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Objective: To understand if autoantibodies account for racial variation in disease severity, we compared autoantibody distribution and associated phenotype between self-identified black and white systemic sclerosis (SSc) patients., Methods: 803 black and 2178 white SSc patients had systematic testing for autoantibodies using Euroimmun (centromere (ACA), RNA-polymerase III (POLR3), Scl70, PM/Scl, NOR90, Th/To, Ku, U3RNP and Ro52) and commercial ELISA (U1RNP). In this observational study, logistic regression was performed to assess the association between self-identified race and outcomes, adjusting for autoantibodies. To estimate whether the effect of race was mediated by autoantibody status, race coefficients from multivariate models including and excluding autoantibodies were compared., Results: Anti-Scl70, anti-U1RNP, anti-U3RNP, anti-Th/To, anti-Ku and anti-NOR90 were more common in the black cohort than in the white cohort, which was enriched for ACA, anti-POLR3 and anti-PM/Scl. Black individuals had a higher prevalence of severe Raynaud's, skin, lung, gastrointestinal and renal disease whereas white individuals had a higher prevalence of severe heart and muscle disease. Adjusting for autoantibodies decreased the effect of race on outcome for telangiectasias, forced vital capacity <70%, pulmonary hypertension and severe lung, heart, muscle and gastrointestinal disease by 11%-44% and increased the association between race and renal crisis and severe kidney disease by 37%-52%., Conclusions: This study is the largest systematic analysis of autoantibody responses in a geographically diverse population of black SSc patients. Black and white individuals with SSc have distinct autoantibody profiles. Autoantibodies explain only a fraction of the effect of race on clinical outcomes, suggesting other factors contribute to disparate outcomes between these groups., Competing Interests: Competing interests: RD received consulting fees from CSL Behring and Astra-Zeneca. LAS received grant funding from Horizon Pharmaceuticals, aTyr Pharmaceuticals and Kinevant Pharmaceuticals and honoraria from Janssen Pharmaceuticals. She served on the data safety monitoring board for Argenx Pharmaceuticals. LC received grant funding from Boehringer Ingelheim and consulting fees from Kyverna, Eicos Sciences, Genentech, IgM Biosciences, Lilly. She participated in an advisory capacity for Mitsubishi Tanabe and Janssen. FB received honoraria from Janssen. RMS received grant funding from Boehringer Ingelheim, Merck and Amgen; he is the CEO of FibroBiologics. JV received consulting fees from TeneoBio, and Conquest; he serves on the data safety monitoring board for Conquest. MDM received grant funding from Prometheus Biosciences, Mitsubishi Tanabe, Boehringer Ingelheiem, Eicos, Corbus and Horizon Pharmaceuticals. She received consulting fees from Cabaletta Pharmaceuticals; she served on the advisory board for Mitsubishi Tanabe and Eicos Sciences. AS has grant support from Kadmon, Arena Pharmaceuticals, Medpace and Eicos Sciences., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objective: This phase 3 study was undertaken to investigate the efficacy and safety of lenabasum, a cannabinoid type 2 receptor agonist, in patients with diffuse cutaneous systemic sclerosis (dcSSc)., Methods: A multinational double-blind study was conducted in 365 dcSSc patients who were randomized and dosed 1:1:1 with lenabasum 20 mg, lenabasum 5 mg, or placebo, each twice daily and added to background treatments, including immunosuppressive therapies (IST)., Results: The primary end point, the American College of Rheumatology combined response index in dcSSc (CRISS) at week 52 for lenabasum 20 mg twice a day versus placebo, was not met, with CRISS score of 0.888 versus 0.887 (P = 0.4972, using mixed models repeated measures [MMRM]). The change in the modified Rodnan skin thickness score (MRSS) at week 52 for lenabasum 20 mg twice a day versus placebo was -6.7 versus -8.1 (P = 0.1183, using MMRM). Prespecified analyses showed higher CRISS scores, greater improvement in MRSS, and lower decline in forced vital capacity in patients on background mycophenolate and those who were taking IST for ≤1 year. No deaths or excess in serious or severe adverse events related to lenabasum were observed., Conclusion: A benefit of lenabasum in dcSSc was not demonstrated. Most patients were treated with background IST, and treatment with mycophenolate mofetil in particular was associated with better outcomes. These findings support the use of IST in the treatment of dcSSc and highlight the challenge of demonstrating a treatment effect when investigational treatment is added to standard of care IST. These findings have relevance to trial design in SSc, as well as to clinical care., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: Systemic sclerosis often has a significant impact on an individual's quality of life. Life satisfaction is a subjective expression of well-being and a key component of quality of life. We examined the associations between functional limitations, social support, and spiritual well-being with life satisfaction and investigated the moderating roles of social support and spiritual well-being on the relationship between functional limitations and life satisfaction in people with systemic sclerosis., Methods: Data were drawn from the baseline University of California Los Angeles Scleroderma Quality of Life Study. Participants completed questionnaires that included demographics, depressive symptoms, functional limitations, social support, and spiritual well-being. The Satisfaction with Life Scale was used to evaluate overall life satisfaction. Data were analyzed using a hierarchical linear regression., Results: Of 206 participants (84% female, 74% White, 52% limited cutaneous subtype, 51% early disease), 38% reported being dissatisfied with their lives. Functional limitations (β = -0.19, p = 0.006), social support (β = 0.18, p = 0.006), and spiritual well-being (β = 0.40, p < 0.001) were associated with life satisfaction, with spiritual well-being emerging as the strongest statistical contributor. However, social support and spiritual well-being did not significantly moderate the relationship between functional limitations and life satisfaction ( p = 0.882 and p = 0.339, respectively)., Conclusion: Spiritual well-being is particularly important in understanding life satisfaction in people with systemic sclerosis. Future longitudinal research is needed to assess and examine spiritual well-being and its impact on life satisfaction in a larger and more diverse systemic sclerosis sample.

