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Objectives To characterize patients with positive anti-topoisomerase I (ATA) in lcSSc. Methods SSc patients enrolled in the EUSTAR cohort with a disease duration of ≤3 years at database entry were considered. We assessed the risk of major organ involvement in the following groups: ATA-lcSSc vs ACA-lcSSc and vs ANA without specificity (ANA)-lcSSc, and ATA-lcSSc vs ATA-dcSSc. Cox regression models with time-dependent covariates were performed with the following outcomes: new-onset interstitial lung disease (ILD), ILD progression [forced vital capacity (FVC) decline ≥10% and ≥5% vs values at ILD diagnosis), primary myocardial involvement (PMI), pulmonary hypertension (PH), any organ involvement and all-cause mortality. Results We included 1252 patients [194 ATA-lcSSc (15.5%)], with 7.7 years (s.d. 3.5) of follow-up. ILD risk was higher in ATA-lcSSc vs ACA- and ANA-lcSSc and similar to ATA-dcSSc, although with less frequent restrictive lung disease. The risk of FVC decline ≥10% (35% of ATA-lcSSc) was lower in ATA-lcSSc than in ATA-dcSSc, whereas FVC decline ≥5% occurs similarly between ATA-lcSSc (58% of patients) and other SSc subsets, including ATA-dcSSc. The risk of PMI was similar in ATA-lcSSc and ANA-lcSSc but lower than in ACA-lcSSc; no difference in PH and mortality risk was observed among lcSSc subsets. The risk of any organ involvement, PMI and PH was lower and the mortality tended to be lower in ATA-lcSSc vs ATA-dcSSc. Conclusion ATA-lcSSc patients have a high risk of ILD, albeit with a lower risk of progression compared with ATA-dcSSc, supporting careful screening for ILD in this subgroup.

Objective To investigate outcomes following the tapering or discontinuation of tocilizumab in patients with diffuse cutaneous SSc (dcSSc) in a real-world setting. Methods Fifteen patients who were treated with tocilizumab for dcSSc were selected from a single-centre cohort database and were evaluated for serial changes in the modified Rodnan total skin thickness score (mRSS) and predicted forced vital capacity (FVC) and the occurrence of clinical worsening events after the introduction of tocilizumab. Results Over 12 months of treatment with tocilizumab, the mRSS decreased from 20.4 ± 10.7 to 12.3 ± 8.5 (P = 0.003) and FVC increased from 84.3 ± 13.7% to 88.5 ± 16.4% (P = 0.04). Tocilizumab was tapered or discontinued in seven and three patients, respectively, after improvement in skin thickening without occurrence or progression of organ manifestations. One (14%) of seven patients who underwent tocilizumab tapering experienced a worsening of skin thickening, while all three patients who discontinued tocilizumab experienced a worsening of skin thickening and/or new development of pericarditis, arthritis, interstitial lung disease or pulmonary arterial hypertension. The additional patient who discontinued tocilizumab due to an adverse event experienced subsequent progression of multiple organ manifestations, including skin, lung, lower gastrointestinal and renal involvement, leading to mortality. Conclusion Our findings suggest potential benefits of prolonged tocilizumab use in dcSSc patients. The discontinuation of tocilizumab can lead to the progression of skin and visceral manifestations. Tapering rather than the discontinuation of tocilizumab is a viable option in dcSSc patients who experience remarkable clinical improvement.

Objectives The double-blind, parallel-group comparison, investigators initiated phase II clinical trial of IDEC-C2B8 (Rituximab) in patients with Systemic sclerosis (DesiReS) trial showed that rituximab is effective in treating skin sclerosis in SSc. However, which patient groups are likely to benefit from rituximab is unknown. Methods We performed post-hoc analysis of prospective data from 54 patients who received rituximab or placebo in the DesiReS trial. Twenty-seven baseline factors were used to investigate subpopulations with different magnitudes of rituximab effect on modified Rodnan skin score (mRSS) change at 24 weeks. Based on a machine-learning algorithm called the causal tree, we explored the combination of predictors needed to identify subpopulations that would respond to rituximab and have good treatment outcomes. Results Three factors were identified as branches of the decision tree: peripheral blood CD19-positive cell counts’, ‘mRSS’, and ‘serum surfactant protein D (SP-D) levels’. It was only in the subpopulation of patients with CD19-positive cell counts of Conclusion SSc patients who have high CD19-positive cell counts and high mRSS are expected to have greater improvement in mRSS with rituximab. When the patients with high CD19-positive cell counts show low mRSS, serum SP-D levels may modify the treatment effect. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT04274257 and UMIN-CTR; https://center6.umin.ac.jp, UMIN000030139.

