and loss of distal esophageal body peristalsis. Consequently, SSc patients may be complicated by erosive esophagitis and eventually by Barrett's esophagus and esophageal adenocarcinoma. Morphea, also known as localized scleroderma, is characterized by predominant skin involvement, with occasional involvement of subjacent muscles and usually sparing the internal organs. The involvement of esophagus in morphea has been studied very scarcely. The proposed study will investigate the esophageal involvement in the two forms of scleroderma (systemic and localized), compare the same and address any need of upper gastrointestinal evaluation in morphea (localized scleroderma) patients. 56 and 31 newly and already diagnosed cases of SSc and morphea respectively were taken up for the study. All the patients were inquired about the dyspeptic symptoms (heartburn and/or acid regurgitation and/or dysphagia). Upper gastrointestinal endoscopy, esophageal manometry and 24-hour pH monitoring were done in 52, 47 and 41 patients of SSc; and 28, 25 and 20 patients of morphea respectively. Esophageal symptoms were present in 39 cases (69.6%) of SSc which were mild in 22 (39.3%), moderate in 14 (25%), severe in three (5.3%); while only four cases (7.1%) of morphea had esophageal symptoms all of which were mild in severity. Reflux esophagitis was seen in 17 cases (32.7%) of SSc and only two cases (7.14%) of morphea. Manometric abnormalities were seen in 32 cases (68.1%) of SSc and none in morphea. Ambulatory 24-hour esophageal pH monitoring documented abnormal reflux in 33 cases (80.5%) of SSc and no such abnormality in morphea. While the esophageal involvement is frequent in SSc, no such motility disorder is seen in morphea. Meticulous upper gastrointestinal tract evaluation is justified only in SSc and not in morphea.
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Influence of the IL6 gene in susceptibility to systemic sclerosis.
Cénit, Maria Carmen; Simeón, Carmen P; Vonk, Madelon C; Callejas-Rubio, Jose L; Espinosa, Gerard; Carreira, Patricia; Blanco, Francisco J; Narvaez, Javier; Tolosa, Carlos; Román-Ivorra, José A; Gómez-García, Inmaculada; García-Hernández, Francisco J; Gallego, María; García-Portales, Rosa; Egurbide, María Victoria; Fonollosa, Vicente; García de la Peña, Paloma; López-Longo, Francisco J; González-Gay, Miguel A; Hesselstrand, Roger; Riemekasten, Gabriela; Witte, Torsten; Voskuyl, Alexandre E; Schuerwegh, Annemie J; Madhok, Rajan; Fonseca, Carmen; Denton, Christopher; Nordin, Annika; Palm, Øyvind; van Laar, Jacob M; Hunzelmann, Nicolas; Distler, Jörg H W; Kreuter, Alexander; Herrick, Ariane; Worthington, Jane; Koeleman, Bobby P; Radstake, Timothy R D J; Martín, Javier
2012-12-01
Systemic sclerosis (SSc) is a genetically complex autoimmune disease; the genetic component has not been fully defined. Interleukin 6 (IL-6) plays a crucial role in immunity and fibrosis, both key aspects of SSc. We investigated the influence of IL6 gene in the susceptibility and phenotype expression of SSc. We performed a large metaanalysis including a total of 2749 cases and 3189 controls from 6 white populations (Germany, The Netherlands, Norway, Spain, Sweden, and United Kingdom). Three IL6 single-nucleotide polymorphisms (SNP; rs2069827, rs1800795, and rs2069840) were selected by SNP tagging and genotyped using TaqMan(®) allele discrimination technology. Individual SNP metaanalysis showed no evidence of association of the 3 IL6 genetic variants with the global disease. Phenotype analyses revealed a significant association between the minor allele of rs2069840 and the limited cutaneous SSc clinical form (Bonferroni p = 0.036, OR 1.14, 95% CI 1.04-1.25). A trend of association between the minor allele of the rs1800795 and the diffuse cutaneous SSc clinical form was also evident (Bonferroni p = 0.072, OR 0.86, 95% CI 0.77-0.96). In the IL6 allelic combination analyses, the GGC allelic combination rs2069827-rs1800795-rs2069840 showed an association with overall SSc (Bonferroni p = 0.016, OR 1.13, 95% CI 1.04-1.23). Our results suggest that the IL6 gene may influence the development of SSc and its progression.
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Qing, Zhao-shen; Ji, Bao-ping; Shi, Bo-lin; Zhu, Da-zhou; Tu, Zhen-hua; Zude, Manuela
2008-06-01
In the present study, improved laser-induced light backscattering imaging was studied regarding its potential for analyzing apple SSC and fruit flesh firmness. Images of the diffuse reflection of light on the fruit surface were obtained from Fuji apples using laser diodes emitting at five wavelength bands (680, 780, 880, 940 and 980 nm). Image processing algorithms were tested to correct for dissimilar equator and shape of fruit, and partial least squares (PLS) regression analysis was applied to calibrate on the fruit quality parameter. In comparison to the calibration based on corrected frequency with the models built by raw data, the former improved r from 0. 78 to 0.80 and from 0.87 to 0.89 for predicting SSC and firmness, respectively. Comparing models based on mean value of intensities with results obtained by frequency of intensities, the latter gave higher performance for predicting Fuji SSC and firmness. Comparing calibration for predicting SSC based on the corrected frequency of intensities and the results obtained from raw data set, the former improved root mean of standard error of prediction (RMSEP) from 1.28 degrees to 0.84 degrees Brix. On the other hand, in comparison to models for analyzing flesh firmness built by means of corrected frequency of intensities with the calibrations based on raw data, the former gave the improvement in RMSEP from 8.23 to 6.17 N x cm(-2).
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Advances in the Evaluation and Management of Esophageal Disease of Systemic Sclerosis
Carlson, Dustin A.; Hinchcliff, Monique; Pandolfino, John E.
2015-01-01
Symptoms of heartburn and dysphagia, as well as objective findings of abnormal esophageal acid exposure and esophageal dysmotility are common in patients with systemic sclerosis (SSc). Treatments for SSc esophageal disease are generally limited to gastroesophageal reflux disease (GERD) treatment with proton pump inhibitors. Progresses made in esophageal diagnostic testing offer the potential for improved clinical characterization of esophageal disease in SSc that may help direct management decisions. In addition to reviewing GERD management in patients with SSc, present and potential uses of endoscopy, reflux monitoring, manometry, impedance planimetry, and endoscopic ultrasound are discussed. PMID:25475597
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Hinchcliff, Monique; Huang, Chiang-Ching; Wood, Tammara A.; Mahoney, J. Matthew; Martyanov, Viktor; Bhattacharyya, Swati; Tamaki, Zenshiro; Lee, Jungwha; Carns, Mary; Podlusky, Sofia; Sirajuddin, Arlene; Shah, Sanjiv J; Chang, Rowland W.; Lafyatis, Robert; Varga, John; Whitfield, Michael L.
2013-01-01
Heterogeneity in systemic sclerosis/SSc confounds clinical trials. We previously identified ‘intrinsic’ gene expression subsets by analysis of SSc skin. Here we test the hypotheses that skin gene expression signatures including intrinsic subset are associated with skin score/MRSS improvement during mycophenolate mofetil (MMF) treatment. Gene expression and intrinsic subset assignment were measured in 12 SSc patients’ biopsies and ten controls at baseline, and from serial biopsies of one cyclophosphamide-treated patient, and nine MMF-treated patients. Gene expression changes during treatment were determined using paired t-tests corrected for multiple hypothesis testing. MRSS improved in four of seven MMF-treated patients classified as the inflammatory intrinsic subset. Three patients without MRSS improvement were classified as normal-like or fibroproliferative intrinsic subsets. 321 genes (FDR <5%) were differentially expressed at baseline between patients with and without MRSS improvement during treatment. Expression of 571 genes (FDR <10%) changed between pre- and post-MMF treatment biopsies for patients demonstrating MRSS improvement. Gene expression changes in skin are only seen in patients with MRSS improvement. Baseline gene expression in skin, including intrinsic subset assignment, may identify SSc patients whose MRSS will improve during MMF treatment, suggesting that gene expression in skin may allow targeted treatment in SSc. PMID:23677167
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Phenotypic Alterations Involved in CD8+ Treg Impairment in Systemic Sclerosis
Negrini, Simone; Fenoglio, Daniela; Parodi, Alessia; Kalli, Francesca; Battaglia, Florinda; Nasi, Giorgia; Curto, Monica; Tardito, Samuele; Ferrera, Francesca; Filaci, Gilberto
2017-01-01
Systemic sclerosis (SSc) is a connective tissue disease characterized by tissue fibrosis, vasculopathy, and autoimmunity. Although the exact pathogenetic mechanisms behind SSc remain to be fully elucidated, a great deal of evidence suggests the existence of an unbalanced ratio between the effector and regulatory arms of the immune system. With regard to the T regulatory (Treg) compartment, we observed that CD8+ Treg subsets display functional defects in SSc-affected patients. Since CD127 down-modulation and CD39 upregulation have been observed on Treg subsets, the phenotypic expression of these molecules was analyzed on the CD8+CD28− Treg precursors and on CD8+ Treg cells generated in vitro through interleukin-10 commitment. Immunophenotypic data from SSc patients were compared to those obtained from healthy subjects. The analyses performed on ex vivo-isolated CD8+CD28− Treg precursors did not show any significant differences in CD39 or CD127 expression as compared to values obtained from healthy donors. On the contrary, in vitro-generated CD8+ Tregs obtained from SSc patients displayed reduced expression of the CD39 molecule as compared to controls. Moreover, the percentage of CD127+ cells was significantly higher in in vitro-generated CD8+ Tregs from SSc patients compared to CD8+ Tregs obtained from healthy donors. Taken together, these findings may indicate an impairment of maturation processes affecting CD8+ Treg cells in SSc patients. This impairment of maturation involves phenotypic alterations that are mainly characterized by a deficient CD39 upregulation and a lack of down-modulation of the CD127 molecule. PMID:28154567
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Experiencing work as a daily challenge: the case of scleroderma.
Mendelson, Cindy; Poole, Janet L; Allaire, Saralynn
2013-01-01
Little is known about the physical and discretionary aspects of work that people with scleroderma (SSc) find difficult. This article describes the findings from a study that explored the challenges and adaptations made by individuals with SSc to continue to work. Thirty-two employed individuals with SSc participated. Participants were predominantly women (82%), white (79%), and well educated (M = 16.9 years). The average age was 47.3 years, and 60.6% were married. Mean disease duration was 9.7 years, and 56.2% had diffuse SSc. Mean years on the job was 10.2 (SD ± 8.8), and 71.9% worked at least 35 hours per week. Participants engaged in a single structured interview about work-related challenges and adaptations. Content and thematic analysis was used to identify key themes across the interviews. Employees with SSc experienced Work as a daily challenge. This central theme described the general work experience for most participants. Three subthemes described their specific experiences: The work environment: Opportunities, challenges, and accommodations; Career planning; and Supportive others. The participants were anxious to find scenarios that allowed them to continue to work. Worksite accommodations and flexibility in scheduling can make the difference between working and disability.
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Meunier, Pauline; Dequidt, Laure; Barnetche, Thomas; Lazaro, Estibaliz; Duffau, Pierre; Richez, Christophe; Couzi, Lionel; Truchetet, Marie-Elise; Seneschal, Julien
2018-06-10
Survival can be threatened in certain forms of systemic sclerosis (SSc) so clear prognostic factors are needed. The aim of this meta-analysis was to assess the association between the presence of digital ulcers (DUs) and mortality in SSc. We performed a systematic review and meta-analysis in the Pubmed and Scopus databases from the earliest records to May 2017. Two research strategies were performed: « systemic sclerosis » and « digital ulcers » (strategy A); « systemic sclerosis » and « mortality » (strategy B). The primary outcome was the mortality associated with the presence of DUs in patients with SSc. The literature search identified 1473 citations. Fifty-nine studies were examined for full text. Ten articles were included for the meta-analysis. SSc patients with DUs had an increased pooled mortality risk: RR = 1.53 (IC 95%: [1.23-1.90]). This meta-analysis revealed a higher mortality in SSc patients with associated DUs. Having DUs may be a predictive factor of developing organ involvement such as pulmonary or cardiovascular events that could be associated with poor survival. It suggests that early screening of DUs in SSc patients is important to identify patients most at risk of poor survival. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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Lambova, Sevdalina; Hermann, W; Muller-Ladner, Ulf
2013-01-01
In the nailfold area, specific diagnostic microvascular abnormalities are easily recognized via capillaroscopic examination in systemic sclerosis (SSc). They are termed "scleroderma" type capillaroscopic pattern, which includes presence of dilated, giant capillaries, haemorrhages, avascular areas, and neoangiogenic capillaries and are observed in the majority of SSc patients (in more than 90%). LeRoy and Medsger (2001) proposed criteria for early diagnosis of SSc with inclusion of the abnormal capillaroscopic changes and suggested to prediagnose SSc prior to the development of other manifestations of the disease. It is a new era in the diagnosis of SSc. At present, an international multicenter project is performed. It aims validation of criteria for very early diagnosis of SSc (project VEDOSS (Very Early Diagnosis of Systemic Sclerosis) and is organized by European League Against Rheumatism (EULAR) Scleroderma Trials and Reasearch. Very recently the first results of the VEDOSS project were processed and new EULAR/ACR (American College of Rheumatology) classification criteria have been validated and published (2013), in which the characteristic capillaroscopic changes have been included. Our observations confirm the high frequency of the specific capillaroscopic changes of the fingers in SSc, which have been found in 97.2% of the cases from the studied patient population. We have performed for the first time capillaroscopic examinations of the toes in SSc. Interestingly,"scleroderma type" capillaroscopic pattern was also found at the toes in a high proportion of patients - 66.7%, but it is significantly less frequent as compared with fingers (97.2%, p<0.05). In our opinion, the examination of the toes of SSc patients should be considered as it suggests an additional opportunity for evaluation of the microvascular changes in these patients although the observed changes are in a lower proportion of cases. Thus, capillaroscopic examination is a cornerstone for the very early diagnosis of SSc. Patients with clinical symptoms of peripheral vasospasm (Raynaud's phenomenon (RP)) in association with puffy fingers and/or sclerodactyly should be carefully examined. Hence, appearance of "scleroderma" type capillaroscopic changes in RP patients should be interpreted in the clinical context, because some of the components of this pattern may be observed in several other connective tissue diseases such as mixed connective tissue disease, undifferentiated connective tissue disease that are termed "scleroderma-like" capillaroscopic changes. Capillaroscopic examination is an obligatory screening method in these cases, but the pathologic capillaroscopic changes are not specific and their interpretation is in clinical context.
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Pulmonary function tests as outcomes for systemic sclerosis interstitial lung disease.
Caron, Melissa; Hoa, Sabrina; Hudson, Marie; Schwartzman, Kevin; Steele, Russell
2018-06-30
Interstitial lung disease (ILD) is the leading cause of morbidity and mortality in systemic sclerosis (SSc). We performed a systematic review to characterise the use and validation of pulmonary function tests (PFTs) as surrogate markers for systemic sclerosis-associated interstitial lung disease (SSc-ILD) progression.Five electronic databases were searched to identify all relevant studies. Included studies either used at least one PFT measure as a longitudinal outcome for SSc-ILD progression ( i.e. outcome studies) and/or reported at least one classical measure of validity for the PFTs in SSc-ILD ( i.e. validation studies).This systematic review included 169 outcome studies and 50 validation studies. Diffusing capacity of the lung for carbon monoxide ( D LCO ) was cumulatively the most commonly used outcome until 2010 when it was surpassed by forced vital capacity (FVC). FVC (% predicted) was the primary endpoint in 70.4% of studies, compared to 11.3% for % predicted D LCO Only five studies specifically aimed to validate the PFTs: two concluded that D LCO was the best measure of SSc-ILD extent, while the others did not favour any PFT. These studies also showed respectable validity measures for total lung capacity (TLC).Despite the current preference for FVC, available evidence suggests that D LCO and TLC should not yet be discounted as potential surrogate markers for SSc-ILD progression. Copyright ©ERS 2018.
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Reasons for Not Participating in Scleroderma Patient Support Groups: A Cross-Sectional Study.
Gumuchian, Stephanie T; Delisle, Vanessa C; Peláez, Sandra; Malcarne, Vanessa L; El-Baalbaki, Ghassan; Kwakkenbos, Linda; Jewett, Lisa R; Carrier, Marie-Eve; Pépin, Mia; Thombs, Brett D
2018-02-01
Peer-led support groups are an important resource for many people with scleroderma (systemic sclerosis; SSc). Little is known, however, about barriers to participation. The objective of this study was to identify reasons why some people with SSc do not participate in SSc support groups. A 21-item survey was used to assess reasons for nonattendance among SSc patients in Canada and the US. Exploratory factor analysis (EFA) was conducted, using the software MPlus 7, to group reasons for nonattendance into themes. A total of 242 people (202 women) with SSc completed the survey. EFA results indicated that a 3-factor model best described the data (χ 2 [150] = 302.7; P < 0.001; Comparative Fit Index = 0.91, Tucker-Lewis Index = 0.88, root mean square error of approximation = 0.07, factor intercorrelations 0.02-0.43). The 3 identified themes, reflecting reasons for not attending SSc support groups were personal reasons (9 items; e.g., already having enough support), practical reasons (7 items; e.g., no local support groups available), and beliefs about support groups (5 items; e.g., support groups are too negative). On average, respondents rated 4.9 items as important or very important reasons for nonattendance. The 2 items most commonly rated as important or very important were 1) already having enough support from family, friends, or others, and 2) not knowing of any SSc support groups offered in my area. SSc organizations may be able to address limitations in accessibility and concerns about SSc support groups by implementing online support groups, better informing patients about support group activities, and training support group facilitators. © 2017, American College of Rheumatology.
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Mahoney, J. Matthew; Taroni, Jaclyn; Martyanov, Viktor; Wood, Tammara A.; Greene, Casey S.; Pioli, Patricia A.; Hinchcliff, Monique E.; Whitfield, Michael L.
2015-01-01
Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by skin and organ fibrosis. The pathogenesis of SSc and its progression are poorly understood. The SSc intrinsic gene expression subsets (inflammatory, fibroproliferative, normal-like, and limited) are observed in multiple clinical cohorts of patients with SSc. Analysis of longitudinal skin biopsies suggests that a patient's subset assignment is stable over 6–12 months. Genetically, SSc is multi-factorial with many genetic risk loci for SSc generally and for specific clinical manifestations. Here we identify the genes consistently associated with the intrinsic subsets across three independent cohorts, show the relationship between these genes using a gene-gene interaction network, and place the genetic risk loci in the context of the intrinsic subsets. To identify gene expression modules common to three independent datasets from three different clinical centers, we developed a consensus clustering procedure based on mutual information of partitions, an information theory concept, and performed a meta-analysis of these genome-wide gene expression datasets. We created a gene-gene interaction network of the conserved molecular features across the intrinsic subsets and analyzed their connections with SSc-associated genetic polymorphisms. The network is composed of distinct, but interconnected, components related to interferon activation, M2 macrophages, adaptive immunity, extracellular matrix remodeling, and cell proliferation. The network shows extensive connections between the inflammatory- and fibroproliferative-specific genes. The network also shows connections between these subset-specific genes and 30 SSc-associated polymorphic genes including STAT4, BLK, IRF7, NOTCH4, PLAUR, CSK, IRAK1, and several human leukocyte antigen (HLA) genes. Our analyses suggest that the gene expression changes underlying the SSc subsets may be long-lived, but mechanistically interconnected and related to a patients underlying genetic risk. PMID:25569146
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Kimmel, Jessica N.; Carlson, Dustin A.; Hinchcliff, Monique; Carns, Mary A.; Aren, Kathleen A; Lee, Jungwha; Pandolfino, John E.
2016-01-01
Background/Aims We aimed to evaluate the associations between SSc-related systemic manifestations and esophageal function using high-resolution manometry (HRM). Methods Patients with SSc that had undergone HRM between 1/2004 and 9/2014 were identified and HRMs were analyzed according to the Chicago Classification. Clinical characteristics were identified via retrospective chart review and compared among motility diagnoses while adjusting for age, gender, race, and SSc-disease duration. Results 79 patients (85% female, ages 25–77) were included. Clinical characteristics were compared between patients with absent contractility (AC, n = 40), ineffective esophageal motility (IEM; n = 15), and normal motility (n = 19); the 5 remaining patients met criteria for other motility diagnoses. Groups differed in severity of skin involvement measured by the modified Rodnan skin score (0–51): AC (adjusted mean 12.6), IEM (4.4), normal (4.3), p = 0.043. Pulmonary function tests [percent predicted FVC and DLCO) were lower in AC (adjusted mean, FVC: 70.3, DLCO 51.1), than IEM (FVC: 92.0; DLCO: 76.9) and normal motility (FVC: 80.0; DLCO: 67.2), p-values 0.057 (FVC) and 0.007 (DLCO). Groups did not differ by SSc-disease duration, autoantibodies, or reported symptoms of dysphagia or reflux. Conclusions In patients with SSc, absent esophageal contractility on HRM was associated with increased skin disease severity and worse lung function. Obtaining HRM to identify SSc patients with more severe esophageal dysfunction could be considered to enable implementation of management strategies in patients potentially at risk for increased morbidity and mortality. PMID:26921101
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Merkel, PA; Silliman, NP; Clements, PJ; Denton, CP; Furst, DE; Mayes, MD; Pope, JE; Polisson, RP; Streisand, JB; Seibold, JR
2012-01-01
Purpose To examine the range and responsiveness to change of clinical outcome measures and study the predictors of clinical response for patients with diffuse cutaneous systemic sclerosis (dcSSc) in the context of clinical trials. Methods Data from 629 patients with dcSSc who participated in 7 multicenter clinical therapeutic trials were combined. Trials used common outcome measures: modified Rodnan skin score (MRSS), the Health Assessment Questionnaire (HAQ), Patient Global Assessment (PtGA), pulmonary function tests (FVC, DLCO), and oral aperture (OAp). Results The combined database included 629 patients: 82% women; mean age = 46.5 ± 11.8 years (range 15–82) with disease duration (months): mean: 19.4 ± 15.9, median = 47.0, range 1.0–144.0. Outcomes tended to improve during trials for patients with more severe disease at study entry and worsen for patients with less severe disease at entry. There were weak negative correlations between baseline values and change over 6 months for MRSS (r = −0.17; p<.0001), HAQ (r = −0.15; p= .002), and PtGA (r = −0.44; p<.0001). Baseline FVC and OAp did not predict change in 6 months. Baseline DLCO values were positively correlated with change in DLCO at 6 months (r= −0.32; p<.0001). Disease duration was mildly negatively predictive of change in MRSS at 6 months (r = −0.27; p<.0001) and substantial bidirectional variation in change in MRSS and HAQ was seen over the spectrum of disease duration. 63% of patients with “early” disease (<18 months) had a decline in MRSS and 37% had an increase in MRSS. 81% of patients with late disease (≥ 18 months) had a decline in MRSS and 19% had an increase in MRSS. 53% of patients with early disease had a decline in HAQ and 47% had an increase in HAQ. 51% of patients with late disease had a decline in HAQ and 49% had an increase in HAQ. Multivariate mixed models did not demonstrate that any baseline variables were strongly predictive of subsequent outcome. These results did not differ when comparing trials of early vs. late disease or trial “completers” vs. “non-completers”. Conclusions Among patients with dcSSc enrolled in clinical trials, standard outcome measures tend to improve for patients with more severe disease at study entry and worsen for patients with less severe disease at entry. Overall, MRSS scores improve during observation periods while HAQ and lung function are mostly static, although there are wide variations in individual changes in these measures. None of these variables, including disease duration, reliably identify groups of subjects whose MRSS will predictably increase or decrease in the course of a clinical trial. These findings have important implications for clinical trial design in scleroderma. PMID:22328195
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Gentil, Coline A; Gammill, Hilary S; Luu, Christine T; Mayes, Maureen D; Furst, Dan E; Nelson, J Lee
2017-03-07
Specific HLA class II alleles are associated with systemic sclerosis (SSc) risk, clinical characteristics, and autoantibodies. HLA nomenclature initially developed with antibodies as typing reagents defining DRB1 allele groups. However, alleles from different DRB1 allele groups encode the same third hypervariable region (3rd HVR) sequence, the primary T-cell recognition site, and 3rd HVR charge differences can affect interactions with T cells. We considered 3rd HVR sequences (amino acids 67-74) irrespective of the allele group and analyzed parental inheritance considered according to the 3rd HVR charge, comparing SSc patients with controls. In total, 306 families (121 SSc and 185 controls) were HLA genotyped and parental HLA-haplotype origin was determined. Analysis was conducted according to DRβ1 3rd HVR sequence, charge, and parental inheritance. The distribution of 3rd HVR sequences differed in SSc patients versus controls (p = 0.007), primarily due to an increase of specific DRB1*11 alleles, in accord with previous observations. The 3rd HVR sequences were next analyzed according to charge and parental inheritance. Paternal transmission of DRB1 alleles encoding a +2 charge 3rd HVR was significantly reduced in SSc patients compared with maternal transmission (p = 0.0003, corrected for analysis of four charge categories p = 0.001). To a lesser extent, paternal transmission was increased when charge was 0 (p = 0.021, corrected for multiple comparisons p = 0.084). In contrast, paternal versus maternal inheritance was similar in controls. SSc patients differed from controls when DRB1 alleles were categorized according to 3rd HVR sequences. Skewed parental inheritance was observed in SSc patients but not in controls when the DRβ1 3rd HVR was considered according to charge. These observations suggest that epigenetic modulation of HLA merits investigation in SSc.
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Schiopu, Elena; Au, Karen M; McMahon, Maureen A; Kaplan, Mariana J; Divekar, Anagha; Singh, Ram R; Furst, Daniel E; Clements, Philip J; Ragvendra, Nagesh; Zhao, Wenpu; Maranian, Paul; Khanna, Dinesh
2014-04-01
SSc is associated with an increased prevalence of atherosclerosis (ATS). This study assessed the prevalence of subclinical ATS as measured by carotid US and explored serum proteins to identify potential biomarkers of SSc-ATS. Forty-six SSc female patients and 46 age- and ethnicity-matched controls underwent carotid US to assess the presence of plaque and carotid intima media thickness (CIMT). Abstracted data included demographics, ATS risk factors and serum measurements [cholesterol, proinflammatory high-density lipoprotein (piHDL), CRP, lipoproteins]. Serum cytokines/proteins analyses included circulating type I IFN activity by quantifying IFN-inducible genes, soluble junctional adhesion molecule A (sJAM-A) and 100 serum proteins by using a microplate-based multiplex platform. Proteins significant at P < 0.05 on bivariate analyses for the presence of plaque were used to develop a composite measure. Patients with SSc had more plaque (45.6% vs 19.5%, P = 0.01) but similar CIMT compared with controls. Multiplex analysis detected significant associations between serum proteins of inflammation, vasculopathy and fibrosis with ATS in SSc, including IL-2, IL-6, CRP, keratinocyte growth factor, intercellular adhesion molecule 1, endoglin, plasminogen activator inhibitor 1 and insulin-like growth factor binding protein 3 associated with carotid plaque. Myeloid progenitor inhibitory factor 1, serum amyloid A, thrombomodulin, N-terminal pro-brain natriuretic peptide (BNP), and Clara cell secretory protein 16 kD correlated with CIMT. The median composite score for the plaque group was 6 and for the no plaque group it was 2 (P < 0.0001). Patients with SSc have a higher prevalence of carotid plaque than matched controls, and patients with SSc-plaque vs patients without plaque have elevated serum proteins implicated in both vasculopathy and fibrosis. Further studies are needed to evaluate the role of these proteins in SSc compared with healthy controls.
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Strange, Adam P; Aguayo, Sebastian; Ahmed, Tarek; Mordan, Nicola; Stratton, Richard; Porter, Stephen R; Parekh, Susan; Bozec, Laurent
2017-01-01
Scleroderma (or systemic sclerosis, SSc) is a disease caused by excess crosslinking of collagen. The skin stiffens and becomes painful, while internally, organ function can be compromised by the less elastic collagen. Diagnosis of SSc is often only possible in advanced cases by which treatment time is limited. A more detailed analysis of SSc may provide better future treatment options and information of disease progression. Recently, the histological stain picrosirius red showing collagen register has been combined with atomic force microscopy (AFM) to study SSc. Skin from healthy individuals and SSc patients was biopsied, stained and studied using AFM. By investigating the crosslinking of collagen at a smaller hierarchical stage, the effects of SSc were more pronounced. Changes in morphology and Young’s elastic modulus were observed and quantified; giving rise to a novel technique, we have termed “quantitative nanohistology”. An increase in nanoscale stiffness in the collagen for SSc compared with healthy individuals was seen by a significant increase in the Young’s modulus profile for the collagen. These markers of stiffer collagen in SSc are similar to the symptoms experienced by patients, giving additional hope that in the future, nanohistology using AFM can be readily applied as a clinical tool, providing detailed information of the state of collagen. PMID:28138238
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Anti-fibrotic characteristics of Vγ9+ γδ T cells in systemic sclerosis.
Markovits, Noa; Bendersky, Anna; Loebstein, Ronen; Brusel, Marina; Kessler, Efrat; Bank, Ilan
2016-01-01
γδ T cells of the Vγ9Vδ2 subtype secrete anti-fibrotic cytokines upon isopentenyl pyrophosphate (IPP) stimulation. In this study, we sought to compare IPP and Zoledronate, an up-regulator of IPP, effects on proliferation and cytokine secretion of Vγ9+ T cells from systemic sclerosis (SSc) patients and healthy controls (HCs). We also examined the effect of IPP-triggered peripheral blood mononuclear cells (PBMC) on fibroblast procolla- gen secretion. PBMC from SSc patients and HCs were stimulated by increasing concentrations of Zoledronate, with or without IPP, and Vγ9+ T cell percentages were calculated using FACScan analysis. Subsequently, PBMC were cultured with IPP or toxic shock syndrome toxin-1 (TSST-1), and contents of the anti-fibrotic cytokines tumour necrosis factor (TNF)-α and interferon (IFN)-γ were measured by ELISA kits. Finally, supernatants of IPP-triggered Vγ9+ T cells from SSc patients were added to fibroblast cultures, and relative intensities of procollagen α1 chains were determined by densinometry. Higher concentrations of Zoledronate were required for maximal proliferation of Vγ9+ T cells in 9 SSc patients compared to 9 HCs, irrespective of exogenous IPP. When compared to stimulation by TSST-1, a non-Vγ9+ selective reagent, secretion of the anti-fibrotic cytokines TNF-α and IFN-γ in response to IPP was relatively diminished in SSc but not in HCs. Reduction of procollagen secretion by fibroblasts cultured with supernatants of IPP-stimulated PBMC was observed only in some SSc patients. Activated Vγ9+ T cells could act as anti-fibrotic mediators in SSc, although decreased responsiveness to IPP may play a role in the pathological fibrosis of this disease.
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Murphy, Susan L; Barber, Mary; Homer, Kristen; Dodge, Carole; Cutter, Gary; Khanna, Dinesh
2018-01-30
To determine feasibility and preliminary effects of an occupational therapy treatment to improve upper extremity (UE) function in patients with early systemic sclerosis (SSc) who have UE contractures. A one-arm pilot clinical rehabilitation trial was conducted at a university health system. Participants with SSc and ≥ 1 UE contracture (n = 21) participated in a total of 8 weekly in-person occupational therapy sessions. The therapy consisted of thermal modalities, tissue mobilization, and UE mobility. Between sessions, participants were instructed to complete UE home exercises. Feasibility was measured by percent enrollment and session attendance and duration. The primary outcome measure was the QuickDASH, secondary and exploratory outcomes included PROMIS physical function, objective UE measures, and skin thickening. Linear mixed models were performed to determine treatment effects on primary and secondary outcomes. Fifty percent (24/48) of potentially eligible participants were interested. Of those, 88% (21/24) enrolled; and nineteen out of 21 (91%) completed all sessions. The mean (SD) age was 47.9 years (± 16.1); 100% had diffuse SSc, and mean disease duration was 3.1 years. At 8 weeks, participants reported statistically significant improvement on QuickDASH and PROMIS physical function measures (p =.0012 and p = .004). Forty-seven and 53% percent of the sample achieved improvements that exceeded minimally important differences. In-person treatment sessions were feasible for individuals with SSc and demonstrated statistically significant and clinically meaningful improvements on UE and physical function. Future studies need to examine effects against a control condition and examine durability of treatment effects. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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Lambova, Sevdalina; Müller-Ladner, Ulf
2011-11-01
The aim of the study was to evaluate capillaroscopic pattern in systemic sclerosis (SSc) patients and its association with disease duration as well as with presence of digital ulcers. Thirty six patients with SSc were included in the study. The severity of Raynaud's phenomenon (RP) at the hands was assessed with VAS (100mm), and the presence of digital ulcers at the hands was documented. Nailfold capillaroscopy was performed by a videocapillaroscope. RP was found as a clinical symptom in 100% (36/36) of the examined SSc patients. In SSc patients with a duration of the disease of less than 3 years, an early phase "scleroderma type" capillaroscopic pattern was found in 50% (5/10) of the cases. In the group of SSc patients with a duration of the disease of more than 3 years, late phase scleroderma type capillaroscopic pattern was found in 26.9% (7/26) of the cases, which was characterized by the presence of extensive, "desert-like" avascular areas and neoangiogenic capillaries. Scleroderma type capillaroscopic pattern was found in 97.2% (35/36) of the cases. Digital ulcers at the hands were found in 36.1% (13/36) of the patients. In 100% of those patients with digital ulcers (13/13), an active type scleroderma like pattern was observed, which is characterized by the presence of frequent giant capillaries, hemorrhages, and avascular areas. An active type scleroderma like pattern was found in 47.2% (17/36) of the patients without digital ulcers. The data show that the presence of digital ulcers at the hands of SSc patients is strongly associated with an active type scleroderma like capillaroscopic pattern. Observation of an active type scleroderma like pattern in patients without digital ulcers may therefore be used as a predictor for the development of trophic changes in the future, an indication for vasoactive medication for the prevention of the development of digital ulcers, and as an additional objective method for the evaluation of disease activity score in SSc.
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Scleroderma and the temporomandibular joint: reconstruction in 2 variants.
MacIntosh, Robert Bruce; Shivapuja, Prasanna-Kumar; Naqvi, Rabia
2015-06-01
This article reviews the pathophysiology of scleroderma (systemic sclerosis [SSc]) and its destructive effects on the mandible in general and the temporomandibular joint (TMJ) in particular. It discusses the considerations of operating on patients with devastating chronic disease and presents 2 cases of TMJ reconstruction in patients with the diagnosis. Two patients with different degrees of SSc involvement underwent TMJ reconstruction with costochondral grafts. The patients represent the surgical considerations pertinent to this disease and different outcomes as determined by the variance in severity of their afflictions. The 2 patients tolerated the surgeries well and exhibited improvement in function in the long-term. One patient thrives and continues to do well despite her SSc approximately 10 years postoperatively; the second patient died of her disease approximately 9 years after her initial surgical care. The experience with these 2 cases showed that patients with SSc can safely undergo TMJ reconstruction with anticipated good results, but that the overall severity of the disease remains paramount in determining the feasibility of corrective surgery under this diagnosis. Copyright © 2015 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.
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Systemic Sclerosis-Associated Pulmonary Arterial Hypertension
Chaisson, Neal F.
2013-01-01
Pulmonary arterial hypertension (PAH) is the leading cause of death in systemic sclerosis (SSc) and affects up to 12% of all patients with SSc, with a 50% mortality rate within 3 years of PAH diagnosis. Compared with the idiopathic form of PAH (IPAH), patients with SSc-associated PAH (SSc-PAH) have a threefold increased risk of death and may receive a diagnosis late in the course of disease because of insidious onset and the high prevalence of cardiac, musculoskeletal, and pulmonary parenchymal comorbidities. Treatment with conventional forms of PAH therapy often yield poor results compared with IPAH cohorts; unfortunately, the exact reasons behind this remain poorly understood but likely include variations in the pathologic mechanisms, differences in cardiovascular response to increasing afterload, and inadequate strategies to detect and treat SSc-PAH early in its course. Current methods for screening and longitudinal evaluation of SSc-PAH, such as the 6-min walk test, transthoracic echocardiography, and MRI, each have notable advantages and disadvantages. We provide an up-to-date, focused review of SSc-PAH and how it differs from IPAH, including pathogenesis, appropriate screening for disease onset, and new approaches to treatment and longitudinal assessment of this disease. PMID:24081346
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Overbeek, Maria J; Boonstra, Anco; Voskuyl, Alexandre E; Vonk, Madelon C; Vonk-Noordegraaf, Anton; van Berkel, Maria P A; Mooi, Wolter J; Dijkmans, Ben A C; Hondema, Laurens S; Smit, Egbert F; Grünberg, Katrien
2011-04-14
Systemic sclerosis (SSc) complicated by pulmonary arterial hypertension (PAH) carries a poor prognosis, despite pulmonary vascular dilating therapy. Platelet-derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR) are potential therapeutic targets for PAH because of their proliferative effects on vessel remodelling. To explore their role in SScPAH, we compared PDGFR- and EGFR-mmunoreactivity in lung tissue specimens from SScPAH. We compared staining patterns with idiopathic PAH (IPAH) and pulmonary veno-occlusive disease (PVOD), as SScPAH vasculopathy differs from IPAH and sometimes displays features of PVOD. Immunoreactivity patterns of phosphorylated PDGFR-β (pPDGFR-β) and the ligand PDGF-B were evaluated to provide more insight into the patterns of PDGFR-b activation. Lung tissue specimens from five SScPAH, nine IPAH, six PVOD patients and five controls were examined. Immunoreactivity was scored for presence, distribution and intensity. All SScPAH and three of nine IPAH cases (P = 0.03) showed PDGFR-β-immunoreactivity in small vessels (arterioles/venules); of five SScPAH vs. two of nine IPAH cases (P = 0.02) showed venous immunoreactivity. In small vessels, intensity was stronger in SScPAH vs. IPAH. No differences were found between SScPAH and PVOD. One of five normal controls demonstrated focally mild immunoreactivity. There were no differences in PDGF-ligand and pPDGFR-b-immunoreactivity between patient groups; however, pPDGFR-b-immunoreactivity tended to be more prevalent in SScPAH small vasculature compared to IPAH. Vascular EGFR-immunoreactivity was limited to arterial and arteriolar walls, without differences between groups. No immunoreactivity was observed in vasculature of normals. PDGFR-β-immunoreactivity in SScPAH is more common and intense in small- and post-capillary vessels than in IPAH and does not differ from PVOD, fitting in with histomorphological distribution of vasculopathy. PDGFR-β immunoreactivity pattern is not paralleled by pPDGFR-β or PDGF-B patterns. PDGFR-β- and EGFR-immunoreactivity of pulmonary vessels distinguishes PAH patients from controls.
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Decuman, Saskia; Smith, Vanessa; Grypdonck, Maria; De Keyser, Filip; Verhaeghe, Sofie
2015-01-01
To describe, from the patient's point of view, the factors influencing the occupational trajectory of patients with systemic sclerosis (SSc). This was a qualitative study designed using grounded theory with constant comparison. Data were collected through semi-structured interviews with 14 patients who fulfilled the American College of Rheumatology or Leroy-Medsger criteria for SSc. Based on our interviews, we found that the occupational trajectory of patients with SSc is influenced by the continuous interplay between four groups of factors. The first group concerns the values patients attribute to work, including identity, normality, financial value, social contact, and structure. The meaning of these values and how they relate to each other underlies the desire to work. A second group of factors is those influencing the balance between daily life, work participation, and medical condition (e.g. job content, flexibility in organising work, and the willingness to ask for accommodations at work). The occupational trajectory is also influenced by external factors, including availability of support, know-ledge of the disease, pressure to work, contact with medical professionals, and existing regulations and the patient's knowledge about them. Finally, the occupational trajectory is influenced by personal factors, including socio-demographics, psychological assets, and disease- and work-related personal factors. The decisions patients with SSc take concerning work depend on an interplay between many factors and, especially, on the patients' personal interpretation of these factors. These need to be taken into account when helping patients with SSc determine their occupational trajectory.
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Preston, Ioana R.; Roberts, Kari E.; Miller, Dave P.; Sen, Ginny P.; Selej, Mona; Benton, Wade W.; Hill, Nicholas S.
2015-01-01
Background— Long-term anticoagulation is recommended in idiopathic pulmonary arterial hypertension (IPAH). In contrast, limited data support anticoagulation in pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc-PAH). We assessed the effect of warfarin anticoagulation on survival in IPAH and SSc-PAH patients enrolled in Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a longitudinal registry of group I PAH. Methods and Results— Patients who initiated warfarin on study (n=187) were matched 1:1 with patients never on warfarin, by enrollment site, etiology, and diagnosis status. Descriptive analyses were conducted to compare warfarin users and nonusers by etiology. Survival analyses with and without risk adjustment were performed from the time of warfarin initiation or a corresponding quarterly update in matched pairs to avoid immortal time bias. Time-varying covariate models were used as sensitivity analyses. Mean warfarin treatment was 1 year; mean international normalized ratios were 1.9 (IPAH) and 2.0 (SSc-PAH). Two-thirds of patients initiating warfarin discontinued treatment before the last study assessment. There was no survival difference with warfarin in IPAH patients (adjusted hazard ratio, 1.37; P=0.21) or in SSc-PAH patients (adjusted hazard ratio, 1.60; P=0.15) in comparison with matched controls. However, SSc-PAH patients receiving warfarin within the previous year (hazard ratio, 1.57; P=0.031) or any time postbaseline (hazard ratio, 1.49; P=0.046) had increased mortality in comparison with warfarin-naïve patients. Conclusions— No significant survival advantage was observed in IPAH patients who started warfarin. In SSc-PAH patients, long-term warfarin was associated with poorer survival than in patients not receiving warfarin, even after adjusting for confounders. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00370214. PMID:26510696
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Dental implants in patients with oral mucosal diseases - a systematic review.
Reichart, P A; Schmidt-Westhausen, A M; Khongkhunthian, P; Strietzel, F P
2016-05-01
To reveal dental implants survival rates in patients with oral mucosal diseases: oral lichen planus (OLP), Sjögren's syndrome (SjS), epidermolysis bullosa (EB) and systemic sclerosis (SSc). A systematic literature search using PubMed/Medline and Embase databases, utilising MeSH and search term combinations identified publications on clinical use implant-prosthetic rehabilitation in patients with OLP, SjS, EB, SSc reporting on study design, number, gender and age of patients, follow-up period exceeding 12 months, implant survival rate, published in English between 1980 and May 2015. After a mean observation period (mOP) of 53·9 months (standard deviation [SD] ±18·3), 191 implants in 57 patients with OLP showed a survival rate (SR) of 95·3% (SD ±21·2). For 17 patients with SjS (121 implants, mOP 48·6 ± 28·7 months), 28 patients with EB (165 implants, mOP 38·3 ± 16·9 months) and five patients with SSc (38 implants, mOP 38·3 ± 16·9 months), the respective SR was 91·7 ± 5·97% (SjS), 98·5 ± 2·7% (EB) and 97·4 ± 4·8% (SSc). Heterogeneity of data structure and quality of reporting outcomes did not allow for further comparative data analysis. For implant-prosthetic rehabilitation of patients suffering from OLP, SjS, EB and SSc, no evidence-based treatment guidelines are presently available. However, no strict contraindication for the placement of implants seems to be justified in patients with OLP, SjS, EB nor SSc. Implant survival rates are comparable to those of patients without oral mucosal diseases. Treatment guidelines as for dental implantation in patients with healthy oral mucosa should be followed. © 2015 John Wiley & Sons Ltd.
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Preston, Ioana R; Roberts, Kari E; Miller, Dave P; Sen, Ginny P; Selej, Mona; Benton, Wade W; Hill, Nicholas S; Farber, Harrison W
2015-12-22
Long-term anticoagulation is recommended in idiopathic pulmonary arterial hypertension (IPAH). In contrast, limited data support anticoagulation in pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc-PAH). We assessed the effect of warfarin anticoagulation on survival in IPAH and SSc-PAH patients enrolled in Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a longitudinal registry of group I PAH. Patients who initiated warfarin on study (n=187) were matched 1:1 with patients never on warfarin, by enrollment site, etiology, and diagnosis status. Descriptive analyses were conducted to compare warfarin users and nonusers by etiology. Survival analyses with and without risk adjustment were performed from the time of warfarin initiation or a corresponding quarterly update in matched pairs to avoid immortal time bias. Time-varying covariate models were used as sensitivity analyses. Mean warfarin treatment was 1 year; mean international normalized ratios were 1.9 (IPAH) and 2.0 (SSc-PAH). Two-thirds of patients initiating warfarin discontinued treatment before the last study assessment. There was no survival difference with warfarin in IPAH patients (adjusted hazard ratio, 1.37; P=0.21) or in SSc-PAH patients (adjusted hazard ratio, 1.60; P=0.15) in comparison with matched controls. However, SSc-PAH patients receiving warfarin within the previous year (hazard ratio, 1.57; P=0.031) or any time postbaseline (hazard ratio, 1.49; P=0.046) had increased mortality in comparison with warfarin-naïve patients. No significant survival advantage was observed in IPAH patients who started warfarin. In SSc-PAH patients, long-term warfarin was associated with poorer survival than in patients not receiving warfarin, even after adjusting for confounders. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00370214. © 2015 The Authors.
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Pharmacotherapy of Systemic Sclerosis
Postlethwaite, Arnold E.; Harris, L. Jeff; Raza, Syed H.; Kodura, Swapna; Akhigbe, Titilola
2010-01-01
Importance of the field Systemic-sclerosis (SSc) is an uncommon autoimmune disease with variable degrees of fibroproliferation in blood vessels and certain organs of the body. Presently, there is no cure for SSc. The purpose of this article is to review the current literature regarding pathogenesis and treatment of complications of SSc. Areas covered in this review All available articles regarding research related to SSc pathogenesis and treatment listed in the PubMed.gov database were searched, relevant articles were then reviewed and used as sources of information for this review. What the reader will gain This review attempts for the reader to highlight some current thought regarding mechanisms of SSc pathogenesis and how autoimmunity relates to vascular changes and fibrogenesis of the disease plus provide a review of results of completed clinical trials and current on-going clinical trials that address organ specific or global therapies for this disease which can aid physicians who provide medical care for patients with SSc. Take home message SSc is a complex autoimmune disease, the pathogenesis of which although not completely understood is under active study, and new insights into pathogenesis are continuously being discovered. Although there is no effective disease modifying treatment for patients with SSc, quality of life, morbidity and mortality can be improved by using targeted therapy directed at affecting the consequences of damage to lungs, blood vessels, kidneys and the gastrointestinal tract. Innovative approaches to treating SSc are under intense investigation. PMID:20210685
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Beretta, Lorenzo; Santaniello, Alessandro; Cappiello, Francesca; Chawla, Nitesh V; Vonk, Madelon C; Carreira, Patricia E; Allanore, Yannick; Popa-Diaconu, D A; Cossu, Marta; Bertolotti, Francesca; Ferraccioli, Gianfranco; Mazzone, Antonino; Scorza, Raffaella
2010-01-01
Systemic sclerosis (SSc) is a multiorgan disease with high mortality rates. Several clinical features have been associated with poor survival in different populations of SSc patients, but no clear and reproducible prognostic model to assess individual survival prediction in scleroderma patients has ever been developed. We used Cox regression and three data mining-based classifiers (Naïve Bayes Classifier [NBC], Random Forests [RND-F] and logistic regression [Log-Reg]) to develop a robust and reproducible 5-year prognostic model. All the models were built and internally validated by means of 5-fold cross-validation on a population of 558 Italian SSc patients. Their predictive ability and capability of generalisation was then tested on an independent population of 356 patients recruited from 5 external centres and finally compared to the predictions made by two SSc domain experts on the same population. The NBC outperformed the Cox-based classifier and the other data mining algorithms after internal cross-validation (area under receiving operator characteristic curve, AUROC: NBC=0.759; RND-F=0.736; Log-Reg=0.754 and Cox= 0.724). The NBC had also a remarkable and better trade-off between sensitivity and specificity (e.g. Balanced accuracy, BA) than the Cox-based classifier, when tested on an independent population of SSc patients (BA: NBC=0.769, Cox=0.622). The NBC was also superior to domain experts in predicting 5-year survival in this population (AUROC=0.829 vs. AUROC=0.788 and BA=0.769 vs. BA=0.67). We provide a model to make consistent 5-year prognostic predictions in SSc patients. Its internal validity, as well as capability of generalisation and reduced uncertainty compared to human experts support its use at bedside. Available at: http://www.nd.edu/~nchawla/survival.xls.
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Gerlicz, Zofia; Dziankowska-Bartkowiak, Bozena; Dziankowska-Zaborszczyk, Elzbieta; Sysa-Jedrzejowska, Anna
2014-01-01
The aim of this study was to determine the characteristic factors for vascular development and maintenance levels as well as correlation between Tie-1 receptors, Tie-2 receptors and the corresponding ligands--angiopoietins--in systemic sclerosis (SSc) patients. Serum levels of Tie-1, Tie-2, Ang-1 and Ang-2 were measured in 25 SSc patients and healthy controls. There was a statistically significant difference in serum Tie-1 (p = 0.009) and Ang-2 (p = 0.001) levels in SSc patients compared with healthy controls. Significant correlations between Tie-1 and Tie-2 (ρ = 0.70, p = 0.0001) and between Tie-1 and Ang-2 (ρ = -0.92, p = 0.002) were found in the SSc group. Serum levels of Tie-2 were positively associated with esophagus changes (U = 2.03, p = 0.041) and Ang-1 was negatively correlated with duration of Raynaud's phenomenon (ρ = -0.75, p = 0.00008). The increase in serum concentration of Tie-1 and Ang-2 in patients with SSc may confirm a molecular imbalance between receptor tyrosine kinases Tie and their ligands. © 2014 S. Karger AG, Basel.
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Tozkir, Hilmi; Pamuk, Omer Nuri; Duymaz, Julide; Gurkan, Hakan; Yazar, Metin; Sari, Gulce; Tanrikulu, Hazel; Pamuk, Gulsum Emel
2016-12-01
There is significant autoantibody production in systemic lupus erythematosus (SLE) and scleroderma (SSc); microchimerism is also thought to play a role in pathogenesis. We determined the frequency of anti-HLA antibodies in SLE and SSc patients and evaluated associated clinical factors. We included 77 SLE patients, 46 SSc patients and 53 healthy controls into the study. Clinical data about the patients were obtained from hospital records. Anti-human leukocyte (anti-HLA) antigen antibody analysis of sera was performed by applying Lifecodes anti-HLA Class I and Class II Screening kits based on xMAP technology. The frequencies of class I and II anti-HLA antibodies were significantly higher in SLE (27.3% and 41.6%) and SSc (26.1% and 41.3%) groups than in healthy controls (1.9% and 5.7%) (all P < 0.001). Frequencies of thrombocytopenia (P = 0.021), anti-ribonucleoprotein (P = 0.037) and anti-Ro (P = 0.027) were significantly higher in the class I antibody-positive SLE group; however, pericarditis was less frequent (P = 0.05). On the other hand, the class II antibody-positive SLE group had more frequent anti-ribosomal P antibody (P = 0.038), but less frequent active disease (P = 0.038). In the SSc group, class I antibody-positive patients had more frequent digital ulcers (P = 0.048) and anti-centromere antibodies (P = 0.01). There was no association of anti-HLA antibodies with pulmonary hypertension and interstitial fibrosis in SSc patients. Both class I and class II antibodies were found to be significantly increased in SLE and SSc. Rather than major organ involvement, anti-HLA antibodies were associated with the presence of other antibodies in both diseases. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.
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Azzouz, Doua F.; Martin, Gabriel V.; Arnoux, Fanny; Balandraud, Nathalie; Martin, Thierry; Dubucquoi, Sylvain; Hachulla, Eric; Farge-Bancel, Dominique; Tiev, Kiet; Cabane, Jean; Bardin, Nathalie; Chiche, Laurent; Martin, Marielle; Caillet, Eléonore C.; Kanaan, Sami B.; Harlé, Jean Robert; Granel, Brigitte; Diot, Elisabeth; Roudier, Jean; Auger, Isabelle; Lambert, Nathalie C.
2016-01-01
In a pilot ProtoArray analysis, we identified 6 proteins out of 9483 recognized by autoantibodies (AAb) from patients with systemic sclerosis (SSc). We further investigated the 6 candidates by ELISA on hundreds of controls and patients, including patients with Systemic Lupus Erythematosus (SLE), known for high sera reactivity and overlapping AAb with SSc. Only 2 of the 6 candidates, Ephrin type-B receptor 2 (EphB2) and Three prime Histone mRNA EXonuclease 1 (THEX1), remained significantly recognized by sera samples from SSc compared to controls (healthy or with rheumatic diseases) with, respectively, 34% versus 14% (P = 2.10−4) and 60% versus 28% (P = 3.10−8). Above all, EphB2 and THEX1 revealed to be mainly recognized by SLE sera samples with respectively 56%, (P = 2.10−10) and 82% (P = 5.10−13). As anti-EphB2 and anti-THEX1 AAb were found in both diseases, an epitope mapping was realized on each protein to refine SSc and SLE diagnosis. A 15-mer peptide from EphB2 allowed to identify 35% of SLE sera samples (N = 48) versus only 5% of any other sera samples (N = 157), including SSc sera samples. AAb titers were significantly higher in SLE sera (P<0.0001) and correlated with disease activity (p<0.02). We could not find an epitope on EphB2 protein for SSc neither on THEX1 for SSc or SLE. We showed that patients with SSc or SLE have AAb against EphB2, a protein involved in angiogenesis, and THEX1, a 3’-5’ exoribonuclease involved in histone mRNA degradation. We have further identified a peptide from EphB2 as a specific and sensitive tool for SLE diagnosis. PMID:27617966
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Analysis of the association between CD40 and CD40 ligand polymorphisms and systemic sclerosis.
Teruel, María; Simeon, Carmen P; Broen, Jasper; Vonk, Madelon C; Carreira, Patricia; Camps, Maria Teresa; García-Portales, Rosa; Delgado-Frías, Esmeralda; Gallego, Maria; Espinosa, Gerard; Beretta, Lorenzo; Airó, Paolo; Lunardi, Claudio; Riemekasten, Gabriela; Witte, Torsten; Krieg, Thomas; Kreuter, Alexander; Distler, Jörg H W; Hunzelmann, Nicolas; Koeleman, Bobby P; Voskuyl, Alexandre E; Schuerwegh, Annemie J; González-Gay, Miguel Angel; Radstake, Timothy R D J; Martin, Javier
2012-06-25
The aim of the present study was to investigate the possible role of CD40 and CD40 ligand (CD40LG) genes in the susceptibility and phenotype expression of systemic sclerosis (SSc). In total, 2,670 SSc patients and 3,245 healthy individuals from four European populations (Spain, Germany, The Netherlands, and Italy) were included in the study. Five single-nucleotide polymorphisms (SNPs) of CD40 (rs1883832, rs4810485, rs1535045) and CD40LG (rs3092952, rs3092920) were genotyped by using a predesigned TaqMan allele-discrimination assay technology. Meta-analysis was assessed to determine whether an association exists between the genetic variants and SSc or its main clinical subtypes. No evidence of association between CD40 and CD40LG genes variants and susceptibility to SSc was observed. Similarly, no significant statistical differences were observed when SSc patients were stratified by the clinical subtypes, the serologic features, and pulmonary fibrosis. Our results do not suggest an important role of CD40 and CD40LG gene polymorphisms in the susceptibility to or clinical expression of SSc.
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Pruinelli, Lisiane; Yadav, Pranjul; Hangsleben, Andrew; Johnson, Jakob; Dey, Sanjoy; McCarty, Maribet; Kumar, Vipin; Delaney, Connie W; Steinbach, Michael; Westra, Bonnie L; Simon, György J
2016-01-01
Sepsis incidents have doubled from 2000 through 2008, and hospitalizations for these diagnoses have increased by 70%. The use of the Surviving Sepsis Campaign (SSC) guidelines can lead to earlier diagnosis and treatment; however, the effectiveness of the SSC guidelines in preventing complications for this population is unclear. The overall purpose of this study was to apply SSC guideline recommendations to EHR data for patients with severe sepsis or septic shock and determine guideline compliance as well as its impact on inpatient mortality and sepsis complications. Propensity Score Matching in conjuction with Bootstrap Simulation were used to match patients with and without exposure to the SSC recommendations. Findings showed that EHR data could be used to estimate compliance with SSC recommendations as well as the effect of compliance on outcomes. Compliance with guideline recommendations ranged from 9% to 100%. For individual recommendations with sufficient data, association with outcomes varied. Checking lactate influenced four outcomes; however, two were negative and two positive. Use of a ventilator for patients with respiratory distress had a positive association with three outcomes.
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Slobodin, Gleb; Ahmad, Mohammad Sheikh; Rosner, Itzhak; Peri, Regina; Rozenbaum, Michael; Kessel, Aharon; Toubi, Elias; Odeh, Majed
2010-01-01
The role and function of T regulatory (Treg) cells have not been fully investigated in patients with systemic sclerosis (SSc). Ten patients with SSc donated 20ml of peripheral blood. Activity (Valentini) and severity (Medsger) scores for SSc were calculated for all patients. Healthy volunteers (controls) were matched to each patient by gender and age. CD4(+) cells were separated using the MACS system. The numbers of Treg cells were estimated by flow cytometry after staining for CD4, CD25, and FoxP3 and calculated as patient-to-control ratio separately for each experiment. Correlations with activity and severity indices of the disease were performed. Twenty-four-hour production of TGF-beta and IL-10 by activated CD4(+) cells was measured by ELISA in culture supernatants. The numbers of Treg cells, expressed as patient-to-control ratio, correlated significantly with both activity and severity indices (r=0.71, p=0.034 and r=0.67, p=0.044, respectively). ELISA-measured production of TGF-beta and IL-10 by CD4(+) cells was similar in patients and controls. Increased numbers of Treg cells are present in patients with SSc, correlating with activity and severity of the disease. This expansion of Treg cells was not accompanied, however, by heightened TGF-beta or IL-10 production. Further studies to elaborate the causes and functional significance of Treg cell expansion in SSc are needed. 2010 Elsevier Inc. All rights reserved.
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Detection of Alveolar Fibrocytes in Idiopathic Pulmonary Fibrosis and Systemic Sclerosis
Phin, Sophie; Debray, Marie-Pierre; Marchal-Somme, Joelle; Tiev, Kiet; Bonay, Marcel; Fabre, Aurélie; Soler, Paul; Dehoux, Monique; Crestani, Bruno
2013-01-01
Background Fibrocytes are circulating precursors for fibroblasts. Blood fibrocytes are increased in patients with idiopathic pulmonary fibrosis (IPF). The aim of this study was to determine whether alveolar fibrocytes are detected in broncho-alveolar lavage (BAL), to identify their prognostic value, and their potential association with culture of fibroblasts from BAL. Methods We quantified fibrocytes in BAL from 26 patients with IPF, 9 patients with Systemic Sclerosis(SSc)-interstitial lung disease (ILD), and 11 controls. BAL cells were cultured to isolate alveolar fibroblasts. Results Fibrocytes were detected in BAL in 14/26 IPF (54%) and 5/9 SSc patients (55%), and never in controls. Fibrocytes were in median 2.5% [0.4–19.7] and 3.0% [2.7–3.7] of BAL cells in IPF and SSc-ILD patients respectively. In IPF patients, the number of alveolar fibrocytes was correlated with the number of alveolar macrophages and was associated with a less severe disease but not with a better outcome. Fibroblasts were cultured from BAL in 12/26 IPF (46%), 5/9 SSc-ILD (65%) and never in controls. The detection of BAL fibrocytes did not predict a positive culture of fibroblasts. Conclusion Fibrocytes were detected in BAL fluid in about half of the patients with IPF and SSc-ILD. Their number was associated with less severe disease in IPF patients and did not associate with the capacity to grow fibroblasts from BAL fluid. PMID:23341987
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Avouac, Jérôme; Huscher, Dörte; Furst, Daniel E; Opitz, Christian F; Distler, Oliver; Allanore, Yannick
2014-01-01
To establish an expert consensus on which criteria are the most appropriate in clinical practice to refer patients with systemic sclerosis (SSc) for right heart catheterisation (RHC) when pulmonary hypertension (PH) is suspected. A three stage internet based Delphi consensus exercise involving worldwide PH experts was designed. In the first stage, a comprehensive list of domains and items combining evidence based indications and expert opinions were obtained. In the second and third stages, experts were asked to rate each item selected in the list. After each of stages 2 and 3, the number of items and criteria were reduced according to a cluster analysis. A literature search and the opinions of 47 experts participating in Delphi stage 1 provided a list of seven domains containing 142 criteria. After stages 2 and 3, these domains and tools were reduced to three domains containing eight tools: clinical (progressive dyspnoea over the past 3 months, unexplained dyspnoea, worsening of WHO dyspnoea functional class, any finding on physical examination suggestive of elevated right heart pressures and any sign of right heart failure), echocardiography (systolic pulmonary artery pressure >45 mm Hg and right ventricle dilation) and pulmonary function tests (diffusion lung capacity for carbon monoxide <50% without pulmonary fibrosis). Among experts in pulmonary arterial hypertension-SSc, a core set of criteria for clinical practice to refer SSc patients for RHC has been defined by Delphi consensus methods. Although these indications are recommended by this expert group to be used as an interim tool, it will be necessary to formally validate the present tools in further studies.
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Maddali Bongi, Susanna; Del Rosso, Angela; Mikhaylova, Svetlana; Baccini, Marco; Matucci Cerinic, Marco
2013-10-01
In patients with systemic sclerosis (SSc), sexual function is somewhat impaired. Our aim was to evaluate sexual function in women with SSc in comparison to controls, and to investigate the association with sociodemographic and disease characteristics, and physical and psychological variables. Forty-six women with SSc and 46 healthy women were assessed for sociodemographic characteristics and gynecological development and administered the Female Sexual Function Index (FSFI), Medical Outcomes Study Short Form-36 (SF-36), Health Assessment Questionnaire (HAQ), Hospital Anxiety and Depression Scale (HADS), Rosenberg Self-Esteem Scale, Coping Orientation to Problems Experienced-New Italian Version, and Functional Assessment of Chronic Illness Therapy-Fatigue Scale. Patients were also assessed for disease duration and subset, Female Sexual Function in SSc, Hand Mobility in Scleroderma test (HAMIS), Cochin Hand Functional Disability Scale, Mouth Handicap in Systemic Sclerosis Scale (MHISS), Disability Sexual and Body Esteem Scale (PDSBE); and fist closure, hand opening, and mouth opening. In patients with SSc, only FSFI desire subscale score was significantly lower (p = 0.035) versus controls. Total FSFI score, similar to controls, was related with Medical Outcomes Study Short Form-36 mental component, HAQ (p = 0.022), MHISS (p = 0.038), and HAMIS (p = 0.037). In SSc, the main factors independently associated with sexual functioning were vaginal dryness [regression coefficient (B) = -0.72; p < 0.001], PDSBE (B = 0.42; p = 0.001), and HADS depression scale (B = -0.23; p = 0.035). Together, these variables explained 70% of the variance in the FSFI total score. In SSc, sexual function, although not different from controls, is influenced by specific disease-related and psychological concerns. Thus it should be included in patient evaluations and assessed in daily clinical practice.
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Quantifying the direct public health care cost of systemic sclerosis
Morrisroe, Kathleen; Stevens, Wendy; Sahhar, Joanne; Ngian, Gene-Siew; Rabusa, Candice; Ferdowsi, Nava; Hill, Catherine; Proudman, Susanna; Nikpour, Mandana
2017-01-01
Abstract To quantify the direct healthcare cost of systemic sclerosis (SSc) and identify its determinants. Healthcare use was captured through data linkage, wherein clinical and medication data for SSc patients from the state of Victoria enrolled in the Australian Scleroderma Cohort Study were linked with the Victorian hospital admissions and emergency presentations data sets, and the Medicare Benefits Schedule which contains all government subsidized ambulatory care services, for the period 2011-2015. Medication cost was determined from the Pharmaceutical Benefits Scheme. Costs were extrapolated to all Australian SSc patients based on SSc prevalence of 21.1 per 100,000 and an Australian population of 24,304,682 in 2015. Determinants of healthcare cost were estimated using logistic regression. Total healthcare utilization cost to the Australian government extrapolated to all Australian SSc patients from 2011 to 2015 was Australian Dollar (AUD)$297,663,404.77, which is an average annual cost of AUD$59,532,680.95 (US Dollar [USD]$43,816,040.08) and annual cost per patient of AUD$11,607.07 (USD$8,542.80). Hospital costs, including inpatient hospitalization and emergency department presentations, accounted for the majority of these costs (44.4% of total), followed by medication cost (31.2%) and ambulatory care cost (24.4%). Pulmonary arterial hypertension (PAH) and gastrointestinal (GIT) involvement were the major determinants of healthcare cost (OR 2.3 and 1.8, P = .01 for hospitalizations; OR 2.8 and 2.0, P = .01 for ambulatory care; OR 7.8 and 1.6, P < .001 and P = .03 for medication cost, respectively). SSc is associated with substantial healthcare utilization and direct economic burden. The most costly aspects of SSc are PAH and GIT involvement. PMID:29310332
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Morrisroe, Kathleen; Stevens, Wendy; Sahhar, Joanne; Ngian, Gene-Siew; Rabusa, Candice; Ferdowsi, Nava; Hill, Catherine; Proudman, Susanna; Nikpour, Mandana
2017-12-01
To quantify the direct healthcare cost of systemic sclerosis (SSc) and identify its determinants. Healthcare use was captured through data linkage, wherein clinical and medication data for SSc patients from the state of Victoria enrolled in the Australian Scleroderma Cohort Study were linked with the Victorian hospital admissions and emergency presentations data sets, and the Medicare Benefits Schedule which contains all government subsidized ambulatory care services, for the period 2011-2015. Medication cost was determined from the Pharmaceutical Benefits Scheme. Costs were extrapolated to all Australian SSc patients based on SSc prevalence of 21.1 per 100,000 and an Australian population of 24,304,682 in 2015. Determinants of healthcare cost were estimated using logistic regression. Total healthcare utilization cost to the Australian government extrapolated to all Australian SSc patients from 2011 to 2015 was Australian Dollar (AUD)$297,663,404.77, which is an average annual cost of AUD$59,532,680.95 (US Dollar [USD]$43,816,040.08) and annual cost per patient of AUD$11,607.07 (USD$8,542.80). Hospital costs, including inpatient hospitalization and emergency department presentations, accounted for the majority of these costs (44.4% of total), followed by medication cost (31.2%) and ambulatory care cost (24.4%). Pulmonary arterial hypertension (PAH) and gastrointestinal (GIT) involvement were the major determinants of healthcare cost (OR 2.3 and 1.8, P = .01 for hospitalizations; OR 2.8 and 2.0, P = .01 for ambulatory care; OR 7.8 and 1.6, P < .001 and P = .03 for medication cost, respectively). SSc is associated with substantial healthcare utilization and direct economic burden. The most costly aspects of SSc are PAH and GIT involvement.