Objective: Hand dysfunction is common in systemic sclerosis (SSc). We undertook this study to evaluate the capacity of autologous adipose-derived regenerative cells (ADRCs) to improve hand function in SSc patients., Methods: The Scleroderma Treatment with Celution Processed Adipose Derived Regenerative Cells Trial was a prospective, randomized, double-blind trial of ADRCs, in which ADRCs were obtained from patients with SSc by small-volume adipose tissue harvest, and the fingers of each patient were injected with ADRCs. The primary end point was change in hand function at 24 and 48 weeks, assessed using the Cochin Hand Function Scale (CHFS). One of the secondary end points included the change in Health Assessment Questionnaire disability index (HAQ DI) at 48 weeks. Separate prespecified analyses were performed for patients with diffuse cutaneous SSc (dcSSc) and those with limited cutaneous SSc (lcSSc)., Results: Eighty-eight patients were randomized to receive ADRCs (n = 48 [32 patients with dcSSc and 16 with lcSSc]) or placebo (n = 40 [19 patients with dcSSc and 21 with lcSSc]). Change in hand function according to CHFS score was numerically higher for the ADRC group compared to the placebo group but did not achieve statistical significance (mean ± SD improvement in the CHFS score at 48 weeks 11.0 ± 12.5 versus 8.9 ± 10.5; P = 0.299). For patients with dcSSc, the between-group difference in the CHFS at 48 weeks was 6.3 points (nominal P = 0.069). For the secondary end point, the dcSSc group exhibited a between-group difference of 0.17 points in the HAQ DI (nominal P = 0.044) at 48 weeks. Of the ADRC-treated patients with dcSSc, 52% reported improvement greater than the minimum clinically important difference for both CHFS and HAQ DI compared to 16% in the placebo group (nominal P = 0.016). Small-volume adipose tissue harvest and ADRC treatment were well tolerated., Conclusion: While the primary end point of this trial was not achieved, efficacy trends were observed in patients with dcSSc. Adipose tissue harvest and ADRC injection were demonstrated to be feasible. Further clinical trials of this intervention in the setting of dcSSc are warranted., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Introduction: Gastrointestinal tract involvement in systemic sclerosis is the most common internal organ involvement. Among the few validated patient-reported outcome measures for gastrointestinal involvement are the University of California Los Angeles Scleroderma Clinical Trial Consortium gastrointestinal tract 2.0 (UCLA-GIT 2.0) and the gastrointestinal problems' visual analog scale (SHAQ-VAS). The latter is a component of the Scleroderma Health Assessment Questionnaire Disability Index. Our aim is to compare the responsiveness of the UCLA-GIT 2.0 total score, single domains, upper and lower gastrointestinal domains, and gastrointestinal problems' visual analog scale of the scleroderma HAQ(SHAQ-GI-VAS) to change in gastrointestinal medication. In addition, we evaluated the correlation between the UCLA-GIT 2.0 and SHAQ-GI-VAS scale in our systemic sclerosis population., Methods: One hundred fifteen systemic sclerosis patients attending the University of California Los Angeles and Seattle outpatient clinics with two or more consecutive visits were enrolled in our study. The UCLA-GIT 2.0 and SHAQ&#95;VAS were completed by all patients at both visits; any change in gastrointestinal medication at the baseline visit was reported. UCLA-GIT 2.0 asks about how the gastrointestinal tract affects the patient over the last week; It consists of 34 questions in seven domains (reflux, distension, soilage, diarrhea, social function, emotional wellbeing, and constipation). THE SHAQ-GI-VAS is a 100-mm horizontal VAS that asks the patient; "In the past week, how much did your gastrointestinal symptoms interfere with your function". These measures were evaluated at two consecutive visits. Any change in gastrointestinal medication at baseline visit was reported. Percent change was calculated to evaluate the change in the values of the UCLA-GIT 2.0 and the SHAQ&#95;GI-VAS, and we dichotomized the patients into two groups according to whether there was a change in gastrointestinal treatment or not. Pearson correlation was used to correlate both tests at baseline., Results: Ninety-eight (85%) of the systemic sclerosis patients were females, mean age: 52 years (standard deviation ± 12.9); median disease duration: 7 (range: 4-11 years), diffuse subtype: 57 patients (50%), median baseline gastrointestinal tract 2.0 was 0.3 (0.1-0.7) and median baseline SHAQ-GI-VAS was 0.8 (0-4.1). Out of the 115 patients, 41 (37.0%) patients needed a change in gastrointestinal medication at baseline visit (Group 1); they were compared to those not changing gastrointestinal medications (Group 2). Responsiveness to gastrointestinal medication treatment change in the form of percent change in total UCLA-GIT 2.0 was significantly more in Group 1 than in Group 2 (-6.6 (standard deviation = 20) in Group 1 vs +6.9 (standard deviation ± 18.8) in Group 2, p value < 0.001). On the contrary, there was no statistically significant difference between percent changes in SHAQ-GI-VAS from the in Group 1 versus Group 2 (59.5 (standard deviation ± 172) in Group 1 vs 51.9 (standard deviation ± 126.4) in Group 2, p value = 0.816). The correlation between the UCLA-GIT 2.0 and the SHAQ&#95;GI-VAS was moderate ( r  = 0.6)., Conclusion: The University of California Los Angeles Scleroderma Clinical Trial Consortium gastrointestinal tract 2.0 and gastrointestinal problems' visual analog scale are utilized to measure gastrointestinal tract involvement in systemic sclerosis. Unlike the gastrointestinal problems' visual analog scale, the gastrointestinal tract 2.0 was responsive to change in gastrointestinal medication while the SHAQ-GI-VAS was not. Hence, the UCLA-GIT 2.0 could be utilized in future trials and observational studies as a measure of systemic sclerosis gastrointestinal responsiveness., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Background: Systemic sclerosis (SSc) is an autoimmune disorder and commonly presents with vascular system involvement and motility disorders in the gastrointestinal (GI) tract. Vinculin is a cytoskeletal protein that plays major roles in cell-cell adhesion and is expressed in the neuromuscular apparatus of the gut. Antibodies to vinculin have been identified as a biomarker of irritable bowel syndrome (IBS). Our aim was to evaluate serum anti-vinculin antibodies in patients with SSc., Methods: Patients were recruited from two SSc centers: group I (GI-enriched group), University of Leeds, UK, and Group II (vascular predominant), University of California, Los Angeles. Serum samples of patients recruited from two SSc centres, Group I ( GI enriched group), University of Leeds, UK and Group II (Vascular predominant), University of California, Los Angeles) were collected. Samples from age- and sex-matched healthy volunteers (N = 88) were used as controls., Results: Group I (GI-enriched group, N = 83) patients were 58 [50-67] years old; 83% were females with a median body mass index (BMI) of 20.3 (21.2 ± 4.5) [18-23]. Group II (vascular-enriched group, N = 72) patients were 58 [50-67] years old; 80% were female, and BMI was 23.9 (21.3-26.9). More subjects in group I had prominent GI involvement (N = 55, 66%) than group II (12, 16%), p ˂ 0.0001. Anti-vinculin antibody levels in SSc group I (1.3 [0.9]) were significantly higher than in HC (0.7 [0.8]; p = 0.002). When pooled, circulating anti-vinculin levels in both SSc groups remained significantly higher than in the HC group (p = 0.02). Higher anti-vinculin levels were associated with higher GI-visual analogue scale (GI-VAS) scores and specifically with GI-VAS scores of ≥ 4 (p < 0.0001)., Conclusion: This study demonstrates that elevated anti-vinculin antibody levels are common in SSc and suggests a potential link between increased anti-vinculin levels and GI tract symptoms., Key Points: • Anti-vinculin antibodies are elevated in systemic sclerosis and are relatively common. • In these SSc patients, anti-vinculin antibodies are associated with higher levels of GI symptoms in SSc. • A potential link between anti-vinculin antibodies and vascular system involvement was shown.