Objectives The aim of this study was to comprehensively identify instruments within relevant domains employed to assess lcSSc since the endorsement of its consensus definition in 1988. The overall objective is to inform the creation of a Combined Response Index for Scleroderma Trials Assessing lcSSc (CRISTAL). Methods MEDLINE and Embase were searched using terms selected to comprehensively retrieve titles and abstracts mentioning both lcSSc and dcSSc, along with those only mentioning lcSSc, SSc sine scleroderma, limited SSc and/or CREST/CRST. Because our initial assessment of the literature revealed that very few studies included only lcSSc subjects, we also assessed literature that included both cutaneous subsets. A total of 3964 titles and abstracts were screened by two reviewers, and 270 articles were selected for data extraction. Results We identified 27 domains encompassing 459 instruments. Instruments from ‘Skin involvement’, ‘Pulmonary involvement’ and ‘Health-related quality of life and general functioning’ were the most frequently retrieved. Among the 15 most represented instruments announced as primary end points in efficacy or effectiveness studies, 7 were clinician-reported outcomes (ROs), 7 were patient ROs, and one was a performance outcome (6 min-walk test). The mean proportion of lcSSc patients in studies of lcSSc, including studies that mention both lcSSc and dcSSc, was 56.4%, demonstrating that this subset is underrepresented in the literature, given that the prevalence of lcSSc ranges from 60% to 80% in national registries and international cohorts. Conclusion This scoping literature review provides a comprehensive identification of domains and outcomes used to assess lcSSc. Our results also highlight that lcSSc is underrepresented in the literature.

Objective SSc reduces upper extremity function and performance of everyday activities; however, there are few evidence-based rehabilitation interventions. This study examined short and longer-term effects of two occupational therapy interventions on hand disability. Methods Participants with diffuse cutaneous SSc were randomized to one of two 18-week interventions: Intensive group, receiving eight weekly in-person occupational therapy sessions with App-delivered home exercises, or App Alone group. The primary outcome was QuickDASH hand disability; secondary outcomes were physical function (PROMIS scale), and total active hand motion. Linear mixed models were used to examine treatment effects. Results Most participants were female (72%); the mean age was 52 years (13.4) (n = 32). There were no significant between-group effects on QuickDASH (P = 1.0; mean change −6.4 on 0–100 scale in both groups at 18 weeks). Left lateral pinch, an exploratory outcome, improved in App Alone compared with Intensive from baseline to 18 weeks. Within groups, the Intensive group had the largest improvements after 8 weeks (−8.5 on QuickDASH; P = 0.03), but then lost gains from 8 to 18 weeks while the App Alone group had modest improvements from baseline to 8 weeks, but then continued to improve. Of completers, 50% had clinically meaningful improvement on QuickDASH in the Intensive group and 64% had improvement in App Alone. Conclusion Both interventions showed beneficial effects on hand disability. Participants in the App Alone group improved equally to the Intensive group at 18 weeks. Our findings provide support for further study into telehealth rehabilitation approaches. Trial registration NCT03482219

Objectives Clinical trials in early diffuse cutaneous systemic sclerosis (SSc) using the modified Rodnan skin score (mRSS) as the primary outcome measure have most often been negative. We wanted to assess how the definition of disease onset (first SSc manifestation vs first non-Raynaud manifestation) and varying lengths of disease duration at trial entry as an inclusion criteria functioned. Our objective was to optimize trial inclusion criteria Methods We used the prospective, observational University of Pittsburgh Scleroderma Cohort to identify early diffuse SSc patients first evaluated between 1980 and 2015. All had Results There was no appreciable difference between using first SSc manifestation compared with first non-Raynaud manifestation as the definition of disease onset. Compared with other disease durations, 70% of patients fitting into trajectories with worsening cutaneous disease over 6 months of follow-up. Longer disease durations demonstrated the majority of patients with trajectories showing an improvement in mRSS (regression to the mean) over 6 months. Conclusions Regardless of whether the first SSc or first non-Raynaud manifestation is used to define disease onset, duration of

Objective To determine whether skin score changes are associated with changes in overall disease severity, function and quality of life in early dcSSc patients. Methods A total of 154 and 128 dcSSc patients from the Canadian Scleroderma Research Group database with 1 and 2 year follow-up and a disease duration ⩽5 years without end-stage organ damage and/or significant comorbidity at the initial visit were included. Skin was assessed using the modified Rodnan skin score (mRSS) and disease severity by the summed Medsger disease severity score (DSS) (without skin domain), physician and patient global assessments, function [HAQ disability index (HAQ-DI)] and quality of life [36-item Short Form Health Survey (SF-36) physical component summary (PCS)]. Analyses were repeated in patients with a disease duration ⩽3 years. Results At 2 years, 64 (50%) patients had improved skin (mRSS decrease of ⩾5 points and/or ⩾25%). Skin improvers had improved summed DSS (P = 0.002); better physician global assessments of disease activity, severity and damage (all P ⩽ 0.003); better HAQ-DI (P = 0.001) and SF-36 PCS (P = 0.005). Changes in the mRSS were positively correlated with changes in summed DSS (P = 0.006) and other disease outcomes. In the 26 (20.3%) patients with worsened skin (mRSS increase of ⩾5 points and/or ⩾25%), the summed DSS and physician global assessments were worse (P = 0.01 and P ⩽ 0.009, respectively). In the subgroup with a disease duration ⩽3 years, similar associations were found. Conclusion At 1 and 2 years, overall disease improvement parallels skin improvement in early dcSSc. This is important for prognosis and reflects the value of mRSS as an outcome measure in trials with these patients.