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Deficient Adipogenesis of Scleroderma Patient and Healthy African American Monocytes
Lee, Rebecca; Reese, Charles; Carmen-Lopez, Gustavo; Perry, Beth; Bonner, Michael; Zemskova, Marina; Wilson, Carole L.; Helke, Kristi L.; Silver, Richard M.; Hoffman, Stanley; Tourkina, Elena
2017-01-01
Monocytes from systemic sclerosis (SSc, scleroderma) patients and healthy African Americans (AA) are deficient in the regulatory protein caveolin-1 leading to enhanced migration toward chemokines and fibrogenic differentiation. While dermal fibrosis is the hallmark of SSc, loss of subcutaneous adipose tissue is a lesser-known feature. To better understand the etiology of SSc and the predisposition of AA to SSc, we studied the adipogenic potential of SSc and healthy AA monocytes. The ability of SSc and healthy AA monocytes to differentiate into adipocyte-like cells (ALC) is inhibited compared to healthy Caucasian (C) monocytes. We validated that monocyte-derived ALCs are distinct from macrophages by flow cytometry and immunocytochemistry. Like their enhanced fibrogenic differentiation, their inhibited adipogenic differentiation is reversed by the caveolin-1 scaffolding domain peptide (CSD, a surrogate for caveolin-1). The altered differentiation of SSc and healthy AA monocytes is additionally regulated by peroxisome proliferator-activated receptor γ (PPARγ) which is also present at reduced levels in these cells. In vivo studies further support the importance of caveolin-1 and PPARγ in fibrogenesis and adipogenesis. In SSc patients, healthy AA, and mice treated systemically with bleomycin, adipocytes lose caveolin-1 and PPARγ and the subcutaneous adipose layer is diminished. CSD treatment of these mice leads to a reappearance of the caveolin-1+/PPARγ+/FABP4+ subcutaneous adipose layer. Moreover, many of these adipocytes are CD45+, suggesting they are monocyte derived. Tracing experiments with injected EGFP+ monocytes confirm that monocytes contribute to the repair of the adipose layer when it is damaged by bleomycin treatment. Our observations strongly suggest that caveolin-1 and PPARγ work together to maintain a balance between the fibrogenic and adipogenic differentiation of monocytes, that this balance is altered in SSc and in healthy AA, and that monocytes make a major contribution to the repair of the adipose layer. PMID:28420992
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Sobanski, Vincent; Launay, David; Hachulla, Eric; Humbert, Marc
2016-02-01
Pulmonary arterial hypertension (PAH) is a severe condition causing significant morbidity and mortality in patients with systemic sclerosis (SSc). Despite the use of specific treatments, SSc-PAH survival remains poorer than in idiopathic PAH (IPAH). Recent therapeutic advances in PAH show a lower magnitude of response in SSc-PAH and a higher risk of adverse events, as compared to IPAH. The multifaceted underlying mechanisms and the multisystem nature of SSc probably explain part of the worse outcomes in SSc-PAH compared to IPAH. This review describes the current management of SSc-PAH with an emphasis on the impact of the different organ involvements in the prognosis and treatment response. An earlier detection of PAH and a better characterization of the clinical phenotypes of SSc-PAH are warranted in clinical practice and future trials. Determinants of prognosis, surrogate markers of clinical improvement or worsening, and relevance of the common endpoints used in clinical trials should be evaluated in this specific population. A multidisciplinary approach in expert referral centers is mandatory for SSc-PAH management.
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Mouthon, Luc; Alami, Sophie; Boisard, Anne-Sophie; Chaigne, Benjamin; Hachulla, Eric; Poiraudeau, Serge
2017-05-30
Systemic sclerosis (SSc) is a chronic connective-tissue disease responsible for reduced life expectancy, disability and a decreased quality of life. In order to optimize patients-physicians relationship and care strategy we aimed to survey views of patients on SSc and its management to reveal potential hurdles and improve health care strategies. A qualitative study combined semi-structured interviews, focus groups, and a direct observation of an information session was performed between November 2008 and January 2009. Twenty-five patients with SSc were included. They encounter difficulties to have a clear representation of their disease. Physical, psychological, and social repercussions of SSc may lead to a psychological distress and different coping strategies, which widely differ among interviewed patients. Patients' views on their therapeutic journey and the management of their disease highlighted strong expectations about patient-physician relationship. These expectations were numerous, complex and sometimes ambivalent. Patients expected physicians to be human and attentive but also involved in research in the field and to provide psychological and affective support to help them to accept the uncertainty of disease evolution and lack of curative treatment. They also expected more individualized management, improvements in diagnosis and follow-up organization, more efforts in education and information, comprehensive behaviors and support from working colleagues and relatives, and increased funding from the health care system. Our results suggest that SSc management could be optimized, particularly with more attention to the patient-practitioner relationship. Patient profiles should be more precisely defined in terms of coping strategies and treatment preferences to propose more individualized options.
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Menéndez Fraga, M D; Cueva Álvarez, M A; Franco Castellanos, M R; Fernández Moral, V; Castro Del Río, M P; Arias Pérez, J I; Fernández León, A; Vázquez Valdés, F
2016-06-01
The implementing of the WHO Surgical Safety Checklist (SSC) has helped to improve patient safety. The aim of this study was to assess the level of compliance of the SSC, and incorporating the non-compliances as «triggers» in the Global Trigger Tool (GTT). Acute Geriatric Hospital (200 beds). Retrospective study, study period: 2011-2014. The SSC formulary and the methodology of the GTT were used for the analysis of electronic medical records and the compliance with the SSC. The NCCP MERP categories were used to assess the severity of the harm. Out of all the electronic medical records (EMR), a total of 227 (23.6%) discharged patients (1.7% of interventions in the four year study period) were analysed. All (100%) of the EMR included the SSC, with 94.4% of the items being completed, and 28.2% of SSC had all items completed in the 3 phases of the process. Surgical adverse events decreased from 16.3% in 2011 to 9.4% in 2014 (P=.2838, not significant), and compliance with all items of SSC was increased from 18.6% to 39.1% (P=.0246, significant). The GTT systematises and evaluates, at low cost, the triggers and incidents/ AEs found in the EMR in order to assess the compliance with the SSC and consider non-compliance of SSC as «triggers» for further analysis. This strategy has never been referred to in the GTT or in the SCC formulary. Copyright © 2016 SECA. Published by Elsevier Espana. All rights reserved.
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Bongi, Susanna Maddali; Ravenni, Giovanni; Ciampi, Benedetta; Del Rosso, Angela; El Aoufy, Khadija
2016-12-01
Foot problems are often present in Systemic Sclerosis (SSc) patients, however studies regarding podiatric problems related to SSc are lacking and there are no data evaluating the foot biomechanical changes. The aim of the present pilot study was to evaluate podiatric problems in an Italian cohort of SSc patients by assessing received podiatric services, foot pain and disability and biomechanical foot deformity. 25 consecutive SSc patients were enrolled from the Division of Rheumatology, University of Florence. All SSc patients were assessed by: Standards of Care for People with Foot Musculoskeletal Health problems: Audit Tool, Foot Function Index (FFI), Weight and non-weight bearing foot joint assessment, (Foot Posture Index (FPI) and Gait Cycle), Health Assessment Questionnaire (HAQ) and Medical Outcomes Survey Short Form 36 (SF-36). Audit Tool - Only 7 (28%) out of the 25 patients with SSc had a specific podiatric assessment and treatment: no patient received a foot health assessment within the first 6 months of disease diagnosis and no patient received information about foot involvement. 1 patient (4%) received foot assessment every year; 1 patient (4%) received specific information about the disease and 5 patients (20%) received information about the benefits of using adapted footwear and insoles. FFI - Values of pain, disability and activity limitations, reported in FFI, are 4.7±5.1, 5.1±3.2 and 3.2±3.1 (M±DS), respectively. Non-weight bearing foot joint assessment shows a rearfoot varus deformity in 64% of patients, forefoot varus deformity in 42% and 6% forefoot valgus deformity. Weight bearing foot joint assessment, through FPI shows a pronated foot 20% of patients with and 34% with highly pronated overall foot posture. Gait analysis shows that 64% of patients has a contact of the calcaneus in invertion while 36% in eversion. In the midstance, 78% have the foot in pronation and 22% in supination, while in propulsion 12% presents a takeoff of the foot in supination and 88% in the pronation. HAQ result is 1.13±0.80, SFI and SMI scales of SF-36 have scores of 32.38±10.65 and 38.67±11.40, respectively. Our results shows that podiatric problems in SSc patients are common, serious but foot assessment and health care are inadequate. Thus, foot health information should be improved in order to better empower patients to self-manage low risk problems and help identify high-risk problems, which require specialist care.
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Grueninger, Patrick; Nikolic, Nikola; Schneider, Joerg; Lattmann, Thomas; Platz, Andreas; Chmiel, Corinne; Meier, Christoph
2015-11-01
To prospectively assess arthroscopic repair of massive cuff tears (MCT) in a highly selective patient group with large subscapularis (SSC) tendon tears by means of clinical results and magnetic resonance imaging (MRI) studies. Between April 2009 and December 2010, 26 patients with MCT were treated with arthroscopic rotator cuff repair. Only lesions involving a large tear of the SSC tendon (Lafosse III or IV) in combination with a complete tear of the supraspinatus (SSP) tendon and a tear of at least the anterior third of the infraspinatus (ISP) tendon were included. Minimum follow-up was 1 year. Pre- and postoperative assessment included a standardized clinical examination, subjective patient outcome, and MRI (structural integrity, fatty muscle infiltration, and muscular mass). Mean follow-up was 17 months (range, 12 to 34 months). MRI was performed in 25 patients. In 21 (84%) the cuff repair was intact. A partial retear of the SSC was found in 2 patients (8%). In 2 patients (8%) a full-thickness retear of the posterosuperior cuff was observed (1 SSP, 1 SSP/ISP). A significant increase of the muscle mass and decrease of fatty infiltration was observed for the SSC and SSP but not for the ISP. The mean Constant-Murley score improved from 36 to 86 points (P < .001) with all its subscores as well (P < .001). Muscular strength improved for the SSC (4.9 v 3.0, P < .001), SSP (4.6 v 2.9, P < .001), and ISP (4.8 v 3.4, P < .001). Overall patient satisfaction was high (3.6 ± 0.8). Arthroscopic repair of MCT involving the ISP, SSP, and large tears of the SSC provides a reliable tendon healing, in particular for the SSC tendon, combined with good functional results. Level IV, therapeutic case series. Copyright © 2015 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.
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Taraborelli, Mara; Ramoni, Véronique; Brucato, Antonio; Airò, Paolo; Bajocchi, Gianluigi; Bellisai, Francesca; Biasi, Domenico; Blagojevic, Jelena; Canti, Valentina; Caporali, Roberto; Caramaschi, Paola; Chiarolanza, Ilaria; Codullo, Veronica; Cozzi, Franco; Cuomo, Giovanna; Cutolo, Maurizio; De Santis, Maria; De Vita, Salvatore; Di Poi, Emma; Doria, Andrea; Faggioli, Paola; Favaro, Maria; Ferraccioli, Gianfranco; Ferri, Clodoveo; Foti, Rosario; Gerosa, Alessandro; Gerosa, Maria; Giacuzzo, Sarah; Giani, Leopoldo; Giuggioli, Dilia; Imazio, Massimo; Iudici, Michele; Iuliano, Annamaria; Leonardi, Roberto; Limonta, Massimiliano; Lojacono, Andrea; Lubatti, Chiara; Matucci-Cerinic, Marco; Mazzone, Antonino; Meroni, Marianna; Meroni, Pier Luigi; Mosca, Marta; Motta, Mario; Muscarà, Marina; Nava, Simona; Padovan, Melissa; Pagani, Giorgio; Paolazzi, Giuseppe; Peccatori, Susanna; Ravagnani, Viviana; Riccieri, Valeria; Rosato, Edoardo; Rovere-Querini, Patrizia; Salsano, Felice; Santaniello, Alessandro; Scorza, Raffaella; Tani, Chiara; Valentini, Gabriele; Valesini, Guido; Vanoli, Massimo; Vigone, Barbara; Zeni, Silvana; Tincani, Angela
2012-06-01
To assess fetal and maternal outcomes in women with systemic sclerosis (SSc). Prospectively collected data on 99 women with SSc from 25 Italian centers were analyzed retrospectively. Women with SSc were observed during 109 pregnancies (from 2000 to 2011), and outcomes were compared to those in the general obstetric population (total of 3,939 deliveries). The maternal age at conception was a mean ± SD 31.8 ± 5.3 years, and the median disease duration at conception was 60 months (range 2-193 months). SSc patients, compared to the general obstetric population, had a significantly increased frequency of preterm deliveries (25% versus 12%) and severe preterm deliveries (<34 weeks of gestation) (10% versus 5%), intrauterine growth restriction (6% versus 1%), and babies with very-low birth weight (5% versus 1%). Results of multivariable analysis showed that corticosteroid use was associated with preterm deliveries (odds ratio [OR] 3.63, 95% confidence interval [95% CI] 1.12-11.78), whereas the use of folic acid (OR 0.30, 95% CI 0.10-0.91) and presence of anti-Scl-70 antibodies (OR 0.26, 95% CI 0.08-0.85) were protective. The disease remained stable in most SSc patients, but there were 4 cases of progression of disease within 1 year from delivery, all in anti-Scl-70 antibody-positive women, 3 of whom had a disease duration of <3 years. Women with SSc can have successful pregnancies, but they have a higher-than-normal risk of preterm delivery, intrauterine growth restriction, and babies with very-low birth weight. Progression of the disease during or after pregnancy is rare, but possible. High-risk multidisciplinary management should be standard for these patients, and pregnancy should be avoided in women with severe organ damage and postponed in women with SSc of recent onset, particularly if the patient is positive for anti-Scl-70 antibodies. Copyright © 2012 by the American College of Rheumatology.
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Gourh, Pravitt; Remmers, Elaine F; Boyden, Steven E; Alexander, Theresa; Morgan, Nadia D; Shah, Ami A; Mayes, Maureen D; Doumatey, Ayo; Bentley, Amy R; Shriner, Daniel; Domsic, Robyn T; Medsger, Thomas A; Steen, Virginia D; Ramos, Paula S; Silver, Richard M; Korman, Benjamin; Varga, John; Schiopu, Elena; Khanna, Dinesh; Hsu, Vivien; Gordon, Jessica K; Saketkoo, Lesley Ann; Gladue, Heather; Kron, Brynn; Criswell, Lindsey A; Derk, Chris T; Bridges, S Louis; Shanmugam, Victoria K; Kolstad, Kathleen D; Chung, Lorinda; Jan, Reem; Bernstein, Elana J; Goldberg, Avram; Trojanowski, Marcin; Kafaja, Suzanne; Maksimowicz-McKinnon, Kathleen M; Mullikin, James C; Adeyemo, Adebowale; Rotimi, Charles; Boin, Francesco; Kastner, Daniel L; Wigley, Fredrick M
2018-05-06
Whole-exome sequencing (WES) studies in systemic sclerosis (SSc) patients of European American (EA) ancestry have identified variants in the ATP8B4 gene and enrichment of variants in genes in the extracellular matrix (ECM)-related pathway increasing SSc susceptibility. Our goal was to evaluate the association of the ATP8B4 gene and the ECM-related pathway with SSc in a cohort of African Americans (AA). SSc patients of AA ancestry were enrolled from 23 academic centers across the United States under the Genome Research in African American Scleroderma Patients (GRASP) consortium. Unrelated AA individuals without serological evidence of autoimmunity enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the two WES studies in EA SSc were selected for gene association testing using the optimized sequence kernel association test (SKAT-O) and pathway analysis by Ingenuity pathway analysis in 379 patients and 411 controls. Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds with about equal proportions of mean European admixture. Using SKAT-O, we examined the association of individual genes that were previously reported in EAs, and none remained significant including ATP8B4 (P U nCorr =0.98). However, we confirm the previously reported association of the ECM-related pathway with enrichment of variants within the COL13A1, COL18A1, COL22A1, COL4A3, COL4A4, COL5A2, PROK1, and SERPINE1 genes (P C orr =1.95×10 -4 ). This is the largest genetic study in AAs with SSc to date, corroborating the role of functional variants aggregating in a fibrotic pathway and increasing SSc susceptibility. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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Sclerostin serum levels in patients with systemic autoimmune diseases
Fernández-Roldán, Concepción; Genre, Fernanda; López-Mejías, Raquel; Ubilla, Begoña; Mijares, Verónica; Cano, Daniel Sánchez; Robles, Concepción López; Callejas-Rubio, José Luis; Fernández, Raquel Ríos; Ruiz, Manuela Expósito; González-Gay, Miguel Á; Centeno, Norberto Ortego
2016-01-01
Systemic autoimmune diseases (SADs) are associated with lower bone mass and an increased risk of fractures. Sclerostin has a pivotal role in bone metabolism. Available data on circulating sclerostin levels in healthy subjects are limited, whereas those in SAD patients are absent. Our objective was to determine circulating sclerostin concentrations in systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Crohn's disease (CD) patients, and to analyze the factors associated with sclerostin concentrations. In this cross-sectional case–control study, serum sclerostin levels were measured in 38 SLE patients, 20 CD patients, 8 SSc patients and 20 healthy controls using a sclerostin ELISA. The mean values of the sclerostin (95% confidence interval) were 35.36 pmol l−1 (12–101) in patients and 33.92 pmol l−1 (2.31–100) in control subjects. The mean sclerostin value was 36.4 pmol l−1 (22.1–48.5) in SLE patients, 26.7 pmol l−1 (17.3–36.3) in CD patients and 51.8 pmol l−1 (26.5–77.1) in SSc patients (P=0.001). Serum sclerostin levels were positively correlated with age (P<0.001), body mass index (BMI) (P=0.01) and lumbar spine Z-score (P=0.001) and negatively with creatinine clearance (P=0.001). Glucocorticoid treatment did not affect sclerostin levels. Sclerostin levels seem to have a heterogeneous pattern in different autoimmune diseases. SLE and SSc patients did not differ from healthy controls regarding sclerostin levels. The CD group had significantly lower values compared with SSc patients. Factors associated with sclerostin levels in autoimmune diseases seem to be the same than in the general population. PMID:26909149
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Sclerostin serum levels in patients with systemic autoimmune diseases.
Fernández-Roldán, Concepción; Genre, Fernanda; López-Mejías, Raquel; Ubilla, Begoña; Mijares, Verónica; Cano, Daniel Sánchez; Robles, Concepción López; Callejas-Rubio, José Luis; Fernández, Raquel Ríos; Ruiz, Manuela Expósito; González-Gay, Miguel Á; Ortego Centeno, Norberto
2016-01-01
Systemic autoimmune diseases (SADs) are associated with lower bone mass and an increased risk of fractures. Sclerostin has a pivotal role in bone metabolism. Available data on circulating sclerostin levels in healthy subjects are limited, whereas those in SAD patients are absent. Our objective was to determine circulating sclerostin concentrations in systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Crohn's disease (CD) patients, and to analyze the factors associated with sclerostin concentrations. In this cross-sectional case-control study, serum sclerostin levels were measured in 38 SLE patients, 20 CD patients, 8 SSc patients and 20 healthy controls using a sclerostin ELISA. The mean values of the sclerostin (95% confidence interval) were 35.36 pmol l(-1) (12-101) in patients and 33.92 pmol l(-1) (2.31-100) in control subjects. The mean sclerostin value was 36.4 pmol l(-1) (22.1-48.5) in SLE patients, 26.7 pmol l(-1) (17.3-36.3) in CD patients and 51.8 pmol l(-1) (26.5-77.1) in SSc patients (P=0.001). Serum sclerostin levels were positively correlated with age (P<0.001), body mass index (BMI) (P=0.01) and lumbar spine Z-score (P=0.001) and negatively with creatinine clearance (P=0.001). Glucocorticoid treatment did not affect sclerostin levels. Sclerostin levels seem to have a heterogeneous pattern in different autoimmune diseases. SLE and SSc patients did not differ from healthy controls regarding sclerostin levels. The CD group had significantly lower values compared with SSc patients. Factors associated with sclerostin levels in autoimmune diseases seem to be the same than in the general population.
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Predictive value of European Scleroderma Group Activity Index in an early scleroderma cohort.
Nevskaya, Tatiana; Baron, Murray; Pope, Janet E
2017-07-01
To estimate the effect of disease activity, as measured by the European Scleroderma Research Group Activity Index (EScSG-AI), on the risk of subsequent organ damage in a large systemic sclerosis (SSc) cohort. Of 421 SSc patients from the Canadian Scleroderma Research Group database with disease duration of ⩽ 3 years, 197 who had no evidence of end-stage organ damage initially and available 3 year follow-up were included. Disease activity was assessed by the EScSG-AI with two variability measures: the adjusted mean EScSG-AI (the area under the curve of the EScSG-AI over the observation period) and persistently active disease/flare. Outcomes were based on the Medsger severity scale and included accrual of a new severity score (Δ ⩾ 1) overall and within organ systems or reaching a significant level of deterioration in health status. After adjustment for covariates, the adjusted mean EScSG-AI was the most consistent predictor of risk across the study outcomes over 3 years in dcSSc: disease progression defined as Δ ⩾ 1 in any major internal organ, significant decline in forced vital capacity and diffusing capacity of carbon monoxide, severity of visceral disease and HAQ Disability Index worsening. In multivariate analysis, progression of lung disease was predicted solely by adjusted mean EScSG-AI, while the severity of lung disease was predicted the adjusted mean EScSG-AI, older age, modified Rodnan skin score (mRSS) and initial severity. The EScSG-AI was associated with patient- and physician-assessed measures of health status and overpowered the mRSS in predicting disease outcomes. Disease activity burden quantified with the adjusted mean EScSG-AI predicted the risk of deterioration in health status and severe organ involvement in dcSSc. The EScSG-AI is more responsive when done repeatedly and averaged. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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Hawley, Daniel P; Baildam, Eileen M; Amin, Tania S; Cruikshank, Mary K; Davidson, Joyce E; Dixon, Jennifer; Martin, Neil S; Ohlsson, Victoria; Pilkington, Clarissa; Rangaraj, Satyapal; Riley, Philip; Sundaramoorthy, Chitra; Walsh, Jo; Foster, Helen E
2012-07-01
To describe pathways of care and referral to paediatric rheumatology from onset of first symptom (noticed by the patient or their family) to diagnosis for children and young people diagnosed with localized scleroderma (LS) or juvenile SSc (jSSc). Retrospective case note audit of patients under paediatric rheumatology care who presented during January 2005-January 2010. Data included disease subtype, sex, age at key points in the referral pathway and health care professional (HCP) contact. All patient and HCP data were pseudo-anonymized in accordance with good clinical practice. Data were from eight UK centres that saw 89 cases: 62 females, 26 males; 73 LS, 16 jSSc. Median time from first symptom to first HCP review was 4 (range 0-72) months (LS) and 1 (range 0-50) month (jSSc). Median time from first symptom to paediatric rheumatology review was 15 (range 1-103) months (LS) and 7 (range 0-50) months (jSSc). Median time from first HCP review to first paediatric rheumatology review was 11 (range 0-103) months (LS) and 2 (range 0-10) months. First HCP seen (74%) was usually a general practitioner. The referring HCP to paediatric rheumatology was usually a dermatologist (56%) for LS. Median time from first symptom to diagnosis was 13 (range 1-102) months (LS) and 8 (range 1-50) months (jSSc). A prolonged interval occurs from first symptom to definitive diagnosis, which may adversely affect outcome. There is a need to raise awareness of this rare diagnosis and facilitate earlier recognition.
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Bacher, Adrienne; Mittoo, Shikha; Hudson, Marie; Tatibouet, Solène; Baron, Murray
2013-07-01
Certain North American Native (NAN) populations are known to have higher rates of systemic sclerosis (SSc) compared to non-NAN; however, little is known of the specific disease characteristics in this population in Canada. This study compares the clinical and serological manifestations of SSc in NAN and white patients. This cross-sectional, multicenter study included subjects enrolled in the Canadian Scleroderma Research Group registry between September 2004 and June 2012. Subjects were evaluated with complete medical histories, physical examinations, and self-questionnaires. Ethnicity was defined by self-report. Disease characteristics were compared between NAN and white patients and multivariate analyses were performed to determine the independent association between ethnicity and various clinical manifestations. Of 1278 patients, 1038 (81%) were white, 71 (6%) were NAN, and 169 (13%) were classified as non-white/non-NAN. There were important differences between NAN and white subjects with SSc. In multivariate analysis adjusting for socioeconomic differences and smoking status, NAN ethnicity was an independent risk factor for the severity of Raynaud phenomenon and more gastrointestinal symptoms, and was associated with a nonsignificant increase in the presence of digital ulcers. NAN patients with SSc have a distinct clinical phenotype. Our study provides a strong rationale to pursue further research into genetic and environmental determinants of SSc.
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Kayser, Cristiane; Sekiyama, Juliana Y; Próspero, Lucas C; Camargo, Cintia Z; Andrade, Luis E C
2013-01-01
Peripheral microangiopathy is a hallmark of systemic sclerosis (SSc) and can be early detected by nailfold capillaroscopy (NFC). This study aimed to examine whether more severe peripheral microangiopathy at NFC are predictive factor for death in SSc patients. 135 SSc patients who performed NFC between June 2001 and July 2009 were included. The following NFC parameters were evaluated: number of capillary loops/mm, avascular score (scored from 0 to 3), and number of enlarged and giant capillary loops. Univariate and multivariate regression models were used to analyse the association of mortality with NFC and clinical parameters. At the time of the analysis (August 2010), 123 patients were alive, and 12 were dead. By univariate analysis, male gender, forced vital capacity <75% predicted, higher number of giant capillary loops, and an avascular score >1.5 on NFC were associated with a significantly increase risk of death. By multivariate analysis, an avascular score >1.5 was the only independent predictor of death (hazard ratio 2.265). Survival rates from diagnosis at 1, 5 and 10 years were lower in patients with avascular score >1.5 (97%, 86%, and 59%, respectively) compared with those with avascular score ≤1.5 (97%, 97%, and 91% respectively) (p=0.009 by log rank test). Avascular scores higher than 1.5 at NFC was an independent predictor of death in SSc, suggesting that NFC can be useful for predicting SSc outcome.
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The needs of patients with systemic sclerosis--what are the difficulties encountered?
Godard, Dominique
2011-03-01
When the diagnosis of systemic sclerosis (SSc) is made and you are told "You have SSc", it is a strange feeling for the patient, because you don't yet know what it is exactly. It is a very intense shock to hear this, and it is also difficult to try to imagine what will follow. There is no cure for SSc; there are just treatments that are capable of reducing the symptoms. The main difficulties and pitfalls encountered by the patients occur: before the diagnosis; during treatment; at the hospital and with the physicians; if surgery is necessary; at home; with family and friends… How do you live with SSc? You need strong, active support to help you to live with this illness; without this, we cannot handle it. The way to communicate, to inform, to consider this disease is changing, because times are changing, patients are changing, and the opinions of the specialists are also changing. Of course it's a long way, but what we, the patients, hope for is to be better understood by you, the doctors. Please pay attention to what we say; we're the ones suffering from this disease. SSc is part of us; we are not merely medical cases! Please think about it. Together we can help you to fight, to find out more, to find a cure. Copyright © 2010 Elsevier B.V. All rights reserved.
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Sandqvist, Gunnel; Scheja, Agneta; Hesselstrand, Roger
2010-09-01
To identify factors, individual and work related, influencing work ability, and to assess the association between work ability and employment status, activities of daily life (ADLs) and quality of life in patients with SSc. Fifty-seven consecutive patients (53 females/4 males) with SSc (47 lcSSc/10 dcSSc) were included. Median age was 58 [interquartile range (IQR) 47-62] years and disease duration 14 (9-19) years. The patients were assessed for socio-demographic characteristics, disease parameters, symptoms, work ability, empowerment and adaptations in a workplace, social support, ADLs and quality of life. Work ability, assessed with the Work Ability Index (WAI) could be evaluated in 48 of 57 patients. The correlation between employment status and WAI was good (r(s) = 0.79, P < 0.001). Thirteen patients had good or excellent WAI, 15 had less good and 20 had poor WAI. There were no significant differences between subgroups of WAI and socio-demographic characteristics, disease duration or degree of skin and lung involvement. However, patients with good WAI expressed milder perceived symptoms (pain, fatigue and impaired hand function; P < 0.001). Patients with better WAI had better competence (P < 0.001), better possibility of adaptations at work (P < 0.01) and impact at work (P < 0.01) than those with poorer WAI. In SSc, pain, fatigue and impaired hand function have a dominant impact on the WAI. Employment interventions should include support in job adaptations as well as self-management strategies to help patients deal with pain and fatigue and to enhance the confidence to perform their work.
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[Fertility preservation in boys: spermatogonial stem cell transplantation and testicular grafting].
Goossens, E; Tournaye, H
2013-09-01
Spermatogonial stem cells (SSC) are the founder cells of spermatogenesis and are responsible for the lifelong production of spermatozoa. The cryopreservation and transplantation of these cells has been proposed as a fertility preservation strategy for young boys at risk for stem cell loss, i.e. patients undergoing chemotherapy for cancer or as a conditioning treatment for bone marrow transplantation. To prevent lifelong sterility in boys, two fertility restoration strategies are being developed: the injection of SSC and the grafting of testicular tissue containing SSC. Depending on the disease of the patient one of these two approaches will be applicable. Grafting has the advantage that SSC can reside within their natural niche, preserving the interactions between germ cells and their supporting cells and may therefore be regarded as the first choice strategy. However, in cases where the risk for malignant contamination of the testicular tissue is real, e.g. leukemia, transplantation of SSC by injection is preferable over grafting. Copyright © 2013 Elsevier Masson SAS. All rights reserved.
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Automated structure and flow measurement - a promising tool in nailfold capillaroscopy.
Berks, Michael; Dinsdale, Graham; Murray, Andrea; Moore, Tonia; Manning, Joanne; Taylor, Chris; Herrick, Ariane L
2018-07-01
Despite increasing interest in nailfold capillaroscopy, objective measures of capillary structure and blood flow have been little studied. We aimed to test the hypothesis that structural measurements, capillary flow, and a combined measure have the predictive power to separate patients with systemic sclerosis (SSc) from those with primary Raynaud's phenomenon (PRP) and healthy controls (HC). 50 patients with SSc, 12 with PRP, and 50 HC were imaged using a novel capillaroscopy system that generates high-quality nailfold images and provides fully-automated measurements of capillary structure and blood flow (capillary density, mean width, maximum width, shape score, derangement and mean flow velocity). Population statistics summarise the differences between the three groups. Areas under ROC curves (A Z ) were used to measure classification accuracy when assigning individuals to SSc and HC/PRP groups. Statistically significant differences in group means were found between patients with SSc and both HC and patients with PRP, for all measurements, e.g. mean width (μm) ± SE: 15.0 ± 0.71, 12.7 ± 0.74 and 11.8 ± 0.23 for SSc, PRP and HC respectively. Combining the five structural measurements gave better classification (A Z = 0.919 ± 0.026) than the best single measurement (mean width, A Z = 0.874 ± 0.043), whilst adding flow further improved classification (A Z = 0.930 ± 0.024). Structural and blood flow measurements are both able to distinguish patients with SSc from those with PRP/HC. Importantly, these hold promise as clinical trial outcome measures for treatments aimed at improving finger blood flow or microvascular remodelling. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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Cells from the skin of patients with systemic sclerosis secrete chitinase 3-like protein 1
Ho, Yuen Yee; Baron, Murray; Recklies, Anneliese D.; Roughley, Peter J.; Mort, John S.
2014-01-01
Background The chitinase-like protein, Chi3L1, is associated with increased fibrotic activity as well as inflammatory processes. The capacity of skin cells from systemic sclerosis (SSc) patients to produce Chi3L1, and the stimulation of its synthesis by cytokines or growth factors known to be associated with SSc, was investigated. Methods Cells were isolated from forearm and/or abdomen skin biopsies taken from SSc patients and normal individuals and stimulated with cytokines and growth factors to assess Chi3L1 expression. Chi3L1-expressing cells were characterized by immunohistochemical staining. Results Chi3L1 was not secreted by skin cells from normal individuals nor was its synthesis induced by any of the cytokines or growth factors investigated. In contrast, Chi3L1 secretion was induced by OSM or IL-1 in cells from all forearm biopsies of SSc patients, and endogenous secretion in the absence of cytokines was detected in several specimens. Patients with Chi3L1-producing cells at both the arm and abdomen had a disease duration of less than 3 years. Endogenous Chi3L1 production was not a property of the major fibroblast population nor of myofibroblasts, but rather was related to the presence of stem-like cells not present in normal skin. Other cells, however, contributed to the upregulation of Chi3L1 by OSM. Conclusions The emergence of cells primed to respond to OSM with increased Chi3L1 production appears to be associated with pathological processes active in SSc. General significance The presence of progenitor cells expressing the chilectin Chi3L1 in SSc skin appears to play a role in the initiation of the disease process. PMID:26675476
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López-Isac, Elena; Martín, Jose-Ezequiel; Assassi, Shervin; Simeón, Carmen P; Carreira, Patricia; Ortego-Centeno, Norberto; Freire, Mayka; Beltrán, Emma; Narváez, Javier; Alegre-Sancho, Juan J; Fernández-Gutiérrez, Benjamín; Balsa, Alejandro; Ortiz, Ana M; González-Gay, Miguel A; Beretta, Lorenzo; Santaniello, Alessandro; Bellocchi, Chiara; Lunardi, Claudio; Moroncini, Gianluca; Gabrielli, Armando; Witte, Torsten; Hunzelmann, Nicolas; Distler, Jörg HW; Riekemasten, Gabriella; van der Helm-van Mil, Annete H; de Vries-Bouwstra, Jeska; Magro-Checa, Cesar; Voskuyl, Alexandre E; Vonk, Madelon C; Molberg, Øyvind; Merriman, Tony; Hesselstrand, Roger; Nordin, Annika; Padyukov, Leonid; Herrick, Ariane; Eyre, Steve; Koeleman, Bobby PC; Denton, Christopher P; Fonseca, Carmen; Radstake, Timothy RDJ; Worthington, Jane; Mayes, Maureen D; Martín, Javier
2017-01-01
Objectives Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that share clinical and immunological characteristics. To date, several shared SSc-RA loci have been identified independently. In this study, we aimed to systematically search for new common SSc-RA loci through an inter-disease meta-GWAS strategy. Methods We performed a meta-analysis combining GWAS datasets of SSc and RA using a strategy that allowed identification of loci with both same-direction and opposing-direction allelic effects. The top single-nucleotide polymorphisms (SNPs) were followed-up in independent SSc and RA case-control cohorts. This allowed us to increase the sample size to a total of 8,830 SSc patients, 16,870 RA patients and 43,393 controls. Results The cross-disease meta-analysis of the GWAS datasets identified several loci with nominal association signals (P-value < 5 × 10-6), which also showed evidence of association in the disease-specific GWAS scan. These loci included several genomic regions not previously reported as shared loci, besides risk factors associated with both diseases in previous studies. The follow-up of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these two diseases (Pcombined = 3.29 × 10-12). In addition, the analysis of the biological relevance of the known SSc-RA shared loci pointed to the type I interferon and the interleukin 12 signaling pathways as the main common etiopathogenic factors. Conclusions Our study has identified a novel shared locus, IRF4, for SSc and RA and highlighted the usefulness of cross-disease GWAS meta-analysis in the identification of common risk loci. PMID:27111665
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A loss of telocytes accompanies fibrosis of multiple organs in systemic sclerosis
Manetti, Mirko; Rosa, Irene; Messerini, Luca; Guiducci, Serena; Matucci-Cerinic, Marco; Ibba-Manneschi, Lidia
2014-01-01
Systemic sclerosis (SSc) is a complex connective tissue disease characterized by fibrosis of the skin and various internal organs. In SSc, telocytes, a peculiar type of stromal (interstitial) cells, display severe ultrastructural damages and are progressively lost from the clinically affected skin. The aim of the present work was to investigate the presence and distribution of telocytes in the internal organs of SSc patients. Archival paraffin-embedded samples of gastric wall, myocardium and lung from SSc patients and controls were collected. Tissue sections were stained with Masson's trichrome to detect fibrosis. Telocytes were studied on tissue sections subjected to CD34 immunostaining. CD34/CD31 double immunofluorescence was performed to unequivocally differentiate telocytes (CD34-positive/CD31-negative) from vascular endothelial cells (CD34-positive/CD31-positive). Few telocytes entrapped in the fibrotic extracellular matrix were found in the muscularis mucosae and submucosa of SSc gastric wall. In the muscle layers and myenteric plexus, the network of telocytes was discontinuous or even completely absent around smooth muscle cells and ganglia. Telocytes were almost completely absent in fibrotic areas of SSc myocardium. In SSc fibrotic lung, few or no telocytes were observed in the thickened alveolar septa, around blood vessels and in the interstitial space surrounding terminal and respiratory bronchioles. In SSc, the loss of telocytes is not restricted to the skin, but it is a widespread process affecting multiple organs targeted by the fibrotic process. As telocytes are believed to be key players in the regulation of tissue/organ homoeostasis, our data suggest that telocyte loss might have important pathophysiological implications in SSc. PMID:24467430
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Cipriani, P; Guiducci, S; Miniati, I; Cinelli, M; Urbani, S; Marrelli, A; Dolo, V; Pavan, A; Saccardi, R; Tyndall, A; Giacomelli, R; Cerinic, M Matucci
2007-06-01
Systemic sclerosis (SSc) is a disorder characterized by vascular damage and fibrosis of the skin and internal organs. Despite marked tissue hypoxia, there is no evidence of compensatory angiogenesis. The ability of mesenchymal stem cells (MSCs) to differentiate into endothelial cells was recently demonstrated. The aim of this study was to determine whether impaired differentiation of MSCs into endothelial cells in SSc might contribute to disease pathogenesis by decreasing endothelial repair. MSCs obtained from 7 SSc patients and 15 healthy controls were characterized. The number of colony-forming unit-fibroblastoid colonies was determined. After culture in endothelial-specific medium, the endothelial-like MSC (EL-MSC) phenotype was assessed according to the surface expression of vascular endothelial growth factor receptors (VEGFRs). Senescence, chemoinvasion, and capillary morphogenesis studies were also performed. MSCs from SSc patients displayed the same phenotype and clonogenic activity as those from controls. In SSc MSCs, a decreased percentage of VEGFR-2+, CXCR4+, VEGFR-2+/CXCR4+ cells and early senescence was detected. After culturing, SSc EL-MSCs showed increased expression of VEGFR-1, VEGFR-2, and CXCR4, did not express CD31 or annexin V, and showed significantly decreased migration after specific stimuli. Moreover, the addition of VEGF and stromal cell-derived factor 1 to cultured SSc EL-MSCs increased their angiogenic potential less than that in controls. Our data strongly suggest that endothelial repair may be affected in SSc. The possibility that endothelial progenitor cells could be used to increase vessel growth in chronic ischemic tissues may open up new avenues in the treatment of vascular damage caused by SSc.
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NASA Astrophysics Data System (ADS)
van Hunen, J.; Zhong, S.
2006-08-01
Small-scale convection (SSC) rolls below the oceanic lithosphere have the tendency to align with the large-scale shearing direction and thus with the plate motion direction relative to the deep mantle. Understanding the timescales of and processes responsible for realignment would contribute significantly to our understanding of the unresolved phenomena in the Pacific such as gravity lineations, small-scale seismic velocity variations, and intraplate volcanism that cannot be explained by hot spots. In this study we examine the evolution of those convection rolls when this relative plate motion direction is suddenly changed, as suggested by the kink in the Hawaii-Emperor seamount chain. Using three-dimensional numerical flow models, we investigate the realignment of SSC rolls after a change in plate motion direction. From the nature of the SSC, it is expected that rheological parameters dominate the characteristics of this realignment. Our results show that this is indeed the case. We find that (1) using constraints from onset timing of SSC, realignment of rolls can occur as fast as within 20 Ma, but might also take much longer, dependent on the rheology; (2) the realignment period is strongly correlated to the sum of large-scale shear stress induced by plate motion and small-scale shear stress from the SSC itself; (3) in a mantle deforming by dislocation creep, realignment occurs faster than by diffusion creep, because dislocation creep SSC is more vigorous; and (4) activation energy has little influence on the realignment time. Possible evidence for the realignment period might come from precise age determination of intraplate volcanism or azimuthal seismic anisotropy.
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Early- versus Late-Onset Systemic Sclerosis
Alba, Marco A.; Velasco, César; Simeón, Carmen Pilar; Fonollosa, Vicent; Trapiella, Luis; Egurbide, María Victoria; Sáez, Luis; Castillo, María Jesús; Callejas, José Luis; Camps, María Teresa; Tolosa, Carles; Ríos, Juan José; Freire, Mayka; Vargas, José Antonio; Espinosa, Gerard
2014-01-01
Abstract Peak age at onset of systemic sclerosis (SSc) is between 20 and 50 years, although SSc is also described in both young and elderly patients. We conducted the present study to determine if age at disease onset modulates the clinical characteristics and outcome of SSc patients. The Spanish Scleroderma Study Group recruited 1037 patients with a mean follow-up of 5.2 ± 6.8 years. Based on the mean ± 1 standard deviation (SD) of age at disease onset (45 ± 15 yr) of the whole series, patients were classified into 3 groups: age ≤30 years (early onset), age between 31 and 59 years (standard onset), and age ≥60 years (late onset). We compared initial and cumulative manifestations, immunologic features, and death rates. The early-onset group included 195 patients; standard-onset group, 651; and late-onset, 191 patients. The early-onset group had a higher prevalence of esophageal involvement (72% in early-onset compared with 67% in standard-onset and 56% in late-onset; p = 0.004), and myositis (11%, 7.2%, and 2.9%, respectively; p = 0.009), but a lower prevalence of centromere antibodies (33%, 46%, and 47%, respectively; p = 0.007). In contrast, late-onset SSc was characterized by a lower prevalence of digital ulcers (54%, 41%, and 34%, respectively; p < 0.001) but higher rates of heart conduction system abnormalities (9%, 13%, and 21%, respectively; p = 0.004). Pulmonary hypertension was found in 25% of elderly patients and in 12% of the youngest patients (p = 0.010). After correction for the population effects of age and sex, standardized mortality ratio was shown to be higher in younger patients. The results of the present study confirm that age at disease onset is associated with differences in clinical presentation and outcome in SSc patients. PMID:24646463
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The prevalence of infectious agents in patients with systemic sclerosis.
Bilgin, Hüseyin; Kocabaş, Hilal; Keşli, Recep
2015-01-01
Systemic sclerosis (SSc) is an autoimmune disease characterized by microvascular injury, excessive extracellular matrix deposition, and fibrosis in the skin and internal organs. Bacterial and viral infectious agents have been suspected to be contributing factors in the development and progression of the pathologic features of SSc. In this study, 30 SSc patients who were admitted to the rheumatology unit of the Konya Training and Research Hospital and 30 healthy controls were included. The presence of 9 different antibodies (IgM and IgG) against Helicobacter pylori, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and parvovirus B19 were investigated in sera samples obtained from the 60 participants using an enzyme-linked immunosorbent assay method. The characteristics of current and past infections with H. pylori, CMV, EBV, and parvovirus B19 were evaluated by determining the seropositivity of the tested bacterial and viral agents. The prevalences of H. pylori, CMV, EBV, and parvovirus B19 were determined to be higher in patients with SSc than in the control group. SSc is associated with a higher rate of certain infections, which deserves further investigation in order to assess the role of infections in disease etiology/pathogenesis.
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Riccieri, Valeria; Spadaro, Antonio; Fuksa, Leos; Firuzi, Omidreza; Saso, Luciano; Valesini, Guido
2008-02-01
Oxidative stress is suggested to be involved in the pathogenesis of systemic sclerosis (SSc). The aim of the present study was to clarify such a hypothesis by determination of four different plasmatic parameters of oxidative stress, and to define its role in the microvascular damage, assessed by nailfold capillaroscopy (NC). Plasma samples of 18 patients with SSc were analyzed. The biomarkers measured were: total antioxidant capacity, hydroperoxides (ROOHs), and sulfhydryl (SH) and carbonyl (CO) groups. Each patient had a detailed clinical assessment and underwent an NC. The results showed significantly increased ROOHs in SSc patients compared to control group (5.02 +/- 0.24 vs 3.28 +/- 0.19 micromol/l; p < 0.05). Plasmatic levels of SH groups were significantly lower in SSc (0.466 +/- 0.08 mmol/l) compared to control group (0.542 +/- 0.04 mmol/l; p < 0.002). Plasma levels of ROOHs correlated with the capillaroscopy semiquantitative rating scale score (p < 0.05) and with the rating system for avascular areas (p < 0.03). The levels of CO groups inversely correlated with modified Rodnan's skin score (p < 0.039) and were lower in patients with pulmonary fibrosis (p < 0.045), while the levels of SH groups were lower in those presenting gastrointestinal involvement (p < 0.029). The obtained data indicate augmented free radical-mediated injury in SSc and also show correlations among oxidative abnormalities, some clinical findings, and signs of a more severe microvascular involvement. These results give more evidence to the connection between oxidative impairment and SSc.
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Herrick, Ariane L; Peytrignet, Sebastien; Lunt, Mark; Pan, Xiaoyan; Hesselstrand, Roger; Mouthon, Luc; Silman, Alan J; Dinsdale, Graham; Brown, Edith; Czirják, László; Distler, Jörg H W; Distler, Oliver; Fligelstone, Kim; Gregory, William J; Ochiel, Rachel; Vonk, Madelon C; Ancuţa, Codrina; Ong, Voon H; Farge, Dominique; Hudson, Marie; Matucci-Cerinic, Marco; Balbir-Gurman, Alexandra; Midtvedt, Øyvind; Jobanputra, Paresh; Jordan, Alison C; Stevens, Wendy; Moinzadeh, Pia; Hall, Frances C; Agard, Christian; Anderson, Marina E; Diot, Elisabeth; Madhok, Rajan; Akil, Mohammed; Buch, Maya H; Chung, Lorinda; Damjanov, Nemanja S; Gunawardena, Harsha; Lanyon, Peter; Ahmad, Yasmeen; Chakravarty, Kuntal; Jacobsen, Søren; MacGregor, Alexander J; McHugh, Neil; Müller-Ladner, Ulf; Riemekasten, Gabriela; Becker, Michael; Roddy, Janet; Carreira, Patricia E; Fauchais, Anne Laure; Hachulla, Eric; Hamilton, Jennifer; İnanç, Murat; McLaren, John S; van Laar, Jacob M; Pathare, Sanjay; Proudman, Susanna M; Rudin, Anna; Sahhar, Joanne; Coppere, Brigitte; Serratrice, Christine; Sheeran, Tom; Veale, Douglas J; Grange, Claire; Trad, Georges-Selim; Denton, Christopher P
2018-04-01
Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. NCT02339441. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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Coghlan, John Gerry; Galiè, Nazzareno; Barberà, Joan Albert; Frost, Adaani E; Ghofrani, Hossein-Ardeschir; Hoeper, Marius M; Kuwana, Masataka; McLaughlin, Vallerie V; Peacock, Andrew J; Simonneau, Gérald; Vachiéry, Jean-Luc; Blair, Christiana; Gillies, Hunter; Miller, Karen L; Harris, Julia H N; Langley, Jonathan; Rubin, Lewis J
2017-01-01
Background Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH. Objective To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial. Methods This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response). Results In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups. Conclusions This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy. Trial registration number NCT01178073, post results. PMID:28039187
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Coghlan, John Gerry; Galiè, Nazzareno; Barberà, Joan Albert; Frost, Adaani E; Ghofrani, Hossein-Ardeschir; Hoeper, Marius M; Kuwana, Masataka; McLaughlin, Vallerie V; Peacock, Andrew J; Simonneau, Gérald; Vachiéry, Jean-Luc; Blair, Christiana; Gillies, Hunter; Miller, Karen L; Harris, Julia H N; Langley, Jonathan; Rubin, Lewis J
2017-07-01
Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH. To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial. This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response). In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups. This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy. NCT01178073, post results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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Lescoat, Alain; Ballerie, Alice; Augagneur, Yu; Morzadec, Claudie; Vernhet, Laurent; Fardel, Olivier; Jégo, Patrick; Jouneau, Stéphane; Lecureur, Valérie
2018-03-17
Macrophages play a central role in the pathogenesis of inflammatory and fibrotic lung diseases. However, alveolar macrophages (AM) are poorly available in humans to perform in vitro studies due to a limited access to broncho-alveolar lavage (BAL). In this study, to identify the best alternative in vitro model for human AM, we compared the phenotype of AM obtained from BAL of patients suffering from three lung diseases (lung cancers, sarcoidosis and Systemic Sclerosis (SSc)-associated interstitial lung disease) to human blood monocyte-derived macrophages (MDMs) differentiated with M-CSF or GM-CSF. The expression of eight membrane markers was evaluated by flow cytometry. Globally, AM phenotype was closer to GM-CSF MDMs. However, the expression levels of CD163, CD169, CD204, CD64 and CD36 were significantly higher in SSc-ILD than in lung cancers. Considering the expression of CD204 and CD36, the phenotype of SSc-AM was closer to MDMs, from healthy donors or SSc patients, differentiated by M-CSF rather than GM-CSF. The comparative secretion of IL-6 by SSc-MDMs and SSc-AM is concordant with these phenotypic considerations. Altogether, these results support the M-CSF MDM model as a relevant in vitro alternative to simulate AM in fibrotic disorders such as SSc.
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Wang, Jia-hua; Qi, Shu-ye; Tang, Zhi-hui; Jia, Shou-xing; Li, Yong-yu
2012-05-01
Visible (Vis)/near infrared (NIR) spectroscopy has been used successfully to measure soluble solids content (SSC) in fruit. However, for practical implementation, the NIR technique needs to be able to compensate for fruit temperature fluctuations, as it was observed that the sample temperature affects the NIR spectrum. A portable Vis/NIR spectrometer was used to collect diffused transmittance spectra of apples at different temperatures (0-30 degrees C). The spectral data of apple at 20 degrees C was used to develop a norm partial least squares (PLS) model. Slope/bias technique was found to well suits to control the accuracy of the calibration model for SSC concerning temperature fluctuations. The correctional PLS models were used to predict the SSC of apple at 0, 10 and 30 degrees C, respectively. The correctional method was found to perform well with Q values of 0.810, 0.822 and 0.802, respectively. When no precautions are taken, the Q value on the SSC may be as small as 0.525-0.680. The results obtained highlight the potential of portable Vis/NIR instruments for assessing internal quality of fruits on site under varying weather conditions.
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Noninvasive imaging techniques in the assessment of scleroderma spectrum disorders.
Murray, Andrea K; Moore, Tonia L; Manning, Joanne B; Taylor, Christopher; Griffiths, Christopher E M; Herrick, Ariane L
2009-08-15
Systemic sclerosis (SSc) affects both microvascular structure and function. Laser Doppler imaging (LDI) and thermal imaging can be used to measure cutaneous blood vessel function. Nailfold capillaroscopy (NC) measures capillary morphology. The aim of this study was to investigate the relationship between capillary morphology and blood flow, and to determine which combination of techniques allows the best discrimination between patients with SSc, primary Raynaud's phenomenon (RP), and healthy controls. NC was performed in 16 patients with SSc, 14 patients with primary RP, and 16 healthy controls. In addition, participants underwent cold stimulus with cold water. Hands were imaged to monitor rewarming and reperfusion. Nailfold morphologic features were measured and baseline images and rewarming curves were analyzed. Significant differences were found between groups (analysis of variance) for capillary morphologic features and rewarming curve characteristics. A correlation (P < 0.001) was found between LDI and thermal imaging at baseline (0.667) and maximum (0.729) blood flow and skin temperature, and for the areas under the rewarming curves (0.684). Receiver operating characteristic curves indicated that NC, thermal imaging, and LDI allowed 89%, 74%, and 72%, respectively, of SSc patient data to be correctly classified versus primary RP patients and controls. NC, LDI, and thermal imaging each independently provide good discrimination between patients with SSc and those with primary RP and healthy controls (NC being the most suitable technique for classifying patient groups). However, a combination of all 3 techniques improves classification. LDI and thermal imaging give equivalent information on dynamic changes in the cutaneous microcirculation; however, these only weakly correspond to capillary morphology.
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Golemati, Christina V; Moutsopoulos, Haralampos M; Vlachoyiannopoulos, Panayiotis G
2013-01-01
The aim of this paper is to assess the psychological characteristics of personality, depression, anxiety, social support and coping strategies of systemic sclerosis (SSc) patients, their inter-correlations and their association with clinical symptoms. Patients with SSc (n=85) were interviewed and compared to rheumatoid arthritis (RA) patients (n=120) and healthy controls (HCs [n=125]). Psychological characteristics were assessed by the following psychometric scales: centre of epidemiological studies of depression (CES-D), hospital anxiety and depression scale (HAD), Eysenck personality questionnaire (EPQ), short form of social support (SSq), life experiences survey (LES) and ways of coping (WoC). Clinical data were collected at the same time of the interview. Both control groups were matched to SSc patients in terms of gender, age and educational status. Data were analysed with SPSS software. Compared to control groups, SSc patients expressed more symptoms of depression and anxiety, showed less extraversion and reported more negative life events. They coped less often with positive reappraisal, problem solving, seeking of support and assertiveness, while they sought more often divine help, and they expressed wishing and denial. Inactive disease was associated with a lower probability of reporting depressive symptoms and negative life events and with a higher probability of positively reevaluating a problem. Lung dysfunction, skin involvement, esophageal problems and oral aperture correlated with psychological features. Complications in psychological well-being characterise patients with SSc. This finding, as well as that of psychological characteristics correlating with organic factors, is an indication for designing supportive psycho-educational programmes as complementary therapies.
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NASA Astrophysics Data System (ADS)
Kilham, N. E.
2009-12-01
Image analysis was applied to assess suspended sediment concentrations (SSC) predicted by a numerical model of 2D hydraulics and sediment transport (Telemac-2D), coupled to a solver for the advection-diffusion equation (SISYPHE) and representing 18 days of flooding over 70 kilometers of the lower Feather-Yuba Rivers. Sisyphe treats the suspended load as a tracer, removed from the flow if the bed shear velocity, u* is lower than an empirically derived threshold (ud* = 7.8E-3 m s-1). Agreement between model (D50 = 0.03 mm) and image-derived SSC (mg L-1) suggests that image interpretation could prove to be a viable approach for verifying spatially-distributed models of floodplain sediment transport if imagery is acquired for a particular flood and at a sufficient spatial and radiometric resolution. However, remotely derived SSC represents the integrated concentration of suspended sediment at the water surface. Hence, comparing SSC magnitudes derived from imagery and numerical modeling requires that a relationship is first established between the total suspended load and the portion of this load suspended within the optical range of the sensor (e.g., Aalto, 1995). Using the optical depth (0.5 m) determined from radiative transfer modeling, surface SSC measured from a 1/14/97 Landsat TM5 image (30 m) were converted to depth-integrated SSC with the Rouse (1937) equation. Surface concentrations were derived using a look-up table for the sensor to convert endmember fractions obtained from a spectral mixture analysis of the image. A two-endmember model (2.0 and 203 mg L-1) was used, with synthetic endmembers derived from optical and radiative transfer modeling and inversion of field spectra collected from the Sacramento and Feather Rivers and matched to measured SSC values. Remotely sensed SSC patterns were then compared to the Telemac results for the same day and time. Modeled concentrations are a function of both the rating curve boundary conditions, and the transport and deposition calculations. At each of three upstream channel boundaries, hourly SSC was derived from instantaneous discharge and SSC records at USGS gages for winter months (December-April) following dam closure on the Feather, Yuba, and Bear Rivers (r2 = 0.61; r2 = 0.81; r2 = 0.55). Model channel concentrations declined downstream from about 90 mg L-1 to 40 mg L-1 as sediment input was depleted through decanting of river water overbank, advection through floodplain channels, and deposition onto the floodplain. Similar downstream declines in the image values suggest that bed and bank erosion downstream of the major gages did not contribute much new sediment two weeks following the flood peak. Model predicted concentrations agree with image derived concentrations to within 10 mg L-1, although the model predicts a more rapid drawdown of floodplain flow than is apparent from the image. Aalto, R., 1995. Discordance between suspended sediment diffusion theory and observed sediment concentration profiles in rivers. M.S., University of Washington, Seattle, WA. Rouse, H.R., 1937. Modern conceptions of the mechanics of turbulence. Transactions, American Society of Civil Engineers, 102: 463-543.
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An Ultrasound Surface Wave Technique for Assessing Skin and Lung Diseases.
Zhang, Xiaoming; Zhou, Boran; Kalra, Sanjay; Bartholmai, Brian; Greenleaf, James; Osborn, Thomas
2018-02-01
Systemic sclerosis (SSc) is a multi-organ connective tissue disease characterized by immune dysregulation and organ fibrosis. Severe organ involvement, especially of the skin and lung, is the cause of morbidity and mortality in SSc. Interstitial lung disease (ILD) includes multiple lung disorders in which the lung tissue is fibrotic and stiffened. The purpose of this study was to translate ultrasound surface wave elastography (USWE) for assessing patients with SSc and/or ILD via measuring surface wave speeds of both skin and superficial lung tissue. Forty-one patients with both SSc and ILD and 30 healthy patients were enrolled in this study. An external harmonic vibration was used to generate the wave propagation on the skin or lung. Three excitation frequencies of 100, 150 and 200 Hz were used. An ultrasound probe was used to measure the wave propagation in the tissue non-invasively. Surface wave speeds were measured on the forearm and upper arm of both left and right arm, as well as the upper and lower lungs, through six intercostal spaces of patients and healthy patients. Viscoelasticity of the skin was calculated by the wave speed dispersion with frequency using the Voigt model. The magnitudes of surface wave speed and viscoelasticity of patients' skin were significantly higher than those of healthy patients (p <0.0001) for each location and each frequency. The surface wave speeds of patients' lung were significantly higher than those of healthy patients (p <0.0001) for each location and each frequency. USWE is a non-invasive and non-ionizing technique for measuring both skin and lung surface wave speed and may be useful for quantitative assessment of SSc and/or ILD. Copyright © 2018 World Federation for Ultrasound in Medicine and Biology. Published by Elsevier Inc. All rights reserved.
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Sternal Skin Conductance: A reasonable surrogate for Hot Flash Measurement?
Pachman, Deirdre R.; Loprinzi, Charles L.; Novotny, Paul J; Satele, Daniel V; Linquist, Breanna M.; Wolf, Sherry; Barton, Debra L.
2013-01-01
Objective The aim of this study was to examine the accuracy of a new sternal skin conductance (SSC) device for the measurement of hot flashes, and secondly, to assess the acceptability of the device by women. Methods Three small descriptive pilot studies were performed utilizing two sequential prototypes of the SSC device developed by an engineering device company in the Midwest. The devices were worn either in a monitored setting for 24 hours or in an ambulatory setting for 5 weeks. During the study period, women recorded hot flashes in a prospective hot flash diary and also answered questions about the acceptability of wearing the SSC device. Results The first prototype was not able to collect any analyzable skin conductance data due to various malfunction issues; including poor conductance and battery failure. However, 16 patients did wear the device for 5 weeks and reported that wearing the device was acceptable, although 31% stated that it did interfere with daily activities. Hot flash data from the second prototype revealed a concordance rate between patient reported and device recorded hot flashes of 24%. Conclusions Findings from these studies support the discordance between SSC recorded and patient reported hot flashes. In addition, the studies reveal further limitations of SSC monitoring, including difficulties with data collection and lack of consistency in interpretation. Based on these results and other recent trials identifying issues with SSC methodology, it is time to find a better physiologic surrogate measure for hot flashes. PMID:23571528
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Khanna, Dinesh; Albera, Carlo; Fischer, Aryeh; Khalidi, Nader; Raghu, Ganesh; Chung, Lorinda; Chen, Dan; Schiopu, Elena; Tagliaferri, Margit; Seibold, James R; Gorina, Eduard
2016-09-01
Systemic sclerosis-associated interstitial lung disease (SSc-ILD) shares a number of clinical features and pathogenic mechanisms with idiopathic pulmonary fibrosis (IPF). This study was designed to evaluate the tolerability of the IPF treatment pirfenidone in SSc-ILD. The known gastrointestinal, skin, and liver adverse events (AE) of pirfenidone are of importance given the involvement of these organs in SSc. All patients received pirfenidone and were randomized 1:1 to either a 2- or 4-week titration starting at 801 mg/day and finishing at a maintenance dose of 2403 mg/day. Patients received pirfenidone for 16 weeks in total. Assessments included treatment-emergent AE (TEAE) and exploratory disease outcomes. Sixty-three patients were randomized; 96.8% experienced a TEAE and more patients reported TEAE during the titration versus the maintenance period. The most commonly reported TEAE were consistent with those observed for pirfenidone in IPF (nausea, headache, fatigue) and were similar regardless of titration schedule. More patients discontinued treatment because of TEAE in the 2- versus 4-week titration group (5 vs 1, respectively); all discontinuation events occurred > 3 weeks after reaching the full dose of pirfenidone. Mycophenolate mofetil (MMF), taken by 63.5% of patients in addition to pirfenidone, did not appear to affect tolerability. Exploratory disease outcomes remained largely unchanged. Pirfenidone showed an acceptable tolerability profile in SSc-ILD, although a longer titration may be associated with better tolerability. Tolerability was not affected by concomitant MMF. The present findings support further investigation of pirfenidone in future clinical trials in patients with SSc-ILD. ClinicalTrials.gov; www.clinicaltrials.gov NCT01933334.
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The effect of weave orientation on the BRDF of tarp samples
NASA Astrophysics Data System (ADS)
Georgiev, Georgi; Butler, James J.
2003-10-01
The results of bi-directional reflectance distribution function (BRDF) measurements of four tarp samples obtained from NASA"s Stennis Space Center (SSC) are presented. The measurements were performed in the Diffuser Calibration Facility (DCaF) at NASA"s Goddard Space Flight Center (GSFC). The samples are of similar material structure but different reflectance. The experimental data were obtained with a Xe arc lamp/monochromator light source as well as laser light sources in the ultraviolet, visible, and near infrared spectral regions. The BRDF data were recorded at four incident zenith angles and at five incident azimuth angles. The dependence of the measured BRDF on weave orientation was analyzed and presented. 8 degree irectional/hemispherical reflectance data were also measured for each tarp sample, and those results are also reported. All results are NIST traceable through calibrated standard plates. The specular and diffuse scatter data obtained from these studies are used by NASA"s SSC in their field-based, vicarious calibration of satellite and airborne remote sensing instruments.
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Lee, Chun Geun; Herzog, Erica L.; Ahangari, Farida; Zhou, Yang; Gulati, Mridu; Lee, Chang-Min; Peng, Xueyan; Feghali-Bostwick, Carol; Jimenez, Sergio A.; Varga, John; Elias, Jack A.
2014-01-01
Interstitial lung disease (ILD) with pulmonary fibrosis is an important manifestation in systemic sclerosis (SSc, scleroderma) where it portends a poor prognosis. However, biomarkers that predict the development and or severity of SSc-ILD have not been validated, and the pathogenetic mechanisms that engender this pulmonary response are poorly understood. In this study, we demonstrate in two different patient cohorts that the levels of chitotriosidase (Chit1) bioactivity and protein are significantly increased in the circulation and lungs of SSc patients compared with demographically matched controls. We also demonstrate that, compared with patients without lung involvement, patients with ILD show high levels of circulating Chit1 activity that correlate with disease severity. Murine modeling shows that in comparison with wild-type mice, bleomycin-induced pulmonary fibrosis was significantly reduced in Chit1−/− mice and significantly enhanced in lungs from Chit1 overexpressing transgenic animals. In vitro studies also demonstrated that Chit1 interacts with TGF-β1 to augment fibroblast TGF-β receptors 1 and 2 expression and TGF-β–induced Smad and MAPK/ERK activation. These studies indicate that Chit1 is potential biomarker for ILD in SSc and a therapeutic target in SSc-associated lung fibrosis and demonstrate that Chit1 augments TGF-β1 effects by increasing receptor expression and canonical and noncanonical TGF-β1 signaling. PMID:22826322
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Koturan, Surya; Ko, Jeong-Hun; Fonseca, Carmen; Harmston, Nathan; Game, Laurence; Martin, Javier; Ong, Voon; Abraham, David J; Denton, Christopher P; Behmoaras, Jacques; Petretto, Enrico
2018-01-01
Objectives Several common and rare risk variants have been reported for systemic sclerosis (SSc), but the effector cell(s) mediating the function of these genetic variants remains to be elucidated. While innate immune cells have been proposed as the critical targets to interfere with the disease process underlying SSc, no studies have comprehensively established their effector role. Here we investigated the contribution of monocyte-derived macrophages (MDMs) in mediating genetic susceptibility to SSc. Methods We carried out RNA sequencing and genome-wide genotyping in MDMs from 57 patients with SSc and 15 controls. Our differential expression and expression quantitative trait locus (eQTL) analysis in SSc was further integrated with epigenetic, expression and eQTL data from skin, monocytes, neutrophils and lymphocytes. Results We identified 602 genes upregulated and downregulated in SSc macrophages that were significantly enriched for genes previously implicated in SSc susceptibility (P=5×10−4), and 270 cis-regulated genes in MDMs. Among these, GSDMA was reported to carry an SSc risk variant (rs3894194) regulating expression of neighbouring genes in blood. We show that GSDMA is upregulated in SSc MDMs (P=8.4×10−4) but not in the skin, and is a significant eQTL in SSc macrophages and lipopolysaccharide/interferon gamma (IFNγ)-stimulated monocytes. Furthermore, we identify an SSc macrophage transcriptome signature characterised by upregulation of glycolysis, hypoxia and mTOR signalling and a downregulation of IFNγ response pathways. Conclusions Our data further establish the link between macrophages and SSc, and suggest that the contribution of the rs3894194 risk variant to SSc susceptibility can be mediated by GSDMA expression in macrophages. PMID:29348297
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Luciano, Laure; Granel, Brigitte; Bernit, Emmanuelle; Harle, Jean-Robert; Baumstarck, Karine; Grimaud, Jean-Charles; Bouvier, Michel; Vitton, Véronique
2016-01-01
In systemic sclerosis (SSc), esophageal and anorectal involvements are frequent and often associated with each other. In clinical practice, esophageal explorations are often prescribed, while anorectal explorations are rarely proposed and therefore, under-recognised. However, it is well documented in the literature that early detection of anorectal dysfunction could delay and/or prevent the onset of symptoms such as fecal incontinence (FI). The main objective was the systematic evaluation and detection of esophageal and anorectal involvements in SSc patients. In this monocentric retrospective study, all patients with SSc addressed in the Department of Functional Digestive Explorations, North Hospital, Marseille for esophageal and anorectal explorations were included. Self-Questionnaires, evaluating the symptoms and quality of life, were filled by patients during their visit. Explorations were performed on the same day: high resolution esophageal manometry (EHRM), 3 Dimensional high resolution anorectal manometry (3DHRARM) and endo anal sonography (EUS). 44 patients (41 women), mean age 59.8±12 years, were included. With regard to the symptoms, 45.5% of patients had gastro-esophageal reflux disease (GERD), 66.9% dysphagia, 65.9% constipation and 77.3% FI. The incidence of esophageal dismotility was 65.9%, anorectal and both upper and lower dysfunction were 43.2%. More than 89% patients with abnormal explorations (EHRM, 3DHRARM or both) were symptomatic. Duration of SSc and altered quality of life was correlated with the severity of digestive involvement. Anorectal dysfunction appears to be closely linked to esophageal involvement in SSc. Their routine screening is undoubtedly essential to limit the occurrence of severe symptoms such as FI.