Background: Abatacept was well tolerated by patients with early diffuse cutaneous systemic sclerosis in a phase 2, double-blind randomised trial, with potential efficacy at 12 months. We report here the results of an open-label extension for 6 months., Methods: Patients (aged ≥18 years) with diffuse cutaneous systemic sclerosis of less than 3 years' duration from their first non-Raynaud's symptom were enrolled into the ASSET trial (A Study of Subcutaneous Abatacept to Treat DiffuseCutaneous Systemic Sclerosis), which is a double-blind trial at 22 sites in Canada, the UK, and the USA. Aftercompletion of 12 months of treatment with either abatacept or placebo, patients received a further 6 months ofabatacept (125 mg subcutaneous every week) in an open-label extension. The primary endpoint of the double-blind trial was modified Rodnan Skin Score (mRSS) at 12 months, which was reassessed at 18 months in the open-label extension. The primary analysis included all participants who completed the double-blind trial and received at least one dose of open-label treatment (modified intention to treat). This trial is registered with ClinicalTrials.gov, NCT02161406., Findings: Between Sept 22, 2014, and March 15, 2017, 88 participants were randomly allocated in the double-blind trial either abatacept (n=44) or placebo (44); 32 patients from each treatment group completed the 6-month open-labelextension. Among patients assigned abatacept, a mean improvement from baseline in mRSS was noted at 12 months (-6·6 [SD 6·4]), with further improvement seen during the open-label extension period (-9·8 [8·1] at month 18). Participants assigned placebo had a mean improvement from baseline in mRSS at 12 months (-3·7 [SD 7·6]), with a further improvement at month 18 (-6·3 [9·3]). Infections during the open-label extension phase occurred in nine patients in the placebo-abatacept group (12 adverse events, one serious adverse event) and in 11 patients in theabatacept-abatacept group (14 adverse events, one serious adverse event). Two deaths occurred during the 12-month double-blind period in the abatacept group, which were related to scleroderma renal crisis; no deaths were recorded during the open-label extension., Interpretation: During the 6-month open-label extension, no new safety signals for abatacept were identified in the treatment of diffuse cutaneous systemic sclerosis. Clinically meaningful improvements in mRSS and other outcome measures were observed in both the abatacept and placebo groups when patients transitioned to open-label treatment. These data support further studies of abatacept in diffuse cutaneous systemic sclerosis., Funding: Bristol-Myers Squibb and National Institutes of Health.