Objectives SSc is characterized by fibrotic changes in the skin and lung, and the mainstay of treatment has been CYC. B cell involvement suggests that rituximab (RTX) may also be of therapeutic benefit. The aim of the study was to compare the efficacy and safety of RTX compared with CYC in retarding the progression of interstitial lung disease and skin manifestations of primary SSc. Methods We randomly assigned 60 patients of dcSSc, age 18-60 years with skin and lung involvement, to monthly pulses of CYC 500 mg/m2 or RTX 1000 mg × 2 doses at 0, 15 days. Primary outcomes were forced vital capacity (FVC) percent predicted at 6 months. Secondary outcomes were: absolute change in litres (FVC-l) at 6 months; modified Rodnan skin scores at 6 months, 6-min walk test, Medsgers score and new onset or worsening of existing pulmonary hypertension by echocardiographic criteria. Results The FVC [%mean (s.d.)] in the RTX group improved from 61.30 (11.28) to 67.52 (13.59), while in the CYC group it declined from 59.25 (12.96) to 58.06 (11.23) at 6 months (P = 0.003). The change of FVC was 1.51 (0.45) l to 1.65 (0.47) l in the RTX group, compared with 1.42 (0.49) to 1.42 (0.46) l in the CYC group. The mRSS changed from 21.77 (9.86) to 12.10 (10.14) in the RTX group and 23.83 (9.28) to 18.33 (7.69) in the CYC group after 6 months. Serious adverse events were more common in the CYC group. Conclusion RTX is a safe and effective alternative to CYC in the primary therapy of skin and lung manifestations of scleroderma. Trial registration Clinical Trials Registry - India, www.ctri.nic.in, CTRI/2017/07/009152.

Objective 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. Methods 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. Results 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. Conclusion 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.

OBJECTIVES The overexpression of IL-12 family cytokines is implicated in the pathogenesis of SSc, but their exact role is still unclear. The aim of this study was to investigate the regulation of extracellular matrix expression by IL-23 and its contribution to the phenotype of SSc. METHODS The mRNA expression was determined by PCR array and real-time PCR. The expression levels of proteins were determined by immunoblotting and immunohistochemical staining. The effect of IL-23 on dermal fibrosis in vivo was examined in a mouse model of SSc induced by bleomycin injection. RESULTS Among the IL-12 family members, IL-23 decreased expression of type I collagen protein in cultured normal dermal fibroblasts. We found that miR-4458 and miR-18a mediated the reduction of collagen expression by IL-23. On the contrary, IL-23 up-regulated type I collagen expression in SSc fibroblasts. The paradoxical effects of IL-23 in SSc fibroblasts were also mediated by the balance between miR-4458 and miR-18a expression. Moreover, we revealed that injection of IL-23 into the mouse skin accelerated skin fibrosis. CONCLUSION This is the first study to report that the balance of two miRNAs is involved in the collagen dysregulation in SSc fibroblasts. Clarification of the regulatory mechanism of tissue fibrosis by IL-23 in SSc skin may lead to a better understanding of this disease and new therapeutic approaches.

Contains fulltext : 171205.pdf (Publisher’s version ) (Closed access) OBJECTIVE: DcSSc is associated with high morbidity related to widespread skin disease and poor prognosis due to earlier and more severe organ involvement. The objective of this study is to derive and validate a simple prediction rule for identifying patients at the time of initial diagnosis of SSc who are likely to progress to dcSSc. METHODS: The Nijmegen cohort consists of 619 SSc patients. Logistic regression was used for predictive modelling. A prediction rule was created by rounding regression coefficients. Patients were stratified as being at low risk (

Objective 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. Methods 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. Results 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. Conclusion 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.

There is new evidence that B-cell depletion could be an effective intervention in patients with SSc. Observational case-control study data from the European League Against Rheumatism Scleroderma Trials and Research group has suggested that rituximab therapy may reduce progression of skin thickening and lung fibrosis, especially in a subgroup with early dcSSc. These positive data remain preliminary and need to be viewed with caution, recognizing the spontaneous regression of skin thickening that may occur during early disease. In this review, we summarize the clinical evidence for the therapeutic use of rituximab in SSc as well as the basic science evidence suggesting that B cells and autoantibodies are the primary drivers of fibrosis in skin and lung tissue. We have also reviewed the parallels between SSc and the other CTDs where B-cell depletion therapy is efficacious.

Objective. Although several miRNAs have been shown to regulate autoimmune pathogenesis by affecting lymphocyte function, the roles of miRNAs in the pathogenesis of SSc remain unclear. Therefore the purpose of this study was to identify miRNAs that play a role in the pathogenesis of SSc by quantitative PCR screening of serum miRNAs. Methods. Ninety-five miRNAs that were predicted to target SSc-related genes [IL-4, TGF-b, CTGF, PDGFB, PDGF receptor (PDGFR) a/b and COL1A2) by in silico analyses were selected. The expression of these miRNAs in sera of SSc patients and healthy controls was measured by quantitative PCR. Involvement of miR-30b, which was most strongly down-regulated in SSc patients, in the regulation of PDGFR-b expression was examined by transfection experiments and 3 0 -untranslated region (3 0 -UTR) target luciferase assays. The expression of miR-30b in skin was evaluated in a bleomycin-induced dermal fibrosis model in mice and in SSc patients. Results. Nineteen of 95 miRNAs were significantly decreased in the sera of SSc patients. Among them, miR-30b was most strongly down-regulated in SSc patients (P = 0.00006) and the levels of miR-30b were inversely correlated with modified Rodnan skin scores. Transfection of a miR-30b mimic repressed PDGFR-b expression in dermal fibroblasts and the activity of a luciferase reporter containing 3 0 -UTR of PDGFR-b. Moreover, the expression of miR-30b was down-regulated in bleomycin-treated sclerotic skin and in affected skin in SSc patients. Conclusion. Down-regulation of miR-30b might be involved in the pathogenesis of SSc.