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Mattsson, M; Boström, C; Mihai, C; Stöcker, J; Geyh, S; Stummvoll, G; Gard, G; Möller, B; Hesselstrand, R; Sandqvist, G; Draghicescu, O; Gherghe, A M; Voicu, M; Distler, O; Smolen, J S; Stamm, T A
2015-08-01
Systemic sclerosis (SSc) is an autoimmune disease where thickening of the skin can lead to reduced body function and limitations in activities. Severe forms can also affect and seriously damage inner organs. Patient-centred rehabilitation emphasises considerations of patients' background, experience and behavior which highlights the need to know if patient-reported outcome measures (PROMs) include such personal factors. To identify and describe personal factors in the experiences of functioning and health of persons with SSc and to examine if and to what extent PROMs in SSc research cover these factors. Data from a qualitative study with focus group interviews were analysed. PROMs in SSc research were identified in a literature review between 2008-2013. Participants were recruited from outpatient clinics at rheumatology department. Sixty-three patients with SSc from four European countries participated. Data from interviews were analysed using a structure of personal factors developed by Geyh et al. Identified PROMs were analysed and linked to main concepts, related to the personal factors, found in the interview data. Nineteen main concepts were related to the area "patterns of experience and behaviour" in the personal factor structure, 16 to "thoughts and beliefs", nine to "feelings", one to "motives" and one to "personal history and biography", respectively. Among the 35 PROMs identified, 15 did not cover any of the identified concepts. Concepts within the area "feelings" were mostly covered by the PROMs. Five of the PROMs covered "patterns of experience and behaviour", while "motives" and "personal history and biography" were not covered at all. Four of the identified PROMs covered concepts within the areas "feelings", "thoughts and beliefs" and "patterns of experience and behaviour" in the same instrument. The Illness Cognition Questionnaire and Illness Behaviour Questionnaire were such PROMs. Patterns of experience and behaviour had the highest number of concepts related to personal factors, but few of the PROMs in SSc research covered these factors. Only a few PROMs covered several personal factors areas in the same instrument. The results would be of value when developing core sets for outcome measurements in SSc.
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Neurologic involvement in scleroderma: a systematic review.
Amaral, Tiago Nardi; Peres, Fernando Augusto; Lapa, Aline Tamires; Marques-Neto, João Francisco; Appenzeller, Simone
2013-12-01
To perform a systematic review of neurologic involvement in Systemic sclerosis (SSc) and Localized Scleroderma (LS), describing clinical features, neuroimaging, and treatment. We performed a literature search in PubMed using the following MeSH terms, scleroderma, systemic sclerosis, localized scleroderma, localized scleroderma "en coup de sabre", Parry-Romberg syndrome, cognitive impairment, memory, seizures, epilepsy, headache, depression, anxiety, mood disorders, Center for Epidemiologic Studies Depression (CES-D), SF-36, Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Patient Health Questionnaire-9 (PHQ-9), neuropsychiatric, psychosis, neurologic involvement, neuropathy, peripheral nerves, cranial nerves, carpal tunnel syndrome, ulnar entrapment, tarsal tunnel syndrome, mononeuropathy, polyneuropathy, radiculopathy, myelopathy, autonomic nervous system, nervous system, electroencephalography (EEG), electromyography (EMG), magnetic resonance imaging (MRI), and magnetic resonance angiography (MRA). Patients with other connective tissue disease knowingly responsible for nervous system involvement were excluded from the analyses. A total of 182 case reports/studies addressing SSc and 50 referring to LS were identified. SSc patients totalized 9506, while data on 224 LS patients were available. In LS, seizures (41.58%) and headache (18.81%) predominated. Nonetheless, descriptions of varied cranial nerve involvement and hemiparesis were made. Central nervous system involvement in SSc was characterized by headache (23.73%), seizures (13.56%) and cognitive impairment (8.47%). Depression and anxiety were frequently observed (73.15% and 23.95%, respectively). Myopathy (51.8%), trigeminal neuropathy (16.52%), peripheral sensorimotor polyneuropathy (14.25%), and carpal tunnel syndrome (6.56%) were the most frequent peripheral nervous system involvement in SSc. Autonomic neuropathy involving cardiovascular and gastrointestinal systems was regularly described. Treatment of nervous system involvement, on the other hand, varied in a case-to-case basis. However, corticosteroids and cyclophosphamide were usually prescribed in severe cases. Previously considered a rare event, nervous system involvement in scleroderma has been increasingly recognized. Seizures and headache are the most reported features in LS en coup de sabre, while peripheral and autonomic nervous systems involvement predominate in SSc. Moreover, recently, reports have frequently documented white matter lesions in asymptomatic SSc patients, suggesting smaller branches and perforating arteries involvement. Copyright © 2013 Elsevier Inc. All rights reserved.
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Luchetti, Michele M; Moroncini, Gianluca; Jose Escamez, Maria; Svegliati Baroni, Silvia; Spadoni, Tatiana; Grieco, Antonella; Paolini, Chiara; Funaro, Ada; Avvedimento, Enrico V; Larcher, Fernando; Del Rio, Marcela; Gabrielli, Armando
2016-09-01
To describe a skin-SCID mouse chimeric model of systemic sclerosis (SSc; scleroderma) fibrosis based on engraftment of ex vivo-bioengineered skin using skin cells derived either from scleroderma patients or from healthy donors. Three-dimensional bioengineered skin containing human keratinocytes and fibroblasts isolated from skin biopsy specimens from healthy donors or SSc patients was generated ex vivo and then grafted onto the backs of SCID mice. The features of the skin grafts were analyzed by immunohistochemistry, and the functional profile of the graft fibroblasts was defined before and after treatment with IgG from healthy controls or SSc patients. Two procedures were used to investigate the involvement of platelet-derived growth factor receptor (PDGFR): 1) nilotinib, a tyrosine kinase inhibitor, was administered to mice before injection of IgG from SSc patient sera (SSc IgG) into the grafts, and 2) human anti-PDGFR monoclonal antibodies were injected into the grafts. Depending on the type of bioengineered skin grafted, the regenerated human skin exhibited either the typical scleroderma phenotype or the healthy human skin architecture. Treatment of animals carrying healthy donor skin grafts with SSc IgG resulted in the appearance of a bona fide scleroderma phenotype, as confirmed by increased collagen deposition and fibroblast activation markers. Results of the experiments involving administration of nilotinib or monoclonal antibodies confirmed the involvement of PDGFR. Our results provide the first in vivo demonstration of the fibrotic properties of anti-PDGFR agonistic antibodies. This bioengineered skin-humanized mouse model can be used to test in vivo the progression of the disease and to monitor response to antifibrotic drugs. © 2016, American College of Rheumatology.
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What tests should you use to assess small intestinal bacterial overgrowth in systemic sclerosis?
Braun-Moscovici, Yolanda; Braun, Marius; Khanna, Dinesh; Balbir-Gurman, Alexandra; Furst, Daniel E
2015-01-01
Small intestinal bacterial overgrowth (SIBO) plays a major role in the pathogenesis of malabsorption in SSc patients and is a source of great morbidity and even mortality, in those patients. This manuscript reviews which tests are valid and should be used in SSc when evaluating SIBO. We performed systematic literature searches in PubMed, Embase and the Cochrane library from 1966 up to November 2014 for English language, published articles examining bacterial overgrowth in SSc (e.g. malabsorption tests, breath tests, xylose test, etc). Articles obtained from these searches were reviewed for additional references. The validity of the tests was evaluated according to the OMERACT principles of truth, discrimination and feasibility. From a total of 65 titles, 22 articles were reviewed and 20 were ultimately extracted to examine the validity of tests for GI morphology, bacterial overgrowth and malabsorption in SSc. Only 1 test (hydrogen and methane breath tests) is fully validated. Four tests are partially validated, including jejunal cultures, xylose, lactulose tests, and 72 hours fecal fat test. Only 1 of a total of 5 GI tests of bacterial overgrowth (see above) is fully validated in SSc. For clinical trials, fully validated tests are preferred, although some investigators use partially validated tests (4 tests). Further validation of GI tests in SSc is needed.
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Yu, Sebastian; Hu, Stephen Chu-Sung; Yu, Hsin-Su; Chin, Yi-Ying; Cheng, Yang-Chun; Lee, Chih-Hung
2018-06-05
Skin physiology measurement is receiving more attention for detecting vasculopathy in systemic sclerosis (SSc). Laser Doppler flowmetry (LDF) is a widely used physiological measurement to assess cutaneous microcirculation. However, findings of LDF may be normal during early stage of microangiopathy in SSc. We hypothesized that cold stress test combined with LDF could detect early-stage microangiopathy in patients with SSc. A 67-year-old male came with multiple ulcerations on his fingers for one year. After excluding diseases such as diabetes mellitus-related peripheral arterial occlusive disease and smoking-related Buerger's disease, the diagnosis of SSc was made according to the 2013 ACR/EULAR criteria. We performed LDF and angiography for a patient with SSc and compared the results. Although occlusions of right ulnar and digital arteries were obvious in angiography, the baseline skin temperature and perfusion unit on right fingers remained within normal limits. While the microcirculatory abnormalities measured by LDF alone are subtle, LDF combined with cold stress test detected a significant slow recovery of skin blood flow 40 minutes after cold immersion. In conclusion, there may be discordance between macrovasculopathy and baseline microcirculatory blood flow in SSc. In such a case, cold immersion test is essential to measure the dynamic change and slow recovery of blood flow.
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Weber, Malte; Weiss, Etienne; Engel, Alfred M
2003-07-01
Scl-70 is the major antigen recognised by autoantibodies in the sera of patients with systemic sclerosis (SSc). The autoantibodies that specifically react with Scl-70 are highly characteristic of the disease and represent valuable markers for the diagnosis of SSc. We describe a novel strategy for cloning autoantibody fragments starting with a small blood sample from an SSc patient. B cells isolated from the collected peripheral blood mononuclear cells (PBMCs) were cultured in vitro using the EL4-B5 system. Anti-Scl-70 IgG-producing cells were pooled for RNA preparation followed by the generation of phagemid libraries of approximately 10(7) independent single-chain Fvs (scFvs). The screening of these libraries by phage display allowed us to isolate four anti-Scl-70 scFvs following three rounds of biopanning. About 10 times more starting blood material was needed to generate scFv libraries of similar size from PBMCs of an SSc patient and only two anti-Scl-70 scFvs were isolated after three rounds of phage selection. Together, this work shows that functional autoantibody fragments can be advantageously cloned after in vitro expansion of B cells. The isolated anti-Scl-70 autoantibody fragments represent useful tools for calibrating SSc diagnostic assays.
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Intestinal microbiome in scleroderma: recent progress.
Volkmann, Elizabeth R
2017-11-01
Our evolving understanding of how gut microbiota affects immune function and homeostasis has led many investigators to explore the potentially pathologic role of gut microbiota in autoimmune diseases. This review will discuss the rapidly advancing field of microbiome research in systemic sclerosis (SSc), an incurable autoimmune disease with significant gastrointestinal morbidity and mortality. Recent reports have identified common perturbations in gut microbiota across different SSc cohorts. Compared with healthy controls, patients with SSc have decreased abundance of beneficial commensal genera (e.g. Faecalibacterium, Clostridium and Bacteroides) and increased abundance of pathbiont genera (e.g. Fusobacterium, Prevotella and Erwinia). Certain genera may protect against (e.g. Bacteroides, Clostridium, and Lactobacillus), or conversely exacerbate (e.g. Fusobacterium and Prevotella) gastrointestinal symptoms in SSc. These genera represent potential targets to avert or treat gastrointestinal dysfunction in SSc. Emerging evidence suggests that alterations in gut microbiota exist in the SSc disease state; however, future basic and clinical studies are needed to ascertain the mechanism by which these alterations perpetuate inflammation and fibrosis in SSc. Therapeutic trials are also needed to investigate whether dietary interventions or fecal transplantation can restore the gut microbial balance and improve health outcomes in SSc. VIDEO ABSTRACT: http://links.lww.com/COR/A38.
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Ingegnoli, Francesca; Carmona, Loreto; Castrejon, Isabel
2017-04-01
The EULAR Outcome Measures Library (OML) is a freely available database of validated patient-reported outcomes (PROs). The aim of this study was to provide a comprehensive review of validated PROs specifically developed for systemic sclerosis (SSc) to feed the EULAR OML. A sensitive search was developed in Medline and Embase to identify all validation studies, cohort studies, reviews, or meta-analyses in which the objective were the development or validation of specific PROs evaluating organ involvement, disease activity or damage in SSc. A reviewer screened title and abstracts, selected the studies, and collected data concerning validation using ad hoc forms based on the COSMIN checklist. From 13,140 articles captured, 74 met the predefined criteria. After excluding two instruments as they were unavailable in English the selected 23 studies provided information on seven SSc-specific PROs on different SSc domains: burden of illness (symptom burden index), functional status (Scleroderma Assessment Questionnaire), functional ability (scleroderma Functional Score), Raynaud's phenomenon (Raynaud's condition score), mouth involvement (Mouth Handicap in SSc), gastro-intestinal involvement (University of California Los Angeles-Scleroderma Clinical Trial Consortium Gastro-Intestinal tract 2.0), and skin involvement (skin self-assessment). Each of them is partially validated and has different psychometric requirements. Seven SSc-specific PROs have a minimum validation and were included in the EULAR OML. Further development in the area of disease-specific PROs in SSc is warranted. Copyright © 2017 Elsevier Inc. All rights reserved.
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[Nailfold capillaroscopy: relevance to the practice of rheumatology].
Souza, Eduardo José do Rosário E; Kayser, Cristiane
2015-01-01
Nailfold capillaroscopy is a simple, low-cost method, that is extremely important in the evaluation of patients with Raynaud's phenomenon and of patients with systemic sclerosis (SSc) spectrum diseases. Besides its importance for the early diagnosis of SSc, nailfold capillaroscopy is a useful tool to identify scleroderma patients with high risk for development of vascular and visceral complications and death. The inclusion of capillaroscopy in the new classification criteria for SSc of the American College of Rheumatology (ACR) and European League Against Rheumatism (Eular) gives a new impetus to the use and dissemination of the method. In this paper, we present a didactic, non-systematic review on the subject, with emphasis on advances recently described. Copyright © 2014 Elsevier Editora Ltda. All rights reserved.
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Riccieri, V; Germano, V; Alessandri, C; Vasile, M; Ceccarelli, F; Sciarra, I; Di Franco, M; Spadaro, A; Valesini, G
2008-01-01
Anti-endothelial cell antibodies (AECA) have been described in systemic sclerosis (SSc) but their clinical relevance is unclear. Aim of this study was to measure serum levels of AECA in 62 SSc patients, examining the main clinical and laboratory features, including nailfold capillaroscopy (NC) abnormalities and looking for any significant association. Fourteen patients (23%) were AECA positive. An "early" NC pattern was observed in 21 patients (34%), an "active" pattern in 24 (39%) and a "late" pattern in 17 cases (27%). In those patients with AECA, a "late" NC pattern was significantly more frequent respect to the "early" and "late" patterns (p<0.05); besides AECA serum levels were significantly higher in the "late" group of patients respect to the other two (p<0.04 and p<0.02 respectively), also showing a significantly more severe modified skin score (mSS) (> or =15) (p<0.04), while those cases with more aggressive NC patterns ("active" and "late") had a more frequent finding of arterial hypertension (p<0.05) and cardiac involvement (p<0.05) respect to those with "early" NC pattern. Thus, advanced NC findings were more frequently found in those patients with higher levels of AECA and their contemporary presence may consent to identify specific SSc subsets i.e., those with higher skin scores and cardiovascular involvement. These data suggest that AECA may have a role in the progression of the endothelial damage and their presence and titer should be considered as an adjunctive risk factor for a more severe disease. We also confirm the diagnostic and prognostic validity for NC in SSc, underlying the importance for an accurate capillaroscopic assessment. The contemporary assessment of these two diagnostic tools can be useful to better define different subset of SSc patients.
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Magnetic resonance imaging of the submandibular-sublingual complex.
Sbarbati, A; Baldassarri, A; Leclercq, F; Merigo, F; Antonakis, K; Boicelli, A
1994-01-01
The submandibular-sublingual complex (SSC) was studied in vivo by magnetic resonance imaging (MRI) at 4.7 and 7.05 Tesla in rat and mouse. A correlation was found between histology and MRI signal. The mainly mucous sublingual gland emitted a more intense signal than the mainly serous submandibular gland. Ventral to the glands, cutis, subcutaneous adipose tissue and two planes of muscular tissue separated by connective laminae were visible in vivo. Autopsy and histology confirmed the in vivo description provided by MRI. The reactivity of the salivary system after pharmacological stimulation was studied in mice at 7.05 Tesla. Stimulation of salivary secretion by pilocarpine nitrate injected in the subcutaneous space ventrally to the SSC resulted in an augmentation of the salivary liquid visible in the oral cavity by MRI. The diffusion of pilocarpine nitrate in the connective tissue located ventrally the SSC and in the glandular parenchyma was also followed in vivo. These results show that MRI is a potentially useful tool for studying the salivary glands in vivo.
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Trends in Maternity Care Practice Skin-to-Skin Contact Indicators: United States, 2007-2015.
Boundy, Ellen O; Perrine, Cria G; Barrera, Chloe M; Li, Ruowei; Hamner, Heather C
2018-05-21
Mother-infant skin-to-skin contact (SSC) immediately after birth helps transition infants to the post-uterine environment and increases the likelihood of breastfeeding initiation and duration. This study examines trends in U.S. maternity practices related to SSC, and variations by facility demographics. Data were from the Maternity Practices in Infant Nutrition and Care (mPINC) surveys (2007-2015), a biennial assessment of all U.S. maternity facilities. Facilities reported how often patients were encouraged to practice mother-infant SSC for ≥30 minutes within 1 hour of uncomplicated vaginal birth and 2 hours of uncomplicated cesarean birth, and how often routine infant procedures are performed while in SSC. We calculated the percentage of maternity facilities reporting these indicators for ≥90% of patients across the United States for each survey year. Estimates by facility characteristics (size, type, and state) were calculated for 2015 only. The percentage of facilities reporting "Most (≥90%)" women, which were encouraged to practice early SSC, increased from 2007 to 2015 following both vaginal (40.4% to 83.0%) and cesarean (29.3% to 69.9%) births. The percentage of facilities reporting routine infant procedures were performed "Almost always (≥90%)," while mother and infant were SSC increased from 16.6% to 49.5% (2007 to 2015) for vaginal births and from 2.2% to 10.7% (2009 to 2015) for cesarean births. Variations in SSC practice by facility type, size, and state were noted. Significant progress has been made in increasing hospital encouragement of early SSC for both vaginal and cesarean births. Continued efforts to support evidence-based maternity practices are needed.
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Khanna, Dinesh; Kaplan, Robert M.; Eckman, Mark H.; Hays, Ron D.; Leonard, Anthony C.; Ginsburg, Shaari S.; Tsevat, Joel
2009-01-01
Objective Assigning utilities to hypothetical health states requires that the health states be described in adequate detail, but there is no agreement on exactly how health states should be described. We assessed utilities from the general public for health states common in scleroderma (SSc) by describing the health states in writing alone vs. with photographs of patients with SSc. Methods Subjects rated several SSc health states on a 0-100 rating scale (RS) and completed computer-assisted time tradeoff (TTO, range: 0.0-1.0) and standard gamble (SG, range: 0.0-1.0) utility assessments. Half of the subjects were assigned to be shown photographs of patients with SSc health states in addition to written health state descriptions whereas the other half were given only the written descriptions. Results Of the 213 subjects, 133 (62%) were female, 138 (65%) were Caucasian, and 62 (29%) were African-Americans. Median RS, TTO, and SG scores for the 5 SSc health states ranged from 20-70; 0.28-0.94; and 0.50-0.90, respectively. In bivariate analyses, showing pictures was associated with lower RS scores for 2 of 5 health states and lower SG values for all 5 health states (P<0.05 for comparison of pictures vs. no pictures), but with no difference in TTO values. Multivariable analyses revealed negative associations between pictures and SG valuations for the 3 most severe SSc health states (R2 range: 0.04-0.08). Conclusion Adding pictures of people with SSc to written health state descriptions can affect valuations of SSc health states, although the effect differs by valuation measurement method and by health state severity. PMID:19015284
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Performance and Structural Evolution of Nano-Scale Infiltrated Solid Oxide Fuel Cell Cathodes
NASA Astrophysics Data System (ADS)
Call, Ann Virginia
Nano-structured mixed ionic and electronic conducting (MIEC) materials have garnered intense interest in electrode development for solid oxide fuel cells due to their high surface areas which allow for effective catalytic activity and low polarization resistances. In particular, composite solid oxide fuel cell (SOFC) cathodes consisting of ionic conducting scaffolds infiltrated with MIEC nanoparticles have exhibited some of the lowest reported polarization resistances. In order for cells utilizing nanostructured moRPhologies to be viable for commercial implementation, more information on their initial performance and long term stability is necessary. In this study, symmetric cell cathodes were prepared via wet infiltration of Sr0.5Sm 0.5CoO3 (SSC) nano-particles via a nitrate process into porous Ce0.9Gd0.1O1.95 (GDC) scaffolds to be used as a model system to investigate performance and structural evolution. Detailed analysis of the cells and cathodes was carried out using electrochemical impedance spectroscopy (EIS). Initial polarization resistances (RP) as low as 0.11 O cm2 at 600ºC were obtained for these SSC-GDC cathodes, making them an ideal candidate for studying high performance nano-structured electrodes. The present results show that the infiltrated cathode microstructure has a direct impact on the initial performance of the cell. Small initial particle sizes and high infiltration loadings (up to 30 vol% SSC) improved initial RP. A simple microstructure-based electrochemical model successfully explained these trends in RP. Further understanding of electrode performance was gleaned from fitting EIS data gathered under varying temperatures and oxygen partial pressures to equivalent circuit models. Both RQ and Gerischer impedance elements provided good fits to the main response in the EIS data, which was associated with the combination of oxygen surface exchange and oxygen diffusion in the electrode. A gas diffusion response was also observed at relatively low pO2. The cells were subjected to life testing at temperatures between 650°C and 800°C for as long as 1500 h. EIS measurements, carried out periodically during the life tests, were done in air at 600°C, a typical expected intermediate-temperature SOFC operating temperature. These were accelerated tests because the aging temperatures > 600ºC should accelerate most degradation processes such as nano-particle coarsening. Long-term RP versus time data was fitted to a combined surface resistance and coarsening kinetics model, and a t0.25 power law coarsening model was found to provide the best fits to the data, suggesting that surface diffusion is the dominant mass transport pathway in SSC-GDC infiltrated cathodes. That is, cathode degradation was due primarily to the coarsening-induced decrease in active SSC surface area. Scanning electron microscopy (SEM) performed after electrochemical life testing confirmed the extent of coarsening of the SSC nanoparticles. The model is used to make predictions regarding long-term stability of infiltrated SSC electrodes, and is also compared with prior results on a similar perovskite MIEC electrode, LSCF. An important new finding is that increasing infiltration loadings yields a marked decrease in the long term degradation rate. Predictions based on accelerated life tests found the lowest possible operating temperature while achieving a degradation rate of 0.5% per kh is 595°C, corresponding to an initial particle size of 40 nm.
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Nakayama, Ayano; Tunnicliffe, David J; Thakkar, Vivek; Singh-Grewal, Davinder; O'Neill, Sean; Craig, Jonathan C; Tong, Allison
2016-07-01
Systemic sclerosis (SSc) is a chronic, progressive autoimmune disease with major end-organ involvement. Much attention has been focused on the management of physical and clinical manifestations; however, the effect of the disease and treatment on the patient's identity, relationships, functioning, and mental well-being are less known. We aimed to describe the patients' perspectives and experiences of living with SSc. Electronic databases were searched to October 2014. Thematic synthesis was used to analyze the findings. We included 26 studies involving 463 patients. Six key themes were identified: distressing appearance transformation (disturbing facial changes, stigmatizing sickness, unrecognizable self), palpable physical limitations (bodily restrictions, frustrating mind-body disconnect, pervasive fatigue, disabling pain), social impairment (breaking intimacy, struggling to fulfill family responsibilities, maintaining work, losing independence), navigating uncertainty (diagnostic ambiguity, medically fending for oneself, unpredictable course of illness), alone and misunderstood (fearful avoidance of fellow patients, invisible suffering), and gradual acceptance and relative optimism (adapting to change and accepting limitations, taking a positive spin, cautious hoping, empowering relationships, valuing medical support). SSc is a rare and unpredictable illness that undermines patients' sense of certainty and control and impairs their self-image, identity, and daily functioning. Patient-centered care that encompasses strategies to promote self-esteem, resilience, and self-efficacy may help to improve treatment satisfaction and health and quality of life outcomes for patients with SSc.
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Doshier, Laura J; Muzaffar, Arshad R; Deidrick, Kathleen Km; Rice, Gale B
2015-01-01
Single-suture craniosynostosis (SSC) is a common craniofacial condition with potential neurocognitive sequelae. To quantify any long-term functional academic and behavioural difficulties of children with SSC as indicated by the need for individualized education programs (IEPs), despite having undergone surgical treatment. Records of all school-age patients from 1992 to 2011 who underwent operative intervention for SSC were identified. Fifty-nine patients' guardians were contacted by telephone to provide informed consent for completion of a mailed standardized questionnaire querying demographic information as well as information regarding the patient's health, family and educational history; specifically whether the patient had ever been provided educational support as delineated in an IEP. The primary outcome measure was the history of the patient being assigned educational support as delineated in an IEP. Thirty-seven consenting guardians completed and returned the standardized questionnaire (response rate 62.7%). Twenty-one patients were male and 16 were female, with an age range of five to 14 years (mean age 10.2 years). Eleven (29.7%) patients had a previous history of or currently were receiving educational support delineated in an IEP. A higher proportion of school-age patients with a history of SSC (status postsurgical intervention) in the present study received educational support delineated in an IEP than the proportion of IEPs in the general student population of the United States (11.3%).
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OX40L blockade protects against inflammation-driven fibrosis
Elhai, Muriel; Avouac, Jérôme; Hoffmann-Vold, Anna Maria; Ruzehaji, Nadira; Amiar, Olivia; Ruiz, Barbara; Brahiti, Hassina; Ponsoye, Matthieu; Fréchet, Maxime; Burgevin, Anne; Pezet, Sonia; Sadoine, Jérémy; Guilbert, Thomas; Nicco, Carole; Akiba, Hisaya; Heissmeyer, Vigo; Subramaniam, Arun; Resnick, Robert; Molberg, Øyvind; Kahan, André; Chiocchia, Gilles; Allanore, Yannick
2016-01-01
Treatment for fibrosis represents a critical unmet need, because fibrosis is the leading cause of death in industrialized countries, and there is no effective therapy to counteract the fibrotic process. The development of fibrosis relates to the interplay between vessel injury, immune cell activation, and fibroblast stimulation, which can occur in various tissues. Immunotherapies have provided a breakthrough in the treatment of immune diseases. The glycoprotein OX40–OX40 ligand (OX40L) axis offers the advantage of a targeted approach to costimulatory signals with limited impact on the whole immune response. Using systemic sclerosis (SSc) as a prototypic disease, we report compelling evidence that blockade of OX40L is a promising strategy for the treatment of inflammation-driven fibrosis. OX40L is overexpressed in the fibrotic skin and serum of patients with SSc, particularly in patients with diffuse cutaneous forms. Soluble OX40L was identified as a promising serum biomarker to predict the worsening of lung and skin fibrosis, highlighting the role of this pathway in fibrosis. In vivo, OX40L blockade prevents inflammation-driven skin, lung, and vessel fibrosis and induces the regression of established dermal fibrosis in different complementary mouse models. OX40L exerts potent profibrotic effects by promoting the infiltration of inflammatory cells into lesional tissues and therefore the release of proinflammatory mediators, thereafter leading to fibroblast activation. PMID:27298374
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[Nutritional evaluation and physical functional ability in scleroderma patients].
Azevedo, Valderilio Feijó; Müller, Carolina de Souza; Rinaldi, Luciane; Bredt, Murilo Cézar; Giovanni, Karizianni; Pereira, Marcela Abou Chami; Volaco, Fernanda Copabianco
2009-01-01
Systemic Sclerosis (SSc) is an inflammatory disease that decreases functional capacity through muscular atrophy, skin sclerosis and loss of joint function. Scleroderma patients suffer from movement's restriction. In addition, the disease affects the nutritional status, compromising the quality of life in varying degrees. The gastrointestinal involvement appears to be the main responsible for the nutritional impairment. To evaluate the physical and nutritional status of patients with SSc. We conducted a cross-sectional and descriptive study in 20 patients with SSc. All patients were evaluated in Physioteraphy Clinic of the Catholic University of Paraná, from July 2003 to April 2004. The evaluation was performed by Bioimpedance Body (BIA), the questionnaires Nutritional Risk Assessment (Determine), Mini Nutritional Assessment of Aging and Health Assessment Questionnaire (HAQ) and Visual Analogue Scale (VAS) for pain. The work muscle ability was assessed by measuring the peak torque of flexor and extensor muscles of the elbow in the isokinetic dynamometer Cybex Norm model 7000. We have calculated the mean and standard deviation for each variable analyzed, in addition to the percentage of peak torque deficit. The values of the VAS ranged from zero to 97.8 mm (mean: 48.9 +/- 32.9 mm). The HAQ scores ranged from zero to 2.75 (average: 0.95 +/- 0.8). The average BMI was 22.4 +/- 3.9 kg / m2. The average deficit of mass was: 1.3 +/- 2.1 kg. Ten patients had high nutritional risk. 1 patient was malnourished and 15 were at high risk for malnutrition. The average peak torque to the muscle groups of elbows was 19.2 +/- 5 N / m to the flexor and 21.9 +/-6.6 N/m for the extensors, with an average deficit of 17% and 13% for the both groups. We found that SSc patients were in poor nutritional status and had decreased functional and physical capacity by the weakening of the muscles of the elbow demonstrated by the isokinetic evaluation. We concluded that our SSc patients were at high risk for malnutrition and this may indicate that scleroderma patients need a better nutritional orientation. We do consider that SSc patients also must be included in physical activity programs in order to achieve better physical performance.
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Altered expression of CD63 and exosomes in scleroderma dermal fibroblasts.
Nakamura, Kayo; Jinnin, Masatoshi; Harada, Miho; Kudo, Hideo; Nakayama, Wakana; Inoue, Kuniko; Ogata, Aki; Kajihara, Ikko; Fukushima, Satoshi; Ihn, Hironobu
2016-10-01
Exosomes are small vesicles shed from various cells. They contain proteins, lipids, and nucleic acids, and are regarded as a tool of cell-cell communication. To reveal the putative role of exosomes in systemic sclerosis (SSc), and to elucidate the effect of exosomes on wound healing. The expression of common markers for exosomes (CD63, CD9, and CD81) and type I collagen were examined with real-time PCR, immunohistochemical analysis, ELISA, immunoblotting, and flow cytometry. The effect of serum-derived exosomes on wound healing was tested on full-thickness wounds in the mid-dorsal skin of BALB/c mice. The expression levels of CD63 as well as CD9 and CD81 tended to be increased in SSc dermal fibroblasts compared to normal fibroblasts. Increased exosomes in a cultured media of SSc fibroblasts stimulated the expression levels of type I collagen in normal fibroblasts. As the mechanism, collagen-related microRNA levels in SSc fibroblast-derived exosomes were dysregulated, indicating that both the amount and the content of exosomes were altered in SSc. On the other hand, SSc sera showed significantly decreased exosome levels compared to normal sera. The frequencies of vascular involvements, including skin ulcers or pitting scars, were significantly increased in patients with decreased serum exosome levels. The healing of mice wounds was accelerated by treatment with serum-derived exosomes. Vascular abnormalities in SSc may account for the decreased serum exosome levels by the disturbed transfer of exosomes from the skin tissue to the blood stream. Our study suggests the possibility that SSc patients with vascular involvements have decreased serum exosome levels, which causes the delay of wound healing due to down-regulation of collagen, resulting in higher susceptibility to pitting scars and/or ulcers. Exosome research will lead to a detailed understanding of SSc pathogenesis and new therapeutic approaches. Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
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Ndosi, Mwidimi; Alcacer-Pitarch, Begonya; Allanore, Yannick; Del Galdo, Francesco; Frerix, Marc; García-Díaz, Sílvia; Hesselstrand, Roger; Kendall, Christine; Matucci-Cerinic, Marco; Mueller-Ladner, Ulf; Sandqvist, Gunnel; Torrente-Segarra, Vicenç; Schmeiser, Tim; Sierakowska, Matylda; Sierakowska, Justyna; Sierakowski, Stanslaw; Redmond, Anthony
2018-02-20
The aim of this study was to adapt the Systemic Sclerosis Quality of Life Questionnaire (SScQoL) into six European cultures and validate it as a common measure of quality of life in systemic sclerosis (SSc). This was a seven-country (Germany, France, Italy, Poland, Spain, Sweden and UK) cross-sectional study. A forward-backward translation process was used to adapt the English SScQoL into target languages. SScQoL was completed by patients with SSc, then data were validated against the Rasch model. To correct local response dependency, items were grouped into the following subscales: function, emotion, sleep, social and pain and reanalysed for fit to the model, unidimensionality and cross-cultural equivalence. The adaptation of the SScQoL was seamless in all countries except Germany. Cross-cultural validation included 1080 patients with a mean age 58.0 years (SD 13.9) and 87% were women. Local dependency was evident in individual country data. Grouping items into testlets corrected the local dependency in most country specific data. Fit to the model, reliability and unidimensionality was achieved in six-country data after cross-cultural adjustment for Italy in the social subscale. The SScQoL was then calibrated into an interval level scale. The individual SScQoL items have translated well into five languages and overall, the scale maintained its construct validity, working well as a five-subscale questionnaire. Measures of quality of life in SSc can be directly compared across five countries (France, Poland Spain, Sweden and UK). Data from Italy are also comparable with the other five countries although require an adjustment. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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Update on the pathogenesis of Scleroderma: focus on circulating progenitor cells.
Brunasso, Alexandra Maria Giovanna; Massone, Cesare
2016-01-01
In systemic sclerosis (SSc), the development of fibrosis seems to be a consequence of the initial ischemic process related to an endothelial injury. The initial trigger event in SSc is still unknown, but circulating progenitor cells (CPCs) might play a key role. Such cells have the ability to traffic into injury sites, exhibiting inflammatory features of macrophages, tissue remodeling properties of fibroblasts, and vasculogenesis functions of endothelial cells. The different subsets of CPCs described thus far in SSc arise from a pool of circulating monocyte precursors (CD14 (+) cells) and probably correspond to a different degree of differentiation of a single cell of origin. Several subsets of CPCs have been described in patients with SSc, all have a monocytic origin but may or may not express CD14, and all of these cells have the ability to give origin to endothelial cells, or collagen (Col)-producing cells, or both. We were able to identify six subsets of CPCs: pluripotent stem cells (CD14 (+), CD45 (+), and CD34 (+)), monocyte-derived multipotential cells (MOMCs) or monocyte-derived mesenchymal progenitors (CD14 (+), CD45 (+), CD34 (+), Col I (+), CD11b (+), CD68 (+), CD105 (+), and VEGFR1 (+)), early endothelial progenitor cells (EPCs) or monocytic pro-angiogenic hematopoietic cells or circulating hematopoietic cells (CD14 (+), CD45 (+), CD34 (low/-), VEGFR2 (+/-), CXCR4 (+), c-kit (+), and DC117 (+)), late EPCs (CD14 (-), CD133 (+), VEGFR2 (+), CD144 (+) [VE-cadherin (+)], and CD146 (+)), fibroblast-like cells (FLCs)/circulating Col-producing monocytes (CD14 (+), CD45 (+), CD34 (+/-), and Col I (+)), and fibrocytes (CD14 (-), CD45 (+), CD34 (+), Col I (+), and CXCR4 (+)). It has been demonstrated that circulating CD14 (+) monocytes with an activated phenotype are increased in patients with SSc when compared with normal subjects. CD14 (+), CD34 (+), and Col I (+) spindle-shaped cells have been found in increased numbers in lungs of SSc patients with interstitial lung disease. Elevated blood amounts of early EPCs have been found in patients with SSc by different groups of researchers and such levels correlate directly with the interstitial lung involvement. The prevalence of hematopoietic markers expressed by CPCs that migrate from blood into injury sites in SSc differs and changes according to the degree of differentiation. CXCR4 is the most commonly expressed marker, followed by CD34 and CD45 at an end stage of differentiation. Such difference also indicates a continuous process of cell differentiation that might relate to the SSc clinical phenotype (degree of fibrosis and vascular involvement). A deeper understanding of the role of each subtype of CPCs in the development of the disease will help us to better classify patients in order to offer them targeted approaches in the future.
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Intravenous immunogobulin therapy for severe gastrointestinal involvement in systemic sclerosis.
Clark, Kristina E N; Etomi, Oseme; Denton, Christopher P; Ong, Voon H; Murray, Charles D
2015-01-01
Gastrointestinal (GI) disease is one of the major causes of morbidity in patients with systemic sclerosis (SSc). The most common manifestation of GI disease is oesophageal involvement affecting 70-90% of patients. Severe GI disease is uncommon, but results in symptoms such as early satiety, pseudo-obstruction, weight loss and malnutrition. The pathogenesis is relatively poorly understood, and management focuses on symptomatic control rather than immunomodulation. We describe two cases of patients with SSc myositis overlap syndrome with severe GI involvement who demonstrated improvements in swallowing, early satiety and diarrhoea following the administration of intravenous immunoglobulin (IVIg). Clinical data related to the two cases were collected by review of medical records. GI complications range from mild symptoms to debilitating and life threatening. We propose that IVIg may have an immunomodulatory effect in a subset of patients with SSc myositis overlap syndrome.
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Effects of rituximab in connective tissue disorders related interstitial lung disease.
Lepri, Gemma; Avouac, Jerome; Airò, Paolo; Anguita Santos, Francisco; Bellando-Randone, Silvia; Blagojevic, Jelena; Garcia Hernàndez, Francisco; Gonzalez Nieto, Jose Antonio; Guiducci, Serena; Jordan, Suzana; Limaye, Vidya; Maurer, Britta; Selva-O'Callaghan, Albert; Riccieri, Valeria; Distler, Oliver; Matucci-Cerinic, Marco; Allanore, Yannick
2016-01-01
Interstitial lung disease (ILD) is a key prognostic factor in connective tissue disorders (CTDs). The aim of our study was to assess the changes in pulmonary functional tests (PFTs) in various CTDs, including anti-synthetase syndrome (SYN), systemic sclerosis (SSc) and mixed connective tissue disorder (MCTD), following the use of rituximab therapy. A multicentre retrospective analysis of patients with ILD secondary to SYN (n=15), MCTD (n=6) and SSc (n=23). PFTs were performed at baseline and at 1 and 2 years of follow-up. The primary outcome was the change in forced vital capacity (FVC) at 1 year. In the SYN population, median FVC changed from 53.0% (42.0-90.0) at baseline to 51.4% (45.6-85.0) at 1 year and 63.0 (50-88) (p=0.6) at 2 years (p=0.14). In SSc, FVC changed from 81.0% (66.0-104.0) at baseline to 89.0% (65.0-113.0) at 1 year (p=0.1) and 74.5 (50-91) at 2 years (p=0.07). In the MCTD population, FVC changed from 64.5% (63.0-68.0) at baseline to 63.0% (59.0-71.0) at 1 year (p=0.6) and 61 (59-71) after 2 years (p=0.8). DLCO showed a trend for improvement in the SYN population (p=0.06 at 1 year and 0.2 at years) while changes remain non-significant in the SSc and MCTD patients. In SYN patients, the percentage of responders at 1 year for FVC (33.3%) was greater than in SSc (9.5%) (p=0.07) and MCTD (17%) (p=0.45). RTX showed a satisfactory safety profile. A trend of improvement of PFTs was observed in SYN patients although not reaching significance, while SSc and MCTD patients were stabilised.
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Foocharoen, Chingching; Tyndall, Alan; Hachulla, Eric; Rosato, Edoardo; Allanore, Yannick; Farge-Bancel, Dominique; Caramaschi, Paola; Airó, Paolo; Nikolaevna, Starovojtova M; Pereira da Silva, José António; Stamenkovic, Bojana; Riemekasten, Gabriela; Rednic, Simona; Sibilia, Jean; Wiland, Piotr; Tarner, Ingo; Smith, Vanessa; Onken, Anna T; Abdel Atty Mohamed, Walid Ahmed; Distler, Oliver; Morović-Vergles, Jadranka; Himsel, Andrea; de la Peña Lefebvre, Paloma Garcia; Hügle, Thomas; Walker, Ulrich A
2012-02-20
Erectile dysfunction (ED) is common in men with systemic sclerosis (SSc) but the demographics, risk factors and treatment coverage for ED are not well known. This study was carried out prospectively in the multinational EULAR Scleroderma Trial and Research database by amending the electronic data-entry system with the International Index of Erectile Function-5 and items related to ED risk factors and treatment. Centres participating in this EULAR Scleroderma Trial and Research substudy were asked to recruit patients consecutively. Of the 130 men studied, only 23 (17.7%) had a normal International Index of Erectile Function-5 score. Thirty-eight per cent of all participants had severe ED (International Index of Erectile Function-5 score ≤ 7). Men with ED were significantly older than subjects without ED (54.8 years vs. 43.3 years, P < 0.001) and more frequently had simultaneous non-SSc-related risk factors such as alcohol consumption. In 82% of SSc patients, the onset of ED was after the manifestation of the first non-Raynaud's symptom (median delay 4.1 years). ED was associated with severe cutaneous, muscular or renal involvement of SSc, elevated pulmonary pressures and restrictive lung disease. ED was treated in only 27.8% of men. The most common treatment was sildenafil, whose efficacy is not established in ED of SSc patients. Severe ED is a common and early problem in men with SSc. Physicians should address modifiable risk factors actively. More research into the pathophysiology, longitudinal development, treatment and psychosocial impact of ED is needed.
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Dogan, Sibel; Akdogan, Ali; Atakan, Nilgün
2013-11-01
Vasculopathy is known to destroy nailfold capillary pattern (NCP) in systemic sclerosis (SSc). There are several methods for the evaluation of NCP of which the most common are dermatoscopy and videocapillaroscopy (VCAP). No study has been reported in the literature comparing these two techniques for their diagnostic value. To compare the diagnostic value of dermatoscopy and VCAP which are widely used to determine changes in the NCP in SSc patients. A total of 382 nailfolds were visualized. NCP was evaluated in 39 SSc patients using dermatoscopy and VCAP. Defined dermatoscopic groups were matched with early, active and late phase NCP groups determined by VCAP for comparisons. Both dermatoscopy and VCAP demonstrated distinct NCP of SSc efficiently. According to dermatoscopic NCP, capillary dilatation, giant capillaries and disrupted vascular configuration were able to be visualized. VCAP revealed early phase NCP in N = 8 (20,5%), active phase in N = 18 (46,2%) and late phase NCP in N = 13 (33.3%) of the patients. Statistical evaluation of grouped data resulted a Cohen kappa value (K) = 0,527. Although VCAP was able to facilitate a more detailed evaluation of NCP, there was no difference between dermatoscopy and VCAP for the identification of distinct NCP in SSc. We suggest that dermatoscopy is efficient enough to identify pathognomonic changes in NCP in SSc as well as VCAP and find dermatoscopy as a very easy applicable and convenient method than VCAP although VCAP facilitates a more detailed evaluation of NCP. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Schouffoer, Anne; Ndosi, Mwidimi E; Vliet Vlieland, Thea P M; Meesters, Jorit J L
2016-02-01
The Dutch Educational Needs Assessment Tool (D-ENAT) systematically assesses educational needs of patients with rheumatic diseases. The present study aims to describe the educational needs of Dutch patients with systemic sclerosis (SSc). The D-ENAT was sent to 155 SSc patients registered at the outpatient clinic of a university hospital. The D-ENAT consists of 39 items in seven domains. "Each domain has different number of items therefore we normalized each domain score: (domain score/maximum) × 100) and expressed in percentage to enable comparisons between domains." A total D-ENAT score (0-156) is calculated by summing all 39 items. In addition, age, disease duration, gender, educational level, present information need (yes/no) and information need (1-4; wanting to know nothing-everything) were recorded. Univariate regression analysis was used to examine factors associated with the D-ENAT scores. The response rate was 103 out of 155 (66 %). The mean % of educational needs scores (0-100 %; lowest-highest) were 49 % for "D-ENAT total score," 46 % for "Managing pain," 41 % for "Movement," 43 % for "Feelings," 59 % for "Disease process," 44 % for "Treatments from health professionals," 61 % for "Self-help measures" and 51 % for "Support systems." No associations between the D-ENAT total score and age, disease duration, gender and educational level were found. The D-ENAT demonstrated its ability to identify educational needs of Dutch SSc patients. SSc patients demonstrated substantial educational needs, especially in the domains: "Disease process" and "Self-help measures." The validity and practical applicability of the D-ENAT to make an inventory of SSc patients' educational needs require further investigation.
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Xiao, Hua; Zhang, Guang-Feng; Liao, Xiang-Ping; Li, Xiao-Jie; Zhang, Jian; Lin, Haobo; Chen, Zhe; Zhang, Xiao
2018-02-01
To determine whether pirfenidone attenuates lung fibrosis by interfering with the hedgehog (Hh) signalling pathway in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). Twenty-five SSc-ILD patients (20 first visit, five who underwent pirfenidone treatment for 6 months) and 10 healthy controls were recruited. Lung tissues were obtained by open-chest surgery, and primary lung fibroblasts were isolated, cultured and stimulated with pirfenidone. The levels of the proteins glioma-associated oncogene 1 (GLI1), suppressor of fused (Sufu), α-smooth muscle actin, and fibronectin in lung tissues or fibroblasts were determined by Western blotting. The messenger RNA levels of GLI1, glioma-associated oncogene 2, protein patched homolog 1, and Sufu in lung tissues or fibroblasts were determined by quantitative reverse-transcription polymerase chain reaction. Meanwhile, the levels of phosphorylation glycogen synthase kinasep-3β (pGSK-3β), phosphorylation SMAD2 (pSMAD2), and phosphorylation c-Jun N-terminal kinase (pJNK) in fibroblasts were determined by Western blotting. Hh pathway activation was increased in the lung tissue of SSc-ILD patients and was decreased by pirfenidone, Sufu was upregulated in lung fibroblasts isolated from SSc-ILD patients after pirfenidone challenge, and pirfenidone inhibited the phosphorylation of GSK-3β signalling. Pirfenidone has anti-fibrotic effects in SSc-ILD patients by interfering with both the Hh signalling pathway and the GSK-3β signalling pathway via the regulation of Sufu expression. These results might promote its use in other Hh driven lung diseases such as idiopathic pulmonary fibrosis and especially the interstitial lung disease associated with connective tissue diseases. © 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.
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Gentile, Daniela; Lazzerini, Pietro E.; Gamberucci, Alessandra; Natale, Mariarita; Selvi, Enrico; Vanni, Francesca; Alì, Alessandra; Taddeucci, Paolo; Del-Ry, Silvia; Cabiati, Manuela; Della-Latta, Veronica; Abraham, David J.; Morales, Maria A.; Fulceri, Rosella; Laghi-Pasini, Franco; Capecchi, Pier L.
2017-01-01
Objectives: Systemic sclerosis (SSc) is a connective tissue disorder presenting fibrosis of the skin and internal organs, for which no effective treatments are currently available. Increasing evidence indicates that the P2X7 receptor (P2X7R), a nucleotide-gated ionotropic channel primarily involved in the inflammatory response, may also have a key role in the development of tissue fibrosis in different body districts. This study was aimed at investigating P2X7R expression and function in promoting a fibrogenic phenotype in dermal fibroblasts from SSc patients, also analyzing putative underlying mechanistic pathways. Methods: Fibroblasts were isolated by skin biopsy from 9 SSc patients and 8 healthy controls. P2X7R expression, and function (cytosolic free Ca2+ fluxes, α-smooth muscle actin [α-SMA] expression, cell migration, and collagen release) were studied. Moreover, the role of cytokine (interleukin-1β, interleukin-6) and connective tissue growth factor (CTGF) production, and extracellular signal-regulated kinases (ERK) activation in mediating P2X7R-dependent pro-fibrotic effects in SSc fibroblasts was evaluated. Results: P2X7R expression and Ca2+ permeability induced by the selective P2X7R agonist 2′-3′-O-(4-benzoylbenzoyl)ATP (BzATP) were markedly higher in SSc than control fibroblasts. Moreover, increased αSMA expression, cell migration, CTGF, and collagen release were observed in lipopolysaccharides-primed SSc fibroblasts after BzATP stimulation. While P2X7-induced cytokine changes did not affect collagen production, it was completely abrogated by inhibition of the ERK pathway. Conclusion: In SSc fibroblasts, P2X7R is overexpressed and its stimulation induces Ca2+-signaling activation and a fibrogenic phenotype characterized by increased migration and collagen production. These data point to the P2X7R as a potential, novel therapeutic target for controlling exaggerated collagen deposition and tissue fibrosis in patients with SSc. PMID:28955239
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Systemic Sclerosis Sine Scleroderma in Mexican Patients. Case Reports.
Vera-Lastra, Olga; Sauceda-Casas, Christian Alexis; Domínguez, María Del Pilar Cruz; Alvarez, Sergio Alberto Mendoza; Sepulceda-Delgado, Jesús
2017-01-03
Systemic sclerosis sine scleroderma (ssSSc) is a form of systemic sclerosis that is characterized by Raynaud's phenomenon (RP), visceral involvement without thickening of skin and anticentromere antibodies (ACA). We studied 10 ssSsc patients with a prevalence of 2%. The clinical signs were: RP 9/10, esophageal manifestations 8/10, pulmonary arterial hypertension 4/10, interstitial lung disease 4/10, cardiac signs 3/10 and ACA 8/10. In patients with RP, esophageal dysmotility, interstitial lung disease and pulmonary arterial hypertension should be tested for ACA in order to establish a prompt diagnosis and treatment of ssSSc. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.
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Sharp, Charlotte A; Akram, Qasim; Hughes, Michael; Muir, Lindsay; Herrick, Ariane L
2016-10-01
Critical digital ischemia is a rare, but serious complication of systemic sclerosis (SSc) and is not always due solely to the non-inflammatory angiopathy that characterizes the SSc disease process. Our objective was to illustrate the range of presentations and causes of critical digital ischemia in patients with SSc in order to highlight how optimal management is dependent upon establishing the correct diagnosis. Five cases exemplifying differential diagnoses were identified and their case notes reviewed in order to extract clinically relevant data and images. A review of the literature was performed in PubMed in English. Causes of critical digital ischemia included typical micro-angiopathic changes and proximal (large vessel) disease. One case highlighted the difficulty of ascertaining whether an inflammatory cause is also present in SSc/SLE overlap syndrome. Two cases demonstrated embolic causes (thromboembolism due to atrial fibrillation and septic emboli). Critical digital ischemia in patients with SSc requires thorough investigation in order to avoid missing additional potentially modifiable causes including large vessel disease, inflammation, embolism, infection, and paraneoplastic syndromes. A firm evidence base for current medical and surgical interventions is lacking, highlighting the need for further research into the optimum management of this rare, but painful, debilitating, and limb-threatening complication of SSc. Copyright © 2016 Elsevier Inc. All rights reserved.
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Digital ulcers in systemic sclerosis.
Hughes, Michael; Herrick, Ariane L
2017-01-01
Digital ulcers (DUs) are a common visible manifestation of the progressive vascular disease that characterizes the SSc disease process. DUs not only impact significantly on patients' quality of life and hand function, but are also a biomarker of internal organ involvement and of disease severity. The aetiology of (digital) vascular disease in SSc is multifactorial, and many of these factors are potentially amenable to therapeutic intervention. The management of DU disease in SSc is multifaceted. Patient education and non-pharmacological interventions (e.g. smoking cessation) should not be neglected. There are a number of drug therapies available to prevent (e.g. phosphodiesterase type-5 inhibitors and ET receptor-1 antagonists) and treat (e.g. i.v. iloprost) DUs. DUs are also important for two other reasons: firstly, as a primary end point in SSc-related clinical trials; and secondly, DUs are included in the ACR/EULAR SSc classification criteria. However, the reliability of rheumatologists to grade DUs is poor to moderate at best, and this poses challenges in both clinical practice and research. The purpose of this review is to provide the reader with a description of the spectrum of DU disease in SSc including pathophysiology, epidemiology and clinical burden, all of which inform the multifaceted approach to management. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Farina, Antonella; Cirone, Mara; York, Michael; Lenna, Stefania; Padilla, Cristina; Mclaughlin, Sarah; Faggioni, Alberto; Lafyatis, Robert; Trojanowska, Maria; Farina, Giuseppina A
2014-04-01
Scleroderma (SSc) is a complex and heterogeneous connective tissue disease mainly characterized by autoimmunity, vascular damage, and fibrosis that mostly involve the skin and lungs. Epstein-Barr virus (EBV) is a lymphotropic γ-herpesvirus that has co-evolved with human species, infecting >95% of the adult population worldwide, and has been a leading candidate in triggering several autoimmune diseases. Here we show that EBV establishes infection in the majority of fibroblasts and endothelial cells in the skin of SSc patients, characterized by the expression of the EBV noncoding small RNAs (EBERs) and the increased expression of immediate-early lytic and latency mRNAs and proteins. We report that EBV is able to persistently infect human SSc fibroblasts in vitro, inducing an aberrant innate immune response in infected cells. EBV-Toll-like receptor (TLR) aberrant activation induces the expression of selected IFN-regulatory factors (IRFs), IFN-stimulated genes (ISGs), transforming growth factor-β1 (TGFβ1), and several markers of fibroblast activation, such as smooth muscle actin and Endothelin-1, and all of these genes play a key role in determining the profibrotic phenotype in SSc fibroblasts. These findings imply that EBV infection occurring in mesenchymal, endothelial, and immune cells of SSc patients may underlie the main pathological features of SSc including autoimmunity, vasculopathy, and fibrosis, and provide a unified disease mechanism represented by EBV reactivation.
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Human adipose mesenchymal stem cells as potent anti-fibrosis therapy for systemic sclerosis.
Maria, Alexandre T J; Toupet, Karine; Maumus, Marie; Fonteneau, Guillaume; Le Quellec, Alain; Jorgensen, Christian; Guilpain, Philippe; Noël, Danièle
2016-06-01
Displaying immunosuppressive and trophic properties, mesenchymal stem/stromal cells (MSC) are being evaluated as promising therapeutic options in a variety of autoimmune and degenerative diseases. Although benefits may be expected in systemic sclerosis (SSc), a rare autoimmune disease with fibrosis-related mortality, MSC have yet to be evaluated in this specific condition. While autologous approaches could be inappropriate because of functional alterations in MSC from patients, the objective of the present study was to evaluate allogeneic and xenogeneic MSC in the HOCl-induced model of diffuse SSc. We also questioned the source of human MSC and compared bone marrow- (hBM-MSC) and adipose-derived MSC (hASC). HOCl-challenged BALB/c mice received intravenous injection of BM-MSC from syngeneic BALB/c or allogeneic C57BL/6 mice, and xenogeneic hBM-MSC or hASC (3 donors each). Skin thickness was measured during the experiment. At euthanasia, histology, immunostaining, collagen determination and RT-qPCR were performed in skin and lungs. Xenogeneic hBM-MSC were as effective as allogeneic or syngeneic BM-MSC in decreasing skin thickness, expression of Col1, Col3, α-Sma transcripts, and collagen content in skin and lungs. This anti-fibrotic effect was not associated with MSC migration to injured skin or with long-term MSC survival. Interestingly, compared with hBM-MSC, hASC were significantly more efficient in reducing skin fibrosis, which was related to a stronger reduction of TNFα, IL1β, and enhanced ratio of Mmp1/Timp1 in skin and lung tissues. Using primary cells isolated from 3 murine and 6 human individuals, this preclinical study demonstrated similar therapeutic effects using allogeneic or xenogeneic BM-MSC while ASC exerted potent anti-inflammatory and remodeling properties. This sets the proof-of-concept prompting to evaluate the therapeutic efficacy of allogeneic ASC in SSc patients. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Cutolo, Maurizio; Vanhaecke, Amber; Ruaro, Barbara; Deschepper, Ellen; Ickinger, Claudia; Melsens, Karin; Piette, Yves; Trombetta, Amelia Chiara; De Keyser, Filip; Smith, Vanessa
2018-06-06
A reliable tool to evaluate flow is paramount in systemic sclerosis (SSc). We describe herein on the one hand a systematic literature review on the reliability of laser speckle contrast analysis (LASCA) to measure the peripheral blood perfusion (PBP) in SSc and perform an additional pilot study, investigating the intra- and inter-rater reliability of LASCA. A systematic search was performed in 3 electronic databases, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In the pilot study, 30 SSc patients and 30 healthy subjects (HS) underwent LASCA assessment. Intra-rater reliability was assessed by having a first anchor rater performing the measurements at 2 time-points and inter-rater reliability by having the anchor rater and a team of second raters performing the measurements in 15 SSc and 30 HS. The measurements were repeated with a second anchor rater in the other 15 SSc patients, as external validation. Only 1 of the 14 records of interest identified through the systematic search was included in the final analysis. In the additional pilot study: intra-class correlation coefficient (ICC) for intra-rater reliability of the first anchor rater was 0.95 in SSc and 0.93 in HS, the ICC for inter-rater reliability was 0.97 in SSc and 0.93 in HS. Intra- and inter-rater reliability of the second anchor rater was 0.78 and 0.87. The identified literature regarding the reliability of LASCA measurements reports good to excellent inter-rater agreement. This very pilot study could confirm the reliability of LASCA measurements with good to excellent inter-rater agreement and found additionally good to excellent intra-rater reliability. Furthermore, similar results were found in the external validation. Copyright © 2018. Published by Elsevier B.V.
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Salek, Kamel El; Hassan, Islam S; Kotrotsou, Aikaterini; Abrol, Srishti; Faro, Scott H; Mohamed, Feroze B; Zinn, Pascal O; Wei, Wei; Li, Nan; Kumar, Ashok J; Weinberg, Jeffrey S; Wefel, Jeffrey S; Kesler, Shelli R; Liu, Ho-Ling Anthony; Hou, Ping; Stafford, R Jason; Prabhu, Sujit; Sawaya, Raymond; Colen, Rivka R
2017-09-21
Preoperative mapping of language areas using fMRI greatly depends on the paradigms used, as different tasks harness distinct capabilities to activate speech processing areas. In this study, we compared the ability of 3 covert speech paradigms: Silent Sentence Completion (SSC), category naming (CAT) and verbal fluency (FAS), in localizing the Wernicke's area and studied the association between genomic markers and functional activation. Fifteen right-handed healthy volunteers and 35 mixed-handed patients were included. We focused on the anatomical areas of posterosuperior, middle temporal and angular gyri corresponding to Wernicke's area. Activity was deemed significant in a region of interest if P < 0.05. Association between fMRI activation and genomic mutation status was obtained. Results demonstrated SSC's superiority at localizing Wernicke's area. SSC demonstrated functional activity in 100% of cancer patients and healthy volunteers; which was significantly higher than those for FAS and CAT. Patients with 1p/19q non-co-deleted had higher extent of activation on SSC (P < 0.02). Those with IDH-1 wild-type were more likely to show no activity on CAT (P < 0.05). SSC is a robust paradigm for localizing Wernicke's area, making it an important clinical tool for function-preserving surgeries. We also found a correlation between tumor genomics and functional activation, which deserves more comprehensive study.
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Rabquer, Bradley J.; Ohara, Ray A.; Stinson, William A.; Campbell, Phillip L.; Amin, M. Asif; Balogh, Beatrix; Zakhem, George; Renauer, Paul A.; Lozier, Ann; Arasu, Eshwar; Haines, G. Kenneth; Kahaleh, Bashar; Schiopu, Elena; Khanna, Dinesh; Koch, Alisa E.
2016-01-01
Objectives. Angiogenesis plays a critical role in SSc (scleroderma). The aim of this study was to examine the expression of growth-regulated protein-γ (Gro-γ/CXCL3), granulocyte chemotactic protein 2 (GCP-2/CXCL6) and their receptor CXCR2 in endothelial cells (ECs) isolated from SSc skin and determine whether these cells mount an angiogenic response towards pro-angiogenic chemokines. The downstream signalling pathways as well as the pro-angiogenic transcription factor inhibitor of DNA-binding protein 1 (Id-1) were also examined. Methods. Skin biopsies were obtained from patients with dcSSc. ECs were isolated via magnetic positive selection. Angiogenesis was measured by EC chemotaxis assay. Results. Gro-γ/CXCL3 and GCP-2/CXCL6 were minimally expressed in both skin types but elevated in SSc serum. Pro-angiogenic chemokine mRNA was greater in SSc ECs than in normal ECs. SSc ECs did not migrate to vascular endothelial growth factor (VEGF), Gro-γ/CXCL3, GCP-2/CXCL6 or CXCL16. The signalling pathways stimulated by these chemokines were also dysregulated. Id-1 mRNA in SSc ECs was lower compared with normal ECs, and overexpression of Id-1 in SSc ECs increased their ability to migrate towards VEGF and CXCL16. Conclusion. Our results show that SSc ECs are unable to respond to pro-angiogenic chemokines despite their increased expression in serum and ECs. This might be due to the differences in the signalling pathways activated by these chemokines in normal vs SSc ECs. In addition, the lower expression of Id-1 also decreases the angiogenic response. The inability of pro-angiogenic chemokines to promote EC migration provides an additional mechanism for the impaired angiogenesis that characterizes SSc. PMID:26705326
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Become your own advocate: Advice from women living with scleroderma
MENDELSON, CINDY; POOLE, JANET L.
2008-01-01
Purpose Systemic sclerosis (SSC) affects 300,000 people in the USA and has a significant effect on an individual’s functional ability. The purpose of this study was to outline the key components of living with the illness and to identify the information that those who are newly diagnosed would need to initiate a successful course of disease self-management. The results will provide the groundwork for development and testing of a self-paced education program for patients with SSC. Method Focus groups were conducted with 11 women diagnosed with SSC. Results Analysis of the transcripts yielded three themes, Secure Effective Medical Management, Live Your Life, and Learn Everything You Can. The thread Become Your Own Advocate wove these three themes together and illustrated that taking control of SSC is ultimately a function of self-advocacy. Conclusion For patients with SSC, taking control of their illness was a necessary component of maintaining the highest quality of life possible. A positive attitude, a strong support system, a commitment to moving forward with life, and access to high-quality, timely information all provided the participants with the tools to develop and implement a strategy of self-advocacy in disease management. PMID:17852224
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2012-01-01
Introduction CD226 genetic variants have been associated with a number of autoimmune diseases and recently with systemic sclerosis (SSc). The aim of this study was to test the influence of CD226 loci in SSc susceptibility, clinical phenotypes and autoantibody status in a large multicenter European population. Methods A total of seven European populations of Caucasian ancestry were included, comprising 2,131 patients with SSc and 3,966 healthy controls. Three CD226 single nucleotide polymorphisms (SNPs), rs763361, rs3479968 and rs727088, were genotyped using Taqman 5'allelic discrimination assays. Results Pooled analyses showed no evidence of association of the three SNPs, neither with the global disease nor with the analyzed subphenotypes. However, haplotype block analysis revealed a significant association for the TCG haplotype (SNP order: rs763361, rs34794968, rs727088) with lung fibrosis positive patients (PBonf = 3.18E-02 OR 1.27 (1.05 to 1.54)). Conclusion Our data suggest that the tested genetic variants do not individually influence SSc susceptibility but a CD226 three-variant haplotype is related with genetic predisposition to SSc-related pulmonary fibrosis. PMID:22531499
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Manifestations of Insomnia in Sleep Apnea: Implications for Screening and Treatment.
Bailes, Sally; Rizzo, Dorrie; Baltzan, Marc; Grad, Roland; Pavilanis, Alan; Creti, Laura; Fichten, Catherine S; Libman, Eva
2016-01-01
The aims of this study were to examine the presence, type, and severity of insomnia complaints in obstructive sleep apnea (OSA) patients and to assess the utility of the Sleep Symptom Checklist (SSC) for case identification in primary care. Participants were 88 OSA patients, 57 cognitive-behavioral therapy for insomnia (CBT-I) patients, and 14 healthy controls (Ctrl). Each completed a sleep questionnaire as well as the SSC, which includes insomnia, daytime functioning, psychological, and sleep disorder subscales. Results showed that OSA patients could be grouped according to 3 insomnia patterns: no insomnia (OSA), n = 21; insomnia (OSA-I), n = 30, with a subjective complaint and disrupted sleep; and noncomplaining poor sleepers (OSA-I-NC), n = 37. Comparisons among the OSA, CBT-I, and Ctrl groups demonstrate distinct profiles on the SSC subscales, indicating its potential utility for both case identification and treatment planning.