Objective: The Brief Satisfaction With Appearance Scale measures two dimensions (Dissatisfaction with Appearance and Social Discomfort) of body image dissatisfaction in systemic sclerosis. This study examined the structural validity of the Brief Satisfaction With Appearance Scale across limited and diffuse systemic sclerosis subtypes, compared body image dissatisfaction by systemic sclerosis subtype, and identified the significant sociodemographic and medical correlates of body image dissatisfaction and whether they differed by subtype., Methods: Participants were 183 adults participating in the University of California, Los Angeles Scleroderma Quality of Life Study with limited cutaneous ( n  = 101) or diffuse cutaneous ( n  = 82) systemic sclerosis who received clinical examinations and completed questionnaires. Multiple-group confirmatory factor analysis, multivariate analysis of variance, and structural equation modeling were used., Results: The Brief Satisfaction With Appearance Scale's two-factor structure fit well for both subtypes. Patients with diffuse systemic sclerosis reported greater body image dissatisfaction on both factors than patients with limited disease. Greater Dissatisfaction with Appearance was associated with younger age and being unmarried for limited patients, and with younger age and increased finger/hand skin involvement for diffuse patients. Greater Social Discomfort was associated with younger age and being unmarried for both subtypes., Conclusion: The Brief Satisfaction With Appearance Scale scores can be meaningfully compared across limited and diffuse systemic sclerosis. Patients with diffuse disease reported more body image dissatisfaction than those with limited disease. Findings demonstrate that both medical and sociodemographic variables are associated with body image dissatisfaction in systemic sclerosis and can be used to identify which patients may be at increased risk for body image dissatisfaction., Competing Interests: Declaration of conflicting interests: Dr D.K. has served as a consultant for Actelion, Acceleron, Bayer, Biogen Idec, CSL Behring, Corbus, Cytori, BMS, Genentech/Roche, GSK, and Sanofi-Aventis and has stock options in Eicos Sciences, Inc. Dr D.E.F. has served as a consultant or on Speaker Bureaus for AbbVie, Actelion, Amgen, BMS, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, UCB, and Janssen., (© The Author(s) 2019.)