Objective. Visfatin is a member of the adipocytokines with pro-fibrotic, pro-inflammatory and immunomodulating properties potentially implicated in the pathogenesis of certain fibrotic and inflammatory autoimmune diseases. In this study, we investigated the clinical significance of serum visfatin levels and its contribution to the developmental process in SSc. Methods. Serum visfatin levels were determined by a specific ELISA in 57 SSc patients and 19 healthy controls. The mRNA levels of target genes were determined in normal and SSc fibroblasts by real-time RT-PCR. The levels of IL-12p70 produced by THP-1 cells were measured by a specific ELISA. Results. Serum visfatin levels were comparable among total SSc, diffuse cutaneous SSc (dcSSc), limited cutaneous SSc and healthy controls. The only finding in a series of analyses regarding the correlation of serum visfatin levels with clinical symptoms and laboratory data was the significantly longer disease duration in dcSSc with elevated serum visfatin levels than in those with normal levels. Consistently, serum visfatin levels were significantly elevated in late-stage dcSSc (disease duration >6 years), but not in early and mid-stage dcSSc compared with healthy controls. In in vitro experiments, visfatin reversed the pro-fibrotic phenotype of SSc dermal fibroblasts and induced the expression of IL-12p70 in THP-1 cells treated with IFN-g plus lipopolysaccharide. Conclusion. Visfatin may contribute to the resolution of skin sclerosis in late-stage dcSSc via a direct anti-fibrotic effect on dermal fibroblasts and Th1 polarization of the immune response.

Objective: To assess patients with SSc who present without circulating antinuclear antibodies (ANA) or Raynaud’s phenomenon (RP).Methods: 5390 patients who fulfilled the ACR criteria for SSc and were enrolled in the EULAR Scleroderma Trials And Research (EUSTAR) database were screened for the absence of both RP and circulating ANA. To differentiate SSc from its mimics, additional information was gathered using a standardized questionnaire. Results: 5378 (99.8%) of the 5390 SSc patients in the EUSTAR database had either detectable ANA or a history of RP. Twelve patients (0.2%) lacked both circulating ANA and RP. Details of the medical history could be obtained for six patients. Three cases were compatible with ANA-negative and RP-negative SSc and were not typical of any known SSc mimic. Four patients had a malignancy: two had breast cancer, one had multiple myeloma with possible scleromyxoedema, and one had bladder carcinoma. There was no temporal relationship between the onset of skin fibrosis and that of the tumor. Although no patient with confirmed nephrogenic systemic fibrosis (NSF) was identified among the cases of ANA-negative and RP-negative SSc, the presentation of one patient could be compatible with that of NSF other than for the absence of chronic kidney disease or of known prior gadolinium exposure. Conclusion: We have identified a very small subgroup of SSc patients who lack both circulating ANA-and RP, none of whom fulfils the diagnostic criteria for any known SSc mimic. Prospective studies are needed to elucidate the clinical presentation, evolution, and outcome of such patients. Objective. To assess patients with SSC who present without circulating ANAs or RP. Methods: Five thousand three hundred and ninety patients who fulfilled the ACR criteria for SSc and were enrolled in the EULAR Scleroderma Trials and Research (EUSTAR) database were screened for the absence of both RP and circulating ANA. To differentiate SSc from its mimics, additional information was gathered using a standardized questionnaire. Results: Five thousand three hundred and seventy-eight (99.8%) of the 5390 SSc patients in the EUSTAR database had either detectable ANA or a history of RP. Twelve (0.2%) patients lacked both circulating ANA and RP. Details of the medical history could be obtained for seven patients. Three cases were compatible with ANA-negative and RP-negative SSc and were not typical of any known SSc mimic. Four patients had a malignancy: two had breast cancer, one had multiple myeloma with possible scleromyxoedema and one had bladder carcinoma. Therewas no temporal relationship between the onset of skin fibrosis and that of the tumour. Although no patient with confirmed nephrogenic systemic fibrosis was identified among the cases of ANA-negative and RP-negative SSc, the presentation of one patient could be compatible with that of nephrogenic systemic fibrosis other than for the absence of chronic kidney disease or of known prior gadolinium exposure. Conclusion: We have identified a very small subgroup of SSc patients who lack both circulating ANA and RP, none of whom fulfils the diagnostic criteria for any known SSc mimic. Prospective studies are needed to elucidate the clinical presentation, evolution and outcome of such patients.