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Esen, Bahar Artım; Yılmaz, Gülden; Uzun, Sami; Ozdamar, Melda; Aksözek, Alper; Kamalı, Sevil; Türkoğlu, Salih; Gül, Ahmet; Ocal, Lale; Aral, Orhan; Inanç, Murat
2012-01-01
Previous studies showed a link between systemic lupus erythematosus (SLE) and Epstein-Barr virus (EBV) infection. We sought to determine the features of serologic response to EBV in SLE patients and whether this response differs from those of systemic sclerosis (SSc) and primary antiphospholipid syndrome (PAPS) patients as well as healthy individuals. Sera from 198 consecutive SLE patients have been tested to detect IgG antibodies to EA/D, EBNA-1, VCA P18 and for comparison, cytomegalovirus (CMV) using commercially available ELISA kits (Trinity Biotech, USA). Forty-six SSc patients and 38 PAPS patients were enrolled as diseased control groups and sixty-five individuals as healthy controls. Significantly more SLE (54%, P = 0.001, OR 5.77, 95% CI 2.8-11.6), SSc (41.3%, P = 0.005, OR 3.4, 95% CI 1.4-8.2) and PAPS sera (36.8%, P = 0.023, OR 2.86, 95% CI 1.14-7.22) reacted against EA/D than healthy controls (16.9%). The mean age of anti-EA/D-positive SLE patients was significantly higher, and their disease duration was longer compared to anti-EA/D-negative SLE patients (41 ± 14 vs. 33.8 ± 10.8 years, P < 0.001 and 100 ± 73 vs. 71 ± 62 months, P = 0.003). In SLE patients, EA/D reactivity was associated with Raynaud's phenomenon and the presence of any anti-ENA antibodies. Although it did not reach a statistical significance, anti-EBNA-1 reactivity was slightly lower in patients with SLE. The frequency of anti-CMV Ig G positivity was found significantly higher in SLE patients (100%) when compared to patients with SSc (95.7%), PAPS (94.7%) and healthy controls (95.4%) (P = 0.035, P = 0.025 and P = 0.015 respectively). Our results support the proposed link between EBV and SLE. The finding that SSc and PAPS patients also have increased frequency of anti-EA/D response has revealed that this immune interaction may not be unique to patients with SLE, and there may be a common mechanism involving EBV in these autoimmune diseases.
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Retrocochlear impairments in systemic sclerosis: a case report study.
Valente, Julia de Souza Pinto; Corona, Ana Paula
2017-12-07
To report three cases of patients with Systemic Sclerosis (SSc) and retrocochlear impairments. This is a case report of three individuals with SSc and retrocochlear impairments assisted at a rheumatology outpatient clinic. All individuals underwent Brainstem Auditory Evoked Potential (BAEP) and, when necessary, audiometry. All three individuals presented sensorineural hearing loss. Although no retrocochlear impairment was identified in the basic audiologic evaluation, the BAEP results were altered. Retrocochlear impairments were present in the individuals under study, both in the absolute latencies and interpeak interval, thereby demanding the attention of rheumatologists and speech-language pathologists to such changes during the monitoring of SSc patients. The results also show a need for epidemiological studies on the theme.
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Morrisroe, Kathleen; Sudararajan, Vijaya; Stevens, Wendy; Sahhar, Joanne; Zochling, Jane; Roddy, Janet; Proudman, Susanna; Nikpour, Mandana
2018-01-01
To evaluate work productivity and its economic burden in SSc patients. Consecutive SSc patients enrolled in the Australian Scleroderma Cohort Study were mailed questionnaires assessing employment (Workers' Productivity and Activity Impairment Questionnaire and a custom-made questionnaire) and health-related quality of life (HRQoL) (36-item Short Form Health Survey and Patient-Reported Outcomes Measurement Information System 29). Linear regression methods were used to determine factors associated with work productivity. Among 476 patients submitting responses, 55.2% <65 years of age were employed. Unemployed patients were older at the time of survey completion (57.1 vs 53.7 years; P < 0.001) and had longer disease duration from first SSc clinical manifestation (16.2 vs 14.9 years; P = 0.01) than employed patients. The mean age at unemployment onset was 13.2 years below the average Australian retirement age. Of those working in the week prior to completing the survey, 16.0% reported missing work (absenteeism) due to their SSc, accounting for 32.9% of their working week. Reduced productivity while at work (presenteeism) accounted for 22% of their working week. Annual costs per patient as a consequence of unemployment and reduced productivity equated to a total of AUD$67 595.40. Factors independently associated with reduced work productivity were presence of synovitis and sicca symptoms, while tertiary education protected against work impairment. Patients with low HRQoL scores also had low work productivity. SSc is associated with considerable unemployment and reduced productivity, which in turn is associated with a substantial economic burden and poor HRQoL. Raising awareness and identifying modifiable factors are possible ways of reducing this burden. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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Martyanov, Viktor; Whitfield, Michael L
2016-01-01
The goal of this review is to summarize recent advances into the pathogenesis and treatment of systemic sclerosis (SSc) from genomic and proteomic studies. Intrinsic gene expression-driven molecular subtypes of SSc are reproducible across three independent datasets. These subsets are a consistent feature of SSc and are found in multiple end-target tissues, such as skin and esophagus. Intrinsic subsets as well as baseline levels of molecular target pathways are potentially predictive of clinical response to specific therapeutics, based on three recent clinical trials. A gene expression-based biomarker of modified Rodnan skin score, a measure of SSc skin severity, can be used as a surrogate outcome metric and has been validated in a recent trial. Proteome analyses have identified novel biomarkers of SSc that correlate with SSc clinical phenotypes. Integrating intrinsic gene expression subset data, baseline molecular pathway information, and serum biomarkers along with surrogate measures of modified Rodnan skin score provides molecular context in SSc clinical trials. With validation, these approaches could be used to match patients with the therapies from which they are most likely to benefit and thus increase the likelihood of clinical improvement.
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NASA Astrophysics Data System (ADS)
Greensill, Colin V.; Walsh, Kerry B.
2000-12-01
Near infrared spectroscopy can be employed in the non-invasive assessment of intact fruit for eating quality attributes such as soluble solid content (SSC). Rapid sorting is dependent on a suitable non-contact geometry of fruit, light source and detector assembly, optimized for a given fruit commodity. An optical system was designed with reference to distribution of SSC and light penetration into rockmelon fruit. SSC of mesocarp tissue was not significantly different over the greater part of the proximal-distal axis of the fruit, particularly in the vicinity of the fruit equator. There was also no consistent variation in SSC of mesocarp tissue with respect to radial position of sampling. Mesocarp SSC was higher (~3% w/v) closer to the seed cavity. The optical sampling system was therefore designed to assess an equatorial position on the fruit. Light penetrating a rockmelon fruit was empirically assessed to be diffuse at a depth of <15 mm from the fruit surface. Signal decreased in an exponential proportionality with depth into the fruit, but was still detectable at depths in excess of the seed cavity of rockmelons. A partial transmittance optical design was employed, with a collimated light source interrupted by a central light stop, and a detector viewing the shadowed region of the sample. This system did not physically contact the sample. It was compared to a system with a light excluding `contacting' shroud between the detector and the fruit surface. The performance of calibrations generated using the non-contact configuration was not significantly different than for the configuration requiring contact.
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Mapping and predicting mortality from systemic sclerosis.
Elhai, Muriel; Meune, Christophe; Boubaya, Marouane; Avouac, Jérôme; Hachulla, Eric; Balbir-Gurman, Alexandra; Riemekasten, Gabriela; Airò, Paolo; Joven, Beatriz; Vettori, Serena; Cozzi, Franco; Ullman, Susanne; Czirják, László; Tikly, Mohammed; Müller-Ladner, Ulf; Caramaschi, Paola; Distler, Oliver; Iannone, Florenzo; Ananieva, Lidia P; Hesselstrand, Roger; Becvar, Radim; Gabrielli, Armando; Damjanov, Nemanja; Salvador, Maria J; Riccieri, Valeria; Mihai, Carina; Szücs, Gabriella; Walker, Ulrich A; Hunzelmann, Nicolas; Martinovic, Duska; Smith, Vanessa; Müller, Carolina de Souza; Montecucco, Carlo Maurizio; Opris, Daniela; Ingegnoli, Francesca; Vlachoyiannopoulos, Panayiotis G; Stamenkovic, Bojana; Rosato, Edoardo; Heitmann, Stefan; Distler, Jörg H W; Zenone, Thierry; Seidel, Matthias; Vacca, Alessandra; Langhe, Ellen De; Novak, Srdan; Cutolo, Maurizio; Mouthon, Luc; Henes, Jörg; Chizzolini, Carlo; Mühlen, Carlos Alberto von; Solanki, Kamal; Rednic, Simona; Stamp, Lisa; Anic, Branimir; Santamaria, Vera Ortiz; De Santis, Maria; Yavuz, Sule; Sifuentes-Giraldo, Walter Alberto; Chatelus, Emmanuel; Stork, Jiri; Laar, Jacob van; Loyo, Esthela; García de la Peña Lefebvre, Paloma; Eyerich, Kilian; Cosentino, Vanesa; Alegre-Sancho, Juan Jose; Kowal-Bielecka, Otylia; Rey, Grégoire; Matucci-Cerinic, Marco; Allanore, Yannick
2017-11-01
To determine the causes of death and risk factors in systemic sclerosis (SSc). Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation. We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile. Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients' survival. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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Jung, Christian; Drummer, Karl; Oelzner, Peter; Figulla, Hans R; Boettcher, Joachim; Franz, Marcus; Betge, Stefan; Foerster, Martin; Wolf, Gunter; Pfeil, Alexander
2015-01-01
Systemic sclerosis (SSc) is a systemic, autoimmune connective tissue disease characterized by vasculopathy and microvascular changes. Fluorescence Optical Imaging (FOI) is a technique used to assess inflammation in patients with arthritis; in this study FOI is used to quantify inflammation in the hand. Endothelial Microparticle (EMP) can reflect damage or activation of the endothelium but also actively modulate processes of inflammation, coagulation and vascular function. The aim of the present study was to quantify EMP and FOI, to determine an association between these microparticles and inflammation and to endothelial function. EMP were quantified in plasma samples of 25 patients (24 female, 1 male, age: 41 ± 9 years) with SSc using flow cytometry. EMP was defined as CD31+/CD42- MP, and CD62+ MP. Perivascular inflammation was assessed using fluorescence optical imaging (FOI) of the hand. Macrovascular endothelial function was non-invasively estimated using the Endopat system. Plasma levels of CD31+/CD42- EMP and CD62+ EMP were lower in patients with SSc compared to controls (both p < 0.05). An impaired endothelial function with an increased hyperemia index was observed. A strong association could be demonstrated between CD62+ EMP and perivascular soft tissue inflammation as assessed by the FOI global score (Spearman, p = 0.002, r = 0.61). EMP indicate molecular vascular damage in SSc; in this study a strong association between EMP and perivascular inflammation as quantified by FOI is demonstrated. Consequently EMP, using FOI, may be a potential marker benefitting the diagnosis and therapy monitoring of patients with SSc with associated Raynaud's phenomenon.
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Interactions between waves, sediment, and turbulence on a shallow estuarine mudflat
MacVean, Lissa J.; Lacy, Jessica R.
2014-01-01
stress, which diffused sediment upward and limited stratification. Our findings highlight a pathway for waves to supply energy to both the production and destruction of turbulence, and demonstrate that in such shallow depths, TKE and SSC can be elevated over more of the water column than predicted by traditional models.
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Update on the pathogenesis of Scleroderma: focus on circulating progenitor cells
Brunasso, Alexandra Maria Giovanna; Massone, Cesare
2016-01-01
In systemic sclerosis (SSc), the development of fibrosis seems to be a consequence of the initial ischemic process related to an endothelial injury. The initial trigger event in SSc is still unknown, but circulating progenitor cells (CPCs) might play a key role. Such cells have the ability to traffic into injury sites, exhibiting inflammatory features of macrophages, tissue remodeling properties of fibroblasts, and vasculogenesis functions of endothelial cells. The different subsets of CPCs described thus far in SSc arise from a pool of circulating monocyte precursors (CD14 + cells) and probably correspond to a different degree of differentiation of a single cell of origin. Several subsets of CPCs have been described in patients with SSc, all have a monocytic origin but may or may not express CD14, and all of these cells have the ability to give origin to endothelial cells, or collagen (Col)-producing cells, or both. We were able to identify six subsets of CPCs: pluripotent stem cells (CD14 +, CD45 +, and CD34 +), monocyte-derived multipotential cells (MOMCs) or monocyte-derived mesenchymal progenitors (CD14 +, CD45 +, CD34 +, Col I +, CD11b +, CD68 +, CD105 +, and VEGFR1 +), early endothelial progenitor cells (EPCs) or monocytic pro-angiogenic hematopoietic cells or circulating hematopoietic cells (CD14 +, CD45 +, CD34 low/−, VEGFR2 +/−, CXCR4 +, c-kit +, and DC117 +), late EPCs (CD14 −, CD133 +, VEGFR2 +, CD144 + [VE-cadherin +], and CD146 +), fibroblast-like cells (FLCs)/circulating Col-producing monocytes (CD14 +, CD45 +, CD34 +/−, and Col I +), and fibrocytes (CD14 −, CD45 +, CD34 +, Col I +, and CXCR4 +). It has been demonstrated that circulating CD14 + monocytes with an activated phenotype are increased in patients with SSc when compared with normal subjects. CD14 +, CD34 +, and Col I + spindle-shaped cells have been found in increased numbers in lungs of SSc patients with interstitial lung disease. Elevated blood amounts of early EPCs have been found in patients with SSc by different groups of researchers and such levels correlate directly with the interstitial lung involvement. The prevalence of hematopoietic markers expressed by CPCs that migrate from blood into injury sites in SSc differs and changes according to the degree of differentiation. CXCR4 is the most commonly expressed marker, followed by CD34 and CD45 at an end stage of differentiation. Such difference also indicates a continuous process of cell differentiation that might relate to the SSc clinical phenotype (degree of fibrosis and vascular involvement). A deeper understanding of the role of each subtype of CPCs in the development of the disease will help us to better classify patients in order to offer them targeted approaches in the future. PMID:27158466
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Endothelin-1, α-Klotho, 25(OH) Vit D levels and severity of disease in scleroderma patients.
Hajialilo, Mehrzad; Noorabadi, Parisa; Tahsini Tekantapeh, Sepideh; Malek Mahdavi, Aida
2017-10-01
Considering the role of endothelin-1 (ET-1) in tissue remodeling and fibrosis during the development of scleroderma as well as the effect of α-Klotho in pathogenesis of calcinosis and/or endothelial cell injury and its correlation with severity of disease, this study aimed to evaluate serum ET-1, α-Klotho and 25(OH) vitamin D levels in patients with limited and diffuse scleroderma compared to healthy subjects. In this cross-sectional study, 60 scleroderma patients according to the ACR/EULAR 2013 criteria and 60 age- and sex-matched healthy controls were included. In patients, clinical examination was performed and Medsger severity scale was assessed. Serum ET-1, soluble α-Klotho and 25(OH)D 3 levels were measured using ELISA kits. The mean ± SD age of patients and controls was 46.2 ± 9.6 and 47.2 ± 7.0 years, respectively. Compared to healthy controls, serum ET-1 was significantly higher in SSc patients (p = 0.001); whilst serum α-Klotho and 25(OH)D 3 were significantly lower in patients (p = 0.001). The most common organs involved in patients were skin, lung, peripheral vascular and gastrointestinal system and the severity of involvement was mainly mild and/or moderate. There were no significant differences in serum ET-1 and α-Klotho levels according to the severity of different organ involvement (p > 0.05). There was no significant correlation between presence or absence of calcinosis and negative or positivity of auto-antibodies with ET-1, α-Klotho and 25(OH)D 3 levels. Although our study revealed higher serum ET-1 and lower serum α-Klotho levels in SSc patients compared to healthy controls, there were not any significant correlations between their serum levels with severity of organ involvement.
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Structural brain differences in school-age children with and without single-suture craniosynostosis.
Aldridge, Kristina; Collett, Brent R; Wallace, Erin R; Birgfeld, Craig; Austin, Jordan R; Yeh, Regina; Feil, Madison; Kapp-Simon, Kathleen A; Aylward, Elizabeth H; Cunningham, Michael L; Speltz, Matthew L
2017-04-01
OBJECTIVE Single-suture craniosynostosis (SSC), the premature fusion of a cranial suture, is characterized by dysmorphology of the craniofacial skeleton. Evidence to suggest that children with SSC are at an elevated risk of mild to moderate developmental delays and neurocognitive deficits is mounting, but the associations among premature suture fusion, neuroanatomy, and neurocognition are unexplained. The goals of this study were to determine 1) whether differences in the brain are present in young children with the 2 most common forms of SSC (sagittal and metopic) several years following surgical correction, and 2) whether the pattern of differences varies by affected suture (sagittal or metopic). Examination of differences in the brains of children with SSC several years after surgery may illuminate the growth trajectory of the brain after the potential constraint of the dysmorphic cranium has been relieved. METHODS The authors compared quantitative measures of the brain acquired from MR images obtained from children with sagittal or metopic craniosynostosis (n = 36) at 7 years of age to those obtained from a group of unaffected controls (n = 27) at the same age. The authors measured the volumes of the whole brain, cerebral cortex, cerebral white matter, cerebral cortex by lobe, and ventricles. Additionally, they measured the midsagittal area of the corpus callosum and its segments and of the cerebellar vermis and its component lobules. Measurements obtained from children with SSC and controls were compared using linear regression models. RESULTS No volume measures of the cerebrum or of the whole brain differed significantly between patients with SSC and controls (p > 0.05). However, ventricle volume was significantly increased in patients with SSC (p = 0.001), particularly in those with sagittal craniosynostosis (p < 0.001). In contrast, the area of the corpus callosum was significantly reduced in patients with metopic synostosis (p = 0.04), particularly in the posterior segments (p = 0.004). Similarly, the area of lobules VI-VII of the cerebellar vermis was reduced in patients with SSC (p = 0.03), with those with metopic craniosynostosis showing the greatest reduction (p = 0.01). CONCLUSIONS The lack of differences in overall brain size or regional differences in the size of the lobes of the cerebrum in children with metopic and sagittal synostosis suggests that the elevated risk of neurodevelopmental deficits is not likely to be associated with differences in the cerebral cortex. Instead, this study showed localized differences between sagittal and metopic craniosynostosis cases as compared with controls in the ventricles and in the midsagittal structures of the corpus callosum and the cerebellum. It remains to be tested whether these structural differences are associated with the increased risk for developmental delay and neurocognitive deficits in children with SSC.
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Leyden, James J
2011-10-01
A rosacea treatment system (cleanser, metronidazole 0.75% gel, hydrating complexion corrector, and sunscreen SPF30) has been developed to treat rosacea. Thirty women with mild or moderate erythema of rosacea on their facial cheeks were randomly assigned to use one of the following for 28 days: the rosacea treatment system (RTS); RTS minus metronidazole (RTS-M); or metronidazole 0.75% gel plus standard skin care (standard cleanser and standard moisturizer/sunscreen) (M+SSC). At day 28, global improvement was evident in 90 percent of patients using RTS, 60 percent using RTS-M, and 67 percent using M+SSC. Erythema was significantly lower with RTS from day 14 onward, and unchanged with M+SSC. The proportion of patients reporting their skin was easily irritated at least sometimes was 40 percent with RTS, 70 percent with RTS-M, and 89 percent with M+SSC. The rosacea treatment system may offer superior efficacy and tolerability to metronidazole plus the standard skin care used in this study.
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Decreased Interleukin-20 Expression in Scleroderma Skin Contributes to Cutaneous Fibrosis
Kudo, Hideo; Jinnin, Masatoshi; Asano, Yoshihide; Trojanowska, Maria; Nakayama, Wakana; Inoue, Kuniko; Honda, Noritoshi; Kajihara, Ikko; Makino, Katsunari; Fukushima, Satoshi; Ihn, Hironobu
2014-01-01
Objective To clarify the role of interleukin-20 (IL-20) in the regulatory mechanism of extracellular matrix expression and to determine the contribution of IL-20 to the phenotype of systemic sclerosis (SSc). Methods Protein and messenger RNA (mRNA) levels of collagen, Fli-1, IL-20, and IL-20 receptor (IL-20R) were analyzed using polymerase chain reaction (PCR) array, immunoblotting, immunohistochemical staining, enzyme-linked immunosorbent assay, and real-time PCR. Results PCR array revealed that IL-20 decreased gene expression of α2(I) collagen (0.03-fold), Smad3 (0.02-fold), and endoglin (0.05-fold) in cultured normal dermal fibroblasts. Fli-1 protein expression was induced by IL-20 (~2-fold). The inhibition of collagen by IL-20, the induction of Fli-1 by IL-20, and the reduction of Smad3 and endoglin by IL-20 were also observed in SSc fibroblasts. Serum IL-20 levels were reduced only slightly in SSc patients but were significantly decreased in patients with scleroderma spectrum disorders (the prodromal stage of SSc) compared with those in normal subjects (111.3 pg/ml versus 180.4 pg/ml; P < 0.05). On the other hand, IL-20 mRNA expression in SSc skin was decreased compared with that in normal skin (P < 0.05), which may result in the induction of collagen synthesis in SSc dermal fibroblasts. IL-20R was expressed in normal and SSc fibroblasts. Moreover, IL-20 supplementation by injection into the skin reversed skin fibrosis induced by bleomycin in mice (~0.5-fold). Conclusion IL-20 reduces basal collagen transcription via Fli-1 induction, while down-regulation of Smad3 and endoglin may cancel the effect of transforming growth factor β in SSc fibroblasts. To confirm the therapeutic value of IL-20 and IL-20R, their function and expression in vivo should be further studied. PMID:24470401
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Decreased interleukin-20 expression in scleroderma skin contributes to cutaneous fibrosis.
Kudo, Hideo; Jinnin, Masatoshi; Asano, Yoshihide; Trojanowska, Maria; Nakayama, Wakana; Inoue, Kuniko; Honda, Noritoshi; Kajihara, Ikko; Makino, Katsunari; Fukushima, Satoshi; Ihn, Hironobu
2014-06-01
To clarify the role of interleukin-20 (IL-20) in the regulatory mechanism of extracellular matrix expression and to determine the contribution of IL-20 to the phenotype of systemic sclerosis (SSc). Protein and messenger RNA (mRNA) levels of collagen, Fli-1, IL-20, and IL-20 receptor (IL-20R) were analyzed using polymerase chain reaction (PCR) array, immunoblotting, immunohistochemical staining, enzyme-linked immunosorbent assay, and real-time PCR. PCR array revealed that IL-20 decreased gene expression of α2(I) collagen (0.03-fold), Smad3 (0.02-fold), and endoglin (0.05-fold) in cultured normal dermal fibroblasts. Fli-1 protein expression was induced by IL-20 (~2-fold). The inhibition of collagen by IL-20, the induction of Fli-1 by IL-20, and the reduction of Smad3 and endoglin by IL-20 were also observed in SSc fibroblasts. Serum IL-20 levels were reduced only slightly in SSc patients but were significantly decreased in patients with scleroderma spectrum disorders (the prodromal stage of SSc) compared with those in normal subjects (111.3 pg/ml versus 180.4 pg/ml; P < 0.05). On the other hand, IL-20 mRNA expression in SSc skin was decreased compared with that in normal skin (P < 0.05), which may result in the induction of collagen synthesis in SSc dermal fibroblasts. IL-20R was expressed in normal and SSc fibroblasts. Moreover, IL-20 supplementation by injection into the skin reversed skin fibrosis induced by bleomycin in mice (~0.5-fold). IL-20 reduces basal collagen transcription via Fli-1 induction, while down-regulation of Smad3 and endoglin may cancel the effect of transforming growth factor β in SSc fibroblasts. To confirm the therapeutic value of IL-20 and IL-20R, their function and expression in vivo should be further studied. Copyright © 2014 by the American College of Rheumatology.
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2014-01-01
Introduction A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy. Methods Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. Results We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis. Conclusion Our results suggest a role of PPARG gene in the development of SSc. PMID:24401602
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Hashim, Peter W; Brooks, Eric D; Persing, John A; Reuman, Hannah; Naples, Adam; Travieso, Roberto; Terner, Jordan; Steinbacher, Derek; Landi, Nicole; Mayes, Linda; McPartland, James C
2015-01-01
Patients with single-suture craniosynostosis (SSC) are at an elevated risk for long-term learning disabilities. Such adverse outcomes indicate that the early development of neural processing in SSC may be abnormal. At present, however, the precise functional derangements of the developing brain remain largely unknown. Event-related potentials (ERPs) are a form of noninvasive neuroimaging that provide direct measurements of cortical activity and have shown value in predicting long-term cognitive functioning. The current study used ERPs to examine auditory processing in infants with SSC to help clarify the developmental onset of delays in this population. Fifteen infants with untreated SSC and 23 typically developing controls were evaluated. ERPs were recorded during the presentation of speech sounds. Analyses focused on the P150 and N450 components of auditory processing. Infants with SSC demonstrated attenuated P150 amplitudes relative to typically developing controls. No differences in the N450 component were identified between untreated SSC and controls. Infants with untreated SSC demonstrate abnormal speech sound processing. Atypicalities are detectable as early as 6 months of age and may represent precursors to long-term language delay. Electrophysiological assessments provide a precise examination of neural processing in SSC and hold potential as a future modality to examine the effects of surgical treatment on brain development.
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Giacomelli, Roberto; Di Cesare, Ernesto; Cipriani, Paola; Ruscitti, Piero; Di Sibio, Alessandra; Liakouli, Vasiliki; Gennarelli, Antonio; Carubbi, Francesco; Splendiani, Alessandra; Berardicurti, Onorina; Di Benedetto, Paola; Ciccia, Francesco; Guggino, Giuliana; Radchenko, Ganna; Triolo, Giovanni; Masciocchi, Carlo
2017-09-01
To evaluate occult cardiac involvement in asymptomatic systemic sclerosis (SSc) patients by pharmacological stress, rest perfusion and delayed enhancement cardiac magnetic resonance (CMR), for a very early identification of patients at higher risk of cardiac-related mortality. Sixteen consecutive patients with definite SSc, fulfilling the American College of Rheumatology/European League Against Rheumatism 2013 classification criteria in less than 1 year from the onset of Raynaud's phenomenon, underwent pharmacological stress, rest perfusion and delayed enhancement CMR. At enrollment, no patient showed signs and/or symptoms suggestive for cardiac involvement. No patient showed traditional cardiovascular risk factors. Both the 12-lead electrocardiogram examination and echocardiographic evaluation did not show any alterations in our cohort. Stress perfusion defects of left ventricle were detected in six out of 16 (37.5%) patients and these defects did not match with the coronary flow distribution. The results showed the presence of two different patterns of stress perfusion defects: sub-endocardial and/or a midmyocardial. The presence of stress perfusion defects did not correlate with any clinical feature of enrolled patients. Myocardial stress perfusion defects may be detected early by pharmacological stress perfusion CMR, a reliable and sensitive technique for the noninvasive evaluation of SSc heart disease, in patients with SSc of recent onset. These defects seem to be independent from traditional risk factors and associated comorbidities, suggesting they are a specific hallmark of the disease. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.
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Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility
Diaz-Gallo, Lina-Marcela; Simeon, Carmen P; Broen, Jasper C; Ortego-Centeno, Norberto; Beretta, Lorenzo; Vonk, Madelon C; Carreira, Patricia E; Vargas, Sofia; Román-Ivorra, José Andrés; González-Gay, Miguel A; Tolosa, Carlos; López-Longo, Francisco Javier; Espinosa, Gerard; Vicente, Esther F; Hesselstrand, Roger; Riemekasten, Gabriela; Witte, Torsten; Distler, Jörg H W; Voskuyl, Alexandre E; Schuerwegh, Annemie J; Shiels, Paul G; Nordin, Annika; Padyukov, Leonid; Hoffmann-Vold, Anna-Maria; Scorza, Raffaella; Lunardi, Claudio; Airo, Paolo; van Laar, Jacob M; Hunzelmann, Nicolas; Gathof, Birgit S; Kreuter, Alexander; Herrick, Ariane; Worthington, Jane; Denton, Christopher P; Zhou, Xiaodong; Arnett, Frank C; Fonseca, Carmen; Koeleman, Bobby PC; Assasi, Shervin; Radstake, Timothy R D J; Mayes, Maureen D; Martín, Javier
2013-01-01
Objective The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc). Patients and methods The case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays. Results We observed evidence of association of the rs6822844 and rs907715 variants with global SSc (pc=6.6E-4 and pc=7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (pc=1.7E-03 and pc=8E-4, respectively). Conclusions These results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases. PMID:23172754
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The involvement of immunoglobulin E isotype switch in scleroderma skin tissue.
Ohtsuka, Tsutomu; Yamazaki, Soji
2005-08-01
The involvement of mast cell, which is activated by immunoglobulin E (IgE), has been reported in the formation of systemic sclerosis (SSc) abnormality. IgE is generated with isotype switch. During isotype switch, switch circles resulting from direct mu to epsilon, or from sequential mu to gamma via epsilon switching will be created. We studied whether switching occurs in SSc. We used nested polymerase chain reaction to analyze the S fragments from switch circles. Fifty-two patients with SSc, and 62 healthy women were studied. Neither of 62 normal skin tissues showed direct switch, nor sequential switch. Neither of seven normal whole blood cells showed direct switch, nor sequential switch. In 52SSc skin tissues, three (5.8%) showed direct switch, and two (3.8%) showed sequential switch. As a result, five (9.6%) of SSc skin tissue showed immunogobulin E class switch. These results were confirmed by DNA sequencing. These results demonstrated that isotype switch to the epsilon locus achieved by direct and/or sequential switch are involved in SSc skin.
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de Rezende, Rodrigo Poubel Vieira; Gismondi, Ronaldo Altenburg; Maleh, Haim Cesar; de Miranda Coelho, Elisa Mendes; Vieira, Carol Sartori; Rosa, Maria Luiza Garcia; Mocarzel, Luis Otavio
2017-12-16
The objective of this study was to assess the mortality profile related to SSc in the state of Rio de Janeiro, Brazil. We retrospectively examined all registered deaths in the region (2006-2015 period) in which the diagnosis of SSc was mentioned on any line of the death certificates (underlying cause of death [UCD], n = 223; non-UCD, n = 151). Besides the analysis of gender, age, and the causes of death, we also compared the mortality from UCDs between individuals whose death causes included SSc (cases) and those whose death causes did not include SSc (deceased controls). For the latter comparison, we used the mortality odds ratio to approximate the cause-specific standardized mortality ratio. We identified 1495 death causes among the 374 SSc cases. The mean age at death of the SSc cases (85% women) was significantly lower than that of the controls (n = 1,294,117) (58.7 vs. 65.5 years, respectively). The main death causes were circulatory system diseases, infections, and respiratory diseases (36%, 34%, and 21% of SSc cases, respectively). Compared to the deceased controls, there were proportionally more deaths among the SSc cases from pulmonary arterial hypertension, lung fibrosis, septicemia, gastrointestinal hemorrhage, other systemic connective tissue diseases, and heart failure (for death age < 50 years). We confirmed the high burden of cardiovascular, respiratory, and infectious causes in this predominantly non-Caucasian sample of SSc patients. Of interest, the percentage of infection-related deaths in our report was about three times higher than that in SSc studies with predominantly Caucasian populations.
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Ingegnoli, Francesca; Schioppo, Tommaso; Allanore, Yannick; Caporali, Roberto; Colaci, Michele; Distler, Oliver; Furst, Daniel E; Hunzelmann, Nicolas; Iannone, Florenzo; Khanna, Dinesh; Matucci-Cerinic, Marco
2018-04-04
Systemic sclerosis (SSc) is an autoimmune chronic disease characterized by vascular impairment, immune dysfunction and collagen deposition. Raynaud's phenomenon (RP) and digital ulcers (DU) are prominent features of SSc. Intravenous (IV) iloprost (ILO), according to the recently updated EULAR recommendations, is indicated for RP after failure of oral therapy. Moreover, IV ILO could be useful in DU healing. IV ILO is currently available mainly on the European market approved for RP secondary to SSc with 3-5 days infusion cycle. Unfortunately, data published varies regarding regimen (dosage, duration and frequency). Up to now, ILO has been studied in small cohorts of patients and in few randomized controlled trials. A systematic review of studies on IV ILO in patients with SSc complicated by DU and RP was performed. Insufficient data were available to perform a meta-analysis according to the GRADE system. We performed a three-stage internet-based Delphi consensus exercise. Three major indications were identified for IV ILO usage in SSc: RP non-responsive to oral therapy, DU healing, and DU prevention. IV ILO should be administered between 0.5 and 2.0ng/kg/min according to patient tolerability with a frequency depending on the indication. Although these suggestions are supported by this expert group to be used in clinical setting, it will be necessary to formally validate the present suggestions in future clinical trials. Copyright © 2018 Elsevier Inc. All rights reserved.
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Grueninger, Patrick; Nikolic, Nikola; Schneider, Joerg; Lattmann, Thomas; Platz, Andreas; Chmiel, Corinne; Meier, Christoph
2014-06-01
The purpose of this study was to prospectively assess the efficacy of arthroscopic repair of isolated high-grade subscapularis (SSC) tendon lesions by means of clinical follow-up combined with magnetic resonance imaging investigations. Between January 2008 and September 2010, 11 patients (9 men and 2 women; mean age, 45 ± 10 years) with Lafosse type III or IV traumatic isolated SSC tendon lesions underwent arthroscopic repair including tenodesis of the long head of the biceps tendon. All patients were preoperatively assessed by clinical examination (Constant-Murley score [CMS]) and contrast-enhanced magnetic resonance arthrography. At 1 year of follow-up, specific clinical SSC tests, the CMS, and the loss of external rotation were evaluated. A native magnetic resonance investigation was performed to assess the structural integrity of the repair. The SSC muscle was compared with its preoperative condition regarding fatty infiltration and size (cross-sectional area). Patient satisfaction was graded from 1 (poor) to 4 (excellent). The mean time interval from trauma to surgery was 3.7 months. A concomitant lesion of the biceps tendon was observed in 10 patients (91%). The mean CMS improved from 44 to 89 points (P < .001). The functional tests showed a significant increase in strength (P < .05) (belly-press test, 4.8 v 2.9; lift-off test, 4.8 v 2.9). The mean loss of external rotation at 0° of abduction was 10° compared with the contralateral side (P < .05). Patient satisfaction was high. Magnetic resonance imaging evaluation showed complete structural integrity of the tendon repair in all studies. The SSC showed a significant decrease in fatty infiltration and increase in the cross-sectional area. Arthroscopic repair of higher-grade isolated SSC lesions provides reliable tendon healing accompanied by excellent functional results 1 year after surgery. Level IV, prospective therapeutic case series. Copyright © 2014 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.
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Doshier, Laura J; Muzaffar, Arshad R; Deidrick, Kathleen KM; Rice, Gale B
2015-01-01
BACKGROUND: Single-suture craniosynostosis (SSC) is a common craniofacial condition with potential neurocognitive sequelae. OBJECTIVE: To quantify any long-term functional academic and behavioural difficulties of children with SSC as indicated by the need for individualized education programs (IEPs), despite having undergone surgical treatment. METHODS: Records of all school-age patients from 1992 to 2011 who underwent operative intervention for SSC were identified. Fifty-nine patients’ guardians were contacted by telephone to provide informed consent for completion of a mailed standardized questionnaire querying demographic information as well as information regarding the patient’s health, family and educational history; specifically whether the patient had ever been provided educational support as delineated in an IEP. The primary outcome measure was the history of the patient being assigned educational support as delineated in an IEP. RESULTS: Thirty-seven consenting guardians completed and returned the standardized questionnaire (response rate 62.7%). Twenty-one patients were male and 16 were female, with an age range of five to 14 years (mean age 10.2 years). Eleven (29.7%) patients had a previous history of or currently were receiving educational support delineated in an IEP. CONCLUSIONS: A higher proportion of school-age patients with a history of SSC (status postsurgical intervention) in the present study received educational support delineated in an IEP than the proportion of IEPs in the general student population of the United States (11.3%). PMID:25821770
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Behavioral Adjustment of Toddler and Preschool-Aged Children with Single-Suture Craniosynostosis*
Kapp-Simon, Kathleen A; Collett, Brent R; Barr-Schinzel, Michael A; Cradock, Mary M; Buono, Lauren A; Pietila, Kristen E; Speltz, Matthew L
2012-01-01
Background The purpose of this study was to confirm initial reports of elevated behavior problems in children with single-suture craniosynostosis (SSC), using multiple informants, longitudinal analyses and a control group. We hypothesized higher levels of maladjustment for children with SSC than comparison children, particularly at the older age and in selected areas of previously observed vulnerability: attention and social adjustment. Method A Child Behavior Checklist (CBCL) was completed when children were ~19 months by 436 mothers (219 with SSC) and 371 fathers (177 with SSC); and at ~37 months by 361 mothers (175 with SSC) and 303 fathers (142 with SSC). A minimum of one caregiver/teacher report was available for 169 of these children (74 with SSC) using the Caregiver-Teacher Report Form (CTRF). Results Average CBCL/CTRF externalizing, internalizing and total scores for all informants were consistently higher (worse) for children with SSC than control group children, but most differences were small and statistically non-significant. No differences associated with suture site were found. At the oldest age point, both mothers and fathers (but not teachers) generated higher average scores for patients than for controls on scales measuring attention and social problems, with small to medium effects sizes (0.20 to 0.32). Conclusion On average toddlers/preschoolers with SSC show behavioral development that is largely indistinguishable from same-aged peers of similar socioeconomic background. The predictive significance of small group differences in attention and social adjustment will be assessed in a follow-up of this cohort at age 7. PMID:22929249
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Cutolo, Maurizio; Herrick, Ariane L; Distler, Oliver; Becker, Mike O; Beltran, Emma; Carpentier, Patrick; Ferri, Clodoveo; Inanç, Murat; Vlachoyiannopoulos, Panayiotis; Chadha-Boreham, Harbajan; Cottreel, Emmanuelle; Pfister, Thomas; Rosenberg, Daniel; Torres, Juan V; Smith, Vanessa
2016-10-01
To identify nailfold videocapillaroscopic features and other clinical risk factors for new digital ulcers (DUs) during a 6-month period in patients with systemic sclerosis (SSc). In this multicenter, prospective, observational cohort study, the videoCAPillaroscopy (CAP) study, we evaluated 623 patients with SSc from 59 centers (14 countries). Patients were stratified into 2 groups: a DU history group and a no DU history group. At enrollment, patients underwent detailed nailfold videocapillaroscopic evaluation and assessment of demographic characteristics, DU status, and clinical and SSc characteristics. Risk factors for developing new DUs were assessed using univariable and multivariable logistic regression (MLR) analyses. Of the 468 patients in the DU history group (mean ± SD age 54.0 ± 13.7 years), 79.5% were female, 59.8% had limited cutaneous SSc, and 22% developed a new DU during follow-up. The strongest risk factors for new DUs identified by MLR in the DU history group included the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs (categorized as 0, 1, 2, or ≥3), and the presence of critical digital ischemia. The receiver operating characteristic (ROC) of the area under the curve (AUC) of the final MLR model was 0.738 (95% confidence interval [95% CI] 0.681-0.795). Internal validation through bootstrap generated a ROC AUC of 0.633 (95% CI 0.510-0.756). This international prospective study, which included detailed nailfold videocapillaroscopic evaluation and extensive clinical characterization of patients with SSc, identified the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs at enrollment, and the presence of critical digital ischemia at enrollment as risk factors for the development of new DUs. © 2016, American College of Rheumatology.
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Herrick, Ariane L.; Distler, Oliver; Becker, Mike O.; Beltran, Emma; Carpentier, Patrick; Ferri, Clodoveo; Inanç, Murat; Vlachoyiannopoulos, Panayiotis; Chadha‐Boreham, Harbajan; Cottreel, Emmanuelle; Pfister, Thomas; Rosenberg, Daniel; Torres, Juan V.; Cutolo, Maurizio; Herrick, Ariane L.; Distler, Oliver; Becker, Mike; Beltran, Emma; Carpentier, Patrick; Ferri, Clodoveo; Inanç, Murat; Vlachoyiannopoulos, Panayiotis; Smith, Vanessa; Erlacher, L; Hirschl, M; Kiener, HP; Pilger, E; Smith, V; Blockmans, D; Wautrecht, J‐C; Becvár, R; Carpentier, P; Frances, C; Lok, C; Sparsa, A; Hachulla, E; Quere, I; Allanore, Y; Agard, C; Riemekasten, G; Hunzelmann, N; Stücker, M; Ahmadi‐Simab, K; Sunderkötter, C; Wohlrab, J; Müller‐Ladner, U; Schneider, M; Vlachoyianopoulos, P; Vassilopoulos, D; Drosos, A; Antonopoulos, A; Balbir‐Gurman, A; Langevitz, P; Rosner, I; Levy, Y; Cutolo, M; Bombardieri, S; Ferraccioli, G; Mazzuca, S; Grassi, W; Lunardi, C; Airó, P; Riccieri, V; Voskuyl, AE; Schuerwegh, A; Santos, L; Rodrigues, AC; Grilo, A; Amaral, MC; Román Ivorra, JA; Castellvi, I; Distler, O; Spertini, F; Müller, R; Inanç, M; Oksel, F; Turkcapar, N; Herrick, A; Denton, C; McHugh, N; Chattopadhyay, C; Hall, F; Buch, M
2016-01-01
Objective To identify nailfold videocapillaroscopic features and other clinical risk factors for new digital ulcers (DUs) during a 6‐month period in patients with systemic sclerosis (SSc). Methods In this multicenter, prospective, observational cohort study, the videoCAPillaroscopy (CAP) study, we evaluated 623 patients with SSc from 59 centers (14 countries). Patients were stratified into 2 groups: a DU history group and a no DU history group. At enrollment, patients underwent detailed nailfold videocapillaroscopic evaluation and assessment of demographic characteristics, DU status, and clinical and SSc characteristics. Risk factors for developing new DUs were assessed using univariable and multivariable logistic regression (MLR) analyses. Results Of the 468 patients in the DU history group (mean ± SD age 54.0 ± 13.7 years), 79.5% were female, 59.8% had limited cutaneous SSc, and 22% developed a new DU during follow‐up. The strongest risk factors for new DUs identified by MLR in the DU history group included the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs (categorized as 0, 1, 2, or ≥3), and the presence of critical digital ischemia. The receiver operating characteristic (ROC) of the area under the curve (AUC) of the final MLR model was 0.738 (95% confidence interval [95% CI] 0.681–0.795). Internal validation through bootstrap generated a ROC AUC of 0.633 (95% CI 0.510–0.756). Conclusion This international prospective study, which included detailed nailfold videocapillaroscopic evaluation and extensive clinical characterization of patients with SSc, identified the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs at enrollment, and the presence of critical digital ischemia at enrollment as risk factors for the development of new DUs. PMID:27111549
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Bossini-Castillo, Lara; Martin, Jose Ezequiel; Broen, Jasper; Simeon, Carmen P; Beretta, Lorenzo; Gorlova, Olga Y; Vonk, Madelon C; Ortego-Centeno, Norberto; Espinosa, Gerard; Carreira, Patricia; García de la Peña, Paloma; Oreiro, Natividad; Román-Ivorra, José Andrés; Castillo, María Jesús; González-Gay, Miguel A; Sáez-Comet, Luis; Castellví, Ivan; Schuerwegh, Annemie J; Voskuyl, Alexandre E; Hoffmann-Vold, Anna-Maria; Hesselstrand, Roger; Nordin, Annika; Lunardi, Claudio; Scorza, Raffaella; van Laar, Jacob M; Shiels, Paul G; Herrick, Ariane; Worthington, Jane; Fonseca, Carmen; Denton, Christopher; Tan, Filemon K; Arnett, Frank C; Assassi, Shervin; Koeleman, Bobby P; Mayes, Maureen D; Radstake, Timothy R D J; Martin, Javier
2013-01-01
Introduction A recent genome-wide association study in European systemic sclerosis (SSc) patients identified three loci (PSORS1C1, TNIP1 and RHOB) as novel genetic risk factors for the disease. The aim of this study was to replicate the previously mentioned findings in a large multicentre independent SSc cohort of Caucasian ancestry. Methods 4389 SSc patients and 7611 healthy controls from different European countries and the USA were included in the study. Six single nucleotide polymorphisms (SNP): rs342070, rs13021401 (RHOB), rs2233287, rs4958881, rs3792783 (TNIP1) and rs3130573 (PSORS1C1) were analysed. Overall significance was calculated by pooled analysis of all the cohorts. Haplotype analyses and conditional logistic regression analyses were carried out to explore further the genetic structure of the tested loci. Results Pooled analyses of all the analysed SNPs in TNIP1 revealed significant association with the whole disease (rs2233287 pMH=1.94×10−4, OR 1.19; rs4958881 pMH=3.26×10−5, OR 1.19; rs3792783 pMH=2.16×10−4, OR 1.19). These associations were maintained in all the subgroups considered. PSORS1C1 comparison showed association with the complete set of patients and all the subsets except for the anti-centromere-positive patients. However, the association was dependent on different HLA class II alleles. The variants in the RHOB gene were not associated with SSc or any of its subsets. Conclusions These data confirmed the influence of TNIP1 on an increased susceptibility to SSc and reinforced this locus as a common autoimmunity risk factor. PMID:22896740
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Serum nitric oxide metabolites and disease activity in patients with systemic sclerosis.
Mok, Mo Yin; Fung, Peter Chin Wah; Ooi, Clara; Tse, Hung Fat; Wong, Yik; Lam, Yui Ming; Wong, Woon Sing; Lau, Chak Sing
2008-03-01
There is no surrogate marker in serum for defining disease activity in scleroderma (SSc). Nitric oxide (NO), which regulates vasodilation and possesses pro-inflammatory actions, has been implicated in the pathogenesis of SSc. We compared serum NO(x) (total nitrate and nitrite) level in SSc patients to healthy controls and evaluated its correlation with detailed symptomatology and scoring systems for various organ involvement. Symptoms and physical findings that suggested disease activity in regard to various organs were documented. Lung function test, high-resolution computed tomographic (HRCT) scan of thorax and echocardiography were performed. Serum NO(x) was measured by chemiluminescence. Serum NO(x) levels in SSc (n = 43) were significantly higher (72.4 +/- 47.8 microM) than age- and sex-matched controls (n = 41; 37.1 +/- 13.5 microM; p < 0.001). Serum NO(x) were not found to be associated with lung fibrosis defined by lung function parameters or inflammation and fibrosis scores on HRCT. Twenty-two patients were found to have elevated serum NO(x) level defined as mean +/- 2 SD of normal controls. Logistic regression analysis revealed that age (OR 1.12, p = 0.02) and elevated pulmonary arterial pressure (PAP) (n = 9; OR 145.3, p = 0.01) were predictive factors for elevated serum NO(x). Prednisolone use was associated with lower serum NO(x) level (OR 0.06, p = 0.04). Elevated PAP of increasing severity was found to be associated with higher level of serum NO(x) (p = 0.004 by trend). Serum NO(x) in SSc patients were elevated compared to healthy controls. Serum NO(x) level was determined by multiple factors including age, prednisolone use, and elevated PAP.
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Thombs, Brett D.; Jewett, Lisa R.; Assassi, Shervin; Baron, Murray; Bartlett, Susan J.; Costa Maia, Angela; El-Baalbaki, Ghassan; Furst, Daniel E.; Gottesman, Karen; Haythornthwaite, Jennifer A.; Hudson, Marie; Ann Impens, PhD; Korner, Annett; Leite, Catarina; Mayes, Maureen D.; Malcarne, Vanessa L.; Motivala, Sarosh J.; Mouthon, Luc; Nielson, Warren R.; Plante, Diane; Poiraudeau, Serge; Poole, Janet L.; Pope, Janet; Sauve, Maureen; Steele, Russell J.; Suarez-Almazor, Maria E.; Taillefer, Suzanne; van den Ende, Cornelia H.; Erin Arthurs, BSc; Bassel, Marielle; Delisle, Vanessa; Milette, Katherine; Leavens, Allison; Razykov, Ilya; Khanna, Dinesh
2014-01-01
Systemic sclerosis (SSc), or scleroderma, is a chronic multisystem autoimmune disorder characterised by thickening and fibrosis of the skin and by the involvement of internal organs such as the lungs, kidneys, gastrointestinal tract, and heart. Because there is no cure, feasibly-implemented and easily accessible evidence-based interventions to improve health-related quality of life (HRQoL) are needed. Due to a lack of evidence, however, specific recommendations have not been made regarding non-pharmacological interventions (e.g. behavioural/psychological, educational, physical/occupational therapy) to improve HRQoL in SSc. The Scleroderma Patient-centred Intervention Network (SPIN) was recently organised to address this gap. SPIN is comprised of patient representatives, clinicians, and researchers from Canada, the USA, and Europe. The goal of SPIN, as described in this article, is to develop, test, and disseminate a set of accessible interventions designed to complement standard care in order to improve HRQoL outcomes in SSc. PMID:22244687
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Systemic sclerosis, birth order and parity.
Russo, Paul A J; Lester, Susan; Roberts-Thomson, Peter J
2014-06-01
A recent study identified increasing birth order to be a risk factor for the development of systemic sclerosis (SSc). This finding supports the theory that transplacental microchimerism may be a key pathological event in the initiation of SSc. We investigated the relationship between birth order and parity and the age of onset of SSc in South Australia. A retrospective analysis of patient data in the South Australian Scleroderma Register was performed. Data were obtained from a mailed questionnaire. Control data was collected prospectively using a similar questionnaire. The relationship between birth order, family size or parity and risk of subsequent development of SSc was analyzed by mixed effects logistic regression analysis. Three hundred and eighty-seven index probands were identified and compared with 457 controls. Controls were well matched for gender, but not for age. No statistically significant relationship was identified between SSc and birth order, parity in females, family size, age at first pregnancy in females or gender of first child in parous females. Our data suggests that parity, age at first pregnancy and the gender of the first child are not relevant factors in our understanding of the epidemiology and pathogenesis of SSc. Birth order and family size in both genders also appears irrelevant. These results argue against microchimerism as being relevant in the pathogenesis of SSc and add further support to the theory that stochastic events may be important in the etiopathogenesis of SSc. © 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.
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Jewett, Lisa R; Kwakkenbos, Linda; Carrier, Marie-Eve; Malcarne, Vanessa L; Bartlett, Susan J; Furst, Daniel E; Gottesman, Karen; Mayes, Maureen D; Assassi, Shervin; Harcourt, Diana; Williamson, Heidi; Johnson, Sindhu R; Körner, Annett; Steen, Virginia; Fox, Rina S; Gholizadeh, Shadi; Mills, Sarah D; Molnar, Jacqueline C; Rice, Danielle B; Thombs, Brett D
2016-01-01
Appearance concerns are common in systemic sclerosis (SSc) and have been linked to younger age and more severe disease. No study has examined their association with sex or race/ethnicity. SSc patients were sampled from the Scleroderma Patient-centered Intervention Network Cohort. Presence of appearance concerns was assessed with a single item, and medical and sociodemographic information were collected. Of 644 patients, appearance concerns were present in 72%, including 421 of 565 women (75%), 42 of 79 men (53%), 392 of 550 patients who identified as White (71%), 35 of 41 who identified as Black (85%), and 36 of 53 who identified as another race/ethnicity (68%). In multivariate analysis, women had significantly greater odds of reporting appearance concerns than men (odds ratio (OR)=2.97, 95% confidence interval (CI)=1.78-4.95, p<.001). Black patients had significantly greater odds of appearance concerns than White patients in unadjusted (OR=2.64, 95% CI=1.01-6.34, p=.030), but not multivariate analysis (OR=1.76, 95% CI=0.67-4.60, p=.250). Compared to a general population sample, appearance concerns were substantially more common in SSc, particularly for men across all age groups and for younger women. The most commonly reported features of concern were related to the face and head, followed by the hands and fingers; this did not differ by sex or race/ethnicity. Appearance concerns were common in SSc. Women were substantially more likely than men to have appearance concerns. Although non-significant in multivariate analysis, Black patients were more likely to have concerns than White patients, likely due to more severe changes in appearance.
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Philippe, Lucas; Gong, Ya-Zhuo; Bahram, Seiamak; Cetin, Semih; Pfeffer, Sébastien; Gottenberg, Jacques-Eric; Wachsmann, Dominique; Georgel, Philippe; Sibilia, Jean
2014-01-01
We evaluated micro (mi) RNA-mediated regulation of BAFF expression in fibroblasts using two concomitant models: (i) synovial fibroblasts (FLS) isolated from healthy controls (N) or Rheumatoid Arthritis (RA) patients; (ii) human dermal fibroblasts (HDF) isolated from healthy controls (N) or Systemic Sclerosis (SSc) patients. Using RT-qPCR and ELISA, we first showed that SScHDF synthesized and released BAFF in response to Poly(I:C) or IFN-γ treatment, as previously observed in RAFLS, whereas NHDF released BAFF preferentially in response to IFN-γ. Next, we demonstrated that miR-30a-3p expression was down regulated in RAFLS and SScHDF stimulated with Poly(I:C) or IFN-γ. Moreover, we demonstrated that transfecting miR-30a-3p mimic in Poly(I:C)- and IFN-γ-activated RAFLS and SScHDF showed a strong decrease on BAFF synthesis and release and thus B cells survival in our model. Interestingly, FLS and HDF isolated from healthy subjects express higher levels of miR-30a-3p and lower levels of BAFF than RAFLS and SScHDF. Transfection of miR-30a-3p antisense in Poly(I:C)- and IFN-γ-activated NFLS and NHDF upregulated BAFF secretion, confirming that this microRNA is a basal repressors of BAFF expression in cells from healthy donors. Our data suggest a critical role of miR-30a-3p in the regulation of BAFF expression, which could have a major impact in the regulation of the autoimmune responses occurring in RA and SSc. PMID:25360821
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Subscale Diffuser Testing, E-3 produces first steam
2007-10-25
Phase 2 of the A-3 Test Facility Subscale Diffuser Risk Mitigation Project at Stennis Space Center reached a milestone Oct. 25 when the E-3 Test Facility produced superheated (500+ degrees) steam for approximately 3 seconds at more than 400 psi. The test team, led by Barry Robinson of NASA's Test Projects Office, followed that success with further tests to lengthen the duration of steam production. On Nov. 1, they were able to maintain a consistent pressure and temperature of steam for 60 seconds. In December, the team began Phase 3 of the testing, providing data for the design and procurement to build the full-scale version of the steam diffuser for SSC's A-3 Test Stand.
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Subscale Diffuser Testing, E-3 produces first steam
NASA Technical Reports Server (NTRS)
2007-01-01
Phase 2 of the A-3 Test Facility Subscale Diffuser Risk Mitigation Project at Stennis Space Center reached a milestone Oct. 25 when the E-3 Test Facility produced superheated (500+ degrees) steam for approximately 3 seconds at more than 400 psi. The test team, led by Barry Robinson of NASA's Test Projects Office, followed that success with further tests to lengthen the duration of steam production. On Nov. 1, they were able to maintain a consistent pressure and temperature of steam for 60 seconds. In December, the team began Phase 3 of the testing, providing data for the design and procurement to build the full-scale version of the steam diffuser for SSC's A-3 Test Stand.
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Ziemek, Jessica; Man, Ada; Hinchcliff, Monique; Varga, John; Simms, Robert W; Lafyatis, Robert
2016-05-01
To determine how well skin symptoms considered specific to SSc are captured by patient reported outcomes currently used for assessing patients with SSc, the SHAQ, or skin disease, the Skindex-29; and how well these symptoms correlate with the extent of skin disease on physical exam and skin pathology. SSc patients completed the scleroderma modification of the Health Assessment Questionnaire (SHAQ), Skindex-29 and a Skin Symptom Assessment questionnaire developed for this study. Correlations were assessed between the Skin Symptom Assessment and SHAQ, Skindex-29, modified Rodnan skin score, and skin pathological features including myofibroblast staining completed on the same date. Tight, hard and rigid/stiff skin symptoms correlated moderately highly with the modified Rodnan skin score (r = 0.445, P = 0.0008; r = 0.486, P = 0.0002; and r = 0.488, P = 0.0002, respectively). Tight skin symptoms correlated moderately with myofibroblast infiltration (r = 0.544, P = 0.0023) and hyalinized collagen (r = 0.442, P = 0.0164), while both hard and rigid/stiff skin correlated moderately with inflammation (r = 0.401, P = 0.0310 and r = 0.513, P = 0.0045), myofibroblast infiltration(r = 0.480, P = 0.0084 and r = 0.527, P = 0.0033) and hyalinized collagen (r = 0.453, P = 0.0137 and r = 0.478, P = 0.0087), while the SHAQ was not found to correlate with any of these pathological changes. In contrast, painful skin symptoms correlated moderately with the SHAQ (r = 0.413, P = 0.0073), and with the three domains of Skindex-29: Symptoms, Emotions and Functioning. Skindex-29 indicates that dcSSc patient skin symptoms are nearly as severe as those of patients with psoriasis or atopic dermatitis. Patient reported skin symptoms correlate with clinical and pathological measures in the skin. A validated patient reported skin symptom instrument might considerably improve evaluation of SSc skin disease. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Hughes, Michael; Ong, Voon H; Anderson, Marina E; Hall, Frances; Moinzadeh, Pia; Griffiths, Bridget; Baildam, Eileen; Denton, Christopher P; Herrick, Ariane L
2015-11-01
Digital vasculopathy (comprising RP, digital ulceration and critical digital ischaemia) is responsible for much of the pain and disability experienced by patients with SSc. However, there is a limited evidence base to guide clinicians in the management of SSc-related digital vasculopathy. Our aim was to produce recommendations that would be helpful for clinicians, especially for those managing patients outside specialist centres. The UK Scleroderma Study Group set up several working groups to develop a number of consensus best practice pathways for the management of SSc-specific complications, including digital vasculopathy. This overview presents the background and best practice consensus pathways for SSc-related RP, digital ulceration and critical ischaemia. Examples of drug therapies, including doses, are suggested in order to inform prescribing practice. A number of treatment algorithms are provided that are intended to provide the clinician with accessible reference tools for use in daily management. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Matatiele, Puleng; Tikly, Mohamed; Tarr, Gareth; Gulumian, Mary
2015-05-20
Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are systemic autoimmune connective tissue diseases that share overlapping clinico-pathological features. It is highly probable that there is an overlap in epigenetic landscapes of both diseases. This study aimed to identify similarities in DNA methylation changes in genes involved in SLE and SSc. Global DNA methylation and twelve genes selected on the basis of their involvement in inflammation, autoimmunity and/or fibrosis were analyzed using PCR arrays in three groups, each of 30 Black South Africans with SLE and SSc, plus 40 healthy control subjects. Global methylation in both diseases was significantly lower (<25 %) than in healthy subjects (>30 %, p = 0.0000001). In comparison to healthy controls, a similar gene-specific methylation pattern was observed in both SLE and SSc. Three genes, namely; PRF1, ITGAL and FOXP3 were consistently hypermethylated while CDKN2A and CD70 were hypomethylated in both diseases. The other genes (SOCS1, CTGF, THY1, CXCR4, MT1-G, FLI1, and DNMT1) were generally hypomethylated in SLE whereas they were neither hyper- nor hypo-methylated in SSc. SSc and SLE patients have a higher global hypomethylation than healthy subjects with specific genes being hypomethylated and others hypermethylated. The majority of genes studied were hypomethylated in SLE compared to SSc. In addition to the commonly known hypomethylated genes in SLE and SSc, there are other hypomethylated genes (such as MT-1G and THY-1) that have not previously been investigated in SLE and SSc though are known to be hypermethylated in cancer.
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Wu, Minghua; Pedroza, Mesias; Lafyatis, Robert; George, Anuh-Teresa; Mayes, Maureen D.; Assassi, Shervin; Tan, Filemon K.; Brenner, Michael B.; Agarwal, Sandeep K.
2014-01-01
Objective Systemic sclerosis (SSc) is a chronic autoimmune disease clinically manifesting as progressive fibrosis of the skin and internal organs. Recent microarray studies demonstrated that cadherin 11 (Cad-11) expression is increased in the affected skin of patients with SSc. The purpose of this study was to examine our hypothesis that Cad-11 is a mediator of dermal fibrosis. Methods Biopsy samples of skin from SSc patients and healthy control subjects were used for real-time quantitative polymerase chain reaction analysis to assess Cad-11 expression and for immunohistochemistry to determine the expression pattern of Cad-11. To determine whether Cad-11 is a mediator of dermal fibrosis, Cad-11–deficient mice and anti–Cad-11 monoclonal antibodies (mAb) were used in the bleomycin-induced dermal fibrosis model. In vitro studies with dermal fibroblasts and bone marrow–derived macrophages were used to determine the mechanisms by which Cad-11 contributes to the development of tissue fibrosis. Results Levels of messenger RNA for Cad-11 were increased in skin biopsy samples from patients with SSc and correlated with the modified Rodnan skin thickness scores. Cad-11 expression was localized to dermal fibroblasts and macrophages in SSc skin. Cad-11–knockout mice injected with bleomycin had markedly attenuated dermal fibrosis, as quantified by measurements of skin thickness, collagen levels, myofibroblast accumulation, and profibrotic gene expression, in lesional skin as compared to the skin of wild-type mice. In addition, anti–Cad-11 mAb decreased fibrosis at various time points in the bleomycin-induced dermal fibrosis model. In vitro studies demonstrated that Cad-11 regulated the production of transforming growth factor β (TGFβ) by macrophages and the migration of fibroblasts. Conclusion These data demonstrate that Cad-11 is a mediator of dermal fibrosis and TGFβ production and suggest that Cad-11 may be a therapeutic target in SSc. PMID:24757152
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White, Michelle C; Peterschmidt, Jennifer; Callahan, James; Fitzgerald, J Edward; Close, Kristin L
2017-06-29
The World Health Organisation Surgical Safety Checklist (SSC) improves surgical outcomes and the research question is no longer 'does the SSC work?' but, 'how to make the SSC work?' Evidence for implementation strategies in low-income countries is sparse and existing strategies are heavily based on long-term external support. Short but effective implementation programs are required if widespread scale up is to be achieved. We designed and delivered a four-day pilot SSC training course at a single hospital centre in the Republic of Congo, and evaluated the implementation after one year. We hypothesised that participants would still be using the checklist over 50% of the time. We taught the four-day SSC training course at Dolisie hospital in February 2014, and undertook a mixed methods impact evaluation based on the Kirkpatrick model in May 2015. SSC implementation was evaluated using self-reported questionnaire with a 3 point Likert scale to assess six key process measures. Learning, behaviour, organisational change and facilitators and inhibitors to change were evaluated with questionnaires, interviews and focus group discussion. Seventeen individuals participated in the training and seven (40%) were available for impact evaluation at 15 months. No participant had used the SSC prior to training. Over half the participants were following the six processes measures always or most of the time: confirmation of patient identity and the surgical procedure (57%), assessment of difficult intubation risk (72%), assessment of the risk of major blood loss (86%), antibiotic prophylaxis given before skin incision (86%), use of a pulse oximeter (86%), and counting sponges and instruments (71%). All participants reported positive improvements in teamwork, organisation and safe anesthesia. Most participants reported they worked in helpful, supportive and respectful atmosphere; and could speak up if they saw something that might harm a patient. However, less than half felt able to challenge those in authority. Our study demonstrates that a 4-day pilot course for SSC implementation resulted in over 50% of participants using the SSC at 15 months, positive changes in learning, behaviour and organisational change, but less impact on hierarchical culture. The next step is to test our novel implementation strategy in a larger hospital setting.
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Herrick, Ariane L; Murray, Andrea
2018-05-01
Most patients with Raynaud's phenomenon (RP) have "benign" primary RP (PRP), but a minority have an underlying cause, for example a connective tissue disease such as systemic sclerosis (SSc). Secondary RP can be associated with structural as well as functional digital vascular changes and can be very severe, potentially progressing to digital ulceration or gangrene. The first step in management is to establish why the patient has RP. This short review discusses the role of nailfold capillaroscopy and thermography in the assessment of RP. Nailfold capillaroscopy examines microvascular structure, which is normal in PRP but abnormal in most patients with SSc: the inclusion of abnormal nailfold capillaries into the 2013 classification criteria for SSc behoves clinicians diagnosing connective tissue disease to be familiar with the technique. For those without access to the gold standard of high magnification videocapillaroscopy, a low magnification dermatoscope or USB microscope can be used. Thermography measures surface temperature and is therefore an indirect measure of blood blow, assessing digital vascular function (abnormal in both PRP and SSc). Until now, the use of thermography has been mainly confined to specialist centres and used mainly in research: this may change with development of mobile phone thermography. Copyright © 2018 Elsevier B.V. All rights reserved.
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Karamanolis, George P; Panopoulos, Stylianos; Karlaftis, Anastasios; Denaxas, Konstantinos; Kamberoglou, Dimitrios; Sfikakis, Petros P; Ladas, Spiros D
2015-06-01
Esophageal involvement in systemic sclerosis (SSc) carries significant morbidity and is empirically managed with domperidone, albeit with questionable efficacy. The oral 5-HT1A receptor agonist buspirone may enhance esophageal peristalsis and lower esophageal sphincter (LES) function in healthy volunteers. We aimed to test the hypothesis that buspirone may exert a beneficial acute effect on esophageal motor dysfunction in symptomatic patients with SSc. Twenty consecutive patients with SSc reporting esophageal symptoms underwent high-resolution manometry before and 30 minutes after administration of buspirone (10 mg). Ten other patients received domperidone (10 mg) and served as control group. Changes in LES resting and residual pressure, amplitude, duration, and velocity of distal esophageal body contractions were examined. Esophageal hypomotility and hypotensive LES was found in 63% and 67% of patients, respectively. Demographic and clinical characteristics, including baseline manometric parameters, were comparable between groups. Resting pressure of LES increased after buspirone from 9.42 ± 2.6 to 11.53 ± 3.4 mmHg (p = 0.0002 by paired t-test), but not after domperidone; a trend for increase of amplitude of contractions was also observed after buspirone (p = 0.09). Comparison of the individual changes revealed that buspirone was superior to domperidone in enhancing LES pressure ( + 2.11 ± 2.0 versus -0.45 ± 2.3 mmHg, p = 0.006). No significant effects of either drug were noted on other examined parameters of esophageal function. The beneficial acute effect of buspirone on impaired LES function associated with SSc suggests a role of 5-HT1A receptor-mediated interactions in these patients. Prospective studies to examine whether buspirone is of long-term therapeutic value for SSc-associated esophageal disease are warranted.