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1 * 08:04 and HLA-DRB1 * 11:02 alleles were associated with overall SSc risk, and the HLA-DRB1 * 08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1 * 13:01 and HLA-DRB1 * 07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1 * 13:01 allele with the ATA + subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1 * 13:01 allele frequency in multiple populations was observed ( r = 0.98, P = 3 × 10 -6 ). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/β allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc., Competing Interests: Competing interest statement: M.D.M. received consulting fees from Mitsubishi Tanabe, Astellas, Boehringer Ingelheim, Gerson Lehrman Group, Smart Analyst, and Guidepoint Global. R.T.D. received consulting fees from Eicos Sciences. D.K. received consulting fees from Actelion, Bristol-Myers Squibb, CSL Behring, Inventiva, EMD Merck-Serono, Sanofi-Aventis, GlaxoSmithKline, Corbus, Cytori, UCB, Bayer, Boehringer Ingelheim, and Genentech-Roche, and research support from Bayer, Bristol-Myers Squibb, and Pfizer, and owns stock or stock options in Eicos Sciences, Inc. (CiViBioPharma, Inc.). L.A.S. received consulting fees from Axon Pharma. H.G. received consulting fees from Pfizer, AbbVie, Actelion, and Horizon Pharmaceuticals. C.T.D. received research support from Gilead, Actelion, and Cytori. V.K.S. received research support from AbbVie. E.J.B. received consulting fees from Genentech. L.C. received consulting fees or served on the board of Reata, Bristol-Myers Squibb, Boehringer-Ingelheim, Eicos, and Mitsubishi Tanabe. S.L.B. and M.J.D. are coauthors on a 2015 research article., (Copyright © 2020 the Author(s). Published by PNAS.)

Objective: T cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc)., Methods: In this 12-month, randomized, double-blind, placebo-controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets., Results: Among 88 participants, the adjusted mean change in the MRSS at 12 months was -6.24 units for those receiving abatacept and -4.49 units for those receiving placebo, with an adjusted mean treatment difference of -1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal-like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively., Conclusion: In this phase II trial, abatacept was well-tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial., (© 2019, American College of Rheumatology.)

Objectives: Validating musculoskeletal ultrasound features of the joints and tendons of the hands in a large scleroderma cohort., Methods: A total of 81 scleroderma patients participated in this prospective, cross-sectional study. Grayscale and power Doppler musculoskeletal ultrasound images of 13 joints and 5 tendons of the wrist and hand were obtained. Clinical assessment included modified Rodnan skin thickness score, joint count, and Scleroderma Health Assessment Questionnaire. Face validity, content validity, construct validity, and feasibility were assessed., Results: Mean age was 53.8 years (range 22-80), 76.5% were females, and disease duration ranged from 0.25 to 29 years. Mean length of the examination was 36 min. Scleroderma Health Assessment Questionnaire-Disability Index correlated with musculoskeletal ultrasound erosions (r = 0.5, p = 0.0003). Skin score correlated with tendinitis grayscale (r = 0.26, p = 0.02). Intra-reader correlation coefficient for musculoskeletal ultrasound was 0.96 for the joints and could not be calculated for tendons because there were too few positive findings. When tendon changes existed, percent of agreement was 77.7%-83.3%., Conclusion: Musculoskeletal ultrasound of 13 joints and 5 tendons of the hands and wrist has face and content validity. Construct validity was shown for the tendons and erosion scores. Feasibility and reliability were partially validated., Competing Interests: Declaration of conflicting interests: A.S.-E., A.B.-A., L.D., S.K., N.H.B., T.W., D.E., and P.C. declare that they have no conflicts of interest. V.K.R. reports support from Genentech, Bristol Meyer Squibb, Pfizer, and Amgen. D.E.F. reports grant/research support from AbbVie, Actelion Pharmaceuticals US, Amgen, BMS, Cytori, GSK, NIH, Novartis Pharmaceutical Corporation, Pfizer Inc., Roche/Genentech, UCB, and Janssen Pharmaceutical Product., (© The Author(s) 2018.)