Objective. Inducible costimulator (ICOS), expressed on activated T cells, and its ligand, ICOS ligand (ICOSL), expressed on antigen-presenting cells, have been considered a single receptorligand pair. Here we investigated the expression of ICOS and ICOSL in patients with SSc. Methods. ICOS expression on peripheral blood T cells, and ICOSL expression on B cells and macrophages was determined by flow cytometry. Expression of ICOS and ICOSL was assessed by immunohistological staining and real-time PCR of lesional skin. Results. ICOS expression levels were specifically increased on both peripheral blood memory T cells and Tregs from early dcSSc patients compared with those from healthy controls. Mean ICOSL expression on B cells or macrophages was comparable between SSc patients and healthy controls. ICOS-expressing T cells, ICOSL-expressing macrophages and mRNA levels of ICOS and ICOSL were increased in the lesional skin of patients with early dcSSc. In vitro ICOS costimulation enhanced production of IFN-g, IL-4 and IL-17A from T cells in SSc patients vs normal controls. Soluble ICOS levels were significantly increased in SSc patients and were negatively associated with the presence of ACAs and positively associated with CRP values. Serum levels of soluble ICOS were more closely associated with clinical features compared with levels of soluble IL-2 receptor. Conclusion. Augmented ICOS signalling may contribute to the pathogenesis of SSc during early progressive disease. Soluble ICOS levels may be used as a serum marker for the activity and severity of SSc.

Objectives microRNAs (miRNAs) play a part in various cellular activities. However, the role of miRNA in SSc is not fully understood. This study investigated the expression and role of miR-92a in SSc patients and evaluated the possibility that miR-92a is involved in the pathogenesis of this disease. Methods Serum samples were obtained from 61 SSc patients. mRNAs were purified from serum and levels of miR-92a and miR-135 were measured with quantitative real-time PCR. miR-92a expression in dermal fibroblasts was also determined by quantitative real-time PCR. Immunoblotting was performed to detect MMP-1 protein. Results The median serum levels of miR-92a, not miR-135, were significantly higher in SSc patients than normal subjects. The constitutive up-regulated miR-92a expression was also found in cultured dermal fibroblasts from SSc skin, which was decreased by the transfection with siRNA of TGF-β. Furthermore, the forced overexpression of miR-92a in normal dermal fibroblasts using miR-92a mimic resulted in the down-regulation of MMP-1 expression. Conclusion The increase of miR-92a in SSc may be due to the stimulation of intrinsic TGF-β activation seen in this disease. There is also a possibility that MMP-1 is the target of miR-92a and that increased miR-92a expression therefore plays a role in excessive collagen accumulation in SSc via the down-regulation of MMP-1. Clarifying the role of miRNAs in SSc may result in a better understanding of this disease and the development of new therapeutic approaches.

Objective. To assess the prevalence of SSc in south-east Norway. Methods. The survey was conducted in south-east Norway with a denominator population of 2 707 012, 56% of the total Norwegian population. All SSc patients living in the study area between 1 January 1999 and 31 December 2009 were included. Patients were identified by five overlapping acquisition routes, including all the rheumatology departments, private rheumatologists and the dermatology department in the study area. Only cases meeting the 1980 ACR and/or the Medsger and LeRoy classification criteria were included. The patients were assigned to three clinical subsets: limited SSc, lcSSc or dcSSc. Results. At the end of the study period, a total of 269 patients fulfilled the ACR and/or the Medsger and LeRoy SSc criteria, giving a point prevalence of 9.9/100 000 (95% CI 8.8, 11.2). The estimated prevalences of lSSc, lcSSc and dcSSc were 1.3/100 000, 6.9/100 000 and 1.8/100 000 (95% CIs 0.9, 1.8; 5.8, 7.8; 1.4, 2.5), respectively. The mean age at onset was 47 years and the female : male ratio was 3.8 : 1. The prevalence estimates of SSc in the 10 different counties in south-east Norway varied between 5.2 and 14.4/100 000 (95% CIs 2.8, 8.8; 10.3, 19.6). Conclusion. This study establishes baseline estimates of the occurrence and disease characteristics in a large, unselected group of Norwegian SSc patients. Our data suggest that the prevalence of SSc in Norway is comparable with other northern European countries, supporting the notion of a northsouth gradient of SSc in Europe with the lowest prevalence in northern Europe.

OBJECTIVE: To evaluate the clinical significance of anti-angiogenic receptor cluster of differentiation 36 (CD36) in serum of patients with SSc. METHODS: We studied 47 SSc patients (28 with lcSSC and 19 with dcSSC) and 38 age- and gender-matched healthy controls. Demographic, clinical, autoantibodies and serological data were prospectively assessed. Peripheral vascular affection was classified into mild, moderate, severe or end-stage based on a vascular severity scale. Soluble CD36 (sCD36) serum levels were measured using ELISA. RESULTS: Serum sCD36 levels were significantly higher in patients with SSc compared with healthy controls (P = 0.045). When the patients were divided into clinical subsets, sCD36 was higher in lcSSc than in healthy controls (P = 0.03). Levels of sCD36 were found to be positively correlated with pulmonary artery systolic pressure (PASP) and negatively correlated with percentage diffusing lung capacity for carbon monoxide (DL(CO)). In the multivariate analysis, 50% of the variation of sCD36 levels could be explained by elevated PASP (0.000), telangiectasias (0.026) and increasing vascular severity (P = 0.003). CONCLUSION: Serum sCD36 levels were higher in SSc patients (particularly the limited subset) than in healthy controls and were found to be correlated with PASP and vascular severity. We conclude that sCD36 may be a marker for elevated PASP and vascular involvement in SSc. To confirm our results we propose that larger scale, multicentre studies with longer evaluation periods are needed.