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Efficacy of Autologous Microfat Graft on Facial Handicap in Systemic Sclerosis Patients
Sautereau, Nolwenn; Daumas, Aurélie; Truillet, Romain; Jouve, Elisabeth; Magalon, Jéremy; Veran, Julie; Casanova, Dominique; Frances, Yves; Magalon, Guy
2016-01-01
Background: Autologous adipose tissue injection is used in plastic surgery for correction of localized tissue atrophy and has also been successfully offered for treatment of localized scleroderma. We aimed to evaluate whether patients with systemic sclerosis (SSc) and facial handicap could also benefit from this therapy. Methods: We included 14 patients (mean age of 53.8 ± 9.6 years) suffering from SSc with facial handicap defined by Mouth Handicap in Systemic Sclerosis Scale (MHISS) score more than or equal to 20, a Rodnan skin score on the face more than or equal to 1, and maximal mouth opening of less than 55 mm. Autologous adipose tissue injection was performed under local anesthesia using the technique of subcutaneous microinjection. The main objective of this study was an improvement of the MHISS score 6 months after the surgical treatment. Results: The procedure was well tolerated. We observed a mean decrease in the MHISS score of 10.7 points (±5.1; P < 0.0001) at 6 months (35% improvement). Secondary efficacy parameters assessing perioral skin sclerosis, maximum mouth opening, sicca syndrome, and facial pain significantly improved at 3 and 6 months postsurgery. At a 6-month follow-up, 75% of patients were satisfied or very satisfied of the adipose tissue microinjection therapy. Conclusions: Our study suggests that subcutaneous perioral microfat injection in patients with SSc is beneficial in the treatment of facial handicap, skin sclerosis, mouth opening limitation, sicca syndrome, and facial pain. Thus, this minimally invasive approach offers a new hope for face therapy for patients with SSc. PMID:27257590
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Efficacy of Autologous Microfat Graft on Facial Handicap in Systemic Sclerosis Patients.
Sautereau, Nolwenn; Daumas, Aurélie; Truillet, Romain; Jouve, Elisabeth; Magalon, Jéremy; Veran, Julie; Casanova, Dominique; Frances, Yves; Magalon, Guy; Granel, Brigitte
2016-03-01
Autologous adipose tissue injection is used in plastic surgery for correction of localized tissue atrophy and has also been successfully offered for treatment of localized scleroderma. We aimed to evaluate whether patients with systemic sclerosis (SSc) and facial handicap could also benefit from this therapy. We included 14 patients (mean age of 53.8 ± 9.6 years) suffering from SSc with facial handicap defined by Mouth Handicap in Systemic Sclerosis Scale (MHISS) score more than or equal to 20, a Rodnan skin score on the face more than or equal to 1, and maximal mouth opening of less than 55 mm. Autologous adipose tissue injection was performed under local anesthesia using the technique of subcutaneous microinjection. The main objective of this study was an improvement of the MHISS score 6 months after the surgical treatment. The procedure was well tolerated. We observed a mean decrease in the MHISS score of 10.7 points (±5.1; P < 0.0001) at 6 months (35% improvement). Secondary efficacy parameters assessing perioral skin sclerosis, maximum mouth opening, sicca syndrome, and facial pain significantly improved at 3 and 6 months postsurgery. At a 6-month follow-up, 75% of patients were satisfied or very satisfied of the adipose tissue microinjection therapy. Our study suggests that subcutaneous perioral microfat injection in patients with SSc is beneficial in the treatment of facial handicap, skin sclerosis, mouth opening limitation, sicca syndrome, and facial pain. Thus, this minimally invasive approach offers a new hope for face therapy for patients with SSc.
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Riccieri, Valeria; Vasile, Massimiliano; Iannace, Nicoletta; Stefanantoni, Katia; Sciarra, Iliana; Vizza, Carmine D; Badagliacca, Roberto; Poscia, Roberto; Papa, Silvia; Mezzapesa, Mario; Nocioni, Martina; Valesini, Guido
2013-08-01
Pulmonary arterial hypertension (PAH) is a complication of SSc due to increased vascular resistance, and abnormal vascularity is a well-known feature of the disease as shown by nailfold videocapillaroscopy (NVC). This study investigated for specific NVC changes in SSc patients with and without PAH to assess any useful difference. Twenty-four SSc patients, 12 with PAH and 12 without, entered the study. Evidence of PAH was defined as increased systolic pulmonary artery pressure (PAP) (≥35 mmHg), indirectly assessed by echocardiography and confirmed by right heart catheterization (mPAP > 25 mmHg). NVC was performed, and a semi-quantitative rating scale, a rating system for avascular areas and a specific NVC pattern evaluation, namely early, active and late, were used. An NVC score >1 was more frequently found in patients with PAH than those without, 11 cases (92%) vs 5 cases (42%) (P = 0.03); an avascular areas grade >1 was present in 10 (83%) and 2 (17%) cases, respectively (P = 0.003); and a more severe NC pattern (active/late) was described in 11 (92%) and 5 (42%) patients, respectively (P = 0.03). When we compared the mPAP with NVC parameters, we found significant correlations between mPAP values and the NVC score (P < 0.005) and with the avascular areas score (P < 0.001). Our results underline the relevance of early microvascular assessment in patients at risk of developing a severe complication such as PAH that can amplify the systemic microvascular impairment in SSc. More severe NVC abnormalities should lead to strict cardiopulmonary surveillance and a complete NVC study is indicated.
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Huang, Xiao-Lei; Wu, Guo-Cui; Wang, Yu-Jie; Yang, Xiao-Ke; Yang, Guo-Jun; Tao, Jin-Hui; Duan, Yu; Yan, Jun-Wei; Li, Xiang-Pei; Ye, Dong-Qing; Wang, Jing
2016-08-01
The aim of our study was to investigate the association of five single nucleotide polymorphisms in interleukin-1 (IL-1) gene with susceptibility to systemic sclerosis (SSc) in a Chinese population. A total of 58 SSc patients and 113 healthy controls were enrolled. TaqMan allele discrimination assay was performed to detect the genotyping of IL-1A -889C/T (rs1800587), IL-1B -511C/T (rs16944), IL-18 -607C/A (rs1946518), IL-18 -137G/C (rs187238) and IL-33 rs7044343. The association between these SNPs and SSc risk was analyzed. Furthermore, a meta-analysis of relevant studies on the association of IL-1A -889C/T (rs1800587) and IL-1B -511C/T (rs16944) with the susceptibility to SSc was performed. Through the genotyping, significant associations for SSc were found for: IL-1A -889C/T genotype frequencies (P = 0.000), dominant model (P = 0.000), recessive model (P = 0.001) and allele T frequency (P = 0.000). Among SSc patients, dyspnea was significantly associated with IL-18 -607C/A genotype frequency and IL-33 rs7044343 allele frequency (P = 0.037, P = 0.042, respectively). In addition, elevated erythrocyte sedimentation rate was significantly associated with IL-18 -137G/C (rs187238) genotype and allele frequency (P = 0.019, P = 0.006, respectively). While meta-analysis showed there was no significant association between IL-1A -889C/T polymorphism and SSc, for IL-1B -511C/T (rs16944), significant associations were found in the comparison of allele C versus T (OR 1.267, 95 % CI 1.016-1.580) by combined different outcomes. Results showed that IL-1A -889C/T (rs1800587) was associated with SSc susceptibility in the Chinese population. However, this association was not supported by a meta-analysis of all relevant studies. Further investigations are required to verify our findings.
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Taroni, Jaclyn N; Greene, Casey S; Martyanov, Viktor; Wood, Tammara A; Christmann, Romy B; Farber, Harrison W; Lafyatis, Robert A; Denton, Christopher P; Hinchcliff, Monique E; Pioli, Patricia A; Mahoney, J Matthew; Whitfield, Michael L
2017-03-23
Systemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by skin fibrosis. Internal organ involvement is heterogeneous. It is unknown whether disease mechanisms are common across all involved affected tissues or if each manifestation has a distinct underlying pathology. We used consensus clustering to compare gene expression profiles of biopsies from four SSc-affected tissues (skin, lung, esophagus, and peripheral blood) from patients with SSc, and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension, and derived a consensus disease-associate signature across all tissues. We used this signature to query tissue-specific functional genomic networks. We performed novel network analyses to contrast the skin and lung microenvironments and to assess the functional role of the inflammatory and fibrotic genes in each organ. Lastly, we tested the expression of macrophage activation state-associated gene sets for enrichment in skin and lung using a Wilcoxon rank sum test. We identified a common pathogenic gene expression signature-an immune-fibrotic axis-indicative of pro-fibrotic macrophages (MØs) in multiple tissues (skin, lung, esophagus, and peripheral blood mononuclear cells) affected by SSc. While the co-expression of these genes is common to all tissues, the functional consequences of this upregulation differ by organ. We used this disease-associated signature to query tissue-specific functional genomic networks to identify common and tissue-specific pathologies of SSc and related conditions. In contrast to skin, in the lung-specific functional network we identify a distinct lung-resident MØ signature associated with lipid stimulation and alternative activation. In keeping with our network results, we find distinct MØ alternative activation transcriptional programs in SSc-associated PF lung and in the skin of patients with an "inflammatory" SSc gene expression signature. Our results suggest that the innate immune system is central to SSc disease processes but that subtle distinctions exist between tissues. Our approach provides a framework for examining molecular signatures of disease in fibrosis and autoimmune diseases and for leveraging publicly available data to understand common and tissue-specific disease processes in complex human diseases.
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Chen, Shipei; Wu, Qingnan; Wen, Ming; Wu, Qingsheng; Li, Jiaqi; Cui, Yi; Pinna, Nicola; Fan, Yafei; Wu, Tong
2018-06-13
To meet the demands of long cycle life under high rate for lithium-ion batteries, the advancement of anode materials with stable structural properties is necessarily demanded. Such promotion needs to design reasonable structure to facilitate the transportation of electron and lithium ions (Li + ). Herein, a novel C/Fe 3 O 4 sea-sponge-like structure was synthesized by ultrasonic spray pyrolysis following thermal decomposition process. On the basis of sea-sponge carbon (SSC) excellences in electronic conductivity and short Li + diffusion pathway, nano-Fe 3 O 4 anchored on stable SSC skeleton can deliver high electrochemical performance with long cycle life under high rate. During electrochemical cycling, well-dispersed nano-Fe 3 O 4 in ∼6 nm not only averts excessive pulverization and is enveloped by solid electrolyte interphase film, but also increases Li + diffusion efficiency. The much improved electrochemical properties showed a capacity of around 460 mAh g -1 at a high rate of 1.5C with a retention rate of 93%, which is maintained without degradation up to 1000 cycles (1C = 1000 mA g -1 ).
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Calderone, Alicia; Stevens, Wendy; Prior, David; Nandurkar, Harshal; Gabbay, Eli; Proudman, Susanna M; Williams, Trevor; Celermajer, David; Sahhar, Joanne; Wong, Peter K K; Thakkar, Vivek; Dwyer, Nathan; Wrobel, Jeremy; Chin, Weng; Liew, Danny; Staples, Margaret; Buchbinder, Rachelle; Nikpour, Mandana
2016-12-08
Systemic sclerosis (SSc) is a severe and costly multiorgan autoimmune connective tissue disease characterised by vasculopathy and fibrosis. One of the major causes of SSc-related death is pulmonary arterial hypertension (PAH), which develops in 12-15% of patients with SSc and accounts for 30-40% of deaths. In situ thrombosis in the small calibre peripheral pulmonary vessels resulting from endothelial dysfunction and an imbalance of anticoagulant and prothrombotic mediators has been implicated in the complex pathophysiology of SSc-related PAH (SSc-PAH), with international clinical guidelines recommending the use of anticoagulants for some types of PAH, such as idiopathic PAH. However, anticoagulation has not become part of standard clinical care for patients with SSc-PAH as only observational evidence exists to support its use. Therefore, we present the rationale and methodology of a phase III randomised controlled trial (RCT) to evaluate the efficacy, safety and cost-effectiveness of anticoagulation in SSc-PAH. This Australian multicentre RCT will compare 2.5 mg apixaban with placebo, in parallel treatment groups randomised in a 1:1 ratio, both administered twice daily for 3 years as adjunct therapy to stable oral PAH therapy. The composite primary outcome measure will be the time to death or clinical worsening of PAH. Secondary outcomes will include functional capacity, health-related quality of life measures and adverse events. A cost-effectiveness analysis of anticoagulation versus placebo will also be undertaken. Ethical approval for this RCT has been granted by the Human Research Ethics Committees of all participating centres. An independent data safety monitoring board will review safety and tolerability data for the duration of the trial. The findings of this RCT are to be published in open access journals. ACTRN12614000418673, Pre-results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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Calderone, Alicia; Stevens, Wendy; Prior, David; Nandurkar, Harshal; Gabbay, Eli; Proudman, Susanna M; Williams, Trevor; Celermajer, David; Sahhar, Joanne; Wong, Peter K K; Thakkar, Vivek; Dwyer, Nathan; Wrobel, Jeremy; Chin, Weng; Liew, Danny; Staples, Margaret; Buchbinder, Rachelle; Nikpour, Mandana
2016-01-01
Introduction Systemic sclerosis (SSc) is a severe and costly multiorgan autoimmune connective tissue disease characterised by vasculopathy and fibrosis. One of the major causes of SSc-related death is pulmonary arterial hypertension (PAH), which develops in 12–15% of patients with SSc and accounts for 30–40% of deaths. In situ thrombosis in the small calibre peripheral pulmonary vessels resulting from endothelial dysfunction and an imbalance of anticoagulant and prothrombotic mediators has been implicated in the complex pathophysiology of SSc-related PAH (SSc-PAH), with international clinical guidelines recommending the use of anticoagulants for some types of PAH, such as idiopathic PAH. However, anticoagulation has not become part of standard clinical care for patients with SSc-PAH as only observational evidence exists to support its use. Therefore, we present the rationale and methodology of a phase III randomised controlled trial (RCT) to evaluate the efficacy, safety and cost-effectiveness of anticoagulation in SSc-PAH. Methods and analysis This Australian multicentre RCT will compare 2.5 mg apixaban with placebo, in parallel treatment groups randomised in a 1:1 ratio, both administered twice daily for 3 years as adjunct therapy to stable oral PAH therapy. The composite primary outcome measure will be the time to death or clinical worsening of PAH. Secondary outcomes will include functional capacity, health-related quality of life measures and adverse events. A cost-effectiveness analysis of anticoagulation versus placebo will also be undertaken. Ethics and dissemination Ethical approval for this RCT has been granted by the Human Research Ethics Committees of all participating centres. An independent data safety monitoring board will review safety and tolerability data for the duration of the trial. The findings of this RCT are to be published in open access journals. Trial registration number ACTRN12614000418673, Pre-results. PMID:27932335
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Bossini-Castillo, Lara; Martin, Jose-Ezequiel; Broen, Jasper; Gorlova, Olga; Simeón, Carmen P.; Beretta, Lorenzo; Vonk, Madelon C.; Luis Callejas, Jose; Castellví, Ivan; Carreira, Patricia; José García-Hernández, Francisco; Fernández Castro, Mónica; Coenen, Marieke J.H.; Riemekasten, Gabriela; Witte, Torsten; Hunzelmann, Nicolas; Kreuter, Alexander; Distler, Jörg H.W.; Koeleman, Bobby P.; Voskuyl, Alexandre E.; Schuerwegh, Annemie J.; Palm, Øyvind; Hesselstrand, Roger; Nordin, Annika; Airó, Paolo; Lunardi, Claudio; Scorza, Raffaella; Shiels, Paul; van Laar, Jacob M.; Herrick, Ariane; Worthington, Jane; Denton, Christopher; Tan, Filemon K.; Arnett, Frank C.; Agarwal, Sandeep K.; Assassi, Shervin; Fonseca, Carmen; Mayes, Maureen D.; Radstake, Timothy R.D.J.; Martin, Javier
2012-01-01
A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [PMH= 1.92 × 10−5 odds ratio (OR) = 1.19] as the genetic variant with the firmest independent association observed in the analyzed GWAS peak of association. After the first follow-up phase, only the association of rs3790567 was consistent (PMH= 4.84 × 10−3 OR = 1.12). The second follow-up phase confirmed this finding (Pχ2 = 2.82 × 10−4 OR = 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (PMH= 2.82 × 10−9 OR = 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis. PMID:22076442
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Scleroderma prevalence: demographic variations in a population-based sample.
Bernatsky, S; Joseph, L; Pineau, C A; Belisle, P; Hudson, M; Clarke, A E
2009-03-15
To estimate the prevalence of systemic sclerosis (SSc) using population-based administrative data, and to assess the sensitivity of case ascertainment approaches. We ascertained SSc cases from Quebec physician billing and hospitalization databases (covering approximately 7.5 million individuals). Three case definition algorithms were compared, and statistical methods accounting for imperfect case ascertainment were used to estimate SSc prevalence and case ascertainment sensitivity. A hierarchical Bayesian latent class regression model that accounted for possible between-test dependence conditional on disease status estimated the effect of patient characteristics on SSc prevalence and the sensitivity of the 3 ascertainment algorithms. Accounting for error inherent in both the billing and the hospitalization data, we estimated SSc prevalence in 2003 at 74.4 cases per 100,000 women (95% credible interval [95% CrI] 69.3-79.7) and 13.3 cases per 100,000 men (95% CrI 11.1-16.1). Prevalence was higher for older individuals, particularly in urban women (161.2 cases per 100,000, 95% CrI 148.6-175.0). Prevalence was lowest in young men (in rural areas, as low as 2.8 cases per 100,000, 95% CrI 1.4-4.8). In general, no single algorithm was very sensitive, with point estimates for sensitivity ranging from 20-73%. We found marked differences in SSc prevalence according to age, sex, and region. In general, no single case ascertainment approach was very sensitive for SSc. Therefore, using data from multiple sources, with adjustment for the imperfect nature of each, is an important strategy in population-based studies of SSc and similar conditions.
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Arana-Guajardo, Ana Cecilia; Barrera-Torres, Gustavo; Villarreal-Alarcón, Miguel Ángel; Vega-Morales, David; Esquivel-Valerio, Jorge Antonio
2017-12-16
The esophageal involvement in systemic sclerosis (SSc) causes impact in the morbidity and mortality. High resolution manometry assesses esophageal involvement. Our aim was to categorize esophageal motor disorder in patients with SSc by HRM. We carried out an observational, descriptive and cross-sectional study. All patients underwent HRM as well as semi-structured interviews to assess frequency and severity of upper GI symptoms. Patients also completed the gastroesophageal reflux questionnaire (Carlsson-Dent). We included 19 patients with SSc, 1 with morphea, and 1 with scleroderma sine scleroderma. Dysphagia and heartburn were the most frequent symptoms (61% each). We found an abnormal HRM in 15 (71.4%) patients. We found no statistically significant association between clinical or demographic variables and an abnormal HRM, or between any upper GI symptom and HRM findings. We observed a high prevalence of esophageal symptoms and of HRM abnormalities. However, there was no clear association between symptomatology and HRM findings. HRM does not seem to accurately predict upper GI symptomatology. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.
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Keck, Andrea D; Foocharoen, Chingching; Rosato, Edoardo; Smith, Vanessa; Allanore, Yannick; Distler, Oliver; Stamenkovic, Bojana; Pereira Da Silva, José Antonio; Hadj Khelifa, Sondess; Denisov, Lev N; Hachulla, Eric; García de la Peña Lefebvre, Paloma; Sibilia, Jean; Airò, Paolo; Caramaschi, Paola; Müller-Ladner, Ulf; Wiland, Piotr; Walker, Ulrich A
2014-04-01
The objective of this study was to analyse an association between nailfold capillary abnormalities and the presence and severity of erectile dysfunction (ED) in men with SSc. A cross-sectional analysis of the prospective European League Against Rheumatism (EULAR) Scleroderma Trial and Research database was performed. Men with SSc were included if they had undergone nailfold capillaroscopy and simultaneous ED assessment with the 5-item International Index for Erectile Function (IIEF-5). Eighty-six men met the inclusion criteria. Eight men (9.3%) had not had sexual intercourse and could not be assigned an IIEF-5 score. Sixty-nine of the 78 men (88.5%) with an IIEF-5 score had nailfold capillary abnormalities, of whom 54 (78.3%) suffered from ED. Nine men (11.5%) had no nailfold capillary abnormalities, of whom six (66.7%) had ED (P = 0.44). ED was more frequent in older men (P = 0.002) and in men with diffuse disease (P = 0.06). Men with abnormal capillaroscopy had a higher median EULAR disease activity than men without (P = 0.02), a lower diffusing capacity of the lung (P = 0.001) and a higher modified Rodnan skin score (P = 0.04), but mean IIEF-5 scores did not differ [15.7 (S.D. 6.2) vs 15.7 (S.D. 6.3)]. IIEF-5 scores did not differ between men with early (n = 12), active (n = 27) or late (n = 27) patterns (IIEF-5 scores of 17.9, 16.3 and 14.7, respectively). There were no differences in the prevalence of early, active and late capillaroscopy patterns between men with or without ED. Neither the presence or absence of abnormal capillaroscopy findings nor the subdivision into early, active and late patterns is associated with coexistent ED in SSc.
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Marcu-Malina, Victoria; Balbir-Gurman, Alexandra; Dardik, Rima; Braun-Moscovici, Yolanda; Segel, Michael J.; Bank, Ilan
2014-01-01
Objectives: Infusions of aminobisphonates (ABP) activate Vγ9δ2T cells in vivo and induce an acute inflammatory response in 30% of patients treated for osteoporosis. Following the observation of digital thrombosis in a systemic sclerosis (SSc) patient after treatment with an intravenous ABP, zoledronate (Zol), we evaluated whether patient and control peripheral blood (PB) mononuclear cell (MC, PBMC) acquire a prothrombotic phenotype in response to Zol. Results: Vγ9δ2T cells of both patients and healthy donors (HD) upregulated the CD69 activation antigen and secreted tumor necrosis factor (TNF)α in response to Zol in vitro. In addition, exposure to either Zol or lipopolysaccharide (LPS), or to both additively, induced expression of the highly procoagulant, tissue factor (TF)-1 on CD14+ monocytes. Importantly, only Zol-induced TF-1 was blocked by a monoclonal antibody to TNFα. Interestingly, we found that SSc, but not HD, Vδ1+ T cells were concurrently activated by Zol to produce interleukin (IL)-4. Addition of plasma from the blood of the SSc patient who developed critical digital ischemia after infusion of Zol, but neither plasma from a second patient with no adverse clinical response to Zol infusion nor of a HD, strongly enhanced Zol-induced monocyte TF-1, which could still be blocked by anti-TNFα. Conclusion: Aminobisphonates induced secretion of TNFα by Vγ9δ2+ T cells may lead to TNFα-dependent induction of procoagulant TF-1 induction on monocytes. In certain clinical settings, e.g., SSc, TF-1+ monocytes could play a role in triggering clinically relevant thrombosis. PMID:25250025
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Messerli, Markus; Aschwanden, Rebecca; Buslau, Michael; Hersberger, Kurt E; Arnet, Isabelle
2017-01-01
Objectives To assess subjective swallowing difficulties (SD) with medication intake and their practical consequences in patients suffering from systemic sclerosis (SSc) with a novel self-report questionnaire. Design and setting Based on a systematic literature review, we developed a self-report questionnaire and got it approved by an expert panel. Subsequently, we sent the questionnaire by post mail to SSc patients of the European Center for the Rehabilitation of Scleroderma Rheinfelden, Switzerland. Participants Patients were eligible if they were diagnosed with SSc, treated at the center, and were of age ≥18 years at the study start. Main outcome measures Prevalence and pattern of SD with oral medication intake, including localization and intensity of complaints. Results The questionnaire consisted of 30 items divided into five sections Complaints, Intensity, Localization, Coping strategies, and Adherence. Of the 64 SSc patients eligible in 2014, 43 (67%) returned the questionnaire. Twenty patients reported SD with medication intake (prevalence 47%), either currently (11; 26%) or in the past that had been overcome (9; 21%). Self-reported SD were localized mostly in the larynx (43%) and esophagus (34%). They were of moderate (45%) or strong to unbearable intensity (25%). Modification of the dosage form was reported in 40% of cases with SD. Adherence was poor for 20 (47%) patients and was not associated with SD (p=0.148). Conclusion Our novel self-report questionnaire is able to assess the pattern of complaints linked to medication intake, that is, localization and intensity. It may serve as a guide for health care professionals in selecting the most suitable therapy option, enabling tailored counseling to reduce inappropriate medication modifications. PMID:29033556
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Mouthon, Luc; Carpentier, Patrick H; Lok, Catherine; Clerson, Pierre; Gressin, Virginie; Hachulla, Eric; Bérezné, Alice; Diot, Elisabeth; Van Kien, Aurélie Khau; Jego, Patrick; Agard, Christian; Duval-Modeste, Anne-Bénédicte; Sparsa, Agnès; Puzenat, Eve; Richard, Marie-Aleth
2017-06-01
Ischemic digital ulcers (DU) represent a major complication of systemic sclerosis (SSc). We investigated the impact of controlling the ulcerative disease on disability, pain, and quality of life in SSc patients receiving bosentan. ECLIPSE (Study AC-052-517) is a 2-year prospective, multicenter, and observational study. Patients with SSc who experienced at least 1 DU in the previous year and received bosentan were included between October 2009 and March 2011. Disability scores [Cochin Hand Function Scale (CHFS) and Health Assessment Questionnaire Disability Index (HAQ-DI)], pain scores (visual analog scale), and quality-of-life scores (SF-36) were collected at inclusion and 1 year later (primary endpoint). A controlled ulcerative disease was defined by the absence of ongoing/new DU episode between inclusion and 1-year follow-up. Data were available at 1 year for 120 patients out of 190 included. During follow-up, 46 (38.3%) patients experienced a new DU episode. The number of DU per patient decreased from 1.4 ± 1.8 at inclusion to 0.6 ± 1.6 (p < 0.0001) at 1 year. Disability scores decreased from 1.0 ± 0.7 to 0.9 ± 0.7 (p = 0.04) for the HAQ-DI and from 29 ± 20 to 25 ± 20 (p = 0.005) for the CHFS; the pain score decreased from 4.3 ± 3.1 to 2.9 ± 2.8 (p < 0.0001). This improvement was attributed to patients with a controlled ulcerative disease (48.3%), who significantly improved HAQ-DI (p = 0.04), CHFS (p = 0.04), and pain score (p = 0.046). In patients with SSc, control of the ulcerative disease for 1 year was associated with significant attenuation of hand disability. Copyright © 2017 Elsevier Inc. All rights reserved.
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Unfolding the pathogenesis of scleroderma through genomics and epigenomics.
Tsou, Pei-Suen; Sawalha, Amr H
2017-09-01
With unknown etiology, scleroderma (SSc) is a multifaceted disease characterized by immune activation, vascular complications, and excessive fibrosis in internal organs. Genetic studies, including candidate gene association studies, genome-wide association studies, and whole-exome sequencing have supported the notion that while genetic susceptibility to SSc appears to be modest, SSc patients are genetically predisposed to this disease. The strongest genetic association for SSc lies within the MHC region, with loci in HLA-DRB1, HLA-DQB1, HLA-DPB1, and HLA-DOA1 being the most replicated. The non-HLA genes associated with SSc are involved in various functions, with the most robust associations including genes for B and T cell activation and innate immunity. Other pathways include genes involved in extracellular matrix deposition, cytokines, and autophagy. Among these genes, IRF5, STAT4, and CD247 were replicated most frequently while SNPs rs35677470 in DNASE1L3, rs5029939 in TNFAIP3, and rs7574685 in STAT4 have the strongest associations with SSc. In addition to genetic predisposition, it became clear that environmental factors and epigenetic influences also contribute to the development of SSc. Epigenetics, which refers to studies that focus on heritable phenotypes resulting from changes in chromatin structure without affecting the DNA sequence, is one of the most rapidly expanding fields in biomedical research. Indeed extensive epigenetic changes have been described in SSc. Alteration in enzymes and mediators involved in DNA methylation and histone modification, as well as dysregulated non-coding RNA levels all contribute to fibrosis, immune dysregulation, and impaired angiogenesis in this disease. Genes that are affected by epigenetic dysregulation include ones involved in autoimmunity, T cell function and regulation, TGFβ pathway, Wnt pathway, extracellular matrix, and transcription factors governing fibrosis and angiogenesis. In this review, we provide a comprehensive overview of the current findings of SSc genetic susceptibility, followed by an extensive description and a systematic review of epigenetic research that has been carried out to date in SSc. We also summarize the therapeutic potential of drugs that affect epigenetic mechanisms, and outline the future prospective of genomics and epigenomics research in SSc. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Farina, Antonella; Peruzzi, Giovanna; Lacconi, Valentina; Lenna, Stefania; Quarta, Silvia; Rosato, Edoardo; Vestri, Anna Rita; York, Michael; Dreyfus, David H; Faggioni, Alberto; Morrone, Stefania; Trojanowska, Maria; Farina, G Alessandra
2017-02-28
Monocytes/macrophages are activated in several autoimmune diseases, including systemic sclerosis (scleroderma; SSc), with increased expression of interferon (IFN)-regulatory genes and inflammatory cytokines, suggesting dysregulation of the innate immune response in autoimmunity. In this study, we investigated whether the lytic form of Epstein-Barr virus (EBV) infection (infectious EBV) is present in scleroderma monocytes and contributes to their activation in SSc. Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) depleted of the CD19+ cell fraction, using CD14/CD16 negative-depletion. Circulating monocytes from SSc and healthy donors (HDs) were infected with EBV. Gene expression of innate immune mediators were evaluated in EBV-infected monocytes from SSc and HDs. Involvement of Toll-like receptor (TLR)8 in viral-mediated TLR8 response was investigated by comparing the TLR8 expression induced by infectious EBV to the expression stimulated by CL075/TLR8/agonist-ligand in the presence of TLR8 inhibitor in THP-1 cells. Infectious EBV strongly induced TLR8 expression in infected SSc and HD monocytes in vitro. Markers of activated monocytes, such as IFN-regulated genes and chemokines, were upregulated in SSc- and HD-EBV-infected monocytes. Inhibiting TLR8 expression reduced virally induced TLR8 in THP-1 infected cells, demonstrating that innate immune activation by infectious EBV is partially dependent on TLR8. Viral mRNA and proteins were detected in freshly isolated SSc monocytes. Microarray analysis substantiated the evidence of an increased IFN signature and altered level of TLR8 expression in SSc monocytes carrying infectious EBV compared to HD monocytes. This study provides the first evidence of infectious EBV in monocytes from patients with SSc and links EBV to the activation of TLR8 and IFN innate immune response in freshly isolated SSc monocytes. This study provides the first evidence of EBV replication activating the TLR8 molecular pathway in primary monocytes. Immunogenicity of infectious EBV suggests a novel mechanism mediating monocyte inflammation in SSc, by which EBV triggers the innate immune response in infected cells.
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Tourkina, Elena; Bonner, Michael; Oates, James; Hofbauer, Ann; Richard, Mathieu; Znoyko, Sergei; Visconti, Richard P; Zhang, Jing; Hatfield, Corey M; Silver, Richard M; Hoffman, Stanley
2011-07-01
Interstitial lung disease (ILD) is a major cause of morbidity and mortality in scleroderma (systemic sclerosis, or SSc). Fibrocytes are a monocyte-derived cell population implicated in the pathogenesis of fibrosing disorders. Given the recently recognized importance of caveolin-1 in regulating function and signaling in SSc monocytes, in the present study we examined the role of caveolin-1 in the migration and/or trafficking and phenotype of monocytes and fibrocytes in fibrotic lung disease in human patients and an animal model. These studies fill a gap in our understanding of how monocytes and fibrocytes contribute to SSc-ILD pathology. We found that C-X-C chemokine receptor type 4-positive (CXCR4+)/collagen I-positive (ColI+), CD34+/ColI+ and CD45+/ColI+ cells are present in SSc-ILD lungs, but not in control lungs, with CXCR4+ cells being most prevalent. Expression of CXCR4 and its ligand, stromal cell-derived factor 1 (CXCL12), are also highly upregulated in SSc-ILD lung tissue. SSc monocytes, which lack caveolin-1 and therefore overexpress CXCR4, exhibit almost sevenfold increased migration toward CXCL12 compared to control monocytes. Restoration of caveolin-1 function by administering the caveolin scaffolding domain (CSD) peptide reverses this hypermigration. Similarly, transforming growth factor β-treated normal monocytes lose caveolin-1, overexpress CXCR4 and exhibit 15-fold increased monocyte migration that is CSD peptide-sensitive. SSc monocytes exhibit a different phenotype than normal monocytes, expressing high levels of ColI, CD14 and CD34. Because ColI+/CD14+ cells are prevalent in SSc blood, we looked for such cells in lung tissue and confirmed their presence in SSc-ILD lungs but not in normal lungs. Finally, in the bleomycin model of lung fibrosis, we show that CSD peptide diminishes fibrocyte accumulation in the lungs. Our results suggest that low caveolin-1 in SSc monocytes contributes to ILD via effects on cell migration and phenotype and that the hyperaccumulation of fibrocytes in SSc-ILD may result from the altered phenotype and migratory activity of their monocyte precursors.
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2011-01-01
Interstitial lung disease (ILD) is a major cause of morbidity and mortality in scleroderma (systemic sclerosis, or SSc). Fibrocytes are a monocyte-derived cell population implicated in the pathogenesis of fibrosing disorders. Given the recently recognized importance of caveolin-1 in regulating function and signaling in SSc monocytes, in the present study we examined the role of caveolin-1 in the migration and/or trafficking and phenotype of monocytes and fibrocytes in fibrotic lung disease in human patients and an animal model. These studies fill a gap in our understanding of how monocytes and fibrocytes contribute to SSc-ILD pathology. We found that C-X-C chemokine receptor type 4-positive (CXCR4+)/collagen I-positive (ColI+), CD34+/ColI+ and CD45+/ColI+ cells are present in SSc-ILD lungs, but not in control lungs, with CXCR4+ cells being most prevalent. Expression of CXCR4 and its ligand, stromal cell-derived factor 1 (CXCL12), are also highly upregulated in SSc-ILD lung tissue. SSc monocytes, which lack caveolin-1 and therefore overexpress CXCR4, exhibit almost sevenfold increased migration toward CXCL12 compared to control monocytes. Restoration of caveolin-1 function by administering the caveolin scaffolding domain (CSD) peptide reverses this hypermigration. Similarly, transforming growth factor β-treated normal monocytes lose caveolin-1, overexpress CXCR4 and exhibit 15-fold increased monocyte migration that is CSD peptide-sensitive. SSc monocytes exhibit a different phenotype than normal monocytes, expressing high levels of ColI, CD14 and CD34. Because ColI+/CD14+ cells are prevalent in SSc blood, we looked for such cells in lung tissue and confirmed their presence in SSc-ILD lungs but not in normal lungs. Finally, in the bleomycin model of lung fibrosis, we show that CSD peptide diminishes fibrocyte accumulation in the lungs. Our results suggest that low caveolin-1 in SSc monocytes contributes to ILD via effects on cell migration and phenotype and that the hyperaccumulation of fibrocytes in SSc-ILD may result from the altered phenotype and migratory activity of their monocyte precursors. PMID:21722364
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Sexual dysfunction in married women with Systemic Sclerosis
Frikha, Faten; Masmoudi, Jawaher; Saidi, Noura; Bahloul, Zouhir
2014-01-01
Introduction Sexuality is an often neglected area in patients with rheumatic disease. The aim of this study is to assess sexual functioning and quality of life in a group of married women with Systemic Sclerosis (SSc). Methods This is a horizontal study for descriptive and analytical purposes. Married women with SSc were interviewed about their sexual functioning and their quality of life. Results A total of ten patients who met the criteria have accepted to participate to the study. Their mean age was 52, 4± 8,2 years. Eight women thought that the disease had affected their sexual activity. All patients reported a decrease in the frequency of intercourse since the onset of their disease. Eight of the sample reported a diminished desire for a sexual relationship. The reasons were fatigue, altered body image and pain. The assessment of sexual functioning using the Female sexual function index (FSFI) showed a mean FSFI score at 14,2±7,8 with nine women scoring in the range associated with sexual dysfunction (SD) (<26). All the subscales were affected. Our patients reported a mean total score on WHOQOL-brief (World Health Quality of Life-Brief Version) of 60 out of 120 indicating a moderate altered quality of life. Depression has been identified as determinants of impaired sexual function. Conclusion The prevalence of SD in women with SSc is high when a specific questionnaire is used to assess it. These results indicate that in daily practice, inquiring about sexuality and screening for depressive symptoms is indicated for every patient with SSc. PMID:25452828
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Lagoo, Janaka; Lopushinsky, Steven R; Haynes, Alex B; Bain, Paul; Flageole, Helene; Skarsgard, Erik D; Brindle, Mary E
2017-01-01
Objective To examine the effectiveness and meaningful use of paediatric surgical safety checklists (SSCs) and their implementation strategies through a systematic review with narrative synthesis. Summary background data Since the launch of the WHO SSC, checklists have been integrated into surgical systems worldwide. Information is sparse on how SSCs have been integrated into the paediatric surgical environment. Methods A broad search strategy was created using Pubmed, Embase, CINAHL, Cochrane Central, Web of Science, Science Citation Index and Conference Proceedings Citation Index. Abstracts and full texts were screened independently, in duplicate for inclusion. Extracted study characteristic and outcomes generated themes explored through subgroup analyses and idea webbing. Results 1826 of 1921 studies were excluded after title and abstract review (kappa 0.77) and 47 after full-text review (kappa 0.86). 20 studies were of sufficient quality for narrative synthesis. Clinical outcomes were not affected by SSC introduction in studies without implementation strategies. A comprehensive SSC implementation strategy in developing countries demonstrated improved outcomes in high-risk surgeries. Narrative synthesis suggests that meaningful compliance is inconsistently measured and rarely achieved. Strategies involving feedback improved compliance. Stakeholder-developed implementation strategies, including team-based education, achieved greater acceptance. Three studies suggest that parental involvement in the SSC is valued by parents, nurses and physicians and may improve patient safety. Conclusions A SSC implementation strategy focused on paediatric patients and their families can achieve high acceptability and good compliance. SSCs’ role in improving measures of paediatric surgical outcome is not well established, but they may be effective when used within a comprehensive implementation strategy especially for high-risk patients in low-resource settings. PMID:29042377
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Martin, Jose-Ezequiel; Assassi, Shervin; Diaz-Gallo, Lina-Marcela; Broen, Jasper C.; Simeon, Carmen P.; Castellvi, Ivan; Vicente-Rabaneda, Esther; Fonollosa, Vicente; Ortego-Centeno, Norberto; González-Gay, Miguel A.; Espinosa, Gerard; Carreira, Patricia; Camps, Mayte; Sabio, Jose M.; D'alfonso, Sandra; Vonk, Madelon C.; Voskuyl, Alexandre E.; Schuerwegh, Annemie J.; Kreuter, Alexander; Witte, Torsten; Riemekasten, Gabriella; Hunzelmann, Nicolas; Airo, Paolo; Beretta, Lorenzo; Scorza, Raffaella; Lunardi, Claudio; Van Laar, Jacob; Chee, Meng May; Worthington, Jane; Herrick, Arianne; Denton, Christopher; Fonseca, Carmen; Tan, Filemon K.; Arnett, Frank; Zhou, Xiaodong; Reveille, John D.; Gorlova, Olga; Koeleman, Bobby P.C.; Radstake, Timothy R.D.J.; Vyse, Timothy; Mayes, Maureen D.; Alarcón-Riquelme, Marta E.; Martin, Javier
2013-01-01
Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are two archetypal systemic autoimmune diseases which have been shown to share multiple genetic susceptibility loci. In order to gain insight into the genetic basis of these diseases, we performed a pan-meta-analysis of two genome-wide association studies (GWASs) together with a replication stage including additional SSc and SLE cohorts. This increased the sample size to a total of 21 109 (6835 cases and 14 274 controls). We selected for replication 19 SNPs from the GWAS data. We were able to validate KIAA0319L (P = 3.31 × 10−11, OR = 1.49) as novel susceptibility loci for SSc and SLE. Furthermore, we also determined that the previously described SLE susceptibility loci PXK (P = 3.27 × 10−11, OR = 1.20) and JAZF1 (P = 1.11 × 10−8, OR = 1.13) are shared with SSc. Supporting these new discoveries, we observed that KIAA0319L was overexpressed in peripheral blood cells of SSc and SLE patients compared with healthy controls. With these, we add three (KIAA0319L, PXK and JAZF1) and one (KIAA0319L) new susceptibility loci for SSc and SLE, respectively, increasing significantly the knowledge of the genetic basis of autoimmunity. PMID:23740937
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Martin, Jose-Ezequiel; Assassi, Shervin; Diaz-Gallo, Lina-Marcela; Broen, Jasper C; Simeon, Carmen P; Castellvi, Ivan; Vicente-Rabaneda, Esther; Fonollosa, Vicente; Ortego-Centeno, Norberto; González-Gay, Miguel A; Espinosa, Gerard; Carreira, Patricia; Camps, Mayte; Sabio, Jose M; D'alfonso, Sandra; Vonk, Madelon C; Voskuyl, Alexandre E; Schuerwegh, Annemie J; Kreuter, Alexander; Witte, Torsten; Riemekasten, Gabriella; Hunzelmann, Nicolas; Airo, Paolo; Beretta, Lorenzo; Scorza, Raffaella; Lunardi, Claudio; Van Laar, Jacob; Chee, Meng May; Worthington, Jane; Herrick, Arianne; Denton, Christopher; Fonseca, Carmen; Tan, Filemon K; Arnett, Frank; Zhou, Xiaodong; Reveille, John D; Gorlova, Olga; Koeleman, Bobby P C; Radstake, Timothy R D J; Vyse, Timothy; Mayes, Maureen D; Alarcón-Riquelme, Marta E; Martin, Javier
2013-10-01
Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are two archetypal systemic autoimmune diseases which have been shown to share multiple genetic susceptibility loci. In order to gain insight into the genetic basis of these diseases, we performed a pan-meta-analysis of two genome-wide association studies (GWASs) together with a replication stage including additional SSc and SLE cohorts. This increased the sample size to a total of 21,109 (6835 cases and 14,274 controls). We selected for replication 19 SNPs from the GWAS data. We were able to validate KIAA0319L (P = 3.31 × 10(-11), OR = 1.49) as novel susceptibility loci for SSc and SLE. Furthermore, we also determined that the previously described SLE susceptibility loci PXK (P = 3.27 × 10(-11), OR = 1.20) and JAZF1 (P = 1.11 × 10(-8), OR = 1.13) are shared with SSc. Supporting these new discoveries, we observed that KIAA0319L was overexpressed in peripheral blood cells of SSc and SLE patients compared with healthy controls. With these, we add three (KIAA0319L, PXK and JAZF1) and one (KIAA0319L) new susceptibility loci for SSc and SLE, respectively, increasing significantly the knowledge of the genetic basis of autoimmunity.
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Duleba, Wânia; Teodoro, Andreia C.; Debenay, Jean-Pierre; Gubitoso, Silas; Pregnolato, Leonardo Antônio; Lerena, Laura Misailidis; Prada, Silvio Miranda; Bevilacqua, José Eduardo
2018-01-01
The Dutos e Terminais do Centro Sul (DTCS) is one of the largest petroleum terminals of the South America located in the São Sebastião Channel (SSC) on the southeastern Brazilian coast. The aims of this study were to compare the sediment quality near the DTCS with that of several sites in the SSC region including the Araçá (AR) domestic sewage outfall and to assess the efficiency of the DTCS wastewater treatment plant. To achieve these goals, textural, geochemical, and living benthic foraminifera results were analyzed for the DTCS, AR, and SSC regions. Sediments in the DTCS area were silty with high concentrations of total organic carbon (1.7–2.4%), total nitrogen (0.2–0.3%), total sulfur (0.4–0.6%), and total (0.12–0.18%) and inorganic phosphorous (0.07–0.11%). These values were higher than those in sediments collected in the SSC and Araçá regions. The sediments’ concentrations of As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn in the SSC and AR regions were lower than their corresponding probable effect levels (PELs). However, sediments near the DTCS were enriched with As, Cu, and Ni, whose concentrations exceeded their corresponding threshold effect levels (TELs). Around the DTCS outfall diffusers, living foraminiferal densities and diversities were lower than those for the other areas studied. In the DTCS area, it was necessary to search 50 to 190 cm3 of sediment to find 100 live specimens. In the SSC and Araçá areas, a maximum of 40 cm3 of sediment was enough to locate 100 live specimens. The lower density and diversity of living foraminifera around the DTCS than around the other areas illustrates the impact of the environmental stress caused by the presence of pollutants. These results indicate that the wastewater treatment plant efficiency is low and its discharge of pollutants from petrochemical waste liquids affects the benthic fauna around the DTCS in a potentially harmful manner. PMID:29432425
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Mechanisms in the loss of capillaries in systemic sclerosis: angiogenesis versus vasculogenesis
Manetti, Mirko; Guiducci, Serena; Ibba-Manneschi, Lidia; Matucci-Cerinic, Marco
2010-01-01
Abstract Systemic sclerosis (SSc, scleroderma) is a chronic, multisystem connective tissue disorder affecting the skin and various internal organs. Although the disease is characterized by a triad of widespread microangiopathy, fibrosis and autoimmunity, increasing evidence indicates that vascular damage is a primary event in the pathogenesis of SSc. The progressive vascular injury includes persistent endothelial cell activation/damage and apoptosis, intimal thickening, delamination, vessel narrowing and obliteration. These profound vascular changes lead to vascular tone dysfunction and reduced capillary blood flow, with consequent tissue ischemia and severe clinical manifestations, such as digital ulceration or amputation, pulmonary arterial hypertension and scleroderma renal crisis. The resulting tissue hypoxia induces complex cellular and molecular mechanisms in the attempt to recover endothelial cell function and tissue perfusion. Nevertheless, in SSc patients there is no evidence of significant angiogenesis and the disease evolves towards chronic tissue ischemia, with progressive and irreversible structural changes in multiple vascular beds culminating in the loss of capillaries. A severe imbalance between pro-angiogenic and angiostatic factors may also lead to impaired angiogenic response during SSc. Besides insufficient angiogenesis, defective vasculogenesis with altered numbers and functional defects of bone marrow-derived endothelial progenitor cells may contribute to the vascular pathogenesis of SSc. The purpose of this article is to review the contribution of recent studies to the understanding of the complex mechanisms of impaired vascular repair in SSc. Indeed, understanding the pathophysiology of SSc-associated vascular disease may be the key in dissecting the disease pathogenesis and developing novel therapies. Either angiogenic or vasculogenic mechanisms may potentially become in the future the target of therapeutic strategies to promote capillary regeneration in SSc. PMID:20132409
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Microbial and metabolic multi-omic correlations in systemic sclerosis patients.
Bellocchi, Chiara; Fernández-Ochoa, Álvaro; Montanelli, Gaia; Vigone, Barbara; Santaniello, Alessandro; Milani, Christian; Quirantes-Piné, Rosa; Borrás-Linares, Isabel; Ventura, Marco; Segura-Carrettero, Antonio; Alarcón-Riquelme, Marta Eugenia; Beretta, Lorenzo
2018-06-01
Intestinal microbiota has been associated with systemic autoimmune diseases, yet the functional consequences of these associations are elusive. We characterized the fecal microbiota (16S rRNA gene amplification and sequencing) and the plasma metabolome (high-performance liquid chromatography coupled to mass spectrometry) in 59 patients with systemic sclerosis (SSc) and 28 healthy controls (HCs). Microbial and metabolic data were cross-correlated to find meaningful associations after extensive data mining analysis and internal validation. Our data show that a reduced model of nine bacteria is capable of differentiating HCs from SSc patients. SSc gut microbiota is characterized by a reduction in protective butyrate-producing bacteria and by an increase in proinflammatory noxious genera, especially Desulfovibrio. From the metabolic point of view, a multivariate model with 17 metabolite intermediates well distinguished cases from controls. The most interesting peaks we found were identified as glycerophospholipid metabolites and benzene derivatives. The microbial and metabolic data showed significant interactions between Desulfovibrio and alpha-N-phenylacetyl-l-glutamine and 2,4-dinitrobenzenesulfonic acid. Our data suggest that in SSc, intestinal microbiota is characterized by proinflammatory alterations subtly entwined with the metabolic state. Desulfovibrio is a relevant actor in gut dysbiosis that may promote intestinal damage and influence amino acid metabolism. © 2018 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals Inc. on behalf of The New York Academy of Sciences.
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Plasmacytoid dendritic cells promote systemic sclerosis with a key role for TLR8.
Ah Kioon, Marie Dominique; Tripodo, Claudio; Fernandez, David; Kirou, Kyriakos A; Spiera, Robert F; Crow, Mary K; Gordon, Jessica K; Barrat, Franck J
2018-01-10
Systemic sclerosis (SSc) is a multisystem life-threatening fibrosing disorder that lacks effective treatment. The link between the inflammation observed in organs such as the skin and profibrotic mechanisms is not well understood. The plasmacytoid dendritic cell (pDC) is a key cell type mediating Toll-like receptor (TLR)-induced inflammation in autoimmune disease patients, including lupus and skin diseases with interface dermatitis. However, the role of pDCs in fibrosis is less clear. We show that pDCs infiltrate the skin of SSc patients and are chronically activated, leading to secretion of interferon-α (IFN-α) and CXCL4, which are both hallmarks of the disease. We demonstrate that the secretion of CXCL4 is under the control of phosphatidylinositol 3-kinase δ and is due to the aberrant presence of TLR8 on pDCs of SSc patients, which is not seen in healthy donors or in lupus pDCs, and that CXCL4 primarily acts by potentiating TLR8- but also TLR9-induced IFN production by pDCs. Depleting pDCs prevented disease in a mouse model of scleroderma and could revert fibrosis in mice with established disease. In contrast, the disease was exacerbated in mice transgenic for TLR8 with recruitment of pDCs to the fibrotic skin, whereas TLR7 only partially contributed to the inflammatory response, indicating that TLR8 is the key RNA-sensing TLR involved in the establishment of fibrosis. We conclude that the pDC is an essential cell type involved in the pathogenesis of SSc and its removal using depleting antibodies or attenuating pDC function could be a novel approach to treat SSc patients. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Matsushita, Takashi; Hasegawa, Minoru; Matsushita, Yukiyo; Echigo, Takeshi; Wayaku, Takamasa; Horikawa, Mayuka; Ogawa, Fumihide; Takehara, Kazuhiko; Sato, Shinichi
2007-02-01
Serum levels of B-cell activating factor belonging to the tumor necrosis factor family (BAFF), a potent B-cell survival factor, are elevated in patients with systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis and systemic sclerosis (SSc). The objective of this study was to determine serum BAFF levels and relate the results to the clinical features in patients with organ-specific autoimmune diseases of the skin, such as localized scleroderma and autoimmune bullous diseases. Serum BAFF levels were examined by enzyme-linked immunosorbent assay in 44 patients with localized scleroderma, 20 with pemphigus vulgaris/pemphigus foliaceus, 20 with bullous pemphigoid and 30 healthy controls. Twenty patients with SSc and 20 with SLE were also examined as disease controls. Serum BAFF levels were elevated in localized scleroderma patients compared with healthy controls. Concerning localized scleroderma subgroups, patients with generalized morphea, the severest form of localized scleroderma, had higher serum BAFF levels than linear scleroderma or morphea patients. The BAFF levels of generalized morphea were comparable with those of SSc or SLE. Furthermore, serum BAFF levels correlated positively with antihistone antibody levels and the severity of skin lesion as well as the number of skin lesions. By contrast, serum BAFF levels were not significantly elevated in patients with pemphigus or pemphigoid. These results suggest that BAFF may be contributing to autoimmunity and disease development in localized scleroderma.
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Guillevin, Loïc; Hunsche, Elke; Denton, Christopher P; Krieg, Thomas; Schwierin, Barbara; Rosenberg, Daniel; Matucci-Cerinic, Marco
2013-01-01
Digital ulcers (DUs) are frequent manifestations of systemic scleroderma (SSc). This study assessed functional limitations due to DUs among patients enrolled in the Digital Ulcer Outcome (DUO) Registry, an international, multicentre, observational registry of SSc patients with DU disease. Patients completed at enrolment a DU-specific functional assessment questionnaire with a 1-month recall period, measuring impairment in work and daily activities, and hours of help needed from others. Physician-reported clinical parameters were used to describe the population. For patients who completed at least part of the questionnaire, descriptive analyses were performed for overall results, and stratified by number of DUs at enrolment. This study included 2327 patients who completed at least part of the questionnaire. For patients with 0, 1-2, and ≥3 DUs at enrolment, mean overall work impairment during the prior month among employed/self-employed patients was 28%, 42%, and 48%, respectively. Across all included patients, ability to perform daily activities was impaired on average by 35%, 54%, and 63%, respectively. Patients required a mean of 2.0, 8.7, and 8.8 hours of paid help and 17.0, 35.9, and 63.7 hours of unpaid help, respectively, due to DUs in the prior month. Patients with DUs had more complications and medication use than patients with no DUs. With increasing number of DUs, SSc patients reported more impairment in work and daily activities and required more support from others.
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BARON, MURRAY; HUDSON, MARIE; TATIBOUET, SOLÈNE; STEELE, RUSSELL; LO, ERNEST; GRAVEL, SABRINA; GYGER, GENEVIÈVE; SAYEGH, TAREK EL; POPE, JANET; FONTAINE, AUDREY; MASETTO, ARIEL; MATTHEWS, DEBORA; SUTTON, EVELYN; THIE, NORMAN; JONES, NIALL; COPETE, MARIA; KOLBINSON, DEAN; MARKLAND, JANET; NOGUEIRA, GETULIO; ROBINSON, DAVID; FRITZLER, MARVIN; GORNITSKY, MERVYN
2015-01-01
Objective Systemic sclerosis (SSc; scleroderma) is associated with decreased saliva production and interincisal distance, more missing teeth, and periodontal disease. We undertook this study to determine the clinical correlates of SSc with these oral abnormalities. Methods Subjects were recruited from the Canadian Scleroderma Research Group cohort. Detailed dental and clinical examinations were performed according to standardized protocols. Associations between dental abnormalities and selected clinical and serologic manifestations of SSc were examined. Results One hundred sixty-three SSc subjects were included: 90% women, mean ± SD age 56 ± 11 years, mean ± SD disease duration 14 ± 8 years, 72% with limited cutaneous disease, and 28% with diffuse cutaneous disease. Decreased saliva production was associated with Sjögren’s syndrome–related autoantibodies (β = −43.32; 95% confidence interval [95% CI] −80.89, −5.75), but not with disease severity (β = −2.51; 95% CI −8.75, 3.73). Decreased interincisal distance was related to disease severity (β = −1.02; 95% CI −1.63, −0.42) and the modified Rodnan skin thickness score (β = −0.38; 95% CI −0.53, −0.23). The number of missing teeth was associated with decreased saliva production (relative risk [RR] 0.97; 95% CI 0.94, 0.99), worse hand function (RR 1.52; 95% CI 1.13, 2.02), and the presence of gastroesophageal reflux disease (GERD; RR 1.68 [95% CI 1.14, 2.46]). No clinical or serologic variables were correlated with periodontal disease. Conclusion In SSc, diminished interincisal distance is related to overall disease severity. Decreased saliva production is related to concomitant Sjögren’s syndrome antibodies. Tooth loss is associated with poor upper extremity function, GERD, and decreased saliva. The etiology of excess periodontal disease is likely multifactorial and remains unclear. PMID:25303223
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Sambataro, Domenico; Sambataro, Gianluca; Zaccara, Eleonora; Maglione, Wanda; Polosa, Riccardo; Afeltra, Antonella M V; Vitali, Claudio; Del Papa, Nicoletta
2014-10-09
Nailfold videocapillaroscopy (NVC) in systemic sclerosis (SSc) is a procedure commonly used for patient classification and subsetting, but not to define disease activity (DA). This study aimed to evaluate whether the number of micro-haemorrhages (MHE), micro-thrombosis (MT), giant capillaries (GC), and normal/dilated capillaries (Cs) in NVC could predict DA in SSc. Eight-finger NVC was performed in 107 patients with SSc, and the total number of MHE/MT, GC, and the mean number of Cs were counted and defined as number of micro-haemorrhages (NEMO), GC and Cs scores, respectively. The European Scleroderma Study Group (ESSG) index constituted the gold standard for DA assessment, and scores ≥ 3.5 and = 3 were considered indicative of high and moderate activity, respectively. NEMO and GC scores were positively correlated with ESSG index (R = 0.65, P < 0.0001, and R = 0.47, P <0.0001, respectively), whilst Cs score showed a negative correlation with that DA index (R = -0.30, P <0.001). The area under the curve (AUC) of receiver operating characteristic plots, obtained by NEMO score sensitivity and specificity values in classifying patients with ESSG index ≥ 3.5, was significantly higher than the corresponding AUC derived from either GC or Cs scores (P <0.03 and P <0.0006, respectively). A modified score, defined by the presence of a given number of MHE/MT and GC, had a good performance in classifying active patients (ESSG index ≥ 3, sensitivity 95.1%, specificity 84.8%, accuracy 88.7%). MHE/MT and GC appear to be good indicators of DA in SSc, and enhances the role of NVC as an easy technique to identify active patients.
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Elhaj, Mona; Charles, Julio; Pedroza, Claudia; Liu, Xiaochun; Zhou, Xiaodong; Estrada-Y-Martin, Rosa M.; Gonzalez, Emilio B.; Lewis, Dorothy E.; Draeger, Hilda T.; Kim, Sarah; Arnett, Frank C.; Mayes, Maureen D.; Assassi, Shervin
2013-01-01
Objective To examine the predictive significance of 2 pneumoproteins, surfactant protein D (SP-D) and CC-chemokine ligand 18 (CCL18), for the course of systemic sclerosis (SSc)-related interstitial lung disease. Methods The pneumoproteins were determined in the baseline plasma samples of 266 patients with early SSc enrolled in the GENISOS observational cohort. They also were measured in 83 followup patient samples. Pulmonary function tests were obtained annually. The primary outcome was decline in forced vital capacity (FVC percentage predicted) over time. The predictive significance for longterm change in FVC was investigated by a joint analysis of longitudinal measurements (sequentially obtained FVC percentage predicted) and survival data. Results SP-D and CCL18 levels were both higher in patients with SSc than in matched controls (p < 0.001 and p = 0.015, respectively). Baseline SP-D levels correlated with lower concomitantly obtained FVC (r = −0.27, p < 0.001), but did not predict the short-term decline in FVC at 1 year followup visit or its longterm decline rate. CCL18 showed a significant correlation with steeper short-term decline in FVC (p = 0.049), but was not a predictor of its longterm decline rate. Similarly, a composite score of SP-D and CCL18 was a significant predictor of short-term decline in FVC but did not predict its longterm decline rate. Further, the longitudinal change in these 2 pneumoproteins did not correlate with the concomitant percentage change in FVC. Conclusion SP-D correlated with concomitantly obtained FVC, while CCL18 was a predictor of short-term decline in FVC. However, neither SP-D nor CCL18 was a longterm predictor of FVC course in patients with early SSc. PMID:23588945
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Kwakkenbos, Linda; Arthurs, Erin; van den Hoogen, Frank H. J.; Hudson, Marie; van Lankveld, Wim G. J. M.; Baron, Murray; van den Ende, Cornelia H. M.; Thombs, Brett D.
2013-01-01
Objectives Increasingly, medical research involves patients who complete outcomes in different languages. This occurs in countries with more than one common language, such as Canada (French/English) or the United States (Spanish/English), as well as in international multi-centre collaborations, which are utilized frequently in rare diseases such as systemic sclerosis (SSc). In order to pool or compare outcomes, instruments should be measurement equivalent (invariant) across cultural or linguistic groups. This study provides an example of how to assess cross-language measurement equivalence by comparing the Center for Epidemiologic Studies Depression (CES-D) scale between English-speaking Canadian and Dutch SSc patients. Methods The CES-D was completed by 922 English-speaking Canadian and 213 Dutch SSc patients. Confirmatory factor analysis (CFA) was used to assess the factor structure in both samples. The Multiple-Indicator Multiple-Cause (MIMIC) model was utilized to assess the amount of differential item functioning (DIF). Results A two-factor model (positive and negative affect) showed excellent fit in both samples. Statistically significant, but small-magnitude, DIF was found for 3 of 20 items on the CES-D. The English-speaking Canadian sample endorsed more feeling-related symptoms, whereas the Dutch sample endorsed more somatic/retarded activity symptoms. The overall estimate in depression scores between English and Dutch was not influenced substantively by DIF. Conclusions CES-D scores from English-speaking Canadian and Dutch SSc patients can be compared and pooled without concern that measurement differences may substantively influence results. The importance of assessing cross-language measurement equivalence in rheumatology studies prior to pooling outcomes obtained in different languages should be emphasized. PMID:23326538
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Factors associated with oral hygiene practices among adults with systemic sclerosis
Yuen, Hon K.; Hant, Faye N.; Hatfield, Corey; Summerlin, Lisa M.; Smith, Edwin A.; Silver, Richard M.
2013-01-01
OBJECTIVE To identify factors associated with oral hygiene practices in adults with systemic sclerosis (SSc) METHODS In this cross-sectional study, 178 dentate adults with SSc received an oral examination which included measurement of oral aperture, assessment of manual dexterity to perform oral hygiene, as well as completion of the Center of Epidemiological Studies Depression (CES-D) Scale, and an oral health-related questionnaire. RESULTS Multivariable logistic regression modeling showed male, minority and high CES-D scores (i.e., clinically significant symptoms of depression) were associated with less likelihood of participants brushing teeth at least twice daily, but the presence of self-reported dry mouth symptoms increased the likelihood of toothbrushing. Having a dental visit in the past 12 months, and use of an adapted flossing or interdental cleaning device were significantly associated with daily dental flossing; however, having difficulty flossing teeth reduced the likelihood of daily flossing. CONCLUSIONS Overall, demographic variables were strongly associated with toothbrushing frequency, whereas, flossing self-efficacy and barriers were strongly associated with dental flossing frequency in adults with SSc. The results suggest that dental health professionals should take mental health into consideration when educating patients with SSc to improve their oral hygiene, and consider making referrals for patients exhibiting suspected clinically significant depressive symptoms to mental health professionals for further evaluation and treatment. In addition, an appropriate adapted flossing or interdental cleaning device should be recommended to increase dental flossing practices in this patient population. PMID:24128049
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Granel, Brigitte; Daumas, Aurélie; Jouve, Elisabeth; Harlé, Jean-Robert; Nguyen, Pierre-Sébastien; Chabannon, Christian; Colavolpe, Nathalie; Reynier, Jean-Charles; Truillet, Romain; Mallet, Stéphanie; Baiada, Antoine; Casanova, Dominique; Giraudo, Laurent; Arnaud, Laurent; Veran, Julie; Sabatier, Florence; Magalon, Guy
2015-12-01
In patients with systemic sclerosis (scleroderma, SSc), impaired hand function greatly contributes to disability and reduced quality of life, and is insufficiently relieved by currently available therapies. Adipose tissue-derived stromal vascular fraction (SVF) is increasingly recognised as an easily accessible source of regenerative cells with therapeutic potential in ischaemic or autoimmune diseases. We aimed to measure for the first time the safety, tolerability and potential efficacy of autologous SVF cells local injections in patients with SSc with hand disability. We did an open-label, single arm, at one study site with 6-month follow-up among 12 female SSc patients with Cochin Hand Function Scale score >20/90. Autologous SVF was obtained from lipoaspirates, using an automated processing system, and subsequently injected into the subcutaneous tissue of each finger in contact with neurovascular pedicles. Primary outcome was the number and the severity of adverse events related to SVF-based therapy. Secondary endpoints were changes in hand disability and fibrosis, vascular manifestations, pain and quality of life from baseline to 2 and 6 months after cell therapy. All enrolled patients had surgery, and there were no dropouts or patients lost to follow-up. No severe adverse events occurred during the procedure and follow-up. Four minor adverse events were reported and resolved spontaneously. A significant improvement in hand disability and pain, Raynaud's phenomenon, finger oedema and quality of life was observed. This study outlines the safety of the autologous SVF cells injection in the hands of patients with SSc. Preliminary assessments at 6 months suggest potential efficacy needing confirmation in a randomised placebo-controlled trial on a larger population. GFRS (Groupe Francophone de Recherche sur la Sclérodermie). NCT01813279. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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El-Rabbat M, Sarah; Mahmoud, Nermeen K; Gheita, Tamer A
2017-04-11
To describe the frequencies of fibromyalgia syndrome (FMS) in various rheumatic diseases; rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Behçets disease (BD) patients and to study the relation to clinical manifestations and quality of life (QoL). 160 patients (50 RA, 50 SLE, 30 SSc and 30 BD) and matched corresponding healthy controls were included. Disease activity was assessed using disease activity score in 28 joints (DAS28) for RA, SLE Disease Activity index (SLEDAI), modified Rodnan skin score for SSc and BD Current Activity Form (BDCAF). The QoL was also recorded. Severity in FMS cases was estimated using the revised Fibromyalgia Impact Questionnaire score. In the RA, SLE, SSc and BD patients, FMS was found in 14%, 18%, 6.67% and 3.33% respectively compared to 2.1%, 3%, 3.3% and 0% in their corresponding controls. In RA patients, DAS28 was significantly higher in those with FMS (p=0.009) and significantly correlated with both Widespread Pain Index (WPI) (p=0.011) and Symptom Severity (SS) scale (p=0.012). The QoL scale in those with FMS was significantly worse (62.3±7.9) compared to those without (71.7±14.4) (p=0.023). In SLE patients, The WPI and SS both significantly correlated with the presence of thrombosis (r=0.28, p=0.049 and r=0.43, p=0.002 respectively). The SS scale tended to correlate with the SLEDAI (r=0.28, p=0.05). In BD patients, BDCAF and WPI significantly correlated (p=0.03). Fibromyalgia syndrome is more frequent in rheumatic diseases, could be related to the disease activity in RA and BD patients and to thrombosis in SLE and affected the QoL in RA. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.
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Haustein, U F; Weber, B; Seikowski, K
1995-02-01
In 12 patients suffering from systemic sclerosis (SSc) the influence of autogenic training on the plasma level of the neuropeptides substance P and vasoactive intestinal peptide (VIP) was studied. Compared with healthy controls the SSc patients exhibited significantly elevated levels of substance P (mean +/- SD: 7.1 +/- 3.2 pmol/l vs 1.6 +/- 1.6 pmol/l). Apart from variations the VIP plasma concentration did not significantly differ from that in healthy controls (mean +/- SD 10.7 +/- 7.1 pmol/l versus 12.0 +/- 5.3 pmol/l). Autogenic training did not bring about any significant changes in the plasma levels of neuropeptides.
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Pediatric Scleroderma –Systemic and Localized Forms
Torok, Kathryn S.