Objective: 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 that increase SSc susceptibility. This study was undertaken to evaluate the association of the ATP8B4 gene and the ECM-related pathway with SSc in a cohort of African American (AA) patients., Methods: SSc patients of AA ancestry were enrolled from 23 academic centers across the US under the Genome Research in African American Scleroderma Patients consortium. Unrelated AA individuals without serologic evidence of autoimmunity who were enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the 2 WES studies in EA patients with 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., Results: Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds, with roughly equal proportions of mean European admixture. Using SKAT-O, we examined the association of individual genes that were previously reported in EA patients and none remained significant, including ATP8B4 (P = 0.98). However, we confirmed 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 (corrected P = 1.95 × 10 -4 )., Conclusion: In the largest genetic study in AA patients with SSc to date, our findings corroborate the role of functional variants that aggregate in a fibrotic pathway and increase SSc susceptibility., (© 2018, American College of Rheumatology.)

Objectives: The Scleroderma Patient-centered Intervention Network (SPIN) Cohort is a web-based cohort designed to collect patient-reported outcomes at regular intervals as a framework for conducting trials of psychosocial, educational, self-management and rehabilitation interventions for patients with SSc. The aim of this study was to present baseline demographic, medical and patient-reported outcome data of the SPIN Cohort and to compare it with other large SSc cohorts., Methods: Descriptive statistics were used to summarize SPIN Cohort characteristics; these were compared with published data of the European Scleroderma Trials and Research (EUSTAR) and Canadian Scleroderma Research Group (CSRG) cohorts., Results: Demographic, organ involvement and antibody profile data for SPIN (N = 1125) were generally comparable with that of the EUSTAR (N = 7319) and CSRG (N = 1390) cohorts. There was a high proportion of women and White patients in all cohorts, though relative proportions differed. Scl70 antibody frequency was highest in EUSTAR, somewhat lower in SPIN, and lowest in CSRG, consistent with the higher proportion of interstitial lung disease among dcSSc patients in SPIN compared with in CSRG (48.5 vs 40.3%). RNA polymerase III antibody frequency was highest in SPIN and remarkably lower in EUSTAR (21.1 vs 2.4%), in line with the higher prevalence of SSc renal crisis (4.5 vs 2.1%) in SPIN., Conclusion: Although there are some differences, the SPIN Cohort is broadly comparable with other large prevalent SSc cohorts, increasing confidence that insights gained from the SPIN Cohort should be generalizable, although it should be noted that all three cohorts include primarily White participants.

Skin ulcers in scleroderma (SSc) patients are considered a major challenge, both in clinical assessment and treatment decisions. The objective of our study is to assess ultrasonographic (US) morphology of skin ulcers in SSc patients and evaluate if US will be of value in enhancing our clinical information and influence our management plans. We examined a convenience sample of 21 skin ulcers reported in 10 SSc patients by US. We used a previously published US definition of normal skin and developed a preliminary US definition of skin ulcer. Skin ulcers were evaluated by gray scale (GS) and power Doppler (PD) and separated into ulcer and non-ulcer lesions; pain and ulcer measures were obtained using visual analogue scales (VAS). Lesions were characterized and ulcers were clinically and sonographically measured. Ten patients presenting with 21 skin lesions were examined by US. Applying our US definition of skin ulcer, all ulcers were available to measure by ultrasound. Eight lesions were sonographically defined as ulcers, and 13 lesions as non-ulcer lesions. Three ulcers had high PD signals suggestive of infection requiring antibiotic treatment and were monitored for 2 weeks showing a decrease of the pain, VAS, and PD signals. Five lesions showed subclinical calcinosis. This is the first study to show the promising role of US in defining skin ulcers of SSc patients. US may support the assessment of morphology and extent of skin ulcers in SSc and can be a helpful tool for detecting underlying pathology.

Fibrosis is the end result of most inflammatory conditions, but its pathogenesis remains unclear. We demonstrate that, in animals and humans with systemic fibrosis, plasmacytoid DCs (pDCs) are unaffected or are reduced systemically (spleen/peripheral blood), but they increase in the affected organs (lungs/skin/bronchoalveolar lavage). A pivotal role of pDCs was shown by depleting them in vivo, which ameliorated skin and/or lung fibrosis, reduced immune cell infiltration in the affected organs but not in spleen, and reduced the expression of genes and proteins implicated in chemotaxis, inflammation, and fibrosis in the affected organs of animals with bleomycin-induced fibrosis. As with animal findings, the frequency of pDCs in the lungs of patients with systemic sclerosis correlated with the severity of lung disease and with the frequency of CD4+ and IL-4+ T cells in the lung. Finally, treatment with imatinib that has been reported to reduce and/or prevent deterioration of skin and lung fibrosis profoundly reduced pDCs in lungs but not in peripheral blood of patients with systemic sclerosis. These observations suggest a role for pDCs in the pathogenesis of systemic fibrosis and identify the increased trafficking of pDCs to the affected organs as a potential therapeutic target in fibrotic diseases.