Objective. Although the incidence of dcSSc is higher in African-American and Hispanic populations compared with European Caucasian patients, it is not clear whether there are differences in subsequent disease course. Also, the potential impact of gender on the disease course of dcSSc is not well defined. Our objective was to assess the course of modified Rodnan skin score (MRSS), HAQ-disability index (HAQ-DI) and forced vital capacity per cent (FVC%) predicted between men vs women and three ethnic groups with dcSSc participating in three randomized clinical trials (RCTs). Method. Data from RCTs (n = 495) were pooled and analysed. Baseline characteristics were compared in men vs women and among ethnic groups. A linear mixed effects model was used to assess the predictors of MRSS, HAQ-DI and FVC%. The primary independent variables were time-in-study and its interaction with gender and ethnicity. The models were adjusted for other covariates that were significant at baseline between gender and ethnicity analyses. Results. Men had lower HAQI-DI scores compared with women (P

Objectives. Male microchimerism (Mc) persisting from pregnancy has been found at greater frequencies and/or higher quantities in women with scleroderma (SSc) compared with controls, suggesting a possible role in disease development. Moreover, women with an HLA-compatible child have a higher risk to develop SSc. We tested the hypothesis, on our French SSc cohort, that women with lcSSc and dcSSc, two distinct clinical subsets, have a different profile in terms of Mc and HLA compatibility in families. Methods. We studied 98 women (52 lcSSc and 46 dcSSc) for male Mc, by real-time PCR, in their whole blood and/or peripheral blood mononuclear cells (PBMC). Similarly, 91 matched healthy women were analysed. Complete HLA-DRB1 typing was obtained for 58 SSc and 68 control families (proband/children). Results. Women with lcSSc (N ¼ 50) had male Mc more often in their whole blood than women with dcSSc (N ¼ 40, 20 vs 5%, P ¼ 0.038), but not significantly more than controls. By contrast, women with dcSSc (N ¼ 36) hold Mc more often in PBMC (25 vs 9%), but not significantly and have greater quantities than controls (N ¼ 82, P ¼ 0.048). This contrast is also visible in feto-maternal HLA-DRB1 compatibility, which was increased only among women with lcSSc (N ¼ 33) compared with controls (N ¼ 68, P ¼ 0.003). Conclusion. For the first time, we showed that women with lcSSc and dcSSc hold male Mc in different blood compartments. Furthermore, a distinct pattern between the two SSc subtypes is observed for feto-maternal HLA-DRB1 compatibility. These results suggest a different mechanism behind each type of disease.

Objectives. In SSc, diagnosis and classification is based mainly on skin sclerosis. Herein, we investigated in a large multicentre cohort, to what extent skin sclerosis reflects organ involvement and additional clinical symptoms. Methods. A total of 1200 SSc patients from the register of the German Systemic Sclerosis Network (DNSS), classified as either IcSSc or dcSSc, were analysed for their serological characteristics, clinical symptoms and organ manifestations in relation to skin involvement measured by the modified Rodnan skin score (mRSS). Results. SSc patients with different mRSS did not differ significantly in their disease duration and in most of the clinical symptoms. They showed a similar distribution of most organ manifestations such as pulmonary arterial hypertension as well as cardiac, renal and nervous system involvement. More severe skin thickening was found to be associated with pulmonary fibrosis and gastrointestinal symptoms, as well as with digital ulcers and musculoskeletal involvement. Conclusions. In patients with SSc, potentially life-threatening complications and clinical symptoms with high impact on the quality of life occur independently from the extent of skin sclerosis. The diagnosis in SSc patients with a low mRSS could be missed or they could be insufficiently treated.

Objectives. To examine the frequency and correlates of fatigue and its impact on physical and social functioning in patients with scleroderma, and to investigate whether fatigue mediates an association between pain and physical function. Methods. One hundred and seven scleroderma patients attending an academic scleroderma specialty centre completed measures of fatigue, sleep, pain, depressive symptoms, and physical and social functioning. Patients had received a comprehensive clinical assessment with a diagnosis of limited or diffuse scleroderma from their attending rheumatologist. Results. In this sample of scleroderma patients, 76% reported experiencing fatigue and 61% of these patients reported fatigue as one of their three most distressing symptoms. Patients endorsing greater pain had higher levels of self-reported fatigue, as did those reporting greater depression and poorer functioning. Multiple regression analyses indicated that global fatigue was a significant cross-sectional correlate of physical, but not social, functioning after controlling for depressive symptoms, level of education, poor sleep quality and disease subtype. However, global fatigue did not predict physical function when pain was included in the analyses. Conclusions. Our findings indicate that fatigue is common in scleroderma and that pain and fatigue are significant determinants of physical functioning for patients with limited and diffuse disease subtypes. Future research should investigate whether effective pain treatments reduce symptoms of fatigue, as well as identify other possible causes of fatigue in order to improve quality of life for scleroderma patients.