2012-01-01
Synopsis statement Pediatric scleroderma includes two major groups of clinical entities, systemic sclerosis (SSc) and localized scleroderma (LS). Although both share a common pathophysiology, with an initial inflammatory phase associated with endothelial activation, and a later fibrotic phase evidenced by collagenization of tissue and appreciable skin thickness, their clinical manifestations differ. LS is typically confined to the skin and underlying subcutis, and though not fatal like SSc, up to a quarter of the patients may have extracutaneous disease manifestations, such as arthritis and uveitis. While any organ may be affected in SSc, vascular (Raynaud’s phenomenon), cutaneous (skin thickening), GI, pulmonary and musculoskeletal involvement are most commonly seen in children. Auto-antibody profiles in childhood onset SSc can assist in predicting internal organ involvement. Treatment for both forms of scleroderma targets the active inflammatory stage and halts disease progression; however, progress still needs to be made towards the development of a more effective anti-fibrotic therapy to help reverse disease damage. PMID:22560576
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Cheng, Jasmine Z; Wilcox, Pearce G; Glaspole, Ian; Corte, Tamera J; Murphy, Darra; Hague, Cameron J; Ryerson, Christopher J
2017-11-01
The objectives of this study were to determine the prevalence and characteristics of cough in idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (HP) and systemic sclerosis-associated interstitial lung disease (SSc-ILD). Cough severity was measured in consecutive patients with IPF (n = 77), HP (n = 32) and SSc-ILD (n = 67) using a 10-cm visual analogue scale (VAS). Dyspnoea and quality of life were measured using established questionnaires. Cough severity was compared across ILD subtypes and predictors of cough severity were determined using multivariate analysis. Cough was more common in IPF and chronic HP compared to SSc-ILD (87% and 83% vs 68%, P = 0.02). The median (interquartile range) VAS score was 39 (17-65) in the IPF cohort, 29 (11-48) in HP and 18 (0-33) in SSc-ILD (P < 0.0001). Cough was more often productive in chronic HP and IPF (63% and 43% vs 21%, P < 0.001). Cough severity was independently predicted only by ILD diagnosis and higher dyspnoea score. Cough severity was not associated with other common causes of cough. Cough was a significant predictor of quality of life in IPF and SSc-ILD with adjustment for age, sex, dyspnoea and ILD severity; however, cough was not associated with quality of life in chronic HP. Cough is more frequent, more severe and more often productive in IPF and chronic HP compared to SSc-ILD, despite similar ILD severity in these cohorts. Cough severity is strongly and independently associated with dyspnoea and pulmonary function, and is a significant contributor to reduced quality of life in both IPF and SSc-ILD. © 2017 Asian Pacific Society of Respirology.
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Hasegawa, Minoru; Takehara, Kazuhiko
2012-12-01
Systemic sclerosis (SSc) is a connective tissue disease characterized by tissue fibrosis. Although the pathogenesis remains unclear, a variety of cells contribute to the fibrotic process via interactions with each other and production of various cytokines. Recent literature related to the immunologic pathogenesis and future strategies for treating the fibrosis of SSc are discussed and, especially, this literature-based review that includes the authors' perspective, focused on leukocytes and cytokines. A PubMed search for articles published between January 2005 and January 2012 was conducted using the following keywords: systemic sclerosis, leukocyte, cytokine, growth factor, and chemokine. The reference lists of identified articles were searched for further articles. Targeting profibrogenic cytokines, including transforming growth factor-β, is still a very active area of research in SSc and most cellular studies have focused on the roles of fibroblasts in SSc. However, a growing number of recent studies indicate a role for B cells in the development of SSc and other autoimmune diseases such as systemic lupus erythematosus. Therefore, B-cell-targeted therapies, including currently available monoclonal antibodies against CD19, CD20, CD22, and B-cell-activating factor, belonging to the tumor necrosis factor family represent possible treatment options. Furthermore, the modulation of T-cell costimulatory molecules such as a recombinant fusion protein of cytotoxic T-lymphocyte antigen-4 may be as effective in SSc as it is in treating other autoimmune diseases. Approaches to antagonize interleukin (IL)-1, IL-6, or IL-17A signaling may also be attractive. This review describes recent advances in the treatment of fibrosis in SSc patients focused on immunologic strategies, such as leukocyte- or cytokine-targeted therapies. Copyright © 2012 Elsevier Inc. All rights reserved.
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Hager, W David; Collins, Irina; Tate, Janet P; Azrin, Michael; Foley, Raymond; Lakshminarayanan, Santha; Rothfield, Naomi F
2013-07-01
The cause for shortness of breath among systemic sclerosis (SSc) patients is often lacking. We sought to characterize the hemodynamics of these patients by using simple isotonic arm exercise during cardiac catheterization. Catheterization was performed in 173 SSc patients when resting echocardiographic pulmonary systolic pressures were <40 but >40 mmHg post stress. Patients with resting mean pulmonary arterial pressures (mPAP) ≤ 25 and pulmonary arterial wedge pressures (PAWP) ≤ 15 mmHg exercised with 1-pound hand weights. Normal exercise was defined as a change in mPAP divided by the change in cardiac output (CO) (ΔmPAP/ΔCO) ratio ≤ 2 for patients <50 years (≤3 for >50). An abnormal ΔmPAP/ΔCO ratio, an exercise transpulmonary gradient (TPG) ≥ 15, a PAWP < 20, a ΔTPG > ΔPAWP and a pulmonary vascular resistance (PVR) which increased defined exercise-induced pulmonary arterial hypertension (EIPAH). An abnormal ΔmPAP/ΔCO ratio, an exercise TPG < 15, a PAWP ≥ 20, a ΔTPG < ΔPAWP and a drop in PVR defined left ventricular diastolic dysfunction (DD). Twelve patients without SSc served as controls. Pulmonary pressures increased with exercise in 53 patients. Six had EIPAH and 47 had DD. With exercise, mPAP and PAWP were 20 ± 4 and 13 ± 2 in controls, 36 ± 3 and 12 ± 4 in EIPAH and 34 ± 6 and 26 ± 4 in DD. Control ΔmPAP/ΔCO was 0.8 ± 0.7, 7.5 ± 3.9 in EIPAH and 9.1 ± 7.2 in DD. Rest and exercise TPG was normal for control and DD patients but increased (12 ± 4 to 23 ± 4) in EIPAH (P < 0.0001). PVR decreased in DD but increased in EIPAH with exercise. Exercise during catheterization elucidates the pathophysiology of dyspnea and distinguishes EIPAH from the more common DD in SSc patients. © 2012 John Wiley & Sons Ltd.
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Noncanonical transforming growth factor β signaling in scleroderma fibrosis
Trojanowska, Maria
2014-01-01
Purpose of review Persistent transforming growth factor β (TGF-β) signaling is the major factor contributing to scleroderma (SSc) fibrosis. This review will summarize recent progress on the noncanonical TGF-β signaling pathways and their role in SSc fibrosis. Recent findings Canonical TGF-β signaling involves activation of the TGF-β receptors and downstream signal transducers Smad2/3. The term noncanonical TGF-β signaling includes a variety of intracellular signaling pathways activated by TGF-β independently of Smad2/3 activation. There is evidence that these pathways play important role in SSc fibrosis. In a subset of SSc fibroblasts, a multiligand receptor complex consisting of TGF-β and CCN2 receptors drives constitutive activation of the Smad1 pathway. CCN2 is also a primary effector of this pathway, thus establishing an autocrine loop that amplifies TGF-β signaling. SSc fibroblasts also demonstrate reduced expression of endogenous antagonists of TGF-β signaling including transcriptional repressors, Friend leukemia integration-1 and perixosome proliferator-activated receptor-γ, as well as inhibitor of Smad3 phosphorylation, PTEN. PTEN is a key mediator of the cross-talk between the sphingosine kinase and the TGF-β pathways. Summary Discovery of the role of noncanonical TGF-β signaling in fibrosis offers new molecular targets for the antifibrotic therapies. Due to the heterogeneous nature of SSc, knowledge of these pathways could help to tailor the therapy to the individual patient depending on the activation status of a specific profibrotic pathway. PMID:19713852
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Characterisation of the immune response to type I collagen in scleroderma
Warrington, Kenneth J; Nair, Usha; Carbone, Laura D; Kang, Andrew H; Postlethwaite, Arnold E
2006-01-01
This study was conducted to examine the frequency, phenotype, and functional profile of T lymphocytes that proliferate in response to type I collagen (CI) in patients with scleroderma (SSc). Peripheral blood mononuclear cells (PBMCs) from SSc patients, healthy controls, and rheumatoid arthritis disease controls were labeled with carboxy-fluorescein diacetate, succinimidyl ester (CFSE), cultured with or without antigen (bovine CI) for 14 days, and analysed by flow cytometry. Surface markers of proliferating cells were identified by multi-color flow cytometry. T-cell lines were derived after sorting for proliferating T cells (CFSElow). Cytokine expression in CI-responsive T cells was detected by intracellular staining/flow cytometry and by multiplex cytokine bead assay (Bio-Plex). A T-cell proliferative response to CI was detected in 8 of 25 (32%) SSc patients, but was infrequent in healthy or disease controls (3.6%; p = 0.009). The proliferating T cells expressed a CD4+, activated (CD25+), memory (CD45RO+) phenotype. Proliferation to CI did not correlate with disease duration or extent of skin involvement. T-cell lines were generated using in vitro CI stimulation to study the functional profile of these cells. Following activation of CI-reactive T cells, we detected intracellular interferon (IFN)-γ but not interleukin (IL)-4 by flow cytometry. Supernatants from the T-cell lines generated in vitro contained IL-2, IFN-γ, GM-CSF (granulocyte macrophage-colony-stimulating factor), and tumour necrosis factor-α, but little or no IL-4 and IL-10, suggesting that CI-responsive T cells express a predominantly Th1 cytokine pattern. In conclusion, circulating memory CD4 T cells that proliferate to CI are present in a subset of patients with SSc, but are infrequent in healthy or disease controls. PMID:16879746
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Mehta, Heena; Goulet, Philippe-Olivier; Nguyen, Vinh; Pérez, Gemma; Koenig, Martial; Senécal, Jean-Luc; Sarfati, Marika
2016-12-01
DNA Topoisomerase I (TopoI) is a candidate autoantigen for diffuse cutaneous systemic sclerosis (dcSSc) associated with fatal lung disease. Dendritic cells (DCs) contribute to bleomycin-induced lung fibrosis. However, the possibility that TopoI-loaded DCs are involved in the initiation and/or perpetuation of dcSSc has not been explored. Here, we show that immunization with TopoI peptide-loaded DCs induces anti-TopoI autoantibody response and long-term fibrosis. Mice were repeatedly immunized with unpulsed DCs or DCs loaded with either TOPOIA or TOPOIB peptides, selected from different regions of TopoI. At week 12 after initial DC immunization, TOPOIA DCs but not TOPOIB DCs immunization induced mixed inflammation and fibrosis in lungs and skin. At a late time point (week 18), both TOPOIA DCs and TOPOIB DCs groups displayed increased alpha-smooth muscle actin expression in lungs and dermis along with skin fibrosis distal from the site of injection when compared with unpulsed DCs. Both TopoI peptide-DC-immunized groups developed IgG2a anti-TopoI autoantibody response. At week 10, signs of perivascular, peribronchial, and parenchymal pulmonary inflammation were already observed in the TOPOIA DCs group, together with transient elevation in bronchoalveolar lavage cell counts, IL-17A expression, and CXCL4 production, a biomarker of early human dcSSc. Collectively, TopoI peptide DCs induce progressive autoantibody response as well as development of protracted skin and lung dcSSc-like disease. Pronounced lung inflammation, transient IL-17A, and CXCL4 expression precede fibrosis development. Our immunization strategy, that uses self immune system and autoantigen, will help to further investigate the pathogenesis of this complex autoimmune disorder with unmet medical needs.
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A3 Subscale Rocket Hot Fire Testing
NASA Technical Reports Server (NTRS)
Saunders, G. P.; Yen, J.
2009-01-01
This paper gives a description of the methodology and results of J2-X Subscale Simulator (JSS) hot fire testing supporting the A3 Subscale Diffuser Test (SDT) project at the E3 test facility at Stennis Space Center, MS (SSC). The A3 subscale diffuser is a geometrically accurate scale model of the A3 altitude simulating rocket test facility. This paper focuses on the methods used to operate the facility and obtain the data to support the aerodynamic verification of the A3 rocket diffuser design and experimental data quantifying the heat flux throughout the facility. The JSS was operated at both 80% and 100% power levels and at gimbal angle from 0 to 7 degrees to verify the simulated altitude produced by the rocket-rocket diffuser combination. This was done with various secondary GN purge loads to quantify the pumping performance of the rocket diffuser. Also, special tests were conducted to obtain detailed heat flux measurements in the rocket diffuser at various gimbal angles and in the facility elbow where the flow turns from vertical to horizontal upstream of the 2nd stage steam ejector.
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2007-09-13
Tests begun at Stennis Space Center's E Complex Sept. 13 evaluated a liquid oxygen lead for engine start performance, part of the A-3 Test Facility Subscale Diffuser Risk Mitigation Project at SSC's E-3 Test Facility. Phase 1 of the subscale diffuser project, completed Sept. 24, was a series of 18 hot-fire tests using a 1,000-pound liquid oxygen and gaseous hydrogen thruster to verify maximum duration and repeatability for steam generation supporting the A-3 Test Stand project. The thruster is a stand-in for NASA's developing J-2X engine, to validate a 6 percent scale version of A-3's exhaust diffuser. Testing the J-2X at altitude conditions requires an enormous diffuser. Engineers will generate nearly 4,600 pounds per second of steam to reduce pressure inside A-3's test cell to simulate altitude conditions. A-3's exhaust diffuser has to be able to withstand regulated pressure, temperatures and the safe discharge of the steam produced during those tests. Before the real thing is built, engineers hope to work out any issues on the miniature version. Phase 2 testing is scheduled to begin this month.
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Hax, Vanessa; Bredemeier, Markus; Didonet Moro, Ana Laura; Pavan, Thaís Rohde; Vieira, Marcelo Vasconcellos; Pitrez, Eduardo Hennemann; da Silva Chakr, Rafael Mendonça; Xavier, Ricardo Machado
2017-10-01
Interstitial lung disease (ILD) is currently the primary cause of death in systemic sclerosis (SSc). Thoracic high-resolution computed tomography (HRCT) is considered the gold standard for diagnosis. Recent studies have proposed several clinical algorithms to predict the diagnosis and prognosis of SSc-ILD. To test the clinical algorithms to predict the presence and prognosis of SSc-ILD and to evaluate the association of extent of ILD with mortality in a cohort of SSc patients. Retrospective cohort study, including 177 SSc patients assessed by clinical evaluation, laboratory tests, pulmonary function tests, and HRCT. Three clinical algorithms, combining lung auscultation, chest radiography, and percentage predicted forced vital capacity (FVC), were applied for the diagnosis of different extents of ILD on HRCT. Univariate and multivariate Cox proportional models were used to analyze the association of algorithms and the extent of ILD on HRCT with the risk of death using hazard ratios (HR). The prevalence of ILD on HRCT was 57.1% and 79 patients died (44.6%) in a median follow-up of 11.1 years. For identification of ILD with extent ≥10% and ≥20% on HRCT, all algorithms presented a high sensitivity (>89%) and a very low negative likelihood ratio (<0.16). For prognosis, survival was decreased for all algorithms, especially the algorithm C (HR = 3.47, 95% CI: 1.62-7.42), which identified the presence of ILD based on crackles on lung auscultation, findings on chest X-ray, or FVC <80%. Extensive disease as proposed by Goh et al. (extent of ILD > 20% on HRCT or, in indeterminate cases, FVC < 70%) had a significantly higher risk of death (HR = 3.42, 95% CI: 2.12-5.52). Survival was not different between patients with extent of 10% or 20% of ILD on HRCT, and analysis of 10-year mortality suggested that a threshold of 10% may also have a good predictive value for mortality. However, there is no clear cutoff above which mortality is sharply increased. Clinical algorithms had a good diagnostic performance for extents of SSc-ILD on HRCT with clinical and prognostic relevance (≥10% and ≥20%), and were also strongly related to mortality. Non-HRCT-based algorithms could be useful when HRCT is not available. This is the first study to replicate the prognostic algorithm proposed by Goh et al. in a developing country. Copyright © 2017 Elsevier Inc. All rights reserved.
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Evaluation of Vitamin B12 Deficiency and Associated Factors in Patients With Systemic Sclerosis.
Tas Kilic, Diler; Akdogan, Ali; Kilic, Levent; Sari, Alper; Erden, Abdulsamet; Armagan, Berkan; Kilickaya, Muhammed; Kalyoncu, Umut; Turhan, Turan; Kiraz, Sedat; Karaahmetoglu, Selma
2018-01-30
In patients with systemic sclerosis (SSc) gastrointestinal (GI) involvement, nutritional status and medications may lead to cobalamin (Vit B12) deficiency. We aimed to determine the frequency and the potential causes of Vit B12 deficiency in SSc patients. We conducted a cross-sectional analysis of 62 SSc patients in a single center in 1 year period. Medical history and physical examination of patients were reevaluated. Data about organ involvements were obtained from hospital file records. The nutritional status of the patients was assessed with Malnutrition Universal Screening Tool (MUST). Vit B12, homocysteine (except in three patients) and Helicobacter Pylori Immunoglobulin G (H. Pylori IgG) levels were measured in all patients. Vit B12 deficiency was considered as serum Vit B12 level <200 pg/mL or being on Vit B12 replacement therapy. Serum Vit B12 levels of the patients were also grouped as low (<200 pg/mL), borderline (200-300 pg/mL) and normal (>300 pg/mL). Plasma homocysteine levels of the patients were classified as elevated (>9 μmol/L) and hyperhomocysteinemia (>15 μmol/L). Mann-Whitney U and Kruskal-Wallis tests were used to compare parameters among the groups. Correlation was tested by Spearman's correlation coefficient. Forty-four (71.0%) patients were defined as Vit B12 deficient; 22 had Vit B12 level <200 pg/mL (four were on Vit B12 replacement therapy) and the remaining 22 had Vit B12 >200 pg/mL and were already on Vit B12 replacement therapy. The percentage of the patients with hyperhomocysteinemia was significantly higher in the group with Vit B12 <200 pg/mL as compared to other groups (P = 0.004) but only 33.3% (7/21) of the patients with Vit B12 <200 pg/mL had hyperhomocysteinemia. There were no statistically significant differences between patients with and without Vit B12 deficiency regarding age, mean disease duration, MUST scores, mean hemoglobin levels, H. Pylori IgG positivity and organ involvements (P > 0.05 for all). Vit B12 deficiency is frequent in SSc and has multiple causes. All patients should be monitored for Vit B12 deficiency. The homocysteine levels seem unlikely to be helpful for confirmation of Vit B12 deficiency.
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Pauling, John D; Shipley, Jacqueline A; Hart, Darren J; McGrogan, Anita; McHugh, Neil J
2015-07-01
Evaluate objective assessment of digital microvascular function using laser speckle contrast imaging (LSCI) in a cross-sectional study of patients with primary Raynaud phenomenon (RP) and systemic sclerosis (SSc), comparing LSCI with both infrared thermography (IRT) and subjective assessment using the Raynaud Condition Score (RCS) diary. Patients with SSc (n = 25) and primary RP (n = 18) underwent simultaneous assessment of digital perfusion using LSCI and IRT with a cold challenge on 2 occasions, 2 weeks apart. The RCS diary was completed between assessments. The relationship between objective and subjective assessments of RP was evaluated. Reproducibility of LSCI/IRT was assessed, along with differences between primary RP and SSc, and the effect of sex. There was moderate-to-good correlation between LSCI and IRT (Spearman rho 0.58-0.84, p < 0.01), but poor correlation between objective assessments and the RCS diary (p > 0.05 for all analyses). Reproducibility of IRT and LSCI was moderate at baseline (ICC 0.51-0.63) and immediately following cold challenge (ICC 0.56-0.86), but lower during reperfusion (ICC 0.3-0.7). Neither subjective nor objective assessments differentiated between primary RP and SSc. Men reported lower median daily frequency of RP attacks (0.82 vs 1.93, p = 0.03). Perfusion using LSCI/IRT was higher in men for the majority of assessments. Objective and subjective methods provide differing information on microvascular function in RP. There is good convergent validity of LSCI with IRT and acceptable reproducibility of both modalities. Neither subjective nor objective assessments could differentiate between primary RP and SSc. Influence of sex on subjective and objective assessment of RP warrants further evaluation.
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Diagnostic performance of indirect MR arthrography for the diagnosis of rotator cuff tears at 3.0 T.
Lee, Ji Hyun; Yoon, Young Cheol; Jee, Sukkyung
2015-06-01
Indirect magnetic resonance (MR) arthrography is a non-invasive method for shoulder imaging. However, there are no studies that have examined the diagnostic performance of indirect MR arthrography for the diagnosis of rotator cuff tears in a large patient population. To assess the diagnostic performance of indirect fast spin-echo (FSE) MR arthrography for the diagnosis of rotator cuff tears at 3.0 T. A total of 149 patients who had undergone indirect shoulder MR arthrography followed by arthroscopic surgery were enrolled in this retrospective study. Two musculoskeletal radiologists evaluated images from each patient for the presence of supraspinatus-infraspinatus (SSP-ISP) or subscapularis (SSC) tendon tears. Using the arthroscopic findings as the reference standard, the overall diagnostic performance and detection rates for SSP-ISP and SSC tendon tears were calculated. The sensitivity, specificity, and accuracy of readers I and II for the diagnosis of SSP-ISP tendon tears were 94% and 95%, 89% and 85%, and 93% and 93%, respectively. The sensitivity of imaging for detection of SSP-ISP tendon tears by readers I and II were 100% and 100% for full-thickness tears and 84% and 86% for partial-thickness tears, respectively. The sensitivity, specificity, and accuracy of readers I and II for the diagnosis of SSC tendon tears were 80% and 76%, 89% and 93%, and 85% and 85%, respectively. Indirect MR arthrography is useful for the detection of SSP-ISP and SSC tendon tears. © The Foundation Acta Radiologica 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
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Is there an association between glaucoma and capillaroscopy in patients with systemic sclerosis?
Gomes, Beatriz Fiuza; Souza, Rebeca; Valadão, Thiago; Kara-Junior, Newton; Moraes, Haroldo Vieira; Santhiago, Marcony R
2018-02-01
To evaluate the relationship between glaucoma diagnosis and the nailfold capillaroscopy pattern in patients with systemic sclerosis. An observational study in a cohort of patients with SSc was conducted. Patients with at least one nailfold videocapillaroscopy and one ophthalmology examination at the same year were included. Data collected were: age, sex; type of systemic sclerosis according to the degree of skin impairment, self-reported ethnicity, disease duration, current use and dosage of systemic corticosteroid, current use and dosage of bosentan ® , intraocular pressure, central corneal thickness, diagnosis of glaucoma and capillaroscopy pattern. Thirty-one patients with systemic sclerosis were enrolled, 23% had glaucoma. There was no statistically significant association between glaucoma diagnosis and the capillaroscopic pattern (p = 0.86). There was also no significant difference (p = 0.66) regarding intraocular pressure between patients with mild (13.9 ± 3.8 mmHg) and severe capillaroscopic pattern (14.4 ± 2.8 mmHg). The odds ratio of glaucoma for severe capillaroscopic pattern compared to mild was 1.6 (95% confidence interval: 0.3-9.5). Up to 23% of patients with SSc have glaucoma. The high prevalence of glaucoma in SSc suggests a possible systemic vascular disturbance as the cause. However, there seems to be no significant association between the capillaroscopy pattern and glaucoma in systemic sclerosis. Further research is required to improve the understanding of glaucoma in the context of systemic sclerosis.
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Improved Assessment Strategies for Vapor Intrusion Passive Samplers and Building Pressure Control
2013-09-01
pressure control. Matrix Analyte Method Container Holding Time (Days) Vapor Radon McHugh , Hammond, Nickels , and Hartman, 2008 Tedlar ® bag 14...2: Diffusive Sampling,” ISO 16017-2:2003. McHugh T. E., D. E. Hammond, T. Nickels , and B. Hartman. 2008. “Use of Radon Measurements for Evaluation...Control I. D. Rivera-Duarte D. B. Chadwick SSC Pacific T. McAlary H. Groenevelt T. Creamer D. Bertrand Geosyntec Consultants, Inc. T. McHugh
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Jaeger, Veronika K; Distler, Oliver; Maurer, Britta; Czirják, Laszlo; Lóránd, Veronika; Valentini, Gabriele; Vettori, Serena; Del Galdo, Francesco; Abignano, Giuseppina; Denton, Christopher; Nihtyanova, Svetlana; Allanore, Yannick; Avouac, Jerome; Riemekasten, Gabriele; Siegert, Elise; Huscher, Dörte; Matucci-Cerinic, Marco; Guiducci, Serena; Frerix, Marc; Tarner, Ingo H; Garay Toth, Beata; Fankhauser, Beat; Umbricht, Jörg; Zakharova, Anastasia; Mihai, Carina; Cozzi, Franco; Yavuz, Sule; Hunzelmann, Nicolas; Rednic, Simona; Vacca, Alessandra; Schmeiser, Tim; Riccieri, Valeria; García de la Peña Lefebvre, Paloma; Gabrielli, Armando; Krummel-Lorenz, Brigitte; Martinovic, Duska; Ancuta, Codrina; Smith, Vanessa; Müller-Ladner, Ulf; Walker, Ulrich A
2018-03-01
The multisystem manifestations of SSc can greatly impact patients' quality of life. The aim of this study was to identify factors associated with disability in SSc. SSc patients from the prospective DeSScipher cohort who had completed the scleroderma health assessment questionnaire (SHAQ), a disability score that combines the health assessment questionnaire and five visual analogue scales, were included in this analysis. The effect of factors possibly associated with disability was analysed with multiple linear regressions. The mean SHAQ and HAQ scores of the 944 patients included were 0.87 (s.d. = 0.66) and 0.92 (s.d. = 0.78); 59% of the patients were in the mild to moderate difficulty SHAQ category (0 ⩽ SHAQ < 1), 34% in the moderate to severe disability category (1 ⩽ SHAQ < 2) and 7% in the severe to very severe disability category (2 ⩽ SHAQ ⩽ 3). The means of the visual analogue scales scores were in order of magnitude: overall disease severity (37 mm), RP (31 mm), pulmonary symptoms (24 mm), gastrointestinal symptoms (20 mm) and digital ulcers (19 mm). In multiple regression, the main factors associated with high SHAQ scores were the presence of dyspnoea [modified New York Heart Association (NYHA) class IV (regression coefficient B = 0.62), modified NYHA class III (B = 0.53) and modified NYHA class II (B = 0.21; all vs modified NYHA class I)], FM (B = 0.37), muscle weakness (B = 0.27), digital ulcers (B = 0.20) and gastrointestinal symptoms (oesophageal symptoms, B = 0.16; stomach symptoms, B = 0.15; intestinal symptoms, B = 0.15). SSc patients perceive dyspnoea, pain, digital ulcers, muscle weakness and gastrointestinal symptoms as the main factors driving their level of disability, unlike physicians who emphasize objective measures of disability. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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Penile involvement in Systemic Sclerosis: New Diagnostic and Therapeutic Aspects
Aversa, Antonio; Bruzziches, Roberto; Francomano, Davide; Rosato, Edoardo; Salsano, Felice; Spera, Giovanni
2010-01-01
Systemic Sclerosis (SSc) is a connective tissue disorder featuring vascular alterations and an immunological activation leading to a progressive and widespread fibrosis of several organs such as the skin, lung, gastrointestinal tract, heart, and kidney. Men with SSc are at increased risk of developing erectile dysfunction (ED) because of the evolution of early microvascular tissutal damage into corporeal fibrosis. The entity of penile vascular damage in SSc patients has been demonstrated by using Duplex ultrasonography and functional infra-red imaging and it is now clear that this is a true clinical entity invariably occurring irrespective of age and disease duration and constituting the ‘‘sclerodermic penis”. Once-daily phosphodiesterase type-5 (PDE5) inhibitors improve both sexual function and vascular measures of cavernous arteries by improving surrogate markers of endothelial dysfunction, that is, plasma endothelin-1 and adrenomedullin levels, which may play a potential role in preventing progression of penile fibrosis and ED. Also, the beneficial effect of long-term PDE5i add-on therapy to SSc therapy in the treatment of Raynaud's phenomenon is described. PMID:20981315
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Autoantigenicity of nucleolar complexes.
Welting, Tim J M; Raijmakers, Reinout; Pruijn, Ger J M
2003-10-01
Autoantibodies targeting nucleolar autoantigens (ANoA) are most frequently found in sera from patients with systemic sclerosis (SSc, also designated scleroderma) or with SSc overlap syndromes. During the last decade an extensive number of nucleolar components have been identified and this allowed a more detailed analysis of the identity of nucleolar autoantigens. This review intends to give an overview of the molecular composition of the major (families of) autoantigenic nucleolar complexes, to provide some insight into their functions and to summarise the data concerning their autoantigenicity.
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A portable device for detecting fruit quality by diffuse reflectance Vis/NIR spectroscopy
NASA Astrophysics Data System (ADS)
Sun, Hongwei; Peng, Yankun; Li, Peng; Wang, Wenxiu
2017-05-01
Soluble solid content (SSC) is a major quality parameter to fruit, which has influence on its flavor or texture. Some researches on the on-line non-invasion detection of fruit quality were published. However, consumers desire portable devices currently. This study aimed to develop a portable device for accurate, real-time and nondestructive determination of quality factors of fruit based on diffuse reflectance Vis/NIR spectroscopy (520-950 nm). The hardware of the device consisted of four units: light source unit, spectral acquisition unit, central processing unit, display unit. Halogen lamp was chosen as light source. When working, its hand-held probe was in contact with the surface of fruit samples thus forming dark environment to shield the interferential light outside. Diffuse reflectance light was collected and measured by spectrometer (USB4000). ARM (Advanced RISC Machines), as central processing unit, controlled all parts in device and analyzed spectral data. Liquid Crystal Display (LCD) touch screen was used to interface with users. To validate its reliability and stability, 63 apples were tested in experiment, 47 of which were chosen as calibration set, while others as prediction set. Their SSC reference values were measured by refractometer. At the same time, samples' spectral data acquired by portable device were processed by standard normalized variables (SNV) and Savitzky-Golay filter (S-G) to eliminate the spectra noise. Then partial least squares regression (PLSR) was applied to build prediction models, and the best predictions results was achieved with correlation coefficient (r) of 0.855 and standard error of 0.6033° Brix. The results demonstrated that this device was feasible to quantitatively analyze soluble solid content of apple.
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NASA Technical Reports Server (NTRS)
Pagnutti, Mary; Ryan, Robert E.; Holekamp, Kara; Harrington, Gary; Frisbie, Troy
2006-01-01
A simple and cost-effective, hyperspectral sun photometer for radiometric vicarious remote sensing system calibration, air quality monitoring, and potentially in-situ planetary climatological studies, was developed. The device was constructed solely from off the shelf components and was designed to be easily deployable for support of short-term verification and validation data collects. This sun photometer not only provides the same data products as existing multi-band sun photometers but also the potential of hyperspectral optical depth and diffuse-to-global products. As compared to traditional sun photometers, this device requires a simpler setup, less data acquisition time and allows for a more direct calibration approach. Fielding this instrument has also enabled Stennis Space Center (SSC) Applied Sciences Directorate personnel to cross-calibrate existing sun photometers. This innovative research will position SSC personnel to perform air quality assessments in support of the NASA Applied Sciences Program's National Applications program element as well as to develop techniques to evaluate aerosols in a Martian or other planetary atmosphere.
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Fattal, Ittai; Shental, Noam; Molad, Yair; Gabrielli, Armando; Pokroy-Shapira, Elisheva; Oren, Shirly; Livneh, Avi; Langevitz, Pnina; Pauzner, Rachel; Sarig, Ofer; Gafter, Uzi; Domany, Eytan; Cohen, Irun R
2014-01-01
Systemic lupus erythematosus (SLE) is an autoimmune disease that can attack many different body organs; the triggering event is unknown. SLE has been associated with more than 100 different autoantibody reactivities – anti-dsDNA is prominent. Nevertheless, autoantibodies to dsDNA occur in only two-thirds of SLE patients. We previously reported the use of an antigen microarray to characterize SLE serology. We now report the results of an expanded study of serology in SLE patients and scleroderma (SSc) patients compared with healthy controls. The analysis validated and extended previous findings: two-thirds of SLE patients reacted to a large spectrum of self-molecules that overlapped with their reactivity to dsDNA; moreover, some SLE patients manifested a deficiency of natural IgM autoantibodies. Most significant was the finding that many SLE patients who were negative for autoantibodies to dsDNA manifested abnormal antibody responses to Epstein–Barr virus (EBV): these subjects made IgG antibodies to EBV antigens to which healthy subjects did not respond or they failed to make antibodies to EBV antigens to which healthy subjects did respond. This observation suggests that SLE may be associated with a defective immune response to EBV. The SSc patients shared many of these serological abnormalities with SLE patients, but differed from them in increased IgG autoantibodies to topoisomerase and centromere B; 84% of SLE patients and 58% of SSc patients could be detected by their abnormal antibodies to EBV. Hence an aberrant immune response to a ubiquitous viral infection such as EBV might set the stage for an autoimmune disease. PMID:24164500
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Fattal, Ittai; Shental, Noam; Molad, Yair; Gabrielli, Armando; Pokroy-Shapira, Elisheva; Oren, Shirly; Livneh, Avi; Langevitz, Pnina; Pauzner, Rachel; Sarig, Ofer; Gafter, Uzi; Domany, Eytan; Cohen, Irun R
2014-02-01
Systemic lupus erythematosus (SLE) is an autoimmune disease that can attack many different body organs; the triggering event is unknown. SLE has been associated with more than 100 different autoantibody reactivities - anti-dsDNA is prominent. Nevertheless, autoantibodies to dsDNA occur in only two-thirds of SLE patients. We previously reported the use of an antigen microarray to characterize SLE serology. We now report the results of an expanded study of serology in SLE patients and scleroderma (SSc) patients compared with healthy controls. The analysis validated and extended previous findings: two-thirds of SLE patients reacted to a large spectrum of self-molecules that overlapped with their reactivity to dsDNA; moreover, some SLE patients manifested a deficiency of natural IgM autoantibodies. Most significant was the finding that many SLE patients who were negative for autoantibodies to dsDNA manifested abnormal antibody responses to Epstein-Barr virus (EBV): these subjects made IgG antibodies to EBV antigens to which healthy subjects did not respond or they failed to make antibodies to EBV antigens to which healthy subjects did respond. This observation suggests that SLE may be associated with a defective immune response to EBV. The SSc patients shared many of these serological abnormalities with SLE patients, but differed from them in increased IgG autoantibodies to topoisomerase and centromere B; 84% of SLE patients and 58% of SSc patients could be detected by their abnormal antibodies to EBV. Hence an aberrant immune response to a ubiquitous viral infection such as EBV might set the stage for an autoimmune disease. © 2013 John Wiley & Sons Ltd.
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Oxygen Transport Membrane Reactors for Oxy-Fuel Combustion and Carbon Capture Purposes
NASA Astrophysics Data System (ADS)
Falkenstein-Smith, Ryan L.
This thesis investigates oxygen transport membrane reactors (OTMs) for the application of oxy-fuel combustion. This is done by evaluating the material properties and oxygen permeability of different OTM compositions subjected to a variety of operating conditions. The scope of this work consists of three components: (1) evaluate the oxygen permeation capabilities of perovskite-type materials for the application of oxy-fuel combustion; (2) determine the effects of dual-phase membrane compositions on the oxygen permeation performance and membrane characteristics; and (3) develop a new method for estimating the oxygen permeation performance of OTMs utilized for the application of oxy-fuel combustion. SrSc0.1Co0.9O3-delta (SSC) is selected as the primary perovskite-type material used in this research due to its reported high ionic and electronic conductive properties and chemical stability. SSC's oxygen ion diffusivity is investigated using a conductivity relaxation technique and thermogravimetric analysis. Material properties such as chemical structure, morphology, and ionic and electronic conductivity are examined by X-ray diffraction (XRD), Scanning Electron Microscope (SEM), and conductivity testing using a four-probe method, respectively. Oxygen permeation tests study the oxygen permeability OTMs under modified membrane temperatures, sweeping gas flow rates, sweeping gas compositions, membrane configurations, and membrane compositions. When utilizing a pure CO2 sweeping gas, the membrane composition was modified with the addition of Sm0.2Ce0.8O1.9-delta (SDC) at varying wt.% to improve the membranes mechanical stability. A newly developed method to evaluate the oxygen permeation performance of OTMs is also presented by fitting OTM's oxygen permeability to the methane fraction in the sweeping gas composition. The fitted data is used to estimate the overall performance and size of OTMs utilized for the application of oxy-fuel combustion. The findings from this research show that under a wide range of membrane temperatures and in a variety of atmospheres, a pure SSC OTM can achieve superior surface exchange and oxygen chemical diffusion coefficients compared to other commonly studied materials. SSC's high oxygen permeability (>1 ml.min -1.cm-2) demonstrates the material's candidacy for the application of oxy-fuel combustion. However, in the presence of rich CO 2 atmospheres, SSC shows mechanical and chemical instabilities due to the carbonate formation on the perovskite structure. The addition of SDC in the membrane composition produces a dual-phase OTM which is observed to improve the oxygen permeation flux when subjected to pure CO2 sweeping gases. When subjected to pure methane sweeping gases, dual-phase OTM compositions exhibits lower oxygen permeability compared to the single-phase SSC OTM. Despite the decline in the oxygen permeation flux, some dual-phase compositions still exhibit a high oxygen permeability, indicating their potential for the application of oxy-fuel combustion. Furthermore, a newly developed method for evaluating OTMs for the application of oxy-fuel combustion is presented in a portion of this work. This new method calculates key components such as the average oxygen permeation flux, approximate effective surface area, and the impact of additional recirculated exhaust into the incoming sweeping gas to provide a detailed understanding of OTM's application for oxy-fuel combustion. The development of this approach will aid in the evaluation of newly developed materials and create a new standard for implementing OTMs for the application of oxy-fuel combustion.
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McCoy, Sara S; Reed, Tamra J; Berthier, Celine C; Tsou, Pei-Suen; Liu, Jianhua; Gudjonsson, Johann E; Khanna, Dinesh; Kahlenberg, J Michelle
2017-11-01
SSc is a devastating disease that results in fibrosis of the skin and other organs. Fibroblasts are a key driver of the fibrotic process through deposition of extracellular matrix. The mechanisms by which fibroblasts are induced to become pro-fibrotic remain unclear. Thus, we examined the ability of SSc keratinocytes to promote fibroblast activation and the source of this effect. Keratinocytes were isolated from skin biopsies of 9 lcSSc, 10 dcSSc and 13 control patients. Conditioned media was saved from the cultures. Normal fresh primary fibroblasts were exposed to healthy control and SSc keratinocyte conditioned media in the presence or absence of neutralizing antibodies for TGF-β. Gene expression was assessed by microarrays and real-time PCR. Immunocytochemistry was performed for α-smooth muscle actin (α-SMA), collagen type 1 (COL1A1) and CCL5 expression. SSc keratinocyte conditioned media promoted fibroblast activation, characterized by increased α-SMA and COL1A1 mRNA and protein expression. This effect was independent of TGF-β. Microarray analysis identified upregulation of nuclear factor κB (NF-κB) and downregulation of peroxisome proliferator-activated receptor γ (PPAR-γ) pathways in both SSc subtypes. Scleroderma keratinocytes exhibited increased expression of NF-κB-regulated cytokines and chemokines and lesional skin staining confirmed upregulation of CCL5 in basal keratinocytes. Scleroderma keratinocytes promote the activation of fibroblasts in a TGF-β-independent manner and demonstrate an imbalance in NF-κB1 and PPAR-γ expression leading to increased cytokine and CCL5 production. Further study of keratinocyte mediators of fibrosis, including CCL5, may provide novel targets for skin fibrosis therapy. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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Lee, Jae-Ho; Park, Jeung-Jin; Choi, Gi-Choong; Byun, Im-Gyu; Park, Tae-Joo; Lee, Tae-Ho
2013-01-01
Biological reuse of spent sulfidic caustic (SSC) originating from oil refineries is a promising method for the petrochemical industry because of low handling cost. SSC typically contains high concentrations of sulfur, with the most dominant sulfur compounds being sulfide (S(2-)). SSC is also characterized by a high pH and elevated alkalinity up to 5-15% by weight. Because of these characteristics, SSC can be used for denitrification of NO3(-)-N in the biological nitrogen removal process as both the electron donor and buffering agent in sulfur-utilizing autotrophic denitrification. In this study, two kinds of SSC (SSC I, SSC II) produced from two petrochemical companies were used for autotrophic denitrification in a field-scale wastewater treatment plant (WWTP). The effluent total nitrogen (TN) concentration in this process was about 10.5 mg/L without any external carbon sources and the nitrification efficiency was low, about 93.0%, because of alkalinity deficiency in the influent. The injection of SSC I, but not SSC II, promoted nitrification efficiency, which was attributed to the difference in the NaOH/S ratio between SSC I and II. SSC was injected based on sulfide concentration of SSC required to denitrify NO3(-)-N in the WWTP. SSC I had higher NaOH/S than SSC II and thus could supply more alkalinity for nitrification than SSC II. On the other hand, additional TN removal of about 9.0% was achieved with the injection of both SSCs. However, denitrification efficiency was not proportionally increased with increasing SSC injection because of NO3(-)-N deficiency in the anoxic tank due to the limited capacity of the recycling pump. For the same reason, sulfate concentration, which is the end product of sulfur-utilizing autotrophic denitrificaiton in the effluent, was also not increased with increasing SSC injection.
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Kuwahara, Y; Shima, Y; Shirayama, D; Kawai, M; Hagihara, K; Hirano, T; Arimitsu, J; Ogata, A; Tanaka, T; Kawase, I
2008-07-01
No objective method to measure skin involvement in SSc has been established. We developed a novel method using a computer-linked device to simultaneously quantify physical properties of the skin such as hardness, elasticity and viscosity. Skin hardness was calculated by measuring the depth of an indenter pressed onto the skin. The Voigt model was used to calculate skin elasticity, viscosity, visco-elastic ratio and relaxation time by analysing the waveform of skin surface behaviour. The results were compared with the modified Rodnan skin score (mRSS) obtained at 17 sites on the bodies of 20 SSc patients and 20 healthy controls. A functional assessment questionnaire was administered to determine how skin hardness represents a patient's disability. We also examined intra- and inter-observer variability to determine the reliability of this method. The crude hardness obtained with this device correlated well with the standard hardness specified by the American Society for Testing and Materials (ASTM, r = 0.957). A close relationship between hardness and total mRSS was also observed (r = 0.832). Skin elasticity correlated positively, and relaxation time negatively with mRSS. Functional disability correlated more closely with skin hardness (r = 0.643) than with mRSS (r = 0.517). Intra- and inter-observer variabilities were 7.63 and 19.76%, respectively, which were lower than those reported for mRSS. Increases in hardness and elasticity as well as shortening of relaxation time constitute objective characteristics of skin involvement in SSc. The system devised by us proved to be able to assess skin abnormalities of SSc with high reliability.
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Sierakowska, Matylda; Sierakowski, Stanisław; Sierakowska, Justyna; Horton, Mike; Ndosi, Mwidimi
2015-03-01
To undertake cross-cultural adaptation and validation of the educational needs assessment tool (ENAT) for use with people with rheumatoid arthritis (RA) and systemic sclerosis (SSc) in Poland. The study involved two main phases: (1) cross-cultural adaptation of the ENAT from English into Polish and (2) Cross-cultural validation of Polish Educational Needs Assessment Tool (Pol-ENAT). The first phase followed an established process of cross-cultural adaptation of self-report measures. The second phase involved completion of the Pol-ENAT by patients and subjecting the data to Rasch analysis to assess the construct validity, unidimensionality, internal consistency and cross-cultural invariance. An adequate conceptual equivalence was achieved following the adaptation process. The dataset for validation comprised a total of 278 patients, 237 (85.3 %) of which were female. In each disease group (145, RA and 133, SSc), the 7 domains of the Pol-ENAT were found to fit the Rasch model, X (2)(df) = 16.953(14), p = 0.259 and 8.132(14), p = 0.882 for RA and SSc, respectively. Internal consistency of the Pol-ENAT was high (patient separation index = 0.85 and 0.89 for SSc and RA, respectively), and unidimensionality was confirmed. Cross-cultural differential item functioning (DIF) was detected in some subscales, and DIF-adjusted conversion tables were calibrated to enable cross-cultural comparison of data between Poland and the UK. Using a standard process in cross-cultural adaptation, conceptual equivalence was achieved between the original (UK) ENAT and the adapted Pol-ENAT. Fit to the Rasch model, confirmed that the construct validity, unidimensionality and internal consistency of the ENAT have been preserved.
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Makino, Katsunari; Jinnin, Masatoshi; Hirano, Ayaka; Yamane, Keitaro; Eto, Mitsuhiko; Kusano, Takamitsu; Honda, Noritoshi; Kajihara, Ikko; Makino, Takamitsu; Sakai, Keisuke; Masuguchi, Shinichi; Fukushima, Satoshi; Ihn, Hironobu
2013-04-15
Systemic and localized scleroderma (SSc and LSc) is characterized by excessive deposition of collagen and tissue fibrosis in the skin. Although they have fundamental common characteristics including autoimmunity, little is known about the exact mechanism that mediates the excessive collagen expression in these disorders. In the current study, we tried to evaluate the possibility that microRNAs (miRNAs) play some roles in the pathogenesis of fibrosis seen in these diseases. miRNA expression patterns were evaluated by miRNA array analysis, real-time PCR, and in situ hybridization. The function of miRNAs in dermal fibroblasts was assessed using miRNA inhibitors, precursors, or protectors. In the mouse model of bleomycin-induced dermal sclerosis, the overexpression of miRNAs was performed by i.p. miRNA injection. We demonstrated let-7a expression was downregulated in SSc and LSc skin both in vivo and in vitro, compared with normal or keloid skin. The inhibition or overexpression of let-7a in human or mouse skin fibroblasts affected the protein expression of type I collagen or luciferase activity of collagen 3'-untranslated region. Also, we found let-7a was detectable and quantitative in the serum and investigated serum let-7a levels in patients with SSc or LSc. let-7a concentration was significantly decreased in these patients, especially in LSc patients. Moreover, we revealed that the intermittent overexpression of let-7a in the skin by i.p. miRNA injection improved the skin fibrosis induced by bleomycin in mice. Investigation of more detailed mechanisms of miRNA-mediated regulation of collagen expression may lead to new therapeutic approaches against SSc and LSc.
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Mazzotti, N G; Bredemeier, M; Brenol, C V; Xavier, R M; Cestari, T F
2014-03-01
Systemic sclerosis (SSc) is characterized by target-organ fibrosis and microvascular dysfunction, which can be assessed using nailfold capillaroscopy. Dermoscopy is a useful and easily performed method for diagnosing skin lesions. To compare conventional capillaroscopy, using the gold-standard method (conventional stereomicroscope nailfold capillaroscopy; SNFC), with polarized light noncontact dermoscopy (PNCD) and nonpolarized light contact dermoscopy (NPCD), and to evaluate their accuracy in diagnosing characteristic SSc-related alterations. The study enrolled 45 patients with SSc. Capillaroscopy images and photographs were taken with three devices, SNFC, NPCD and PNCD, and these images were randomly analysed by a blinded observer. The scleroderma pattern was found in 83% of patients. PNCD and NPCD were highly sensitive in identifying the presence of focal capillary loss (96.4% and 100%, respectively), haemorrhage (96.2% and 92%, respectively), and scleroderma (91.9%, 94.6%), and showed high specificity for haemorrhage and enlarged loops. The intra-observer kappa values for detection of the scleroderma pattern by SNFC images, NPCD and PNCD were moderate to good: (κ = 0.71 (95% CI 0.44-0.95), κ = 0.60 (95% CI 0.35-0.83) and κ = 0.60 (95% CI 0.32-0.86), respectively. Evaluation of haemorrhage presence gave high kappa values for all methods: κ = 0.77 (95% CI 0.57-0.95), κ = 0.90 (95% CI 0.76-1.00) and κ = 0.95 (95% CI 0.85-1.00), respectively. Both polarized and nonpolarized dermoscopy are reliable methods for valuation of nailfold capillaroscopy in patients with SSc. They are easy to perform, with good rates of accuracy and results that are comparable with traditional capillaroscopy. © 2013 British Association of Dermatologists.
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Kwakkenbos, Linda; Minton, Ollie; Stone, Patrick C; Alexander, Susanna; Baron, Murray; Hudson, Marie; Thombs, Brett D
2015-07-01
Fatigue is a crucial determinant of quality of life across rheumatic diseases, but the lack of agreed-upon standards for identifying clinically significant fatigue hinders research and clinical management. Case definition criteria for cancer-related fatigue were proposed for inclusion in the International Classification of Diseases. The objective was to evaluate whether the cancer-related fatigue case definition performed equivalently in women with breast cancer and systemic sclerosis (SSc) and could be used to identify patients with chronic illness-related fatigue. The cancer-related fatigue interview (case definition criteria met if ≥ 5 of 9 fatigue-related symptoms present with functional impairment) was completed by 291 women with SSc and 278 women successfully treated for breast cancer. Differential item functioning was assessed with the multiple indicator multiple cause model. Items 3 (concentration) and 10 (short-term memory) were endorsed significantly less often by women with SSc compared with cancer, controlling for responses on other items. Omitting these 2 items from the case definition and requiring 4 out of the 7 remaining symptoms resulted in a similar overall prevalence of cancer-related fatigue in the cancer sample compared with the original criteria (37.4% vs 37.8%, respectively), with 97.5% of patients diagnosed identically with both definitions. Prevalence of chronic illness-related fatigue was 36.1% in SSc using 4 of 7 symptoms. The cancer-related fatigue criteria can be used equivalently to identify patients with chronic illness-related fatigue when 2 cognitive fatigue symptoms are omitted. Harmonized definitions and measurement of clinically significant fatigue will advance research and clinical management of fatigue in rheumatic diseases and other conditions.
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Clinical phenotypes and survival of pre-capillary pulmonary hypertension in systemic sclerosis.
Launay, David; Montani, David; Hassoun, Paul M; Cottin, Vincent; Le Pavec, Jérôme; Clerson, Pierre; Sitbon, Olivier; Jaïs, Xavier; Savale, Laurent; Weatherald, Jason; Sobanski, Vincent; Mathai, Stephen C; Shafiq, Majid; Cordier, Jean-François; Hachulla, Eric; Simonneau, Gérald; Humbert, Marc
2018-01-01
Pre-capillary pulmonary hypertension (PH) in systemic sclerosis (SSc) is a heterogeneous condition with an overall bad prognosis. The objective of this study was to identify and characterize homogeneous phenotypes by a cluster analysis in SSc patients with PH. Patients were identified from two prospective cohorts from the US and France. Clinical, pulmonary function, high-resolution chest tomography, hemodynamic and survival data were extracted. We performed cluster analysis using the k-means method and compared survival between clusters using Cox regression analysis. Cluster analysis of 200 patients identified four homogenous phenotypes. Cluster C1 included patients with mild to moderate risk pulmonary arterial hypertension (PAH) with limited or no interstitial lung disease (ILD) and low DLCO with a 3-year survival of 81.5% (95% CI: 71.4-88.2). C2 had pre-capillary PH due to extensive ILD and worse 3-year survival compared to C1 (adjusted hazard ratio [HR] 3.14; 95% CI 1.66-5.94; p = 0.0004). C3 had severe PAH and a trend towards worse survival (HR 2.53; 95% CI 0.99-6.49; p = 0.052). Cluster C4 and C1 were similar with no difference in survival (HR 0.65; 95% CI 0.19-2.27, p = 0.507) but with a higher DLCO in C4. PH in SSc can be characterized into distinct clusters that differ in prognosis.
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Stennis Space Center Environmental Geographic Information System
NASA Technical Reports Server (NTRS)
Lovely, Janette; Cohan, Tyrus
2000-01-01
As NASA's lead center for rocket propulsion testing, the John C. Stennis Space Center (SSC) monitors and assesses the off-site impacts of such testing through its Environmental Office (SSC-EO) using acoustical models and ancillary data. The SSC-EO has developed a geographical database, called the SSC Environmental Geographic Information System (SSC-EGIS), that covers an eight-county area bordering the NASA facility. Through the SSC-EGIS, the Enivronmental Office inventories, assesses, and manages the nearly 139,000 acres that comprise Stennis Space Center and its surrounding acoustical buffer zone. The SSC-EGIS contains in-house data as well as a wide range of data obtained from outside sources, including private agencies and local, county, state, and U.S. government agencies. The database comprises cadastral/geodetic, hydrology, infrastructure, geo-political, physical geography, and socio-economic vector and raster layers. The imagery contained in the database is varied, including low-resolution imagery, such as Landsat TM and SPOT; high-resolution imagery, such as IKONOS and AVIRIS; and aerial photographs. The SSC-EGIS has been an integral part of several major projects and the model upon which similar EGIS's will be developed for other NASA facilities. The Corps of Engineers utilized the SSC-EGIS in a plan to establish wetland mitigation sites within the SSC buffer zone. Mississippi State University employed the SSC-EGIS in a preliminary study to evaluate public access points within the buffer zone. The SSC-EO has also expressly used the SSC-EGIS to assess noise pollution modeling, land management/wetland mitigation assessment, environmental hazards mapping, and protected areas mapping for archaeological sites and for threatened and endangered species habitats. The SSC-EO has several active and planned projects that will also make use of the SSC-EGIS during this and the coming fiscal year.
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Determinants of exercise-induced pulmonary arterial hypertension in systemic sclerosis.
Voilliot, Damien; Magne, Julien; Dulgheru, Raluca; Kou, Seisyou; Henri, Christine; Laaraibi, Saloua; Sprynger, Muriel; Andre, Béatrice; Pierard, Luc A; Lancellotti, Patrizio
2014-05-15
Exercise-induced pulmonary arterial hypertension (EIPH) in systemic sclerosis (SSc) has already been observed but its determinants remain unclear. The aim of this study was to determine the incidence and the determinants of EIPH in SSc. We prospectively enrolled 63 patients with SSc (age 54±3years, 76% female) followed in CHU Sart-Tilman in Liège. All patients underwent graded semi-supine exercise echocardiography. Systolic pulmonary arterial pressure (sPAP) was derived from the peak velocity of the tricuspid regurgitation jet and adding the estimation of right atrial pressure, both at rest and during exercise. Resting pulmonary arterial hypertension (PH) was defined as sPAP > 35 mmHg and EIPH as sPAP > 50 mmHg during exercise. The following formulas were used: mean PAP (mPAP) = 0.61 × sPAP + 2, left atrial pressure (LAP)=1.9+1.24 × left ventricular (LV) E/e' and pulmonary vascular resistance (PVR)=(mPAP-LAP)/LV cardiac output (CO) and slope of mPAP-LVCO relationship=changes in mPAP/changes in LVCO. Resting PH was present in 3 patients (7%) and 21 patients developed EIPH (47%). Patients with EIPH had higher resting LAP (10.3 ± 2.2 versus 8.8 ± 2.3 mmHg; p = 0.03), resting PVR (2.6 ± 0.8 vs. 1.4 ± 1.1 Woods units; p=0.004), exercise LAP (13.3 ± 2.3 vs. 9 ± 1.7 mmHg; p < 0.0001), exercise PVR (3.6 ± 0.7 vs. 2.1 ± 0.9 Woods units; p = 0.02) and slope of mPAP-LVCO (5.8 ± 2.4 vs. 2.9 ± 2.1 mmHg/L/min; p < 0.0001). After adjustment for age and gender, exercise LAP (β=3.1 ± 0.8; p=0.001) and exercise PVR (β=7.9 ± 1.7; p=0.0001) were independent determinants of exercise sPAP. EIPH is frequent in SSc patients and is mainly related to both increased exercise LV filling pressure and exercise PVR. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
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Ek, Weronica; Sahlqvist, Anna-Stina; Crooks, Lucy; Sgonc, Roswitha; Dietrich, Hermann; Wick, Georg; Ekwall, Olov; Andersson, Leif; Carlborg, Örjan; Kämpe, Olle; Kerje, Susanne
2012-10-01
Systemic sclerosis (SSc) or scleroderma is a rare, autoimmune, multi-factorial disease characterized by early microvascular alterations, inflammation, and fibrosis. Chickens from the UCD-200 line develop a hereditary SSc-like disease, showing all the hallmarks of the human disorder, which makes this line a promising model to study genetic factors underlying the disease. A backcross was generated between UCD-200 chickens and its wild ancestor - the red jungle fowl and a genome-scan was performed to identify loci affecting early (21 days of age) and late (175 days of age) ischemic lesions of the comb. A significant difference in frequency of disease was observed between sexes in the BC population, where the homogametic males were more affected than females, and there was evidence for a protective W chromosome effect. Three suggestive disease predisposing loci were mapped to chromosomes 2, 12 and 14. Three orthologues of genes implicated in human SSc are located in the QTL region on chromosome 2, TGFRB1, EXOC2-IRF4 and COL1A2, as well as CCR8, which is more generally related to immune function. IGFBP3 is also located within the QTL on chromosome 2 and earlier studies have showed increased IGFBP3 serum levels in SSc patients. To our knowledge, this study is the first to reveal a potential genetic association between IGFBP3 and SSc. Another gene with an immunological function, SOCS1, is located in the QTL region on chromosome 14. These results illustrate the usefulness of the UCD-200 chicken as a model of human SSc and motivate further in-depth functional studies of the implicated candidate genes. Copyright © 2012 Elsevier Ltd. All rights reserved.
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Almeida, Mónica; Ribeiro, Orquídea; Aragão, Irene; Costa-Pereira, Altamiro; Cardoso, Teresa
2013-04-23
Higher compliance with Surviving Sepsis Campaign (SSC) recommendations has been associated with lower mortality. The authors evaluate differences in compliance with SSC 6-hour bundle according to hospital entrance time (day versus night) and its impact on hospital mortality. Prospective cohort study of all patients with community-acquired severe sepsis admitted to the intensive care unit of a large university tertiary care hospital, over 3.5 years with a follow-up until hospital discharge. Time to compliance with each recommendation of the SSC 6-hour bundle was calculated according to hospital entrance period: day (08:30 to 20:30) versus night (20:30 to 08:30). For the same periods, clinical staff composition and the number of patients attending the emergency department (ED) was also recorded. In this period 300 consecutive patients were included. Compliance rate was (night vs. day): serum lactate measurement 57% vs. 49% (P = 0.171), blood cultures drawn 59% vs. 37% (P < 0.001), antibiotics administration in the first 3 hours 33% vs. 18% (P = 0.003), central venous pressure >8 mmHg 45% vs. 29% (P = 0.021), and central venous oxygen saturation (SvcO₂) >70%, 7% vs. 2% (P = 0.082); fluids were administered in all patients with hypotension in both periods and vasopressors were administered in patients with hypotension not responsive to fluids in 100% vs. 99%. Time to get specific actions done was also different (night vs. day): serum lactate measurement (4.5 vs. 7 h, P = 0.018), blood cultures drawn (4 vs. 8 h, P < 0.001), antibiotic administration (5 vs. 8 h, P < 0.001), central venous pressure (8 vs. 11 h, P = 0.01), and SvcO₂ monitoring (2.5 vs. 11 h, P = 0.222). The composition of the nursing team was the same around the clock; the medical team was reduced at night with a higher proportion of less differentiated doctors. The number of patients attending the Emergency Department was lower overnight. Hospital mortality rate was 34% in patients entering in the night period vs. 40% in those entering during the day (P = 0.281). Compliance with SSC recommendations was higher at night. A possible explanation might be the increased nurse to patient ratio in that period. Adjustment of the clinical team composition to the patients' demand is needed to increase compliance and improve prognosis.
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Evaluation of membrane-bound and soluble forms of human leucocyte antigen-G in systemic sclerosis.
Contini, P; Negrini, S; Murdaca, G; Borro, M; Puppo, F
2018-04-16
Systemic sclerosis (SSc) is a complex disease characterized by immune dysregulation, extensive vascular damage and widespread fibrosis. Human leucocyte antigen-G (HLA-G) is a non-classic class I major histocompatibility complex (MHC) molecule characterized by complex immunomodulating properties. HLA-G is expressed on the membrane of different cell lineages in both physiological and pathological conditions. HLA-G is also detectable in soluble form (sHLA-G) deriving from the shedding of surface isoforms (sHLA-G1) or the secretion of soluble isoforms (HLA-G5). Several immunosuppressive functions have been attributed to both membrane-bound and soluble HLA-G molecules. The plasma levels of sHLA-G were higher in SSc patients (444·27 ± 304·84 U/ml) compared to controls (16·74 ± 20·58 U/ml) (P < 0·0001). The plasma levels of transforming growth factor (TGF)-β were higher in SSc patients (18 937 ± 15 217 pg/ml) compared to controls (11 099 ± 6081 pg/ml; P = 0·003), and a significant correlation was found between TGF-β and the plasma levels of total sHLA-G (r = 0·65; P < 0·01), sHLA-G1 (r = 0·60; P = 0·003) and HLA-G5 (r = 0·47; P = 0·02). The percentage of HLA-G-positive monocytes (0·98 ± 1·72), CD4 + (0·37 ± 0·68), CD8 + (2·05 ± 3·74) and CD4 + CD8 + double-positive cells (14·53 ± 16·88) was higher in SSc patients than in controls (0·11 ± 0·08, 0·01 ± 0·01, 0·01 ± 0·01 and 0·39 ± 0·40, respectively) (P < 0·0001). These data indicate that in SSc the secretion and/or shedding of soluble HLA-G molecules and the membrane expression of HLA-G by peripheral blood mononuclear cells (PBMC) is clearly elevated, suggesting an involvement of HLA-G molecules in the immune dysregulation of SSc. © 2018 British Society for Immunology.
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Nguyen-Kim, Thi Dan Linh; Maurer, Britta; Suliman, Yossra A; Morsbach, Fabian; Distler, Oliver; Frauenfelder, Thomas
2018-04-01
To evaluate usability of slice-reduced sequential computed tomography (CT) compared to standard high-resolution CT (HRCT) in patients with systemic sclerosis (SSc) for qualitative and quantitative assessment of interstitial lung disease (ILD) with respect to (I) detection of lung parenchymal abnormalities, (II) qualitative and semiquantitative visual assessment, (III) quantification of ILD by histograms and (IV) accuracy for the 20%-cut off discrimination. From standard chest HRCT of 60 SSc patients sequential 9-slice-computed tomography (reduced HRCT) was retrospectively reconstructed. ILD was assessed by visual scoring and quantitative histogram parameters. Results from standard and reduced HRCT were compared using non-parametric tests and analysed by univariate linear regression analyses. With respect to the detection of parenchymal abnormalities, only the detection of intrapulmonary bronchiectasis was significantly lower in reduced HRCT compared to standard HRCT (P=0.039). No differences were found comparing visual scores for fibrosis severity and extension from standard and reduced HRCT (P=0.051-0.073). All scores correlated significantly (P<0.001) to histogram parameters derived from both, standard and reduced HRCT. Significant higher values of kurtosis and skewness for reduced HRCT were found (both P<0.001). In contrast to standard HRCT histogram parameters from reduced HRCT showed significant discrimination at cut-off 20% fibrosis (sensitivity 88% kurtosis and skewness; specificity 81% kurtosis and 86% skewness; cut-off kurtosis ≤26, cut-off skewness ≤4; both P<0.001). Reduced HRCT is a robust method to assess lung fibrosis in SSc with minimal radiation dose with no difference in scoring assessment of lung fibrosis severity and extension in comparison to standard HRCT. In contrast to standard HRCT histogram parameters derived from the approach of reduced HRCT could discriminate at a threshold of 20% lung fibrosis with high sensitivity and specificity. Hence it might be used to detect early disease progression of lung fibrosis in context of monitoring and treatment of SSc patients.
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NASA Technical Reports Server (NTRS)
Allgood, Daniel C.; Graham, Jason S.; Ahuja, Vineet; Hosangadi, Ashvin
2010-01-01
Simulation technology can play an important role in rocket engine test facility design and development by assessing risks, providing analysis of dynamic pressure and thermal loads, identifying failure modes and predicting anomalous behavior of critical systems. Advanced numerical tools assume greater significance in supporting testing and design of high altitude testing facilities and plume induced testing environments of high thrust engines because of the greater inter-dependence and synergy in the functioning of the different sub-systems. This is especially true for facilities such as the proposed A-3 facility at NASA SSC because of a challenging operating envelope linked to variable throttle conditions at relatively low chamber pressures. Facility designs in this case will require a complex network of diffuser ducts, steam ejector trains, fast operating valves, cooling water systems and flow diverters that need to be characterized for steady state performance. In this paper, we will demonstrate with the use of CFD analyses s advanced capability to evaluate supersonic diffuser and steam ejector performance in a sub-scale A-3 facility at NASA Stennis Space Center (SSC) where extensive testing was performed. Furthermore, the focus in this paper relates to modeling of critical sub-systems and components used in facilities such as the A-3 facility. The work here will address deficiencies in empirical models and current CFD analyses that are used for design of supersonic diffusers/turning vanes/ejectors as well as analyses for confined plumes and venting processes. The primary areas that will be addressed are: (1) supersonic diffuser performance including analyses of thermal loads (2) accurate shock capturing in the diffuser duct; (3) effect of turning duct on the performance of the facility (4) prediction of mass flow rates and performance classification for steam ejectors (5) comparisons with test data from sub-scale diffuser testing and assessment of confidence levels in CFD based flowpath modeling of the facility. The analyses tools used here expand on the multi-element unstructured CFD which has been tailored and validated for impingement dynamics of dry plumes, complex valve/feed systems, and high pressure propellant delivery systems used in engine and component test stands at NASA SSC. The analyses performed in the evaluation of the sub-scale diffuser facility explored several important factors that influence modeling and understanding of facility operation such as (a) importance of modeling the facility with Real Gas approximation, (b) approximating the cluster of steam ejector nozzles as a single annular nozzle, (c) existence of mixed subsonic/supersonic flow downstream of the turning duct, and (d) inadequacy of two-equation turbulence models in predicting the correct pressurization in the turning duct and expansion of the second stage steam ejectors. The procedure used for modeling the facility was as follows: (i) The engine, test cell and first stage ejectors were simulated with an axisymmetric approximation (ii) the turning duct, second stage ejectors and the piping downstream of the second stage ejectors were analyzed with a three-dimensional simulation utilizing a half-plane symmetry approximation. The solution i.e. primitive variables such as pressure, velocity components, temperature and turbulence quantities were passed from the first computational domain and specified as a supersonic boundary condition for the second simulation. (iii) The third domain comprised of the exit diffuser and the region in the vicinity of the facility (primary included to get the correct shock structure at the exit of the facility and entrainment characteristics). The first set of simulations comprising the engine, test cell and first stage ejectors was carried out both as a turbulent real gas calculation as well as a turbulent perfect gas calculation. A comparison for the two cases (Real Turbulent and Perfect gas turbulent) of the Ma Number distribution and temperature distributions are shown in Figures 1 and 2 respectively.