Objectives: To assess the reliability and the minimal clinically important differences (MCID) for FVC% predicted in the Scleroderma Lung Study I and II., Methods: Using data from SLS I and II (N=300), we evaluated the test-retest reliability for FVC% predicted (FVC%; screening vs. baseline) using intra-class correlation (ICC). MCID estimates at 12 months were calculated in the pooled cohort (SLS-I and II) using 2 anchors: Transition Dyspnea Index (≥change of 1.5 units for improvement and worsening, respectively) and the SF-36 Health Transition question: "Compared to one year ago, how would you rate your health in general now?", where "somewhat better" or "somewhat worse" were defined as the MCID estimates. We next assessed the association of MCID estimates for improvement and worsening of FVC% with patient reported outcomes (PROs) and computer-assisted quantitation of extent of fibrosis (QLF) and of total ILD (QILD) on HRCT., Results: Reliability of FVC%, assessed at a mean of 34 days, was 0.93 for the pooled cohort. The MCID estimates for the pooled cohort at 12 months for FVC% improvement ranged from 3.0 % to 5.3% and for worsening from -3.0% to -3.3%. FVC% improvement by ≥MCID was associated with either statistically significant or numerical improvements in some PROs, QILD, and QLF, while FVC% worsening ≥MCID was associated with statistically significant or numerical worsening of PROs, QILD, and QLF., Conclusion: FVC% has acceptable test-retest reliability, and we have provided the MCID estimates for FVC% in SSc-ILD based changes at 12 months from baseline in two clinical trials. Clinical trial registration available at www.clinicaltrials.gov, IDs NCT00004563 and NCT00883129.

Objective: To assess the efficacy of mycophenolate mofetil (MMF) and cyclophosphamide (CYC) on modified Rodnan skin score (MRSS) in participants enrolled in the Scleroderma Lung Study (SLS) I and II., Methods: SLS I participants received daily oral CYC or matching placebo for 1 year, whereas SLS II participants received daily MMF for 2 years or daily oral CYC for 1 year followed by placebo for second year. We assessed the impact of MMF and CYC on the MRSS in SLS II over a 24-month period. We also compared the change in MRSS in patients with diffuse cutaneous systemic sclerosis (dcSSc) assigned to CYC and MMF in SLS II and SLS I versus placebo in SLS I over a 24-month period using a linear mixed model., Results: In SLS II, the baseline mean ± SD MRSS was 14.0 ± 10.6 units for CYC and 15.3 ± 10.4 units for MMF; 58.5% were classified as dcSSc. CYC and MMF were associated with statistically significant improvements in MRSS from baseline over the period of 24 months in dcSSc (P < 0.05 at each time point), but there were no differences between the 2 groups. In the dcSSc subgroup, the change in MRSS from baseline to all 6-month visits was similar in SLS II groups (MMF, CYC, pooled cohort [MMF + CYC]) and in the SLS I CYC group and showed statistically significant improvements compared to SLS I placebo at 12, 18, and 24 months (P < 0.05)., Conclusion: In SLS II, MMF and CYC treatment resulted in improvements in MRSS in patients with dcSSc over 24 months. In addition, MMF and CYC treatment resulted in statistically significant improvements in MRSS in patients with dcSSc when compared with the SLS I placebo group., (© 2017, American College of Rheumatology.)

Background: Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma., Methods: We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score., Results: In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group., Conclusions: Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).

Gene-level analysis of ImmunoChip or genome-wide association studies (GWAS) data has not been previously reported for systemic sclerosis (SSc, scleroderma). The objective of this study was to analyze genetic susceptibility loci in SSc at the gene level and to determine if the detected associations were shared in African-American and White populations, using data from ImmunoChip and GWAS genotyping studies. The White sample included 1833 cases and 3466 controls (956 cases and 2741 controls from the US and 877 cases and 725 controls from Spain) and the African American sample, 291 cases and 260 controls. In both Whites and African Americans, we performed a gene-level analysis that integrates association statistics in a gene possibly harboring multiple SNPs with weak effect on disease risk, using Versatile Gene-based Association Study (VEGAS) software. The SNP-level analysis was performed using PLINK v.1.07. We identified 4 novel candidate genes (STAT1, FCGR2C, NIPSNAP3B, and SCT) significantly associated and 4 genes (SERBP1, PINX1, TMEM175 and EXOC2) suggestively associated with SSc in the gene level analysis in White patients. As an exploratory analysis we compared the results on Whites with those from African Americans. Of previously established susceptibility genes identified in Whites, only TNFAIP3 was significant at the nominal level (p = 6.13x10-3) in African Americans in the gene-level analysis of the ImmunoChip data. Among the top suggestive novel genes identified in Whites based on the ImmunoChip data, FCGR2C and PINX1 were only nominally significant in African Americans (p = 0.016 and p = 0.028, respectively), while among the top novel genes identified in the gene-level analysis in African Americans, UNC5C (p = 5.57x10-4) and CLEC16A (p = 0.0463) were also nominally significant in Whites. We also present the gene-level analysis of SSc clinical and autoantibody phenotypes among Whites. Our findings need to be validated by independent studies, particularly due to the limited sample size of African Americans.