Objective. Systemic sclerosis (SSc) is a rare, heterogeneous disease, which affects different organs and therefore requires interdisciplinary diagnostic and therapeutic management. To improve the detection and follow-up of patients presenting with different disease manifestations, an interdisciplinary registry was founded with contributions from different subspecialties involved in the care of patients with SSc. Methods. A questionnaire was developed to collect a core set of clinical data to determine the current disease status. Patients were grouped into five descriptive disease subsets, i.e. lcSSc, dcSSc, SSc sine scleroderma, overlap-syndrome and UCTD with scleroderma features. Results. Of the 1483 patients, 45.5% of patients had lcSSc and 32.7% dcSSc. Overlap syndrome was diagnosed in 10.9% of patients, while 8.8% had an undifferentiated form. SSc sine scleroderma was present in 1.5% of patients. Organ involvement was markedly different between subsets; pulmonary fibrosis for instance was significantly more frequent in dcSSc (56.1%) than in overlap syndrome (30.6%) or lcSSc (20.8%). Pulmonary hypertension was more common in dcSSc (18.5%) compared with lcSSc (14.9%), overlap syndrome (8.2%) and undifferentiated disease (4.1%). Musculoskeletal involvement was typical for overlap syndromes (67.6%). A family history of rheumatic disease was reported in 17.2% of patients and was associated with early disease onset (P < 0.005). Conclusion. In this nationwide register, a descriptive classification of patients with disease manifestations characteristic of SSc in five groups allows to include a broader spectrum of patients with features of SSc.

Objective. To find an effective, safe immunosuppressive regimen as an alternative to cyclophosphamide (Cy) for the treatment of clinically evident diffuse scleroderma (dSSc)-associated alveolitis of recent onset. Methods. Five consecutive patients with dSSc and recent-onset alveolitis were enrolled and treated with mycophenolate mofetil (MMF) and small (·10 mg/day) doses of predinisolone in this open-label trial. One patient with long-standing fibrosing alveolitis was later added to our cohort. Pulmonary function tests [carbon monoxide diffusing capacity (DLCO) and forced vital capacity (FVC)], pulmonary high-resolution computed tomography (HRCT) scans and clinical assessment were performed before and at specified time-points after enrolment. Cases of significant infections, leucopenia and abdominal pain were recorded. Results. After 4–6 months of MMF therapy, DLCO improved significantly compared with pre-treatment (mean DLCO 75.4% vs 64.2% of predicted value, respectively, P^0.033). Values of FVC also improved, with the difference almost reaching levels of statistical significance (mean FVC 76.2% vs 65.6% of predicted value, P^0.057). Ground glass opacities cleared in three of four patients with recent-onset alveolitis and were reduced in one patient after 6–8 months of treatment. Breathlessness and cough improved by 3 months. A possible treatment failure was seen in one patient. However, in five patients functional and clinical improvement was sustained during the study period. No adverse events were recorded in this ongoing clinical trial. Conclusion. Our preliminary data suggest that in patients with dSSc and recent, clinically apparent alveolitis, early treatment with MMF and small doses of corticosteroids (CS) may represent an effective, well-tolerated and safe alternative therapy.

Objectives. To determine the relationship between clinical features and circulating levels of active transforming growth factor (TGF) beta 1 in the major subsets of systemic sclerosis (SSc).Methods. In a cross-sectional study cases of diffuse cutaneous SSc (dose) (n=27) or limited cutaneous SSc (dose) (n=20) were compared with healthy controls (n=22). Active and total TGF beta 1 was measured in serum and plasma by a high-sensitivity enzyme-linked immunosorbent assay.Results. There were no significant differences between levels of total serum TGF beta 1. However, cases of dcSSc had lower levels of active TGF beta 1 than cases of lcSSc or controls. In addition, more cases of dcSSc (18/27; 66%, P < 0.025) had no detectable active TGF beta 1 than controls (7/22, 32%) or lcSSc (7/20, 35%). In dcSSc, serum active TGF beta 1 levels correlated negatively with skin score and positively with disease duration.Conclusions. Contrary to expectation, levels of active TGF beta 1 are reduced in dcSSc and this correlates with two variables known to associate with disease activity, shorter duration and more extensive skin sclerosis. This suggests that active TGF beta 1 may be sequestered in active involved SSc skin and that serum levels are reduced despite strong evidence implicating TGF beta isoforms in the pathogenesis of fibrosis. Our findings may have implications for systemic TGF beta-trapping therapies in this disease.