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The epidemiology of adults with severe sepsis and septic shock in Scottish emergency departments.
Gray, Alasdair; Ward, Kirsty; Lees, Fiona; Dewar, Colin; Dickie, Sarah; McGuffie, Crawford
2013-05-01
The Surviving Sepsis Campaign (SSC) promotes a bundle approach to the care of septic patients to improve outcome. Some have questioned the capability of delivering the bundle in emergency departments (EDs). The authors report the epidemiology and 6 h bundle compliance of patients with severe sepsis/septic shock presenting to Scottish EDs. Analysis of the previously reported Scottish Trauma Audit Group sepsis database was performed including 20 mainland Scottish EDs. A total of 308,910 attendances were screened (between 2 March and 31 May 2009), and 5285 of 27,046 patients were identified after case note review and included on the database. This analysis includes patients who had severe sepsis/septic shock before leaving the ED. Epidemiological, severity of illness criteria, and ED management data were analysed. 626 patients (median age 73; M/F ratio 1:1; 637 presentations) met entrance criteria. The median number of cases per site was 16 (range 3-103). 561 (88.1%) patients arrived by ambulance. The most common source of infection was the respiratory tract (n=411, 64.5%) The most common physiological derangements were heart rate (n=523, 82.1%), respiratory rate (n=452, 71%) and white cell count (n=432, 67.8%). The median hospital stay was 9 days (IQR 4-17 days). 201 (31.6%) patients were admitted to critical care within 2 days, 130 (20.4%) directly from the ED. 180 patients (28.3%) died. There was poor compliance with all aspect of the SSC resuscitation bundle. Sepsis presentations are of variable frequency but have typical epidemiology and clinical outcomes. SSC bundle resuscitation uptake is poor in Scottish EDs.
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Development and Validation of the Body Concealment Scale for Scleroderma.
Jewett, Lisa R; Malcarne, Vanessa L; Kwakkenbos, Linda; Harcourt, Diana; Rumsey, Nichola; Körner, Annett; Steele, Russell J; Hudson, Marie; Baron, Murray; Haythornthwaite, Jennifer A; Heinberg, Leslie; Wigley, Fredrick M; Thombs, Brett D
2016-08-01
Body concealment is a component of social avoidance among people with visible differences from disfiguring conditions, including systemic sclerosis (SSc). The study objective was to develop a measure of body concealment related to avoidance behaviors in SSc. Initial items for the Body Concealment Scale for Scleroderma (BCSS) were selected using item analysis in a development sample of 93 American SSc patients. The factor structure of the BCSS was evaluated in 742 Canadian patients with single-factor, 2-factor, and bifactor confirmatory factor analysis models. Convergent and divergent validity were assessed by comparing the BCSS total score with the Brief-Satisfaction with Appearance Scale (Brief-SWAP) and measures of depressive symptoms and pain. A 2-factor model (Comparative Fit Index [CFI] 0.99, Tucker-Lewis Index [TLI] 0.98, Root Mean Square Error of Approximation [RMSEA] 0.08) fit substantially better than a 1-factor model (CFI 0.95, TLI 0.94, RMSEA 0.15) for the 9-item BCSS, but the Concealment with Clothing and Concealment of Hands factors were highly correlated (α = 0.79). The bifactor model (CFI 0.99, TLI 0.99, RMSEA 0.08) also fit well. In the bifactor model, the omega coefficient was high for the general factor (ω = 0.80), but low for the Concealment with Clothing (ω = 0.01) and Concealment of Hands (ω = 0.33) factors. The BCSS total score correlated more strongly with the Brief-SWAP Social Discomfort (r = 0.59) and Dissatisfaction with Appearance (r = 0.53) subscales than with measures of depressive symptoms and pain. The BCSS sum score is a valid indicator of body concealment in SSc that extends the concepts of body concealment and avoidance beyond the realms of body shape and weight to concerns of individuals with visible differences from SSc. © 2016, American College of Rheumatology.
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Arnould, Carlyne; Vandervelde, Laure; Batcho, Charles Sèbiyo; Penta, Massimo; Thonnard, Jean-Louis
2012-01-01
Objectives Several ABILHAND Rasch-built manual ability scales were previously developed for chronic stroke (CS), cerebral palsy (CP), rheumatoid arthritis (RA), systemic sclerosis (SSc) and neuromuscular disorders (NMD). The present study aimed to explore the applicability of a generic manual ability scale unbiased by diagnosis and to study the nature of manual ability across diagnoses. Design Cross-sectional study. Setting Outpatient clinic homes (CS, CP, RA), specialised centres (CP), reference centres (CP, NMD) and university hospitals (SSc). Participants 762 patients from six diagnostic groups: 103 CS adults, 113 CP children, 112 RA adults, 156 SSc adults, 124 NMD children and 124 NMD adults. Primary and secondary outcome measures Manual ability as measured by the ABILHAND disease-specific questionnaires, diagnosis and nature (ie, uni-manual or bi-manual involvement and proximal or distal joints involvement) of the ABILHAND manual activities. Results The difficulties of most manual activities were diagnosis dependent. A principal component analysis highlighted that 57% of the variance in the item difficulty between diagnoses was explained by the symmetric or asymmetric nature of the disorders. A generic scale was constructed, from a metric point of view, with 11 items sharing a common difficulty among diagnoses and 41 items displaying a category-specific location (asymmetric: CS, CP; and symmetric: RA, SSc, NMD). This generic scale showed that CP and NMD children had significantly less manual ability than RA patients, who had significantly less manual ability than CS, SSc and NMD adults. However, the generic scale was less discriminative and responsive to small deficits than disease-specific instruments. Conclusions Our finding that most of the manual item difficulties were disease-dependent emphasises the danger of using generic scales without prior investigation of item invariance across diagnostic groups. Nevertheless, a generic manual ability scale could be developed by adjusting and accounting for activities perceived differently in various disorders. PMID:23117570
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Secondary sclerosing cholangitis in critically ill patients.
Peña-Pérez, Carlos Alberto; Ponce-Medrano, Juan Alberto Díaz
2018-01-01
Primary sclerosing cholangitis (PSC) is a rare idiopathic condition with immunopathogenic mechanisms where there is chronic progressive destruction of the biliary tree. Secondary sclerosing cholangitis (SSC) is clinically comparable to PSC, but is caused by specific processes which directly damage the biliary tree; examples include recurrent pancreatitis, bile duct malignancy, congenital bile duct abnormalities. A new cause of SSC has been described during or following significant critical illness associated with severe respiratory insufficiency, vasopressor requirement, shock and sepsis. This condition rapidly progresses to cirrhosis, frequently requiring liver transplantation for definitive management. Copyright: © 2018 Permanyer.
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Jones, Hannah; Santamaria, Nick
2018-06-01
Focus on skin-to-skin contact (SSC) as a family-centered care intervention in Neonatal Intensive Special Care (NISC) Units continues to increase. Previously, SSC has been shown to improve neonatal physiological stability, support brain development, and promote bonding and attachment. Limited research exists investigating SSC duration and neonatal physiological responses. This study examined the relationship between SSC duration and the neonate's oxygen saturation, heart rate (HR), respiratory rate (RR), and temperature. An observational cohort study was conducted at The Royal Women's Hospital NISC Unit in Melbourne, Australia. For each neonate participant, 1 SSC with their parent was studied (parent convenience) and neonatal physiological parameters recorded, with a bivariate correlation used to explore the relationship between the duration of SSC and the percentage of time during SSC that the neonate's physiological variables remained within a target range. No correlation existed between the duration of SSC and the neonatal physiological variables of oxygen saturation, HR, RR, and temperature. However, neonatal oxygen requirement was more often reduced across the duration of SSC. Due to previously documented benefits to neonates physiologically from SSC, and our supportive finding that SSC reduces neonatal oxygen requirement, we believe that this study adds to the evidence to support promotion of SSC in NISC Units. The duration of SSC does not appear to negatively impact the physiological effects to the neonate. Thus, SSC should be encouraged in all NISC Units to be conducted for the length of time the parent is able. This study should be repeated with a larger sample size.
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Barnes, Jammie; Mayes, Maureen D
2012-03-01
To identify the recent data regarding prevalence, incidence, survival, and risk factors for systemic sclerosis (SSc) and to compare these data to previously published findings. SSc disease occurrence data are now available for Argentina, Taiwan, and India and continue to show wide variation across geographic regions. The survival rate is negatively impacted by older age of onset, male sex, scleroderma renal crisis, pulmonary fibrosis, pulmonary arterial hypertension, cancer, and antitopoisomerase and anti-U1 antibodies. It appears that silica exposure confers an increased risk for developing scleroderma, but this exposure accounts for a very small proportion of male patients. Smoking is not associated with increased SSc susceptibility. Malignancies are reported in scleroderma at an increased rate, but the magnitude of this risk and the type of cancer vary among reports. Prevalence and incidence of SSc appears to be greater in populations of European ancestry and lower in Asian groups. Exposure to silica dust appears to be an environmental trigger, but this only accounts for a small proportion of male cases. Evidence for increased risk of neoplasia is suggestive, but the magnitude of the risk and the types of malignancies vary among reports.
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Cutolo, Maurizio; Smith, Vanessa
2013-11-01
Capillaroscopy is a non-invasive and safe tool to morphologically study the microcirculation. In rheumatology it has a dual use. First, it has a role in differential diagnosis of patients with RP. Second, it may have a role in the prediction of clinical complications in CTDs. In SSc, pilot studies have shown predictive associations with peripheral vascular and lung involvement hinting at a role of capillaroscopy as putative biomarker. Also and logically, in SSc, microangiopathy, as assessed by capillaroscopy, has been associated with markers of the disease such as angiogenic/static factors and SSc-specific antibodies. Moreover, morphological assessments of the microcirculation (capillaroscopy) seem to correlate with functional assessments (such as laser Doppler). Because of its clinical and research role, eyes are geared in Europe to expand the knowledge of this tool. Both the European League Against Rheumatism (EULAR) and the ACR are stepping forward to this need.
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An analysis of the kangaroo care intervention using neonatal EEG complexity: a preliminary study.
Kaffashi, F; Scher, M S; Ludington-Hoe, S M; Loparo, K A
2013-02-01
Skin-to-skin contact (SSC) promotes physiological stability and interaction between parents and infants. Temporal analyses of predictability in EEG-sleep time series can elucidate functional brain maturation between SSC and non-SSC cohorts at similar post-menstrual ages (PMAs). Sixteen EEG-sleep studies were performed on eight preterm infants who received 8 weeks of SSC, and compared with two non-SSC cohorts at term (N=126) that include a preterm group corrected to term age and a full term group. Two time series measures of predictability were used for comparisons. The SSC premature neonate group had increased complexity when compared to the non-SSC premature neonate group at the same PMA. Discriminant analysis shows that SSC neonates at 40 weeks PMA are closer to the full term neonate non-SSC group than to the premature non-SSC group at the same PMA; suggesting that the KC intervention accelerates neurophysiological maturation of premature neonates. Based on the hypothesis that EEG-derived complexity increases with neurophysiological maturation as supported by previously published research, SSC accelerates brain maturation in healthy preterm infants as quantified by time series measures of predictability when compared to a similar non-SSC group. Times series methods that quantify predictability of EEG sleep in neonates can provide useful information about altered neural development after developmental care interventions such as SSC. Analyses of this type may be helpful in assessing other neuroprotection strategies. Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
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Sekiyama, Juliana Y; Camargo, Cintia Z; Eduardo, Luís; Andrade, C; Kayser, Cristiane
2013-11-01
To analyze the diagnostic performance and reliability of different parameters evaluated by widefield nailfold capillaroscopy (NFC) with those obtained by video capillaroscopy in patients with Raynaud’s phenomenon (RP). Two hundred fifty-two individuals were assessed, including 101 systemic sclerosis (SSc; scleroderma) patients,61 patients with undifferentiated connective tissue disease, 37 patients with primary RP, and 53 controls. Widefield NFC was performed using a stereomicroscope under 10–25 x magnification and direct measurement of all parameters. Video capillaroscopy was performed under 200 x magnification, with the acquirement of 32 images per individual (4 fields per finger in 8 fingers). The following parameters were analyzed in 8 fingers of the hands (excluding thumbs) by both methods: number of capillaries/mm, number of enlarged and giant capillaries, microhemorrhages, and avascular score.Intra- and interobserver reliability was evaluated by performing both examinations in 20 individuals on 2 different days and by 2 long-term experienced observers. There was a significant correlation (P < 0.000) between widefield NFC and video capillaroscopy in the comparison of all parameters. Kappa values and intraclass correlation coefficient analysis showed excellent intra- and interobserver reproducibility for all parameters evaluated by widefield NFC and video capillaroscopy. Bland-Altman analysis showed high agreement of all parameters evaluated in both methods. According to receiver operating characteristic curve analysis, both methods showed a similar performance in discriminating SSc patients from controls. Widefield NFC and video capillaroscopy are reliable and accurate methods and can be used equally for assessing peripheral microangiopathy in RP and SSc patients. Nonetheless, the high reliability obtained may not be similar for less experienced examiners.
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Delisle, Vanessa C.; Kwakkenbos, Linda; Hudson, Marie; Baron, Murray; Thombs, Brett D.
2014-01-01
Objectives Center for Epidemiologic Studies Depression (CES-D) Scale scores in English- and French-speaking Canadian systemic sclerosis (SSc) patients are commonly pooled in analyses, but no studies have evaluated the metric equivalence of the English and French CES-D. The study objective was to examine the metric equivalence of the CES-D in English- and French-speaking SSc patients. Methods The CES-D was completed by 1007 English-speaking and 248 French-speaking patients from the Canadian Scleroderma Research Group Registry. Confirmatory factor analysis (CFA) was used to assess the factor structure in both samples. The Multiple-Indicator Multiple-Cause (MIMIC) model was utilized to assess differential item functioning (DIF). Results A two-factor model (Positive and Negative affect) showed excellent fit in both samples. Statistically significant, but small-magnitude, DIF was found for 3 of 20 CES-D items, including items 3 (Blues), 10 (Fearful), and 11 (Sleep). Prior to accounting for DIF, French-speaking patients had 0.08 of a standard deviation (SD) lower latent scores for the Positive factor (95% confidence interval [CI]−0.25 to 0.08) and 0.09 SD higher scores (95% CI−0.07 to 0.24) for the Negative factor than English-speaking patients. After DIF correction, there was no change on the Positive factor and a non-significant increase of 0.04 SD on the Negative factor for French-speaking patients (difference = 0.13 SD, 95% CI−0.03 to 0.28). Conclusions The English and French versions of the CES-D, despite minor DIF on several items, are substantively equivalent and can be used in studies that combine data from English- and French-speaking Canadian SSc patients. PMID:25036894
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Schulman, S; Angerås, U; Bergqvist, D; Eriksson, B; Lassen, M R; Fisher, W
2010-01-01
The definition of major bleeding varies between studies on surgical patients, particularly regarding the criteria for surgical wound-related bleeding. This diversity contributes to the difficulties in comparing data between trials. The Scientific and Standardization Committee (SSC), through its subcommittee on Control of Anticoagulation, of the International Society on Thrombosis and Haemostasis has previously published a recommendation for a harmonized definition of major bleeding in non-surgical studies. That definition has been adopted by the European Medicines Agency and is currently used in several non-surgical trials. A preliminary proposal for a parallel definition for surgical studies was presented at the 54(th) Annual Meeting of the SSC in Vienna, July 2008. Based on those discussions and further consultations with European and North American surgeons with experience from clinical trials a definition has been developed that should be applicable to all agents that interfere with hemostasis. The definition and the text that follows have been reviewed and approved by relevant co-chairs of the subcommittee and by the Executive Committee of the SSC. The intention is to seek approval of this definition from the regulatory authorities to enhance its incorporation into future clinical trial protocols.
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Campioni, Diana; Lo Monaco, Andrea; Lanza, Francesco; Moretti, Sabrina; Ferrari, Luisa; Fotinidi, Maria; La Corte, Renato; Cuneo, Antonio; Trotta, Francesco
2008-08-01
There is still controversy regarding the role of circulating endothelial and progenitor cells (CECs/CEPs) in the pathogenesis of systemic sclerosis (SSc). Using a sequential Boolean gating strategy based on a 4-color flow cytometric protocol, an increased number of CD31(pos)/CD184(pos)(CXCR4)/CD34(pos)/CD45(pos) and CD31(pos)/CD117(pos) (c-kit-R) /CD34(pos)/ CD45(pos) hematopoietic circulating progenitor cells (HCPCs) was detected in SSc patients compared with healthy subjects. In SSc, no circulating mature and progenitor endothelial cells were observed, while an enhanced generation of erythroid progenitor cells was found to be correlated with the presence of CD117+ HCPCs. The presence of freshly detected CXCR4posHCPC was correlated either to the in vitro cultured spindle-shaped endothelial like cells (SELC) with an endo/myelomonocytic profile or to SDF-1 and VEGF serum level. These data are related to more fibrotic clinical features of the disease, thus supporting a possible role of these cells in fibrosis.
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Adherence to surviving sepsis guidelines among pediatric intensivists
Thabet, Farah C.; Zahraa, Jihad N.; Chehab, May S.
2017-01-01
Objectives: To assess the compliance with the 2006 American College of Critical Care-Pediatric Advanced Life Support (ACCM-PALS) guidelines for sepsis management, and the 2012 surviving sepsis campaign (SSC), for the management of pediatric patients with sepsis and to identify the main barriers to adherence to these guidelines. Methods: In November 2015, a prospective cohort study in which a web based electronic survey using a case scenario to explore the usual management of a child with severe sepsis was designed and sent to all consultant pediatric intensivists practicing in Kingdom of Saudi Arabia (KSA). Adherences to 2012 SSC guidelines and to 4 algorithmic time-specific goals outlined in the ACCM-PALS guidelines were measured. Results: Sixty-one (76%) of 80 consultant pediatric intensivists working in KSA responded to the survey. Of the 61 respondents, 94% reported administering antibiotics within one hour of the child presentation, 98% reported starting resuscitation by giving fluid boluses, 93% reported starting vasopressor if the patient remained hypotensive despite fluid resuscitation, and 86% reported they would start hydrocortisone in case of catecholamine refractory shock. In total, 80% of the intensivists reported full adherence to all of the 4 components in the ACCM-PALS bundle; 50% reported that the absence of a locally written protocol was the main barrier to adherence to the SSC guidelines. Conclusion: Pediatric intensivists reported good adherence to the 2006 ACCM-PALS guidelines and 2012 SSC guidelines with some variability in interpretation of the recommendations. The absence of a written protocol was the main reported barrier to adherence to these guidelines. PMID:28578440
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Adherence to surviving sepsis guidelines among pediatric intensivists. A national survey.
Thabet, Farah C; Zahraa, Jihad N; Chehab, May S
2017-06-01
To assess the compliance with the 2006 American College of Critical Care-Pediatric Advanced Life Support (ACCM-PALS) guidelines for sepsis management, and the 2012 surviving sepsis campaign (SSC), for the management of pediatric patients with sepsis and to identify the main barriers to adherence to these guidelines. Methods: In November 2015, a prospective cohort study in which a web based electronic survey using a case scenario to explore the usual management of a child with severe sepsis was designed and sent to all consultant pediatric intensivists practicing in Kingdom of Saudi Arabia (KSA). Adherences to 2012 SSC guidelines and to 4 algorithmic time-specific goals outlined in the ACCM-PALS guidelines were measured. Results: Sixty-one (76%) of 80 consultant pediatric intensivists working in KSA responded to the survey. Of the 61 respondents, 94% reported administering antibiotics within one hour of the child presentation, 98% reported starting resuscitation by giving fluid boluses, 93% reported starting vasopressor if the patient remained hypotensive despite fluid resuscitation, and 86% reported they would start hydrocortisone in case of catecholamine refractory shock. In total, 80% of the intensivists reported full adherence to all of the 4 components in the ACCM-PALS bundle; 50% reported that the absence of a locally written protocol was the main barrier to adherence to the SSC guidelines. Conclusion: Pediatric intensivists reported good adherence to the 2006 ACCM-PALS guidelines and 2012 SSC guidelines with some variability in interpretation of the recommendations. The absence of a written protocol was the main reported barrier to adherence to these guidelines.
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NASA Astrophysics Data System (ADS)
Dai, Zhijun; Fagherazzi, Sergio; Mei, Xuefei; Gao, Jinjuan
2016-09-01
The temporal evolution of suspended sediment concentration (SSC) in a river debouching into the ocean provides vital insights into erosion processes in the watershed and dictates the evolution of the inner continental shelf. While the delivery of sediment from rivers to the ocean has received special attention in the recent past, few studies focused on the variability and dynamics of river SSC, especially in the Changjiang (Yangtze) river, China, the longest river in Asia. Here, variations in SSC delivered by the Changjiang River to the East China Sea and possible causes of its variability were detected based on a long-term time series of daily SSC and monthly water discharge measured at the Datong gauging station. The SSC data are further compared to a hydrological analysis of yearly precipitation covering the entire catchment. The results indicate the presence of a decline in SSC in the period 1956-2013, which can be divided into three phases: (i) high SSC (0.69 kg/m3) in the wet season and low SSC (0.2 kg/m3) in the dry season from 1956 to 1970; (ii) relative high SSC (0.58 kg/m3) in the wet season and low SSC (0.15 kg/m3) in the dry season from 1971 to 2002; and (iii) low SSC (0.19 kg/m3) in the wet season and very low SSC (0.09 kg/m3) in the dry season after 2002. These three periods have a mean yearly SSC values of 0.62, 0.42, and 0.18 kg/m3, respectively. Compared with 1956-1970, the slope of the rating curve between SSC and water discharge decreased, respectively, by 2% and 30% during the period 1971-2002 and 2002-2013. Soil erosion, dam construction, and banks reinforcement along the Changjiang River are the main causes of SSC variations. Fluctuations in water discharge are also controlling the SSC long-term variations. Specifically, from 1956 to 1970, the effect of soil erosion overrules that of dam impoundment, which is likely responsible for the high SSC; during the period 1970-2002, the influence of dam impoundment increases while that of soil erosion decreases, which together produce a small reduction in SSC. Since 2002, the impact of soil erosion further decreases and large-scale sediment trapping behind the Three Gorges Dam is responsible for the occurrence of extremely low SSC. The results presented herein for the Changjiang River can inform a better management strategy of sediment resources and water quality for both the river and the coast. Our conclusions can be well applied to other rivers discharging in the ocean subject to similar human activities.
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Mahavanakul, Weera; Nickerson, Emma K; Srisomang, Pramot; Teparrukkul, Prapit; Lorvinitnun, Pichet; Wongyingsinn, Mingkwan; Chierakul, Wirongrong; Hongsuwan, Maliwan; West, T Eoin; Day, Nicholas P; Limmathurotsakul, Direk; Peacock, Sharon J
2012-01-01
The Surviving Sepsis Campaign (SSC) guidelines describe best practice for the management of severe sepsis and septic shock in developed countries, but most deaths from sepsis occur where healthcare is not sufficiently resourced to implement them. Our objective was to define the feasibility and basis for modified guidelines in a resource-restricted setting. We undertook a detailed assessment of sepsis management in a prospective cohort of patients with severe sepsis caused by a single pathogen in a 1,100-bed hospital in lower-middle income Thailand. We compared their management with the SSC guidelines to identify care bundles based on existing capabilities or additional activities that could be undertaken at zero or low cost. We identified 72 patients with severe sepsis or septic shock associated with S. aureus bacteraemia, 38 (53%) of who died within 28 days. One third of patients were treated in intensive care units (ICUs). Numerous interventions described by the SSC guidelines fell within existing capabilities, but their implementation was highly variable. Care available to patients on general wards covered the fundamental principles of sepsis management, including non-invasive patient monitoring, antimicrobial administration and intravenous fluid resuscitation. We described two additive care bundles, one for general wards and the second for ICUs, that if consistently performed would be predicted to improve outcome from severe sepsis. It is feasible to implement modified sepsis guidelines that are scaled to resource availability, and that could save lives prior to the publication of international guidelines for developing countries.
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Regional estimation of extreme suspended sediment concentrations using watershed characteristics
NASA Astrophysics Data System (ADS)
Tramblay, Yves; Ouarda, Taha B. M. J.; St-Hilaire, André; Poulin, Jimmy
2010-01-01
SummaryThe number of stations monitoring daily suspended sediment concentration (SSC) has been decreasing since the 1980s in North America while suspended sediment is considered as a key variable for water quality. The objective of this study is to test the feasibility of regionalising extreme SSC, i.e. estimating SSC extremes values for ungauged basins. Annual maximum SSC for 72 rivers in Canada and USA were modelled with probability distributions in order to estimate quantiles corresponding to different return periods. Regionalisation techniques, originally developed for flood prediction in ungauged basins, were tested using the climatic, topographic, land cover and soils attributes of the watersheds. Two approaches were compared, using either physiographic characteristics or seasonality of extreme SSC to delineate the regions. Multiple regression models to estimate SSC quantiles as a function of watershed characteristics were built in each region, and compared to a global model including all sites. Regional estimates of SSC quantiles were compared with the local values. Results show that regional estimation of extreme SSC is more efficient than a global regression model including all sites. Groups/regions of stations have been identified, using either the watershed characteristics or the seasonality of occurrence for extreme SSC values providing a method to better describe the extreme events of SSC. The most important variables for predicting extreme SSC are the percentage of clay in the soils, precipitation intensity and forest cover.
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Differential regulation of cell functions by CSD peptide subdomains
2013-01-01
Background In fibrotic lung diseases, expression of caveolin-1 is decreased in fibroblasts and monocytes. The effects of this deficiency are reversed by treating cells or animals with the caveolin-1 scaffolding domain peptide (CSD, amino acids 82–101 of caveolin-1) which compensates for the lack of caveolin-1. Here we compare the function of CSD subdomains (Cav-A, Cav-B, Cav-C, Cav-AB, and Cav-BC) and mutated versions of CSD (F92A and T90A/T91A/F92A). Methods Migration toward the chemokine CXCL12 and the associated expression of F-actin, CXCR4, and pSmad 2/3 were studied in monocytes from healthy donors and SSc patients. Fibrocyte differentiation was studied using PBMC from healthy donors and SSc patients. Collagen I secretion and signaling were studied in fibroblasts derived from the lung tissue of healthy subjects and SSc patients. Results Cav-BC and CSD at concentrations as low as 0.01 μM inhibited the hypermigration of SSc monocytes and TGFβ-activated Normal monocytes and the differentiation into fibrocytes of SSc and Normal monocytes. While CSD also inhibited the migration of poorly migrating Normal monocytes, Cav-A (and other subdomains to a lesser extent) promoted the migration of Normal monocytes while inhibiting the hypermigration of TGFβ-activated Normal monocytes. The effects of versions of CSD on migration may be mediated in part via their effects on CXCR4, F-actin, and pSmad 2/3 expression. Cav-BC was as effective as CSD in inhibiting fibroblast collagen I and ASMA expression and MEK/ERK signaling. Cav-C and Cav-AB also inhibited collagen I expression, but in many cases did not affect ASMA or MEK/ERK. Cav-A increased collagen I expression in scleroderma lung fibroblasts. Full effects on fibroblasts of versions of CSD required 5 μM peptide. Conclusions Cav-BC retains most of the anti-fibrotic functions of CSD; Cav-A exhibits certain pro-fibrotic functions. Results obtained with subdomains and mutated versions of CSD further suggest that the critical functional residues in CSD depend on the cell type and readout being studied. Monocytes may be more sensitive to versions of CSD than fibroblasts and endothelial cells because the baseline level of caveolin-1 in monocytes is much lower than in these other cell types. PMID:24011378
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Differential regulation of cell functions by CSD peptide subdomains.
Reese, Charles; Dyer, Shanice; Perry, Beth; Bonner, Michael; Oates, James; Hofbauer, Ann; Sessa, William; Bernatchez, Pascal; Visconti, Richard P; Zhang, Jing; Hatfield, Corey M; Silver, Richard M; Hoffman, Stanley; Tourkina, Elena
2013-09-08
In fibrotic lung diseases, expression of caveolin-1 is decreased in fibroblasts and monocytes. The effects of this deficiency are reversed by treating cells or animals with the caveolin-1 scaffolding domain peptide (CSD, amino acids 82-101 of caveolin-1) which compensates for the lack of caveolin-1. Here we compare the function of CSD subdomains (Cav-A, Cav-B, Cav-C, Cav-AB, and Cav-BC) and mutated versions of CSD (F92A and T90A/T91A/F92A). Migration toward the chemokine CXCL12 and the associated expression of F-actin, CXCR4, and pSmad 2/3 were studied in monocytes from healthy donors and SSc patients. Fibrocyte differentiation was studied using PBMC from healthy donors and SSc patients. Collagen I secretion and signaling were studied in fibroblasts derived from the lung tissue of healthy subjects and SSc patients. Cav-BC and CSD at concentrations as low as 0.01 μM inhibited the hypermigration of SSc monocytes and TGFβ-activated Normal monocytes and the differentiation into fibrocytes of SSc and Normal monocytes. While CSD also inhibited the migration of poorly migrating Normal monocytes, Cav-A (and other subdomains to a lesser extent) promoted the migration of Normal monocytes while inhibiting the hypermigration of TGFβ-activated Normal monocytes. The effects of versions of CSD on migration may be mediated in part via their effects on CXCR4, F-actin, and pSmad 2/3 expression. Cav-BC was as effective as CSD in inhibiting fibroblast collagen I and ASMA expression and MEK/ERK signaling. Cav-C and Cav-AB also inhibited collagen I expression, but in many cases did not affect ASMA or MEK/ERK. Cav-A increased collagen I expression in scleroderma lung fibroblasts. Full effects on fibroblasts of versions of CSD required 5 μM peptide. Cav-BC retains most of the anti-fibrotic functions of CSD; Cav-A exhibits certain pro-fibrotic functions. Results obtained with subdomains and mutated versions of CSD further suggest that the critical functional residues in CSD depend on the cell type and readout being studied. Monocytes may be more sensitive to versions of CSD than fibroblasts and endothelial cells because the baseline level of caveolin-1 in monocytes is much lower than in these other cell types.
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Khanna, Dinesh; Hays, Ron D; Furst, Daniel E
2017-09-01
Patients with SSc have the highest mortality among the rheumatic diseases. In addition, SSc is associated with disfigurement, hand contractures, fatigue, poor sleep, severe RP with numbness and tingling of the fingers can lead to decrements in quality of life. This Points to Consider article provides practical considerations for design of trials for functional disability and other health-related quality-of-life issues. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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A Meta-ethnography: Skin-to-Skin Holding From the Caregiver's Perspective.
Vittner, Dorothy; Casavant, Sharon; McGrath, Jacqueline M
2015-06-01
Although the benefits of skin-to-skin care (SSC) are well documented in the literature, practices in the clinical setting remain inconsistent. Although nurses' reported knowledge about SSC has improved, confusion still exists regarding safety and appropriateness. Existing qualitative literature primarily focuses on parents' experiences; yet it is crucial to describe the essence of professional caregivers' experiences to enhance facilitation and implementation of SSC. Most studies surrounding the caregiver's perspective and SSC have focused on barriers that impede implementation or examined the experience from the organizational perspective and general group experiences rather than individual personal experiences with SSC. This meta-ethnography integrated the findings from several discrete studies into a salient interpretative perspective, creating a relevant understanding of the process of SSC as a means of enhancing facilitation and implementation of SSC with hospitalized infants. An ethnographic meta-synthesis of qualitative literature was completed. As a result of this synthesis, the caregivers' experiences were separated into themes to articulate the phenomena juxtaposed from the 8 original studies that influence facilitation of SSC for the parent-infant dyad. Qualitative data analysis uncovered 4 overarching themes: (1) varying thresholds of getting started; (2) defining adequate resources; (3) navigating the demands and complexity of the infant; and (4) balancing parental readiness with infant needs. This ethnographic meta-synthesis confirms nurses have good intentions in supporting SSC practices, yet struggle to meet competing demands in their daily practice. Innovative and practical translations of SSC are needed to normalize SSC as the daily standard for premature infants.
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Willems, Linda M; Redmond, Anthony C; Stamm, Tanja A; Boström, Carina; Decuman, Saskia; Kennedy, Ann Tyrrell; Brozd, Jadranka; Roškar, Sanja; Smith, Vanessa; Vliet Vlieland, Theodora P M; van den Ende, Cornelia H M
2015-01-01
To describe the non-pharmacological care in systemic sclerosis (SSc) provided by European health professionals (HPs) including referrals, treatment targets, interventions, and educational needs. In this observational study, European HPs working in SSc care were invited to complete an online survey through announcements by EUSTAR (European League Against Rheumatism (EULAR) Scleroderma Trials and Research) and FESCA (Federation of European Scleroderma Associations), the EULAR HPs' newsletter, websites of national patient and HP associations, and by personal invitation. In total, 56 HPs, from 14 different European countries and 7 different disciplines, responded to the survey. A total of 133 specific indications for referral were reported, 72% of which could be linked to the International Classification of Functioning, Disability and Health domain "body functions and structures". Of the 681 reported treatment targets 45% was related to "body functions and structures". In total, 105 different interventions were reported as being used to address these treatment targets. Almost all (98%) respondents reported having educational needs, with the topics of management of stiffness (67%), pain (60%), and impaired hand function (56%) being mentioned most frequently. Non-pharmacological care in SSc varies in Europe with respect to the content of interventions, reasons for referral, and treatment targets. Reasons for referral to HPs are not well-aligned to HPs subsequent treatment targets in SSc care suggesting suboptimal communication between physicians and HPs. The wide variations reported indicate a need to consolidate geographically disparate expertise within countries and to develop and improve standards of non-pharmacological care in SSc.
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Incidence of childhood linear scleroderma and systemic sclerosis in the UK and Ireland.
Herrick, Ariane L; Ennis, Holly; Bhushan, Monica; Silman, Alan J; Baildam, Eileen M
2010-02-01
Childhood scleroderma encompasses a rare, poorly understood spectrum of conditions. Our aim was to ascertain the incidence of childhood scleroderma in its different forms in the UK and Ireland, and to describe the age, sex, and ethnicity of the cases. The members of 5 specialist medical associations including pediatricians, dermatologists, and rheumatologists were asked to report all cases of abnormal skin thickening suspected to be localized (including linear) scleroderma or systemic sclerosis (SSc) in children <16 years of age first seen between July 2005 and July 2007. We received notification of 185 potential cases, and 94 valid cases were confirmed: 87 (93%) with localized scleroderma and 7 (7%) with SSc. This gave an incidence rate per million children per year of 3.4 (95% confidence interval [95% CI] 2.7-4.1) for localized scleroderma, including an incidence rate of 2.5 (95% CI 1.8-3.1) for linear scleroderma, and 0.27 (95% CI 0.1-0.5) for SSc. Of the 87 localized cases, 62 (71%) had linear disease. Of localized disease cases, 55 (63%) were female, 71 (82%) were classified as white British, and the patients' mean age when first seen in secondary care was 10.4 years. Of the 7 SSc cases, all were female, 6 (86%) were white British, and the mean age when first seen was 12.1 years. The median delay between onset and being first seen was 13.1 months for localized scleroderma and 7.2 months for SSc. These data provide additional estimates of the incidence of this rare disorder and its subforms.
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Soulaidopoulos, Stergios; Triantafyllidou, Eva; Garyfallos, Alexandros; Kitas, George D; Dimitroulas, Theodoros
2017-08-01
Endothelial dysfunction and microvascular damage constitute the hallmarks of systemic sclerosis (SSc), explaining much of the pathophysiology and clinical manifestations of the disease. Nailfold videocapillaroscopy (NVC) is an established method for the assessment of the microvasculature, aiding in distinguishing different types of structural vascular abnormalities. Until recently, NVC was used in the diagnosis of SSc as well as in the assessment and follow-up of peripheral digital vasculopathy. On the top of digital ulcers, internal organ involvement such as myocardial dysfunction, pulmonary vascular and/or parenchymal lung disease characterizes severe SSc imparting a high risk of mortality. There is growing evidence suggesting that the extent of peripheral microvascular changes reflects the severity of the disease, especially in terms of life-threatening cardiopulmonary complications. The possible use of nailfold videocapillaroscopy as a useful, non-invasive modality to improve the ability to identify patients at higher risk for these devastating complications of the disease remains to be established. The aim of this review is to critically summarize and discuss current literature regarding the relationship between morphological alterations of nailfold dermal papillary vessels and several manifestations of SSc, focusing on visceral organ involvement, as well as their association with surrogate markers of macrovascular disease. Copyright © 2017 Elsevier B.V. All rights reserved.
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2013-01-01
Introduction Pulmonary arterial hypertension (PAH) is a major cause of mortality in systemic sclerosis (SSc). Screening guidelines for PAH recommend multiple investigations, including annual echocardiography, which together have low specificity and may not be cost-effective. We sought to evaluate the predictive accuracy of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in combination with pulmonary function tests (PFT) (‘proposed’ algorithm) in a screening algorithm for SSc-PAH. Methods We evaluated our proposed algorithm (PFT with NT-proBNP) on 49 consecutive SSc patients with suspected pulmonary hypertension undergoing right heart catherisation (RHC). The predictive accuracy of the proposed algorithm was compared with existing screening recommendations, and is presented as sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Results Overall, 27 patients were found to have pulmonary hypertension (PH) at RHC, while 22 had no PH. The sensitivity, specificity, PPV and NPV of the proposed algorithm for PAH was 94.1%, 54.5%, 61.5% and 92.3%, respectively; current European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines achieved a sensitivity, specificity, PPV and NPV of 94.1%, 31.8%, 51.6% and 87.5%, respectively. In an alternate case scenario analysis, estimating a PAH prevalence of 10%, the proposed algorithm achieved a sensitivity, specificity, PPV and NPV for PAH of 94.1%, 54.5%, 18.7% and 98.8%, respectively. Conclusions The combination of NT-proBNP with PFT is a sensitive, yet simple and non-invasive, screening strategy for SSc-PAH. Patients with a positive screening result can be referred for echocardiography, and further confirmatory testing for PAH. In this way, it may be possible to shift the burden of routine screening away from echocardiography. The findings of this study should be confirmed in larger studies. PMID:24246100
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Hoffmann-Vold, Anna-Maria; Tennøe, Anders Heiervang; Garen, Torhild; Midtvedt, Øyvind; Abraityte, Aurelija; Aaløkken, Trond Mogens; Lund, May Britt; Brunborg, Cathrine; Aukrust, Pål; Ueland, Thor; Molberg, Øyvind
2016-08-01
Markers for early identification of progressive interstitial lung disease (ILD) in systemic sclerosis (SSc) are in demand. Chemokine CCL18, which has been linked to pulmonary inflammation, is an interesting candidate, but data have not been consistent. We aimed to assess CCL18 levels in a large, prospective, unselected SSc cohort with longitudinal, paired data sets on pulmonary function and lung fibrosis. Sera from the Oslo University Hospital SSc cohort (n = 298) and healthy control subjects (n = 100) were analyzed for CCL18 by enzyme immunoassay. High CCL18 (>53 ng/mL) was defined using the mean value plus 2 SD in sera obtained from healthy control subjects as the cutoff. High serum CCL18 was identified in 35% (105 of 298). Annual decline in FVC differed significantly between high and low CCL18 subsets (13.3% and 4.7%; P = .016), as did the annual progression rate of lung fibrosis (0.9% [SD, 2.9] and 0.2% [SD, 1.9]). Highest rates of annual FVC decline > 10% (21%) and annual fibrosis progression (1.2%) were seen in patients with high CCL18 and early disease (< 3 years). In multivariate analyses, CCL18 was associated with annual FVC decline > 10% (OR, 1.1; 95% CI, 1.01-1.11) and FVC < 70% at follow-up (OR, 3.1; 95% CI, 1.08-8.83). Survival analyses showed that patients with high CCL18 had reduced 5- and 10-year cumulative survival compared with patients with low CCL18 (85% and 74%, compared with 97% and 89%, respectively; P = .001). The results from this prospective cohort reinforce the notion that high CCL18 may serve as a marker for early identification of progressive ILD in SSc. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
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Cutolo, Maurizio; Ruaro, Barbara; Montagna, Paola; Brizzolara, Renata; Stratta, Emanuela; Trombetta, Amelia Chiara; Scabini, Stefano; Tavilla, Pier Paolo; Parodi, Aurora; Corallo, Claudio; Giordano, Nicola; Paolino, Sabrina; Pizzorni, Carmen; Sulli, Alberto; Smith, Vanessa; Soldano, Stefano
2018-05-02
Myofibroblasts contribute to fibrosis through the overproduction of extracellular matrix (ECM) proteins, primarily type I collagen (COL-1) and fibronectin (FN), a process which is mediated in systemic sclerosis (SSc) by the activation of fibrogenic intracellular signaling transduction molecules, including extracellular signal-regulated kinases 1 and 2 (Erk1/2) and protein kinase B (Akt). Selexipag is a prostacyclin receptor agonist synthesized for the treatment of pulmonary arterial hypertension. The study investigated the possibility for selexipag and its active metabolite (ACT-333679) to downregulate the profibrotic activity in primary cultures of SSc fibroblasts/myofibroblasts and the fibrogenic signaling molecules involved. Fibroblasts from skin biopsies obtained with Ethics Committee (EC) approval from patients with SSc, after giving signed informed consent, were cultured until the 3 rd culture passage and then either maintained in normal growth medium (untreated cells) or independently treated with different concentrations of selexipag (from 30 μM to 0.3 μM) or ACT-333679 (from 10 μM to 0.1 μM) for 48 h. Protein and gene expressions of α-smooth muscle actin (α-SMA), fibroblast specific protein-1 (S100A4), COL-1, and FN were investigated by western blotting and quantitative real-time PCR. Erk1/2 and Akt phosphorylation was investigated in untreated and ACT-333679-treated cells by western botting. Selexipag and ACT-333679 significantly reduced protein synthesis and gene expression of α-SMA, S100A4, and COL-1 in cultured SSc fibroblasts/myofibroblasts compared to untreated cells, whereas FN was significantly downregulated at the protein level. Interestingly, ACT-333679 significantly reduced the phosphorylation of Erk1/2 and Akt in cultured SSc fibroblasts/myofibroblasts. Selexipag and mainly its active metabolite ACT-333679 were found for the first time to potentially interfere with the profibrotic activity of cultured SSc fibroblasts/myofibroblasts at least in vitro, possibly through the downregulation of fibrogenic Erk1/2 and Akt signaling molecules.
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Systematic approach to understanding the pathogenesis of systemic sclerosis.
Zuo, Xiaoxia; Zhang, Lihua; Luo, Hui; Li, Yisha; Zhu, Honglin
2017-10-01
Systemic sclerosis (SSc) is a complex heterogeneous autoimmune disease. Progressive organ fibrosis is a major contributor to SSc mortality. Despite extensive efforts, the underlying mechanism of SSc remains unclear. Efforts to understand the pathogenesis of SSc have included genomics, epigenetics, transcriptomic, proteomic and metabolomic studies in the last decade. This review focuses on recent studies in SSc research based on multi-omics. The combination of these technologies can help us understand the pathogenesis of SSc. This review aims to provide important information for disease identification, therapeutic targets and potential biomarkers. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Schoellhamer, D.H.
2002-01-01
Suspended sediment concentration (SSC) data from San Pablo Bay, California, were analyzed to compare the basin-scale effect of dredging and disposal of dredged material (dredging operations) and natural estuarine processes. The analysis used twelve 3-wk to 5-wk periods of mid-depth and near-bottom SSC data collected at Point San Pablo every 15 min from 1993-1998. Point San Pablo is within a tidal excursion of a dredged-material disposal site. The SSC data were compared to dredging volume, Julian day, and hydrodynamic and meteorological variables that could affect SSC. Kendall's ??, Spearman's ??, and weighted (by the fraction of valid data in each period) Spearman's ??w correlation coefficients of the variables indicated which variables were significantly correlated with SSC. Wind-wave resuspension had the greatest effect on SSC. Median water-surface elevation was the primary factor affecting mid-depth SSC. Greater depths inhibit wind-wave resuspension of bottom sediment and indicate greater influence of less turbid water from down estuary. Seasonal variability in the supply of erodible sediment is the primary factor affecting near-bottom SSC. Natural physical processes in San Pablo Bay are more areally extensive, of equal or longer duration, and as frequent as dredging operations (when occurring), and they affect SSC at the tidal time scale. Natural processes control SSC at Point San Pablo even when dredging operations are occurring.
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Hakoyama, Tsuneo; Yokoyama, Tadashi; Kouchi, Hiroshi; Tsuchiya, Ken-ichi; Kaku, Hisatoshi; Arima, Yasuhiro
2002-11-01
Genes responding to Nod factors were picked up by the application of a differential display method for soybean suspension-cultured cells. Forty-five cDNA fragments derived from such genes were detected. Seven fragments (ssc1-ssc7) were successfully cloned. The putative product of genes corresponding to ssc1 was estimated to be a disease-resistance protein relating to the induction of the plant defense response against pathogens, and that corresponding to ssc7 was a sucrose transporter. Amino acid sequences deduced from full-length cDNA corresponding to ssc2 and ssc4 were investigated, and it was shown that these polypeptides were equipped with a leucine zipper motif and with phosphorylation sites that were targeted by tyrosin kinase and cAMP-dependent protein kinase, respectively. In a differential display experiment, the transcriptional levels of three genes corresponding to ssc2, ssc3 and ssc5 were estimated to be up-regulated at 6 h after initiation of the treatment and the remaining four were estimated to be down-regulated. However, transcription of the genes corresponding to all ssc was clearly repressed within 2 h after initiation of the treatment. Five of them were restored to their transcriptional level 6 h after initiation of the treatment, although the others were repressed throughout the experimental period.
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Maurer, Britta; Suliman, Yossra A.; Morsbach, Fabian; Distler, Oliver; Frauenfelder, Thomas
2018-01-01
Background To evaluate usability of slice-reduced sequential computed tomography (CT) compared to standard high-resolution CT (HRCT) in patients with systemic sclerosis (SSc) for qualitative and quantitative assessment of interstitial lung disease (ILD) with respect to (I) detection of lung parenchymal abnormalities, (II) qualitative and semiquantitative visual assessment, (III) quantification of ILD by histograms and (IV) accuracy for the 20%-cut off discrimination. Methods From standard chest HRCT of 60 SSc patients sequential 9-slice-computed tomography (reduced HRCT) was retrospectively reconstructed. ILD was assessed by visual scoring and quantitative histogram parameters. Results from standard and reduced HRCT were compared using non-parametric tests and analysed by univariate linear regression analyses. Results With respect to the detection of parenchymal abnormalities, only the detection of intrapulmonary bronchiectasis was significantly lower in reduced HRCT compared to standard HRCT (P=0.039). No differences were found comparing visual scores for fibrosis severity and extension from standard and reduced HRCT (P=0.051–0.073). All scores correlated significantly (P<0.001) to histogram parameters derived from both, standard and reduced HRCT. Significant higher values of kurtosis and skewness for reduced HRCT were found (both P<0.001). In contrast to standard HRCT histogram parameters from reduced HRCT showed significant discrimination at cut-off 20% fibrosis (sensitivity 88% kurtosis and skewness; specificity 81% kurtosis and 86% skewness; cut-off kurtosis ≤26, cut-off skewness ≤4; both P<0.001). Conclusions Reduced HRCT is a robust method to assess lung fibrosis in SSc with minimal radiation dose with no difference in scoring assessment of lung fibrosis severity and extension in comparison to standard HRCT. In contrast to standard HRCT histogram parameters derived from the approach of reduced HRCT could discriminate at a threshold of 20% lung fibrosis with high sensitivity and specificity. Hence it might be used to detect early disease progression of lung fibrosis in context of monitoring and treatment of SSc patients. PMID:29850118
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Inder, Maree L; Crowe, Marie T; Luty, Suzanne E; Carter, Janet D; Moor, Stephanie; Frampton, Christopher M; Joyce, Peter R
2015-03-01
This randomized, controlled clinical trial compared the effect of interpersonal and social rhythm therapy (IPSRT) to that of specialist supportive care (SSC) on depressive outcomes (primary), social functioning, and mania outcomes over 26-78 weeks in young people with bipolar disorder receiving psychopharmacological treatment. Subjects were aged 15-36 years, recruited from a range of sources, and the patient groups included bipolar I disorder, bipolar II disorder, and bipolar disorder not otherwise specified. Exclusion criteria were minimal. Outcome measures were the Longitudinal Interval Follow-up Evaluation and the Social Adjustment Scale. Paired-sample t-tests were used to determine the significance of change from baseline to outcome period. Analyses of covariance were used to determine the impact of therapy, impact of lifetime and current comorbidity, interaction between comorbidity and therapy, and impact of age at study entry on depression. A group of 100 participants were randomized to IPSRT (n = 49) or SSC (n = 51). The majority had bipolar I disorder (78%) and were female (76%), with high levels of comorbidity. After treatment, both groups had improved depressive symptoms, social functioning, and manic symptoms. Contrary to our hypothesis, there was no significant difference between therapies. There was no impact of lifetime or current Axis I comorbidity or age at study entry. There was a relative impact of SSC for patients with current substance use disorder. IPSRT and SSC used as an adjunct to pharmacotherapy appear to be effective in reducing depressive and manic symptoms and improving social functioning in adolescents and young adults with bipolar disorder and high rates of comorbidity. Identifying effective treatments that particularly address depressive symptoms is important in reducing the burden of bipolar disorder. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Kumar, Uma; Sankalp, Gokhale; Gokhle, Sankalp S; Sreenivas, V; Kaur, Satbir; Misra, Durgaprasanna
2013-04-01
Pulmonary artery hypertension (PAH) remains the leading cause of morbidity and mortality in systemic sclerosis, while Raynaud's phenomenon and digital ulcers significantly add to the morbidity in systemic sclerosis (SSc). This study was undertaken to evaluate the role of sildenafil in PAH, Raynaud's phenomenon, and digital ulcers in systemic sclerosis patients. A prospective, open-label, uncontrolled pilot study was done at a tertiary care centre in India to study the safety and efficacy of oral sildenafil in PAH, Raynaud's phenomenon, digital infarcts, and ulcers in SSc. Seventeen patients fulfilling ACR classification criteria for scleroderma and having PAH were recruited. Six-minute walk test, WHO class of dyspnoea, severity of Raynaud's phenomenon, and 2D ECHO were performed in all the study subjects at baseline and at 3 months post-treatment. All patients were treated with oral sildenafil 25 mg three times a day for a period of 3 months. The pre- and post-treatment values of mean pulmonary artery pressure (PAP), 6-min walk test, WHO class of dyspnoea, and severity of Raynaud's phenomenon were compared to look for any significant change. Sixteen patients who completed 3-month follow-up had shown statistically significant improvement in 6-min walk test, WHO class of dyspnoea, severity of Raynaud's phenomenon, and mPAP. Also, there was no occurrence of new digital infarcts or ulcers, and existing ulcers showed signs of healing. Sildenafil is highly efficacious cheaper and safe alternative to other available therapies for SSc-associated PAH, Raynaud's phenomenon, and digital infarcts/ulcers.
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Saggar, Rajeev; Khanna, D; Shapiro, S; Furst, D E; Maranian, P; Clements, P; Abtin, F; Dua, Shiv; Belperio, J; Saggar, Rajan
2012-12-01
Exercise-induced pulmonary hypertension (ePH) may represent an early, clinically relevant phase in the spectrum of pulmonary vascular disease. The purpose of this pilot study was to describe the changes in hemodynamics and exercise capacity in patients with systemic sclerosis (SSc) spectrum-associated ePH treated with open-label daily ambrisentan. Patients were treated with ambrisentan, 5 mg or 10 mg once daily, for 24 weeks. At baseline and 24 weeks, patients with SSc spectrum disorders exercised in a supine position, on a lower extremity cycle ergometer. All patients had normal hemodynamics at rest. We defined baseline ePH as a mean pulmonary artery pressure of >30 mm Hg with maximum exercise and a transpulmonary gradient (TPG) of >15 mm Hg. The primary end point was change in pulmonary vascular resistance (PVR) with exercise. Secondary end points included an improvement from baseline in 6-minute walking distance, health-related quality of life assessments, and cardiopulmonary hemodynamics. Of the 12 enrolled patients, 11 completed the study. At 24 weeks there were improvements in mean exercise PVR (85.8 dynes × second/cm(5) ; P = 0.003) and mean distance covered during 6-minute walk (44.5 meters; P = 0.0007). Improvements were also observed in mean exercise cardiac output (1.4 liters/minute; P = 0.006), mean pulmonary artery pressure (-4.1 mm Hg; P = 0.02), and total pulmonary resistance (-93.0 dynes × seconds/cm(5) ; P = 0.0008). Three patients developed resting pulmonary arterial hypertension during the 24 weeks. Exercise hemodynamics and exercise capacity in patients with SSc spectrum-associated ePH improved over 24 weeks with exposure to ambrisentan. Placebo-controlled studies are needed to confirm whether this is a drug-related effect and to determine optimal therapeutic regimens for patients with ePH. Copyright © 2012 by the American College of Rheumatology.
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Paclitaxel modulates TGFbeta signaling in scleroderma skin grafts in immunodeficient mice.
Liu, Xialin; Zhu, Shoukang; Wang, Tao; Hummers, Laura; Wigley, Fredrick M; Goldschmidt-Clermont, Pascal J; Dong, Chunming
2005-12-01
Systemic sclerosis (SSc) is characterized by excessive fibrosis and obliterative vascular lesions. Abnormal TGFbeta activation is implicated in the pathogenesis of SSc. Aberrant TGFbeta/Smad signaling can be controlled by stabilization of microtubules with paclitaxel. SSc and healthy human skin biopsies were incubated in the presence or absence of paclitaxel followed by transplantation into severe combined immunodeficient mice. TGFbeta signaling, fibrosis, and neovessel formation were evaluated by quantitative RT-PCR and immunohistochemical staining. Paclitaxel markedly suppressed Smad2 and Smad3 phosphorylation and collagen deposition in SSc grafts. As a result, the autonomous maintenance/reconstitution of the SSc phenotype was prevented. Remarkably, SSc grafts showed a 2-fold increase in neovessel formation relative to normal grafts, regardless of paclitaxel treatment. Angiogenesis in SSc grafts was associated with a substantial increase in mouse PECAM-1 expression, indicating the mouse origin of the neovascular cells. Low-dose paclitaxel can significantly suppress TGFbeta/Smad activity and lessen fibrosis in SCID mice. Transplantation of SSc skin into SCID mice elicits a strong angiogenesis-an effect not affected by paclitaxel. Although prolonged chemotherapy with paclitaxel at higher doses is associated with pro-fibrotic and anti-angiogenic changes, the findings described here indicate that low-dose paclitaxel may have therapeutic benefits for SSc via modulating TGFbeta signaling.
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Kapanadze, Bagrat; Morris, Erin; Smith, Edwin; Trojanowska, Maria
2010-01-01
Abstract Lack of an adequate experimental model has hindered the ability to fully understand scleroderma (SSc) pathogenesis. Current SSc research is based on the study of cultured fibroblasts from skin biopsies. In depth characterization of the SSc fibroblast phenotype is hindered by the limited lifespan and heterogeneity of these cells. The goal of this study was to isolate high collagen-producing fibroblasts from SSc biopsies and extend their lifespan with hTERT immortalization to enable characterization of their phenotype. Fibroblasts from two pairs of closely matched normal and SSc biopsies were infected with an hTERT lentivirus. Infected colonies were isolated, cultured into clonal cell lines and analysed with respect to profibrotic gene expression. The mRNA levels of nine profibrotic genes were measured by quantitative real-time PCR. Protein levels were assessed by Western blot. The hTERT SSc clones were heterogeneous with regards to expression of the profibrotic genes measured. A subset of the SSc clones showed elevated expression levels of collagen I, connective tissue growth factor and thrombospondin 1 mRNA, while expression of other genes was not significantly changed. Elevated expression of collagen I protein and mRNA was correlative with elevated expression of connective tissue growth factor. Several hTERT clones expressed high levels of pSmad1, Smad1 and TGF-βRI indicative of altered TGF-β signalling. A portion of SSc clones expressed several profibrotic genes. This study demonstrates that select characteristics of the SSc phenotype are expressed in a subset of activated fibroblasts in culture. The clonal SSc cell lines may present a new and useful model to investigate the mechanisms involved in SSc fibrosis. PMID:19432820
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Kapanadze, Bagrat; Morris, Erin; Smith, Edwin; Trojanowska, Maria
2010-05-01
Lack of an adequate experimental model has hindered the ability to fully understand scleroderma (SSc) pathogenesis. Current SSc research is based on the study of cultured fibroblasts from skin biopsies. In depth characterization of the SSc fibroblast phenotype is hindered by the limited lifespan and heterogeneity of these cells. The goal of this study was to isolate high collagen-producing fibroblasts from SSc biopsies and extend their lifespan with hTERT immortalization to enable characterization of their phenotype. Fibroblasts from two pairs of closely matched normal and SSc biopsies were infected with an hTERT lentivirus. Infected colonies were isolated, cultured into clonal cell lines and analysed with respect to profibrotic gene expression. The mRNA levels of nine profibrotic genes were measured by quantitative real-time PCR. Protein levels were assessed by Western blot. The hTERT SSc clones were heterogeneous with regards to expression of the profibrotic genes measured. A subset of the SSc clones showed elevated expression levels of collagen I, connective tissue growth factor and thrombospondin 1 mRNA, while expression of other genes was not significantly changed. Elevated expression of collagen I protein and mRNA was correlative with elevated expression of connective tissue growth factor. Several hTERT clones expressed high levels of pSmad1, Smad1 and TGF-betaRI indicative of altered TGF-beta signalling. A portion of SSc clones expressed several profibrotic genes. This study demonstrates that select characteristics of the SSc phenotype are expressed in a subset of activated fibroblasts in culture. The clonal SSc cell lines may present a new and useful model to investigate the mechanisms involved in SSc fibrosis.
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Takahashi, Yuki; Tamakoshi, Koji; Matsushima, Miyoko; Kawabe, Tsutomu
2011-03-01
There are few studies that compare the physiological and biological efficacies between different early skin-to-skin contacts (SSC) post birth. To investigate physiologically and biochemically how early SSC with different initiation and duration time influence the stress post birth for full-term infants. Non-experimental study. Study I; Thirty-two infants who began SSC 5 min or less [birth SSC, mean initiation time (standard deviation): 1.6 (1.1) min] after birth and 36 infants who did so more than 5 min [very early SSC, 26.3 (5.0) min] in heart rate (HR) and oxygen saturation (SpO(2)) analysis. Study II; Eighteen infants who underwent SSC for 60 min or less [mean initiation time: 7.5 (12.2) min] and 61 infants who did so for more than 60 min [15.3 (12.5) min] in salivary cortisol analysis. HR and SpO(2) measured for 30 min post birth. Salivary cortisol concentration measured at 1 min, 60 min, and 120 min post birth. Birth SSC group reached HR stability of 120-160 bpm significantly faster than very early SSC group by Kaplan-Meier analysis (P=0.001 by log-rank test). As for SpO(2) stability of 92% and 96%, no significantly between-group difference was found. Salivary cortisol levels were significantly lower between 60 and 120 min after birth in SSC group, continuing for more than 60 min compared with SSC group for 60 min or less after adjustment for salivary cortisol level at 1 min besides the infant stress factors (P=0.046). Earlier SSC beginning within 5 min post birth and longer SSC continuing for more than 60 min within 120 min post birth are beneficial for stability of cardiopulmonary dynamics and the reduction of infant stress during the early period post birth. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
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Pediatric scleroderma: systemic or localized forms.
Torok, Kathryn S
2012-04-01
Pediatric scleroderma includes 2 major groups of clinical entities, systemic sclerosis (SSc) and localized scleroderma (LS). Although both share a common pathophysiology, their clinical manifestations differ. LS is typically confined to the skin and underlying subcutis, with up to a quarter of patients showing extracutaneous disease manifestations such as arthritis and uveitis. Vascular, cutaneous, gastrointestinal, pulmonary, and musculoskeletal involvement are most commonly seen in children with SSc. Treatment of both forms targets the active inflammatory stage and halts disease progression; however, progress needs to be made toward the development of more effective antifibrotic therapy to help reverse disease damage. Copyright © 2012 Elsevier Inc. All rights reserved.
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Smith, Vanessa; Riccieri, Valeria; Pizzorni, Carmen; Decuman, Saskia; Deschepper, Ellen; Bonroy, Carolien; Sulli, Alberto; Piette, Yves; De Keyser, Filip; Cutolo, Maurizio
2013-12-01
Assessment of associations of nailfold videocapillaroscopy (NVC) scleroderma (systemic sclerosis; SSc) ("early," "active," and "late") with novel future severe clinical involvement in 2 independent cohorts. Sixty-six consecutive Belgian and 82 Italian patients with SSc underwent NVC at baseline. Images were blindly assessed and classified into normal, early, active, or late NVC pattern. Clinical evaluation was performed for 9 organ systems (general, peripheral vascular, skin, joint, muscle, gastrointestinal tract, lung, heart, and kidney) according to the Medsger disease severity scale (DSS) at baseline and in the future (18-24 months of followup). Severe clinical involvement was defined as category 2 to 4 per organ of the DSS. Logistic regression analysis (continuous NVC predictor variable) was performed. The OR to develop novel future severe organ involvement was stronger according to more severe NVC patterns and similar in both cohorts. In simple logistic regression analysis the OR in the Belgian/Italian cohort was 2.16 (95% CI 1.19-4.47, p = 0.010)/2.33 (95% CI 1.36-4.22, p = 0.002) for the early NVC SSc pattern, 4.68/5.42 for the active pattern, and 10.14/12.63 for the late pattern versus the normal pattern. In multiple logistic regression analysis, adjusting for disease duration, subset, and vasoactive medication, the OR was 2.99 (95% CI 1.31-8.82, p = 0.007)/1.88 (95% CI 1.00-3.71, p = 0.050) for the early NVC SSc pattern, 8.93/3.54 for the active pattern, and 26.69/6.66 for the late pattern versus the normal pattern. Capillaroscopy may be predictive of novel future severe organ involvement in SSc, as attested by 2 independent cohorts.
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Hassoun, D; Dirou, S; Arrigoni, P P; Durant, C; Hamidou, M; Néel, A; Agard, C
2018-05-18
Pleuroparenchymal fibroelastosis (PPFE) is a very rare interstitial lung disease (ILD) characterized by progressive fibrotic lesions of the visceral pleura and the sub-pleural parenchyma, affecting predominantly the upper lobes. PPFE may occur in different contextes like bone marrow or lung transplantations, but also in the context of telomeropathy with mutations of telomerase reverse transcriptase (TERT), telomerase RNA component (TERC) or regulator of telomere elongation helicase 1 (RTEL1) genes. PPFE-like lesions have recently been described in patients with connective tissue disease (CTD)-related ILD. We report here the first detailed case of PPFE associated to systemic sclerosis (SSc) in a woman free of telomeropathy mutations. A caucasian 46 year old woman was followed for SSc in a limited form with anti-centromere Ab since 1998, and seen in 2008 for a routine visit. Her SSc was stable, and she had no respiratory signs. Pulmonary function tests showed an isolated decreased cTLCO at 55.9% (of predicted value). Cardiac ultrasonography was normal. Thoracic CT-scan showed upper lobes predominant mild and focal pleural and subpleural thickenings, suggestive of PPFE, with a slight worsening at 8 years of follow-up. She remained clinically stable. Biology only found a moderate and stable peripheral thrombocytopenia, and sequencing analysis did not find any mutations in TERT and TERC genes. ILD is frequent in SSc but isolated PPFE has never been described so far. In our case, PPFE is not related to telomeropathy, has indolent outcome and seems to have good prognosis. PPFE might be an extremely rare form of SSc-related ILD, although a fortuitous association remains possible.
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75 FR 32372 - Western Pacific Fishery Management Council; Public Meetings
Federal Register 2010, 2011, 2012, 2013, 2014
2010-06-08
... 104th Scientific and Statistical Committee (SSC) and 148th Council meetings to take recommendations and... complete scheduled business. Schedule and Agenda for 104th SSC Meeting: Tuesday, June 22, 2010, 8:30 a.m. 1... a.m. 9. Other Business A. 105th SSC Meeting 10. Summary of SSC Recommendations to the Council 148th...
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Hysteresis in suspended sediment to turbidity relations due to changing particle size distributions
Landers, Mark N.; Sturm, Terry W.
2013-01-01
Turbidity (T) is the most ubiquitous of surrogate technologies used to estimate suspended-sediment concentration (SSC). The effects of sediment size on turbidity are well documented; however, effects from changes in particle size distributions (PSD) are rarely evaluated. Hysteresis in relations of SSC-to-turbidity (SSC~T) for single stormflow events was observed and quantified for a data set of 195 concurrent measurements of SSC, turbidity, discharge, velocity, and volumetric PSD collected during five stormflows in 2009–2010 on Yellow River at Gees Mill Road in metropolitan Atlanta, Georgia. Regressions of SSC-normalized turbidity (T/SSC) on concurrently measured PSD percentiles show an inverse, exponential influence of particle size on turbidity that is not constant across the size range of the PSD. The majority of the influence of PSD on T/SSC is from particles of fine-silt and smaller sizes (finer than 16 microns). This study shows that small changes in the often assumed stability of the PSD are significant to SSC~T relations. Changes of only 5 microns in the fine silt and smaller size fractions of suspended sediment PSD can produce hysteresis in the SSC~T rating that can increase error and produce bias. Observed SSC~T hysteresis may be an indicator of changes in sediment properties during stormflows and of potential changes in sediment sources. Trends in the PSD time series indicate that sediment transport is capacity-limited for sand-sized sediment in the channel and supply-limited for fine silt and smaller sediment from the hillslope.