Objective Evidence shows that peripheral nervous system (PNS) is involved in systemic sclerosis (SSc), but few morphological studies have assessed the ultrastructural pathological modifications. The aim was to study ultrastructural modifications of skin PNS fibres in SSc according to subsets [limited SSc (lSSc) and diffuse SSc (dSSc)] and phases (early and advanced) of the disease. Methods Skin biopsies were taken from the forearms of 23 SSc patients (11 lSSc and 12 dSSc) and 10 controls. Each biopsy was processed for transmission electron microscopy (TEM). Results At TEM, observation in skin from early lSSc, signs of inflammation were evident, while PNS fibres were not damaged. The microvascular wall showed hypertrophic endothelial cells bulging into the lumen. In advanced lSSc, fibrosis prevailed on inflammation and slight ultrastructural alterations of PNS fibres were evident in the papillary derma. In early dSSc, ultrastructural alterations of PNS fibres, similar to those observed in the advanced phase of lSSc, were found together with signs of inflammation and fibrosis. In advanced dSSc, in the papillary and reticular dermis PNS fibres were reduced and showed relevant ultrastructural alterations. Conclusions In SSc, PNS ultrastructure damage is linked to the progression and severity of skin involvement. The alterations evolve from the early to the advanced phase mainly in the diffuse subset. In particular, the severe PNS lesions found in advanced lSSc are already present and widely diffuse in early dSSc and the microvascular involvement in early lSSc seems to precede the modification of the PNS in the skin. Thus, an early therapeutic approach can be useful to reduce the progression of PNS and skin damage in SSc patients.

Objective SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein that modulates cell-cell and cell-extracellular matrix interactions. SPARC expression is restricted mainly to sites of tissue remodelling and wound repair, and is prominent in fibrotic disorders. Single-nucleotide polymorphisms (SNPs) in the SPARC gene are reportedly linked to scleroderma in four ethnic groups: Choctaw Indians, Caucasians, African Americans and Mexican Americans. We set out to reproduce and to positionally clone these disease associations in a set of UK Caucasian scleroderma patients and ethnically matched controls. Methods One hundred and twenty-one scleroderma subjects and 200 controls were genotyped by polymerase chain reaction with sequence-specific primers differing only in the 3' nucleotide corresponding to each allele of the biallelic SNPs. Scleroderma patients were analysed against controls and on the basis of their fibrosing alveolitis status as judged by high-resolution computed tomography evaluation and the extent of cutaneous involvement. Results Eight biallelic SNPs were genotyped: three from the last untranslated exon, which had been described previously, and an additional five novel SNPs: two in the promoter region, one in exon three and two in the 3' untranslated region. Six major haplotypes were constructed across all eight SNP positions. No significant differences in genotype, allele or haplotype frequency were observed between scleroderma and controls or within scleroderma subgroups. Conclusions SNPs in the SPARC gene are not associated with susceptibility to scleroderma. This research adds to the genetic knowledge of the SPARC gene by identifying five novel SNPs spanning the whole gene and inserting these within the context of clearly defined haplotypes.

Objective. Large-vessel arterial disease is increasingly recognized as a major cause of morbidity in autoimmune rheumatic disorders. Recent evidence suggests that scleroderma (systemic sclerosis, SSc) may be linked to altered fibrillin-1 metabolism associated with a defect in chromosome 15q. If this is the case, we may expect to see changes in the arterial wall mechanics of large vessels not clinically involved in the disease process. We undertook a study to determine whether the biomechanical properties and intima-media thickness (IMT) of the elastic carotid artery and the muscular femoral artery are altered in subjects with limited (lcSSc) and diffuse (dcSSc) cutaneous SSc.Methods. Measurements of carotid and femoral wall mechanics were made in 33 patients with lcSSc, 19 patients with dcSSc and 21 control subjects, using a duplex scanner coupled to a Wall Track system. Their age, gender, body mass index, heart rate, systolic and diastolic blood pressures, presumed cardiovascular load, and plasma creatinine, fasting cholesterol, triglyceride and glucose concentrations were also measured.Results. There was a progressive and significant reduction (P < 0.001) in the elastic properties of the carotid artery from the control group (compliance, 16.24 +/- 4.39 %mmHg(-1) x 10(-2)) to the lcSSc group (10.89 +/- 2.43 %mmHg(-1) x 10(-2)) to the dcSSc group (7.65 +/- 2.08 %mmHg(-1) x 10(-2)), even after adjustment for the systemic physiological and biochemical variables studied, which are known to influence the mechanics of arterial walls. There was no apparent difference between the groups in the mean elastic indices of the femoral artery and the IMT of the carotid and femoral arteries.Conclusion. The elastic properties of the carotid artery are significantly altered in SSc, and the two major subsets of SSc may be distinguished by their carotid artery biomechanics. This suggests that connective tissue abnormality occurs at sites not previously assessed.

Renal manifestations occur frequently in scleroderma (SSc). Commonest is a reduction in renal function due to chronic disease but most clinically important is the scleroderma renal crisis (SRC). This life-threatening complication occurs in up to 15% of the cases of dcSSc. Mortality is reduced by use of angiotensin converting enzyme (ACE) inhibitors. Renal outcome can be assessed by quantifying renal function, measuring proteinuria, exploring the frequency of renal crisis episodes and through assessment of renal outcome following SRC-such as frequency and duration of dialysis, or recovery of renal function.