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Blamowska, Marta; Sichting, Martin; Mapa, Koyeli; Mokranjac, Dejana; Neupert, Walter; Hell, Kai
2010-02-12
The co-chaperone Hep1 is required to prevent the aggregation of mitochondrial Hsp70 proteins. We have analyzed the interaction of Hep1 with mitochondrial Hsp70 (Ssc1) and the determinants in Ssc1 that make it prone to aggregation. The ATPase and peptide binding domain (PBD) of Hsp70 proteins are connected by a linker segment that mediates interdomain communication between the domains. We show here that the minimal Hep1 binding entity of Ssc1 consists of the ATPase domain and the interdomain linker. In the absence of Hep1, the ATPase domain with the interdomain linker had the tendency to aggregate, in contrast to the ATPase domain with the mutated linker segment or without linker, and in contrast to the PBD. The closest homolog of Ssc1, bacterial DnaK, and a Ssc1 chimera, in which a segment of the ATPase domain of Ssc1 was replaced by the corresponding segment from DnaK, did not aggregate in Delta hep1 mitochondria. The propensity to aggregate appears to be a specific property of the mitochondrial Hsp70 proteins. The ATPase domain in combination with the interdomain linker is crucial for aggregation of Ssc1. In conclusion, our results suggest that interdomain communication makes Ssc1 prone to aggregation. Hep1 counteracts aggregation by binding to this aggregation-prone conformer.
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Blamowska, Marta; Sichting, Martin; Mapa, Koyeli; Mokranjac, Dejana; Neupert, Walter; Hell, Kai
2010-01-01
The co-chaperone Hep1 is required to prevent the aggregation of mitochondrial Hsp70 proteins. We have analyzed the interaction of Hep1 with mitochondrial Hsp70 (Ssc1) and the determinants in Ssc1 that make it prone to aggregation. The ATPase and peptide binding domain (PBD) of Hsp70 proteins are connected by a linker segment that mediates interdomain communication between the domains. We show here that the minimal Hep1 binding entity of Ssc1 consists of the ATPase domain and the interdomain linker. In the absence of Hep1, the ATPase domain with the interdomain linker had the tendency to aggregate, in contrast to the ATPase domain with the mutated linker segment or without linker, and in contrast to the PBD. The closest homolog of Ssc1, bacterial DnaK, and a Ssc1 chimera, in which a segment of the ATPase domain of Ssc1 was replaced by the corresponding segment from DnaK, did not aggregate in Δhep1 mitochondria. The propensity to aggregate appears to be a specific property of the mitochondrial Hsp70 proteins. The ATPase domain in combination with the interdomain linker is crucial for aggregation of Ssc1. In conclusion, our results suggest that interdomain communication makes Ssc1 prone to aggregation. Hep1 counteracts aggregation by binding to this aggregation-prone conformer. PMID:20007714
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Harrison, Tondi M; Ludington-Hoe, Susan
2015-01-01
Infants with complex congenital heart disease requiring surgical intervention within the first days or weeks of life may be the most seriously ill infants needing intensive nursing and medical care. Skin-to-skin contact (SSC) is well accepted and practiced as a positive therapeutic intervention in premature infants but is not routinely offered to infants in cardiac intensive care units. The physiologic effects of SSC in the congenital heart disease population must be examined before recommending incorporation of SSC into standard care routines. The purpose of this case study was to describe the physiologic response to a single session of SSC in an 18-day-old infant with hypoplastic left heart syndrome. Repeated measures of heart rate, respiratory rate, oxygen saturation, blood pressure, and temperature were recorded 30 minutes before SSC, during SSC (including interruptions for bottle and breast feedings), and 10 minutes after SSC was completed. All physiologic parameters were clinically acceptable throughout the 135-minute observation. This case study provides beginning evidence that SSC is safe in full-term infants after surgery for complex congenital heart disease. Further research with a larger sample is needed to examine the effects of SSC on infant physiology before surgery and earlier in the postoperative time period as well as on additional outcomes such as length of stay, maternal-infant interaction, and neurodevelopment.
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Time parameterizations and spin supplementary conditions of the Mathisson-Papapetrou-Dixon equations
NASA Astrophysics Data System (ADS)
Lukes-Gerakopoulos, Georgios
2017-11-01
The implications of two different time constraints on the Mathisson-Papapetrou-Dixon (MPD) equations are discussed under three spin supplementary conditions (SSCs). For this reason the MPD equations are revisited without specifying the affine parameter and several relations are reintroduced in their general form. The latter allows one to investigate the consequences of combining the Mathisson-Pirani (MP) SSC, the Tulczyjew-Dixon (TD) SSC and the Ohashi-Kyrian-Semerák (OKS) SSC with two affine parameter types: the proper time on one hand and the parameterizations introduced in [Gen. Relativ. Gravit. 8, 197 (1977), 10.1007/BF00763547] on the other. For the MP SSC and the TD SSC it is shown that quantities that are constant of motion for the one affine parameter are not for the other, while for the OKS SSC it is shown that the two affine parameters are the same. To clarify the relation between the two affine parameters in the case of the TD SSC the MPD equations are evolved and discussed.
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Jastram, John D.; Moyer, Douglas; Hyer, Kenneth
2009-01-01
Fluvial transport of sediment into the Chesapeake Bay estuary is a persistent water-quality issue with major implications for the overall health of the bay ecosystem. Accurately and precisely estimating the suspended-sediment concentrations (SSC) and loads that are delivered to the bay, however, remains challenging. Although manual sampling of SSC produces an accurate series of point-in-time measurements, robust extrapolation to unmeasured periods (especially highflow periods) has proven to be difficult. Sediment concentrations typically have been estimated using regression relations between individual SSC values and associated streamflow values; however, suspended-sediment transport during storm events is extremely variable, and it is often difficult to relate a unique SSC to a given streamflow. With this limitation for estimating SSC, innovative approaches for generating detailed records of suspended-sediment transport are needed. One effective method for improved suspended-sediment determination involves the continuous monitoring of turbidity as a surrogate for SSC. Turbidity measurements are theoretically well correlated to SSC because turbidity represents a measure of water clarity that is directly influenced by suspended sediments; thus, turbidity-based estimation models typically are effective tools for generating SSC data. The U.S. Geological Survey, in cooperation with the U.S. Environmental Protection Agency Chesapeake Bay Program and Virginia Department of Environmental Quality, initiated continuous turbidity monitoring on three major tributaries of the bay - the James, Rappahannock, and North Fork Shenandoah Rivers - to evaluate the use of turbidity as a sediment surrogate in rivers that deliver sediment to the bay. Results of this surrogate approach were compared to the traditionally applied streamflow-based approach for estimating SSC. Additionally, evaluation and comparison of these two approaches were conducted for nutrient estimations. Results demonstrate that the application of turbidity-based estimation models provides an improved method for generating a continuous record of SSC, relative to the classical approach that uses streamflow as a surrogate for SSC. Turbidity-based estimates of SSC were found to be more accurate and precise than SSC estimates from streamflow-based approaches. The turbidity-based SSC estimation models explained 92 to 98 percent of the variability in SSC, while streamflow-based models explained 74 to 88 percent of the variability in SSC. Furthermore, the mean absolute error of turbidity-based SSC estimates was 50 to 87 percent less than the corresponding values from the streamflow-based models. Statistically significant differences were detected between the distributions of residual errors and estimates from the two approaches, indicating that the turbidity-based approach yields estimates of SSC with greater precision than the streamflow-based approach. Similar improvements were identified for turbidity-based estimates of total phosphorus, which is strongly related to turbidity because total phosphorus occurs predominantly in particulate form. Total nitrogen estimation models based on turbidity and streamflow generated estimates of similar quality, with the turbidity-based models providing slight improvements in the quality of estimations. This result is attributed to the understanding that nitrogen transport is dominated by dissolved forms that relate less directly to streamflow and turbidity. Improvements in concentration estimation resulted in improved estimates of load. Turbidity-based suspended-sediment loads estimated for the James River at Cartersville, VA, monitoring station exhibited tighter confidence interval bounds and a coefficient of variation of 12 percent, compared with a coefficient of variation of 38 percent for the streamflow-based load.
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Kono, Miyuki; Miura, Naoto; Fujii, Takao; Ohmura, Koichiro; Yoshifuji, Hajime; Yukawa, Naoichiro; Imura, Yoshitaka; Nakashima, Ran; Ikeda, Takaharu; Umemura, Shin-ichiro; Miyatake, Takafumi; Mimori, Tsuneyo
2015-01-01
Objective To examine how connective tissue diseases affect finger-vein pattern authentication. Methods The finger-vein patterns of 68 patients with connective tissue diseases and 24 healthy volunteers were acquired. Captured as CCD (charge-coupled device) images by transmitting near-infrared light through fingers, they were followed up in once in each season for one year. The similarity of the follow-up patterns and the initial one was evaluated in terms of their normalized cross-correlation C. Results The mean C values calculated for patients tended to be lower than those calculated for healthy volunteers. In midwinter (February in Japan) they showed statistically significant reduction both as compared with patients in other seasons and as compared with season-matched healthy controls, whereas the values calculated for healthy controls showed no significant seasonal changes. Values calculated for patients with systemic sclerosis (SSc) or mixed connective tissue disease (MCTD) showed major reductions in November and, especially, February. Patients with rheumatoid arthritis (RA) and patients with dermatomyositis or polymyositis (DM/PM) did not show statistically significant seasonal changes in C values. Conclusions Finger-vein patterns can be used throughout the year to identify patients with connective tissue diseases, but some attention is needed for patients with advanced disease such as SSc. PMID:26701644
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40 CFR 35.6805 - Contents of an SSC.
Code of Federal Regulations, 2013 CFR
2013-07-01
... STATE AND LOCAL ASSISTANCE Cooperative Agreements and Superfund State Contracts for Superfund Response Actions Requirements for Administering A Superfund State Contract (ssc) § 35.6805 Contents of an SSC. The...
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40 CFR 35.6805 - Contents of an SSC.
Code of Federal Regulations, 2011 CFR
2011-07-01
... STATE AND LOCAL ASSISTANCE Cooperative Agreements and Superfund State Contracts for Superfund Response Actions Requirements for Administering A Superfund State Contract (ssc) § 35.6805 Contents of an SSC. The...
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40 CFR 35.6805 - Contents of an SSC.
Code of Federal Regulations, 2010 CFR
2010-07-01
... STATE AND LOCAL ASSISTANCE Cooperative Agreements and Superfund State Contracts for Superfund Response Actions Requirements for Administering A Superfund State Contract (ssc) § 35.6805 Contents of an SSC. The...
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40 CFR 35.6805 - Contents of an SSC.
Code of Federal Regulations, 2012 CFR
2012-07-01
... STATE AND LOCAL ASSISTANCE Cooperative Agreements and Superfund State Contracts for Superfund Response Actions Requirements for Administering A Superfund State Contract (ssc) § 35.6805 Contents of an SSC. The...
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McNearney, Terry A; Sallam, Hanaa S; Hunnicutt, Sonya E; Doshi, Dipti; Chen, Jiande D Z
2013-01-01
We assessed the effects of transcutaneous electrical nerve stimulation (TENS) on neurogastric functioning in scleroderma patients. Seventeen SSc patients underwent 30 min TENS treatment >10Hz at GI acupuncture points PC6 and ST36, once (acute TENS) and then after two weeks of TENS sessions for 30 min twice daily (prolonged TENS). Data collected at Visits 1 and 2 included gastric myoelectrical activity (GMA) by surface electrogastrography (EGG), heart rate variability (HRV) by surface electrocardiography (EKG), GI specific symptoms and health related SF-36 questionnaires. Plasma VIP, motilin and IL-6 levels were determined. Statistical analyses were performed by Student's t-test, Spearman Rank and p-values <0.05 were considered significant. 1. Only after prolonged TENS, the percentages of normal slow waves and average slow wave coupling (especially channels 1, 2 reflecting gastric pacemaker and corpus regions) were significantly increased; 2. the percentage of normal slow waves was significantly correlated to sympathovagal balance; 3. Mean plasma VIP and motilin levels were significantly decreased after acute TENS, (vs. baseline), generally maintained in the prolonged TENS intervals. Compared to baseline, mean plasma IL-6 levels were significantly increased after acute TENS, but significantly decreased after prolonged TENS. 4. After prolonged TENS, the frequency of awakening due to abdominal pain and abdominal bloating were significantly and modestly decreased, respectively. In SSc patients, two weeks of daily TENS improved patient GMA scores, lowered plasma VIP, motilin and IL-6 levels and improved association between GMA and sympathovagal balance. This supports the therapeutic potential of prolonged TENS to enhance gastric myoelectrical functioning in SSc.
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Dinsdale, Graham; Moore, Tonia; O'Leary, Neil; Tresadern, Philip; Berks, Michael; Roberts, Christopher; Manning, Joanne; Allen, John; Anderson, Marina; Cutolo, Maurizio; Hesselstrand, Roger; Howell, Kevin; Pizzorni, Carmen; Smith, Vanessa; Sulli, Alberto; Wildt, Marie; Taylor, Christopher; Murray, Andrea; Herrick, Ariane L
2017-07-01
Our aim was to assess the reliability of nailfold capillary assessment in terms of image evaluability, image severity grade ('normal', 'early', 'active', 'late'), capillary density, capillary (apex) width, and presence of giant capillaries, and also to gain further insight into differences in these parameters between patients with systemic sclerosis (SSc), patients with primary Raynaud's phenomenon (PRP) and healthy control subjects. Videocapillaroscopy images (magnification 300×) were acquired from all 10 digits from 173 participants: 101 patients with SSc, 22 with PRP and 50 healthy controls. Ten capillaroscopy experts from 7 European centres evaluated the images. Custom image mark-up software allowed extraction of the following outcome measures: overall grade ('normal', 'early', 'active', 'late', 'non-specific', or 'ungradeable'), capillary density (vessels/mm), mean vessel apical width, and presence of giant capillaries. Observers analysed a median of 129 images each. Evaluability (i.e. the availability of measures) varied across outcome measures (e.g. 73.0% for density and 46.2% for overall grade in patients with SSc). Intra-observer reliability for evaluability was consistently higher than inter- (e.g. for density, intra-class correlation coefficient [ICC] was 0.71 within and 0.14 between observers). Conditional on evaluability, both intra- and inter-observer reliability were high for grade (ICC 0.93 and 0.78 respectively), density (0.91 and 0.64) and width (0.91 and 0.85). Evaluability is one of the major challenges in assessing nailfold capillaries. However, when images are evaluable, the high intra- and inter-reliabilities suggest that overall image grade, capillary density and apex width have potential as outcome measures in longitudinal studies. Copyright © 2017 Elsevier Inc. All rights reserved.
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Zhang, Ping; Wang, Liyuan; Li, Yanping; Jiang, Ping; Wang, Yanchao; Wang, Pengfei; Kang, Li; Wang, Yuding; Sun, Yi; Jiang, Yunliang
2018-02-15
Porcine circovirus type 2 (PCV2) is the primary cause of post-weaning multisystemic wasting syndrome (PMWS) and other PCV-associated diseases. According to our previous RNA-sequencing analysis, the differences in the susceptibility to PCV2 infection depended on the genetic differences between the Laiwu (LW) and Yorkshire × Landrace crossbred (YL) pigs, but the cellular microRNA (miRNA) that are differentially expressed between the LW and YL pigs before and after PCV2 infection remain to be determined. In this study, high-throughput sequencing was performed to determine the abundance and differential expression of miRNA in lung tissues from PCV2-infected and PCV2-uninfected LW and YL pigs. In total, 295 known and 95 novel miRNA were identified, and 23 known and 25 novel miRNA were significantly differentially expressed in the PCV2-infected vs. PCV2-uninfected LW pigs and/or the PCV2-infected vs. PCV2-uninfected YL pigs. The expression levels of ssc-miR-122, ssc-miR-192, ssc-miR-451, ssc-miR-486, and ssc-miR-504 were confirmed by quantitative real-time PCR (qRT-PCR). Analysis of the potential targets of the four up-regulated miRNA (i.e., ssc-miR-122, ssc-miR-192, ssc-miR-451 and ssc-miR-486) identified pathways and genes that may be important for disease resistance. Among the up-regulated miRNA, ssc-miR-122 can repress the protein expression and viral DNA replication of PCV2 and down-regulate the expression of the nuclear factor of activated T-cells 5 (NFAT5) and aminopeptidase puromycin sensitive (NPEPPS) by binding to their 3' untranslated region (3'UTR) in PK15 cells. Therefore, ssc-miR-122 may indirectly suppress PCV2 infection by targeting genes related to the host immune system, such as NFAT5 and NPEPPS.
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Zhang, Shishuo; Wang, Ruifang; Su, Huijuan; Wang, Biaoxiong; Sizhu, Suolang; Lei, Zhixin; Jin, Meilin; Chen, Huanchun; Cao, Jiyue; Zhou, Hongbo
2017-04-03
The prevalence of swine pandemic H1N1/2009 influenza A virus (SIV-H1N1/2009) in pigs has the potential to generate novel reassortant viruses, posing a great threat to human health. Cellular microRNAs (miRNAs) have been proven as promising small molecules for regulating influenza A virus replication by directly targeting viral genomic RNA. In this study, we predicted potential Sus scrofa (ssc-, swine) miRNAs targeting the genomic RNA of SIV-H1N1/2009 by RegRNA 2.0, and identified ssc-miR-204 and ssc-miR-4331 to target viral HA and NS respectively through dual-luciferase reporter assays. The messenger RNA (mRNA) levels of viral HA and NS were significantly suppressed when newborn pig trachea (NPTr) cells respectively overexpressed ssc-miR-204 and ssc-miR-4331 and were infected with SIV-H1N1/2009, whereas the suppression effect could be restored when respectively decreasing endogenous ssc-miR-204 and ssc-miR-4331 with inhibitors. Because of the importance of viral HA and NS in the life cycle of influenza A virus, ssc-miR-204 and ssc-miR-4331 exhibited an inhibition effect on SIV-H1N1/2009 replication. The antiviral effect was sequence-specific of SIV-H1N1/2009, for the target sites in HA and NS of H5N1 or H9N2 influenza A virus were not conserved. Furthermore, SIV-H1N1/2009 infection reversely downregulated the expression of ssc-miR-204 and ssc-miR-4331, which might facilitate the virus replication in the host. In summary, this work will provide us some important clues for controlling the prevalence of SIV-H1N1/2009 in pig populations.
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Comprehensive approach to systemic sclerosis patients during pregnancy.
Rueda de León Aguirre, Alexandra; Ramírez Calvo, José Antonio; Rodríguez Reyna, Tatiana Sofía
2015-01-01
Systemic sclerosis (SSc) is a connective tissue disease that usually affects women, with a male:female ratio of 1:4-10. It was thought that there was a prohibitive risk of fatal complications in the pregnancies of patients with SSc. It is now known that the majority of these women undergo a normal progression of pregnancy if the right time is chosen and a close obstetric care is delivered. The obstetric risk will depend on the subtype and clinical stage of the disease, and the presence and severity of the internal organ involvement during the pregnancy. The management of these pregnancies should be provided in a specialized center, with a multidisciplinary team capable of identifying and promptly treating complications. Treatment should be limited to drugs with no teratogenic potential, except when renal crises or severe cardiovascular complications develop. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.
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Vujičić, Ana Đorđević; Đukić, Svjetlana Maglajić
2016-01-01
Summary Background Salivary cortisol measurement is a non-invasive method suitable for use in neonatal research. Mother-infant separation after birth represents stress and skin-to-skin contact (SSC) has numerous benefits. The aim of the study was to measure salivary cortisol in mothers and newborns before and after SSC in order to assess the effect of SSC on mothers’ and infants’ stress and to estimate the efficacy of collecting small saliva samples in newborns. Methods Salivary cortisol was measured in 35 mother-infant pairs before and after the first and the fifth SSC in small saliva samples (50 μL) using the high sensitivity Quantitative ELISA-Kit (0.0828 nmol/L) for low cortisol levels detection. Samples were collected with eye sponge during 3 to 5 minutes. Results Cortisol level in mothers decreased after SSC: the highest levels were measured before and the lowest after SSC and the differences in values were significant during both the first (p<0.001) and the fifth SSC (p<0.001). During the first SSC the cortisol level decrease was detected in 14 (40%) and an increase in 21 (60%) newborns, and during the fifth SSC a decrease was detected in 16 (45.7%) and an increase in 19 (54.3%) newborns, without confirmed significance of the difference. Saliva sampling efficacy using eye sponge was 75%. Conclusions Cortisol level decrease in mothers proves the stress reduction during SSC, while variable cortisol levels in infants do not indicate stress reduction and imply the need for further research. The used sampling method appeared to be one of the most optimal considering the sample volume, sampling time and efficacy. PMID:28356870
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Factors affecting suspended-solids concentrations in South San Francisco Bay, California
Schoellhamer, D.H.
1996-01-01
Measurements of suspended-solids concentration (SSC) were made at two depths at three sites in South San Francisco Bay (South Bay) to determine the factors that affect SSC. Twenty-eight segments of reliable and continuous SSC time series data longer than 14 days were collected from late 1991 or 1992 through September 1993. Spectral analysis and singular spectrum analysis were used to relate these data segments to time series of several potential forcing factors, including diurnal and semidiurnal tides, the spring-neap tidal cycle, wind shear, freshwater runoff, and longitudinal density differences. SSC is greatest during summer when a landward wind shear is applied to South Bay by the afternoon sea breeze. About one half the variance of SSC is caused by the spring-neap cycle, and SSC lags the spring-neap cycle by about 2 days. Relatively short duration of slack water limits the duration of deposition of suspended solids and consolidation of newly deposited bed sediment during the tidal cycle, so suspended solids accumulate in the water column as a spring tide is approached and slowly deposit as a neap tide is approached. Perturbations in SSC caused by wind and local runoff from winter storms during the study period were usually much smaller than SSC variations caused by the spring-neap cycle. Variations of SSC at the study sites at tidal timescales are tidally forced, and nonlinear physical processes are significant. Advective transport dominates during spring tides when water with higher SSC due to wind wave resuspension is advected to the main channel from shallow water, but during neap tides, advective transport is less significant. The findings of this and other studies indicate that the tidally averaged transport of suspended solids responds to seasonal variations of wind shear in South Bay.
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Harrison, Tondi M.; Ludington-Hoe, Susan
2014-01-01
Background Infants with complex congenital heart disease requiring surgical intervention within the first days or weeks of life may be the most seriously ill infants needing intensive nursing and medical care immediately after birth. Skin to skin contact (SSC) is well-accepted and practiced as a positive therapeutic intervention in premature infants, but is not routinely offered to infants in cardiac intensive care units. Physiologic effects of SSC in the congenital heart disease population must be examined before recommending incorporation of SSC into standard care routines. Objective The purpose of this case study was to describe the physiologic response to a single session of SSC in an 18-day-old infant with hypoplastic left heart syndrome. Methods Repeated measures of heart rate, respiratory rate, oxygen saturation, blood pressure, and temperature were recorded 30 minutes prior to SSC, during SSC (including interruptions for bottle and breast feedings), and 10 minutes after SSC was completed. Results All physiologic parameters were clinically acceptable throughout the 135-minute observation. Conclusion This case study provides beginning evidence that SSC is safe in full-term infants following surgery for complex congenital heart disease. Further research with a larger sample is needed to examine effects of SSC on infant physiology before surgery and earlier in the postoperative time period as well as on additional outcomes such as length of stay, maternal-infant interaction, and neurodevelopment. PMID:25325374
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Owen, Claire; Ngian, Gene-Siew; Elford, Kathleen; Moore, Owen; Stevens, Wendy; Nikpour, Mandana; Rabusa, Candice; Proudman, Susanna; Roddy, Janet; Zochling, Jane; Hill, Catherine; Sturgess, Allan; Tymms, Kathleen; Youssef, Peter; Sahhar, Joanne
2016-01-01
To report the efficacy and tolerability of mycophenolate mofetil (MMF) and azathioprine (AZA) in the management of systemic sclerosis-associated interstitial lung disease (SSc-ILD). Patients in the Australian Scleroderma Cohort Study treated with at least 3 months of MMF or AZA for SSc-ILD confirmed on high resolution computed tomography (HRCT) chest were identified and their pulmonary function tests (PFTs) retrieved. Individuals with available results for T-1 (12 months prior to treatment commencement), T0 (date of treatment commencement) and at least one subsequent time point were included in the drug efficacy analysis. The Wilcoxon signed-rank test was used to compare absolute FVC at T1, T0, 12 months (T1), 24 months (T2) and 36 months (T3). Analysis of drug tolerability included all identified patients treated with MMF or AZA. 18/22 patients treated with MMF and 29/49 treated with AZA had adequate PFTs for inclusion in the drug efficacy analysis. Median absolute FVC at T1 for MMF treatment was 2.50L, declining to 2.12L at T0 (p=0.02). Following MMF therapy, FVC results were stable at T1 (2.13L, p=0.86), T2 (2.17L, p=0.65) and T3 (2.25L, p=0.78). In the AZA group, a statistically significant decline did not occur prior to treatment, however FVC results remained stable at T1, T2 and T3.Adverse events leading to early discontinuation (<12 months treatment) were less common in the MMF group (4/22 vs. 13/49). Gastrointestinal complications were the main cause of discontinuation in both groups. In patients with SSc-ILD with declining pulmonary function, MMF therapy was associated with stability for up to 36 months. Early adverse events leading to discontinuation occurred less frequently in patients treated with MMF than in AZA treated patients.
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Karamanolis, George P; Panopoulos, Stylianos; Denaxas, Konstantinos; Karlaftis, Anastasios; Zorbala, Alexandra; Kamberoglou, Dimitrios; Ladas, Spiros D; Sfikakis, Petros P
2016-09-01
Acute administration of the oral 5-HT1A receptor agonist buspirone, which is commonly used as an anxiolytic drug, may improve compromised lower esophageal sphincter function. In an open-label trial we assessed the effects of buspirone on esophageal motor function and symptoms in patients with esophageal involvement associated with systemic sclerosis (SSc). Thirty consecutive patients with SSc and symptomatic esophageal involvement, despite treatment with proton pump inhibitors, underwent high resolution manometry and chest computed tomography for assessment of motor function and esophageal dilatation, respectively. Regurgitation, heartburn, dysphagia, and chest pain severity was subjectively scored by visual analog scales. Manometric parameters (primary endpoint) and symptom severity (secondary endpoint) were re-examined after 4-week daily administration of 20 mg buspirone. Other medications remained unchanged. Eight patients did not complete the trial because of buspirone-associated dizziness (n = 2), or nausea (n = 2), or reluctancy to undergo final manometry. In the remaining 22 patients lower esophageal sphincter (LES) resting pressure increased from 7.7 ± 3.9 to 12.2 ± 4.6 mmHg (p = 0.00002) after buspirone administration; other manometric parameters did not change. Statistical analysis revealed negative correlation between individual increases in resting LES pressure and supra-aortic esophageal diameter (r = -0.589, p = 0.017), suggesting a more beneficial effect in patients with less severely affected esophageal function. Heartburn and regurgitation scores decreased at 4 weeks compared to baseline (p = 0.001, and p = 0.022, respectively). Our findings warrant more conclusive evaluation with a double-blind controlled study; however, buspirone could potentially be given under observation for objective improvement in all patients with SSc who report reflux symptoms despite undergoing standard treatment. ClinicalTrials.gov Identifier: NCT02363478 Registered: 21-02-2014.
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Vanryckeghem, Martine; Matthews, Michael; Xu, Peixin
2017-11-08
The aim of this study was to evaluate the usefulness of the Speech Situation Checklist for adults who stutter (SSC) in differentiating people who stutter (PWS) from speakers with no stutter based on self-reports of anxiety and speech disruption in communicative settings. The SSC's psychometric properties were examined, norms were established, and suggestions for treatment were formulated. The SSC was administered to 88 PWS seeking treatment and 209 speakers with no stutter between the ages of 18 and 62. The SSC consists of 2 sections investigating negative emotional reaction and speech disruption in 38 speech situations that are identical in both sections. The SSC-Emotional Reaction and SSC-Speech Disruption data show that these self-report tests differentiate PWS from speakers with no stutter to a statistically significant extent and have great discriminative value. The tests have good internal reliability, content, and construct validity. Age and gender do not affect the scores of the PWS. The SSC-Emotional Reaction and SSC-Speech Disruption seem to be powerful measures to investigate negative emotion and speech breakdown in an array of speech situations. The item scores give direction to treatment by suggesting speech situations that need a clinician's attention in terms of generalization and carry-over of within-clinic therapeutic gains into in vivo settings.
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Facts and controversies in mixed connective tissue disease.
Martínez-Barrio, Julia; Valor, Lara; López-Longo, F Javier
2018-01-12
Mixed connective tissue disease (MCTD) is a systemic autoimmune rheumatic disease (SARD) characterised by the combination of clinical manifestations of systemic lupus erythematosus (SLE), cutaneous systemic sclerosis (SSc) and polymyositis-dermatomyositis, in the presence of elevated titers of anti-U1-RNP antibodies. Main symptoms of the disease are polyarthritis, hand oedema, Raynaud's phenomenon, sclerodactyly, myositis and oesophageal hypomobility. Although widely discussed, most authors today accept MCTD as an independent entity. Others, however, suggest that these patients may belong to subgroups or early stages of certain definite connective diseases, such as SLE or SSc, or are, in fact, SARD overlap syndromes. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.
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The stainless steel crown debate: friend or foe?
Uston, Karen A; Estrella, Maria Regina P
2011-01-01
In this article, we will explore the use of the stainless steel crown (SSC) in dentistry today. For the pediatric population, many factors can affect the choice of restoration, such as the variations between primary and permanent tooth morphology, oral environment, and patient selection. The current literature and dentistry guidelines encourage dentists to make an informed decision when determining the restoration recommended for a carious primary molar. To further help educate dental providers on the topic of SSCs the following items will be reviewed: the indications; techniques for placement; advantages; and drawbacks when compared to alternative restorative materials. Regardless of personal opinion, the SSC should continue to be recognized for its efficiency, cost-effectiveness, and successful treatment modality.
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Collagen degradation products and proinflammatory cytokines in systemic and localized scleroderma.
Becvár, R; Hulejová, H; Braun, M; Stork, J
2007-01-01
The aim of this study was to assess the degradation of collagen type I and proinflammatory cytokines in systemic and localized scleroderma compared with psoriasis and healthy controls. Total 99 individuals were examined - 24 with SSc, 22 with LSc, 39 patients with PsV and 14 healthy controls. U-PD and U-DPD were measured using a sensitive isocratic HPLC method. Serum levels of IL-6 and soluble IL-2R were assayed using commercial ELISA kits. In the SSc group U-PD and U-DPD levels (nmol/mmol creatinine) were increased compared with controls (P = 0.001) and with PsV (P = 0.006). IL-6 levels were increased compared with controls (P = 0.004) and with PsV (P = 0.002). IL-2R concentrations were insignificantly increased in comparison with controls and were lower than in PsV, but the difference was not significant. In the LSc group excretion of U-PD and U-DPD did not differ from controls, but was insignificantly decreased compared with PsV. IL-6 levels were increased compared with controls (P = 0.001) and also with PsV (P = 0.03). IL-2R concentrations were significantly increased in comparison with controls only (P = 0.03). In patients with SSc our data have shown the most intensive collagen degradation and simultaneously an active inflammation, as documented by IL-6, which reflects the pathological processes in the skin and visceral organs compared with PsV patients and healthy individuals. In the LSc group collagen degradation was similar to that in control groups, but a certain inflammatory activity was observed.
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Myc/Mycn-mediated glycolysis enhances mouse spermatogonial stem cell self-renewal
Kanatsu-Shinohara, Mito; Tanaka, Takashi; Ogonuki, Narumi; Ogura, Atsuo; Morimoto, Hiroko; Cheng, Pei Feng; Eisenman, Robert N.; Trumpp, Andreas; Shinohara, Takashi
2016-01-01
Myc plays critical roles in the self-renewal division of various stem cell types. In spermatogonial stem cells (SSCs), Myc controls SSC fate decisions because Myc overexpression induces enhanced self-renewal division, while depletion of Max, a Myc-binding partner, leads to meiotic induction. However, the mechanism by which Myc acts on SSC fate is unclear. Here we demonstrate a critical link between Myc/Mycn gene activity and glycolysis in SSC self-renewal. In SSCs, Myc/Mycn are regulated by Foxo1, whose deficiency impairs SSC self-renewal. Myc/Mycn-deficient SSCs not only undergo limited self-renewal division but also display diminished glycolytic activity. While inhibition of glycolysis decreased SSC activity, chemical stimulation of glycolysis or transfection of active Akt1 or Pdpk1 (phosphoinositide-dependent protein kinase 1 ) augmented self-renewal division, and long-term SSC cultures were derived from a nonpermissive strain that showed limited self-renewal division. These results suggested that Myc-mediated glycolysis is an important factor that increases the frequency of SSC self-renewal division. PMID:28007786
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Myc/Mycn-mediated glycolysis enhances mouse spermatogonial stem cell self-renewal.
Kanatsu-Shinohara, Mito; Tanaka, Takashi; Ogonuki, Narumi; Ogura, Atsuo; Morimoto, Hiroko; Cheng, Pei Feng; Eisenman, Robert N; Trumpp, Andreas; Shinohara, Takashi
2016-12-01
Myc plays critical roles in the self-renewal division of various stem cell types. In spermatogonial stem cells (SSCs), Myc controls SSC fate decisions because Myc overexpression induces enhanced self-renewal division, while depletion of Max, a Myc-binding partner, leads to meiotic induction. However, the mechanism by which Myc acts on SSC fate is unclear. Here we demonstrate a critical link between Myc/Mycn gene activity and glycolysis in SSC self-renewal. In SSCs, Myc/Mycn are regulated by Foxo1, whose deficiency impairs SSC self-renewal. Myc/Mycn-deficient SSCs not only undergo limited self-renewal division but also display diminished glycolytic activity. While inhibition of glycolysis decreased SSC activity, chemical stimulation of glycolysis or transfection of active Akt1 or Pdpk1 (phosphoinositide-dependent protein kinase 1 ) augmented self-renewal division, and long-term SSC cultures were derived from a nonpermissive strain that showed limited self-renewal division. These results suggested that Myc-mediated glycolysis is an important factor that increases the frequency of SSC self-renewal division. © 2016 Kanatsu-Shinohara et al.; Published by Cold Spring Harbor Laboratory Press.
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Hayes, Timothy S.; Cox, Dennis P.; Bliss, James D.; Piatak, Nadine M.; Seal, Robert R.
2015-01-01
This report contains a descriptive model of sediment-hosted stratabound copper (SSC) deposits that supersedes the model of Cox and others (2003). This model is for use in assessments of mineral resource potential. SSC deposits are the second most important sources of copper in the world behind porphyry copper deposits. Around 20 percent of the copper in the world is produced from this class of deposits. They are also the most important sources of cobalt in the world, and they are fourth among classes of ore deposits in production of silver. SSC deposits are the basis of the economies of three countries: Democratic Republic of Congo, Poland, and Zambia. This report provides a description of the key features of SSC deposits; it identifies their tectonic-sedimentary environments; it illustrates geochemical, geophysical, and geoenvironmental characteristics of SSC deposits; it reviews and evaluates hypotheses on how these deposits formed; it presents exploration and assessment guides; and it lists some gaps in our knowledge about the SSC deposits. A summary follows that provides overviews of many subjects concerning SSC deposits.
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Park, S; Lee, J; Park, J; Byun, I; Park, T; Lee, T
2010-01-01
Since spent sulfidic caustic (SSC) produced from petrochemical industry contains a high concentration of alkalinity and sulfide, it was expected that SSC could be used as an electron donor for autotrophic denitrification. To investigate the nitrogen removal performance, a pilot scale Bardenpho process was operated. The total nitrogen removal efficiency increased as SSC dosage increased, and the highest efficiency was observed as 77.5% when SSC was injected into both anoxic tank (1) and (2). FISH analysis was also performed to shed light on the effect of SSC dosage on the distribution ratio of nitrifying bacteria and Thiobacillus denitrificans. FISH results indicated that the relative distribution ratio of ammonia-oxidizing bacteria, Nitrobacter spp., Nitrospira genus and Thiobacillus denitrificans to eubacteria varied little with the pH of the tanks, and SSC injection did not give harmful effect on nitrification efficiency. These results show that SSC can be applied as an electron donor of autotrophic denitrification to biological nitrogen removal process effectively, without any inhibitory effects to nitrifying bacteria and sulfur-utilizing denitrifying bacteria.
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Diagnostic criteria, severity classification and guidelines of systemic sclerosis.
Asano, Yoshihide; Jinnin, Masatoshi; Kawaguchi, Yasushi; Kuwana, Masataka; Goto, Daisuke; Sato, Shinichi; Takehara, Kazuhiko; Hatano, Masaru; Fujimoto, Manabu; Mugii, Naoki; Ihn, Hironobu
2018-06-01
Several effective drugs have been identified for the treatment of systemic sclerosis (SSc). However, in advanced cases, not only their effectiveness is reduced but they may be also harmful due to their side-effects. Therefore, early diagnosis and early treatment is most important for the treatment of SSc. We established diagnostic criteria for SSc in 2003 and early diagnostic criteria for SSc in 2011, for the purpose of developing evaluation of each organ in SSc. Moreover, in November 2013, the American College of Rheumatology and the European Rheumatology Association jointly developed new diagnostic criteria for increasing their sensitivity and specificity, so we revised our diagnostic criteria and severity classification of SSc. Furthermore, we have revised the clinical guideline based on the newest evidence. In particular, the clinical guideline was established by clinical questions based on evidence-based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guideline easy to use and reliable based on the newest evidence, and to present guidance as specific as possible for various clinical problems in treatment of SSc. © 2018 Japanese Dermatological Association.
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NASA Technical Reports Server (NTRS)
Allgood, Daniel C.; Graham, Jason S.; Ahuja, Vineet; Hosangadi, Ashvin
2008-01-01
Simulation technology can play an important role in rocket engine test facility design and development by assessing risks, providing analysis of dynamic pressure and thermal loads, identifying failure modes and predicting anomalous behavior of critical systems. Advanced numerical tools assume greater significance in supporting testing and design of high altitude testing facilities and plume induced testing environments of high thrust engines because of the greater inter-dependence and synergy in the functioning of the different sub-systems. This is especially true for facilities such as the proposed A-3 facility at NASA SSC because of a challenging operating envelope linked to variable throttle conditions at relatively low chamber pressures. Facility designs in this case will require a complex network of diffuser ducts, steam ejector trains, fast operating valves, cooling water systems and flow diverters that need to be characterized for steady state performance. In this paper, we will demonstrate with the use of CFD analyses s advanced capability to evaluate supersonic diffuser and steam ejector performance in a sub-scale A-3 facility at NASA Stennis Space Center (SSC) where extensive testing was performed. Furthermore, the focus in this paper relates to modeling of critical sub-systems and components used in facilities such as the A-3 facility. The work here will address deficiencies in empirical models and current CFD analyses that are used for design of supersonic diffusers/turning vanes/ejectors as well as analyses for confined plumes and venting processes. The primary areas that will be addressed are: (1) supersonic diffuser performance including analyses of thermal loads (2) accurate shock capturing in the diffuser duct; (3) effect of turning duct on the performance of the facility (4) prediction of mass flow rates and performance classification for steam ejectors (5) comparisons with test data from sub-scale diffuser testing and assessment of confidence levels in CFD based flowpath modeling of the facility. The analyses tools used here expand on the multi-element unstructured CFD which has been tailored and validated for impingement dynamics of dry plumes, complex valve/feed systems, and high pressure propellant delivery systems used in engine and component test stands at NASA SSC. The analyses performed in the evaluation of the sub-scale diffuser facility explored several important factors that influence modeling and understanding of facility operation such as (a) importance of modeling the facility with Real Gas approximation, (b) approximating the cluster of steam ejector nozzles as a single annular nozzle, (c) existence of mixed subsonic/supersonic flow downstream of the turning duct, and (d) inadequacy of two-equation turbulence models in predicting the correct pressurization in the turning duct and expansion of the second stage steam ejectors. The procedure used for modeling the facility was as follows: (i) The engine, test cell and first stage ejectors were simulated with an axisymmetric approximation (ii) the turning duct, second stage ejectors and the piping downstream of the second stage ejectors were analyzed with a three-dimensional simulation utilizing a half-plane symmetry approximation. The solution i.e. primitive variables such as pressure, velocity components, temperature and turbulence quantities were passed from the first computational domain and specified as a supersonic boundary condition for the second simulation. (iii) The third domain comprised of the exit diffuser and the region in the vicinity of the facility (primary included to get the correct shock structure at the exit of the facility and entrainment characteristics). The first set of simulations comprising the engine, test cell and first stage ejectors was carried out both as a turbulent real gas calculation as well as a turbulent perfect gas calculation. A comparison for the two cases (Real Turbulent and Perfect gas turbulent) of the Ma Number distribution and temperature distributions are shown in Figures 1 and 2 respectively. The Mach Number distribution shows small yet distinct differences between the two cases such as locations of shocks/shock reflections and a slightly different impingement point on the wall of the diffuser from the expansion at the exit of the nozzle. Similarly the temperature distribution indicates different flow recirculation patterns in the test cell. Both cases capture all the essential flow phenomena such as the shock-boundary layer interaction, plume expansion, expansion of the first stage ejectors, mixing between the engine plume and the first stage ejector flow and pressurization due to the first stage ejectors. The final paper will discuss thermal loads on the walls of the diffuser and cooling mechanisms investigated.
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Environmental Mycobiome Modifiers of Inflammation and Fibrosis in Systemic Sclerosis
2016-09-01
TUBB), and ribosomal proteins), while others are considered specific to SSc despite trace level detection in controls. For ex- ample, multiple SSc...Strong re- activity was seen against all five proteins in SSc with only trace levels detected in controls (Fig. 3a), indicating widespread immune...sequences in SSc RNA-seq data was used to detect microbial sequences in human tissues in an unbiased, quantitative manner. Our studies suggest that
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Sustainable supply chain design: a configurational approach.
Masoumik, S Maryam; Abdul-Rashid, Salwa Hanim; Olugu, Ezutah Udoncy; Raja Ghazilla, Raja Ariffin
2014-01-01
Designing the right supply chain that meets the requirements of sustainable development is a significant challenge. Although there are a considerable number of studies on issues relating to sustainable supply chain design (SSCD) in terms of designing the practices, processes, and structures, they have rarely demonstrated how these components can be aligned to form an effective sustainable supply chain (SSC). Considering this gap in the literature, this study adopts the configurational approach to develop a conceptual framework that could configure the components of a SSC. In this respect, a process-oriented approach is utilized to classify and harmonize the design components. A natural-resource-based view (NRBV) is adopted to determine the central theme to align the design components around. The proposed framework presents three types of SSC, namely, efficient SSC, innovative SSC, and reputed SSC. The study culminates with recommendations concerning the direction for future research.
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Sulfide Stress Cracking Behavior of a Martensitic Steel Controlled by Tempering Temperature
Sun, Yu; Wang, Qian; Gu, Shunjie; He, Zaoneng; Wang, Qingfeng; Zhang, Fucheng
2018-01-01
A medium-carbon Cr–Mo–V martensitic steel was thermally processed by quenching (Q) at 890 °C and tempering (T) at increasing temperatures from 650 °C to 720 °C and the effect of tempering temperature, Tt, on sulfide stress cracking (SSC) behaviors was estimated mainly via double cantilever beam (DCB) and electrochemical hydrogen permeation (EHP) tests and microstructure characterization. The results indicate that the threshold stress intensity factor for SSC, KISSC, increased with increasing Tt. The overall and local H concentration around the inclusions decreased with increasing Tt, due to reductions in the amounts of solute atoms, grain boundaries and dislocations, which effectively prevented SSC initiation. Also, increasing Tt caused an increased fraction of high-angle boundaries, which evidently lowered the SSC propagation rate by more frequently diverting the propagating direction and accordingly restricted SSC propagation. The overall SSC resistance of this Q&T–treated steel was therefore significantly enhanced. PMID:29522494
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The impact of Fli1 deficiency on the pathogenesis of systemic sclerosis
Asano, Yoshihide; Bujor, Andreea M.; Trojanowska, Maria
2013-01-01
Systemic sclerosis (SSc) is an autoimmune inflammatory disease with unknown etiology characterized by microvascular injury and fibrosis of the skin and internal organs. A growing body of evidence suggests that deficiency of the transcription factor Fli1 (Friend leukemia integration-1) has a pivotal role in the pathogenesis of SSc. Fli1 is expressed in fibroblasts, endothelial cells, and immune cells, and has important roles in the activation, differentiation, development, and survival of these cells. Previous studies demonstrated that Fli1 is downregulated in SSc fibroblasts by an epigenetic mechanism and a series of experiments with Fli1-deficient animal models revealed that Fli1 deficiency in fibroblasts and endothelial cells reproduces the histopathologic features of fibrosis and vasculopathy in SSc, respectively. In this article, we review the impact of Fli1 deficiency on the pathogenesis of SSc and discuss a new therapeutic strategy for SSc by targeting the transcription factor Fli1. PMID:20663647
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Sustainable Supply Chain Design: A Configurational Approach
Masoumik, S. Maryam; Raja Ghazilla, Raja Ariffin
2014-01-01
Designing the right supply chain that meets the requirements of sustainable development is a significant challenge. Although there are a considerable number of studies on issues relating to sustainable supply chain design (SSCD) in terms of designing the practices, processes, and structures, they have rarely demonstrated how these components can be aligned to form an effective sustainable supply chain (SSC). Considering this gap in the literature, this study adopts the configurational approach to develop a conceptual framework that could configure the components of a SSC. In this respect, a process-oriented approach is utilized to classify and harmonize the design components. A natural-resource-based view (NRBV) is adopted to determine the central theme to align the design components around. The proposed framework presents three types of SSC, namely, efficient SSC, innovative SSC, and reputed SSC. The study culminates with recommendations concerning the direction for future research. PMID:24523652
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Skin-to-skin care for procedural pain in neonates.
Johnston, Celeste; Campbell-Yeo, Marsha; Disher, Timothy; Benoit, Britney; Fernandes, Ananda; Streiner, David; Inglis, Darlene; Zee, Rebekah
2017-02-16
Skin-to-skin care (SSC), often referred to as 'kangaroo care' (KC) due to its similarity with marsupial behaviour of ventral maternal-infant contact, is one non-pharmacological intervention for pain control in infants. The primary objectives were to determine the effect of SSC alone on pain from medical or nursing procedures in neonates compared to no intervention, sucrose or other analgesics, or additions to simple SSC such as rocking; and to determine the effects of the amount of SSC (duration in minutes), method of administration (e.g. who provided the SSC) of SSC in reducing pain from medical or nursing procedures in neonatesThe secondary objectives were to determine the safety of SSC care for relieving procedural pain in infants; and to compare the SSC effect in different postmenstrual age subgroups of infants. For this update, we used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1); MEDLINE via PubMed (1966 to 25 February 2016); Embase (1980 to 25 February 2016); and CINAHL (1982 to 25 February 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. Studies with randomisation or quasi-randomisation, double- or single-blinded, involving term infants (≥ 37 completed weeks' postmenstrual age (PMA) to a maximum of 44 weeks' PMA and preterm infants (< 37 completed weeks PMA) receiving SSC for painful procedures conducted by healthcare professionals. The main outcome measures were physiological or behavioural pain indicators and composite pain scores. A mean difference (MD) with 95% confidence interval (CI) using a fixed-effect model was reported for continuous outcome measures. We included variations on type of tissue-damaging procedure, provider of care, and duration of SSC. Twenty-five studies (n = 2001 infants) were included. Nineteen studies (n = 1065) used heel lance as the painful procedure, one study combined venepuncture and heel stick (n = 50), three used intramuscular injection (n = 776), one used 'vaccination' (n = 60), and one used tape removal (n = 50). The studies were generally strong and had low or uncertain risk of bias. Blinding of the intervention was not possible, making them subject to high risk, depending on the method of scoring outcomes.Seventeen studies (n = 810) compared SSC to a no-treatment control. Although 15 studies measured heart rate during painful procedures, data from only five studies (n = 161) could be combined for a mean difference (MD) of -10.78 beats per minute (95% CI -13.63 to -7.93) favouring SSC. Meta-analysis of four studies (n = 120) showed no difference in heart rate following the painful procedure (MD 0.08, 95% CI -4.39 to 4.55). Two studies (n = 38) reported heart rate variability with no significant differences. Two studies (n = 101) in a meta-analysis on oxygen saturation at 30 and 60 seconds following the painful procedure did not show a difference. Duration of crying meta-analysis was performed on four studies (n = 133): two (n = 33) investigated response to heel lance (MD = -34.16, 95% CI -42.86 to -25.45), and two (n = 100) following IM injection (MD = -8.83, 95% CI -14.63 to -3.02), favouring SSC. Five studies, one consisting of two substudies (n = 267), used the Premature Infant Pain Profile (PIPP) as a primary outcome, which favoured SCC at 30 seconds (MD -3.21, 95% CI -3.94 to -2.47), at 60 seconds (3 studies; n = 156) (MD -1.64, 95% CI -2.86 to -0.43), and at 90 seconds (n = 156) (MD -1.28, 95% CI -2.53 to -0.04); but at 120 seconds there was no difference (n = 156) (MD 0.07, 95% CI -1.11 to 1.25). No studies on return of heart rate to baseline level, cortisol levels, and facial actions could be combined for meta-analysis findings.Eight studies compared SSC to another intervention with or without a no-treatment control. Two cross-over studies (n = 80) compared mother versus other provider (father, another female) on PIPP scores at 30, 60, 90, and 120 seconds with no significant difference. When SSC was compared to other interventions, there were not enough similar studies to pool results in an analysis. One study compared SSC (n = 640) with and without dextrose and found that the combination was most effective and that SSC alone was more effective than dextrose alone. Similarly, in another study SSC was more effective than oral glucose for heart rate (n = 95). SSC either in combination with breastfeeding or alone was favoured over a no-treatment control, but not different to breastfeeding. One study compared SSC alone and in combination with both sucrose and breastfeeding on heart rate (HR), NIPS scores, and crying time (n = 127). The combinations were more effective than SSC alone for NIPS and crying. Expressed breast milk was compared to SSC in one study (n = 50) and found both equally effective on PIPP scores. There were not enough participants with similar outcomes and painful procedures to compare age groups or duration of SSC. No adverse events were reported in any of the studies. SSC appears to be effective as measured by composite pain indicators with both physiological and behavioural indicators and, independently, using heart rate and crying time; and safe for a single painful procedure. Purely behavioural indicators tended to favour SSC but with facial actions there is greater possibility of observers not being blinded. Physiological indicators were mixed although the common measure of heart rate favoured SSC. Two studies compared mother-providers to others, with non-significant results. There was more heterogeneity in the studies with behavioural or composite outcomes. There is a need for replication studies that use similar, clearly defined outcomes. Studies examining optimal duration of SSC, gestational age groups, repeated use, and long-term effects of SSC are needed. Of interest would be to study synergistic effects of SSC with other interventions.
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Olu, Olushayo; Petu, Amos; Ovberedjo, Martin; Muhongerwa, Diane
2017-01-01
Implementation of new models of development cooperation have been on the increase lately. Coupled with this are calls for use of horizontal development cooperation mechanisms such as South-South Cooperation (SSC) as a way to enhance aid effectiveness in the health sector of developing countries. In this case series, we review recent experiences in the application of SSC initiatives to two public health situations in Africa to demonstrate the veracity of this new paradigm. Our review highlight the immense benefits associated with the use of SSC for health and provide evidence for increasing use of horizontal development coordination mechanisms to strengthen public health services delivery and socioeconomic development among African countries. Opportunities for SSC among African countries include in the areas of disease prevention and control, production of medical products and essential medicines, harmonization of regulatory processes, and health workforce development among others. However, pitfalls such as poor coordination, inadequate political commitment, lack of conducive policy environments, language barrier and inadequate financing opportunities for SSC initiatives present major dilemma for the use of SSC mechanisms. We conclude that the need for a paradigm shift from vertical to horizontal development cooperation needs no further proof but a call to action. We call on the concerned stakeholders to support the establishment of a systematic approach for use of SSC mechanisms in the health sector of Africa, designation of an African Centre of Excellence for SSC in public health and development of a regional mechanism for monitoring and evaluation of SSC initiatives in Africa.
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Olu, Olushayo; Petu, Amos; Ovberedjo, Martin; Muhongerwa, Diane
2017-01-01
Implementation of new models of development cooperation have been on the increase lately. Coupled with this are calls for use of horizontal development cooperation mechanisms such as South-South Cooperation (SSC) as a way to enhance aid effectiveness in the health sector of developing countries. In this case series, we review recent experiences in the application of SSC initiatives to two public health situations in Africa to demonstrate the veracity of this new paradigm. Our review highlight the immense benefits associated with the use of SSC for health and provide evidence for increasing use of horizontal development coordination mechanisms to strengthen public health services delivery and socioeconomic development among African countries. Opportunities for SSC among African countries include in the areas of disease prevention and control, production of medical products and essential medicines, harmonization of regulatory processes, and health workforce development among others. However, pitfalls such as poor coordination, inadequate political commitment, lack of conducive policy environments, language barrier and inadequate financing opportunities for SSC initiatives present major dilemma for the use of SSC mechanisms. We conclude that the need for a paradigm shift from vertical to horizontal development cooperation needs no further proof but a call to action. We call on the concerned stakeholders to support the establishment of a systematic approach for use of SSC mechanisms in the health sector of Africa, designation of an African Centre of Excellence for SSC in public health and development of a regional mechanism for monitoring and evaluation of SSC initiatives in Africa. PMID:29158863
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Sendlhofer, Gerald; Mosbacher, Nina; Karina, Leitgeb; Kober, Brigitte; Jantscher, Lydia; Berghold, Andrea; Pregartner, Gudrun; Brunner, Gernot; Kamolz, Lars Peter
2015-01-01
Background A surgical safety checklist (SSC) was implemented and routinely evaluated within our hospital. The purpose of this study was to analyze compliance, knowledge of and satisfaction with the SSC to determine further improvements. Methods The implementation of the SSC was observed in a pilot unit. After roll-out into each operating theater, compliance with the SSC was routinely measured. To assess subjective and objective knowledge, as well as satisfaction with the SSC implementation, an online survey (N = 891) was performed. Results During two test runs in a piloting unit, 305 operations were observed, 175 in test run 1 and 130 in test run 2. The SSC was used in 77.1% of all operations in test run 1 and in 99.2% in test run 2. Within used SSCs, completion rates were 36.3% in test run 1 and 1.6% in test run 2. After roll-out, three unannounced audits took place and showed that the SSC was used in 95.3%, 91.9% and 89.9%. Within used SSCs, completion rates decreased from 81.7% to 60.6% and 53.2%. In 2014, 164 (18.4%) operating team members responded to the online survey, 160 of which were included in the analysis. 146 (91.3%) consultants and nursing staff reported to use the SSC regularly in daily routine. Conclusion These data show that the implementation of new tools such as the adapted WHO SSC needs constant supervision and instruction until it becomes self-evident and accepted. Further efforts, consisting mainly of hands-on leadership and training are necessary. PMID:25658317
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Increasing precision of turbidity-based suspended sediment concentration and load estimates.
Jastram, John D; Zipper, Carl E; Zelazny, Lucian W; Hyer, Kenneth E
2010-01-01
Turbidity is an effective tool for estimating and monitoring suspended sediments in aquatic systems. Turbidity can be measured in situ remotely and at fine temporal scales as a surrogate for suspended sediment concentration (SSC), providing opportunity for a more complete record of SSC than is possible with physical sampling approaches. However, there is variability in turbidity-based SSC estimates and in sediment loadings calculated from those estimates. This study investigated the potential to improve turbidity-based SSC, and by extension the resulting sediment loading estimates, by incorporating hydrologic variables that can be monitored remotely and continuously (typically 15-min intervals) into the SSC estimation procedure. On the Roanoke River in southwestern Virginia, hydrologic stage, turbidity, and other water-quality parameters were monitored with in situ instrumentation; suspended sediments were sampled manually during elevated turbidity events; samples were analyzed for SSC and physical properties including particle-size distribution and organic C content; and rainfall was quantified by geologic source area. The study identified physical properties of the suspended-sediment samples that contribute to SSC estimation variance and hydrologic variables that explained variability of those physical properties. Results indicated that the inclusion of any of the measured physical properties in turbidity-based SSC estimation models reduces unexplained variance. Further, the use of hydrologic variables to represent these physical properties, along with turbidity, resulted in a model, relying solely on data collected remotely and continuously, that estimated SSC with less variance than a conventional turbidity-based univariate model, allowing a more precise estimate of sediment loading, Modeling results are consistent with known mechanisms governing sediment transport in hydrologic systems.
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Environmental Geographic Information Systems (EGIS) at Stennis Space Center (SSC)
NASA Technical Reports Server (NTRS)
Carr, Hugh; Smoot, James; Parikh, Joy
2004-01-01
This viewgraph presentation includes: 1) Background of SSC Environmental GIS (EGIS); 2) Principal Center Activities; 3) SSC's GIS Applications: a) Environmental Emergency Response Tool, b) CERCLA, c) Facilities Master Planning, d) Natural Resource Management and Site Assessment.
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78 FR 6810 - Western Pacific Fishery Management Council; Public Meetings
Federal Register 2010, 2011, 2012, 2013, 2014
2013-01-31
... Scientific and Statistical Committee (SSC). DATES: The SSC will meet on February 26-28, 2013, between 8:30 a.... Introductions. 2. Approval of Draft Agenda and Assignment of Rapporteurs. 3. Status of the 111th SSC Meeting...
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Surgical Safety Checklist compliance: a job done poorly!
Sparks, Eric A; Wehbe-Janek, Hania; Johnson, Rebecca L; Smythe, W Roy; Papaconstantinou, Harry T
2013-11-01
The Surgical Safety Checklist (SSC) has been introduced as an effective tool for reducing perioperative mortality and complications. Although reported completion rates are high, objective compliance is not well defined. The purpose of this retrospective analysis is to determine SSC compliance as measured by accuracy and completion, and factors that can affect compliance. In September 2010, our institution implemented an adaptation of the World Health Organization's SSC in an effort to improve patient safety and outcomes. A tool was developed for objective evaluation of overall compliance (maximum score 40) that was an aggregate score of completion and accuracy (20 each). Random samples of SSCs were analyzed at specific, predefined, time points throughout the first year after implementation. Procedure start time, operative time, and case complexity were assessed to determine association with compliance. A total of 671 SSCs were analyzed. The participation rate improved from 33% (95 of 285) at week 1 to 94% (249 of 265) at 1 year (p < 0.0001, chi-square test). Mean overall compliance score was 27.7 (± 5.4 SD) of 40 possible points (69.3% ± 13.5% of total possible score; n = 671) and did not change over time. Although completion scores were high (16.9 ± 2.7 out of 20 [84.5% ± 13.6%]), accuracy was poor (10.8 ± 3.4 out of 20 [54.1% ± 16.9%]). Overall compliance score was significantly associated with case start-time (p < 0.05), and operative time and case complexity showed no association. Our data indicate that although implementation of an SSC results in a high level of overall participation and completion, accuracy remained poor. Identification of barriers to effective use is needed, as improper checklist use can adversely affect patient safety. Copyright © 2013 American College of Surgeons. Published by Elsevier Inc. All rights reserved.
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Lüders, Susanne; Friedrich, Stefanie; Ohrndorf, Sarah; Glimm, Anne-Marie; Burmester, Gerd-Rüdiger; Riemekasten, Gabriela; Backhaus, Marina
2017-11-01
Colour Doppler ultrasonography (CDUS) is very important in general vascular diagnostic procedures. Its role in determining the extent of vasculopathy in Systemic Sclerosis (SSc) needs further investigation. The aim of this study was to compare the presence of altered arteries with nailfold capillaroscopy and clinical signs of ischaemia, that is, digital ulcers or pitting scars (DU/PS). A feasible CDUS protocol is provided. Two thousand five hundred and twenty-eight arteries of the fingers, palms and wrists from 79 SSc patients (32 arteries per patient) were examined using CDUS. Furthermore, nailfold capillaroscopy, clinical and laboratory data were evaluated. Narrowed or occluded lumens were seen in 39.8% of all assessable arteries (n = 2489) and 48.9% of all proper palmar digital arteries (n = 1564) but only 15.6% (P < 0.0001) of proximal arteries (n = 924). Fingerwise analyses presented significant coincidence of pathological CDUS findings and DU/PS (P = 0.0009). Pathological CDUS findings were also associated with elevated CRP concentrations, current or past smoking with ⩾20 pack-years, male gender and present or past DU/PS. Receiver operating characteristic curve analysis (area under the curve = 0.727) suggested a cut-off value of ⩾20% pathological vessels (sensitivity: 90.7%; specificity: 47.8%) for the presence of DU/PS. An examination protocol focusing on the right-hand digits II-V (proper palmar digital arteries) revealed similar results (area under the curve = 0.751; sensitivity: 93.0%; specificity: 43.5%). CDUS of hand and finger arteries allows measurement of the extent of SSc vasculopathy, which is associated with clinical signs of chronic malperfusion. A shortened examination protocol of CDUS (right-hand digits II-V; 15 min instead of 45 min examination time) could complement vascular diagnostics in SSc. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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Singh, Kavita; Khan, Shane M; Carvajal–Aguirre, Liliana; Brodish, Paul; Amouzou, Agbessi; Moran, Allisyn
2017-01-01
Background Skin–to–skin contact (SSC) between mother and newborn offers numerous protective effects, however it is an intervention that has been under–utilized. Our objectives are to understand which newborns in Bangladesh and Nigeria receive SSC and whether SSC is associated with the early initiation of breastfeeding. Methods Demographic and Health Survey (DHS) data were used to study the characteristics of newborns receiving SSC for non–facility births in Nigeria (DHS 2013) and for both facility and non–facility births in Bangladesh (DHS 2014). Multivariable logistic regression was used to study the association between SSC and early initiation of breastfeeding after controlling for key socio–demographic, maternal and newborn–related factors. Results Only 10% of newborns in Nigeria and 26% of newborns in Bangladesh received SSC. In the regression models, SSC was significantly associated with the early initiation of breastfeeding in both countries (OR = 1.42, 95% CI 1.15–1.76 for Nigeria; OR = 1.27, 95% CI 1.04–1.55, for Bangladesh). Findings from the regression analysis for Bangladesh revealed that newborns born by Cesarean section had a 67% lower odds of early initiation of breastfeeding than those born by normal delivery (OR = 0.33, 95% CI 0.26–0.43). Also in Bangladesh newborns born in a health facility had a 30% lower odds of early initiation of breastfeeding than those born in non–facility environments (OR = 0.70, 95% CI 0.53–0.92). Early initiation of breastfeeding was significantly associated with parity, urban residence and wealth in Nigeria. Geographic area was significant in the regression analyses for both Bangladesh and Nigeria. Conclusions Coverage of SSC is very low in the two countries, despite its benefits for newborns without complications. SSC has the potential to save newborn lives. There is a need to prioritize training of health providers on the implementation of essential newborn care including SSC. Community engagement is also needed to ensure that all women and their families regardless of residence, socio–economic status, place or type of delivery, understand the benefits of SSC and early initiation of breastfeeding. PMID:29423182
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Singh, Kavita; Khan, Shane M; Carvajal-Aguirre, Liliana; Brodish, Paul; Amouzou, Agbessi; Moran, Allisyn
2017-12-01
Skin-to-skin contact (SSC) between mother and newborn offers numerous protective effects, however it is an intervention that has been under-utilized. Our objectives are to understand which newborns in Bangladesh and Nigeria receive SSC and whether SSC is associated with the early initiation of breastfeeding. Demographic and Health Survey (DHS) data were used to study the characteristics of newborns receiving SSC for non-facility births in Nigeria (DHS 2013) and for both facility and non-facility births in Bangladesh (DHS 2014). Multivariable logistic regression was used to study the association between SSC and early initiation of breastfeeding after controlling for key socio-demographic, maternal and newborn-related factors. Only 10% of newborns in Nigeria and 26% of newborns in Bangladesh received SSC. In the regression models, SSC was significantly associated with the early initiation of breastfeeding in both countries (OR = 1.42, 95% CI 1.15-1.76 for Nigeria; OR = 1.27, 95% CI 1.04-1.55, for Bangladesh). Findings from the regression analysis for Bangladesh revealed that newborns born by Cesarean section had a 67% lower odds of early initiation of breastfeeding than those born by normal delivery (OR = 0.33, 95% CI 0.26-0.43). Also in Bangladesh newborns born in a health facility had a 30% lower odds of early initiation of breastfeeding than those born in non-facility environments (OR = 0.70, 95% CI 0.53-0.92). Early initiation of breastfeeding was significantly associated with parity, urban residence and wealth in Nigeria. Geographic area was significant in the regression analyses for both Bangladesh and Nigeria. Coverage of SSC is very low in the two countries, despite its benefits for newborns without complications. SSC has the potential to save newborn lives. There is a need to prioritize training of health providers on the implementation of essential newborn care including SSC. Community engagement is also needed to ensure that all women and their families regardless of residence, socio-economic status, place or type of delivery, understand the benefits of SSC and early initiation of breastfeeding.
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Genome-wide association study for the level of serum electrolytes in Italian Large White pigs.
Bovo, S; Schiavo, G; Mazzoni, G; Dall'Olio, S; Galimberti, G; Calò, D G; Scotti, E; Bertolini, F; Buttazzoni, L; Samorè, A B; Fontanesi, L
2016-10-01
Calcium, magnesium and phosphorus are essential electrolytes involved in a large number of biological processes. Imbalance of these minerals in blood may indicate clinically relevant conditions and are important in inferring acute or chronic pathologies in humans and animals. In this work, we carried out a genome-wide association study (GWAS) for the level of these three electrolytes in the serum of 843 performance-tested Italian Large White pigs. All pigs were genotyped with the Illumina PorcineSNP60 BeadChip, and GWAS was carried out using genome-wide efficient mixed-model association. For the level of Ca(2+) , eight single nucleotide polymorphisms (SNPs) were significant, considering a false discovery rate (FDR) < 0.05, and another eight were above the moderate association threshold (Pnominal value < 5.00E-05). These SNPs are distributed in four porcine chromosomes (SSC): SSC8, SSC11, SSC12 and SSC13. In particular, a few putative different signals of association detected on SSC13 and one on SSC12 were in genes or close to genes involved in calcium metabolism (P2RY1, RAP2B, SLC9A9, C3orf58, TSC22D2, PLCH1 and CACNB1). Only one SNP (on SSC7) and six SNPs (on SSC2 and SSC7) showed moderate association with the level of magnesium and phosphorus respectively. The association signals for these two latter minerals might identify genes not known thus far for playing a role in their biological functions and regulations. In conclusion, our GWAS contributed to increased knowledge on the role that calcium, magnesium and phosphorus may play in the genetically determined physiological mechanisms affecting the natural variability of mineral levels in mammalian blood. © 2016 Stichting International Foundation for Animal Genetics.