Objective: To evaluate the structural validity of the Rheumatology Attitudes Index (RAI), a widely used measure of rheumatic disease-related helplessness in patients with systemic sclerosis (SSc)., Methods: Patients with physician-confirmed SSc from the University of California, Los Angeles (UCLA) Scleroderma Quality of Life Study (n = 208) received clinical examinations and completed self-report questionnaires. The structural validity of the RAI was examined through confirmatory and exploratory factor analysis (CFA/EFA)., Results: A tenable factor structure was not identified through CFA or EFA., Conclusion: The present structural analysis did not support the use of the RAI with SSc patients.

Purpose: There is a lack of a valid, definition for skin ulcers in SSc to be used in clinical trials. Our aim was to develop a consensus definition for SSc-skin ulcers based on the results of a systematic literature review (SLR) for skin ulcer definitions and expert opinion; and to evaluate its face validity, reliability and feasibility., Methods: SLR for skin ulcer definitions was conducted using PubMed, Web of Science, and Cochrane library for articles published from inception to January 1 st , 2016. SSc experts were to discuss the definitions' categories and vote for the relevant terms. Reliability of the definition were tested in a second expert meeting, seven SSc experts evaluated 7 SSc pts with skin lesions twice. Face validity and feasibility evaluated by sending out case report forms(CRFs) to 4 SSc experts, they were asked to use the definition in 5 pts each., Results: A total of 3464 abstracts and titles were screened, and 446 articles were fully evaluated. Of these, 66 met eligibility criteria and skin ulcer definitions were extracted. SSc experts discussed, refined and voted on the consensus definition using nominal process. Kappa for inter-, intra-rater rater agreement was 0.51, 0.90 respectively. The mean time to decide if the lesion is an ulcer was 7.4 sec. All investigators endorsed the face validity of the new definition in the CRFs., Conclusion: Using a SLR and a nominal technique, we developed a preliminary consensus-based definition of SSc-skin ulcers. Face validity, feasibility and reliability were demonstrated for the developed definition.

Background: 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., Methods: 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., Results: 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., Conclusions: 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., Trial Registry: ClinicalTrials.gov; No.: NCT00883129; URL: www.clinicaltrials.gov., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: 12 months of oral cyclophosphamide has been shown to alter the progression of scleroderma-related interstitial lung disease when compared with placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesised that a 2 year course of mycophenolate mofetil would be safer, better tolerated, and produce longer lasting improvements than cyclophosphamide., Methods: This randomised, double-blind, parallel group trial enrolled patients from 14 US medical centres with scleroderma-related interstitial lung disease meeting defined dyspnoea, pulmonary function, and high-resolution CT (HRCT) criteria. The data coordinating centre at the University of California, Los Angeles (UCLA, CA, USA), randomly assigned patients using a double-blind, double-dummy, centre-blocked design to receive either mycophenolate mofetil (target dose 1500 mg twice daily) for 24 months or oral cyclophosphamide (target dose 2·0 mg/kg per day) for 12 months followed by placebo for 12 months. Drugs were given in matching 250 mg gel capsules. The primary endpoint, change in forced vital capacity as a percentage of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129., Findings: Between Sept 28, 2009, and Jan 14, 2013, 142 patients were randomly assigned to either mycophenolate mofetil (n=69) or cyclophosphamide (n=73). 126 patients (mycophenolate mofetil [n=63] and cyclophosphamide [n=63]) with acceptable baseline HRCT studies and at least one outcome measure were included in the primary analysis. The adjusted % predicted FVC improved from baseline to 24 months by 2·19 in the mycophenolate mofetil group (95% CI 0·53-3·84) and 2·88 in the cyclophosphamide group (1·19-4·58). The course of the % FVC did not differ significantly between the two treatment groups based on the prespecified primary analysis using a joint model (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, the within-treatment change from baseline to 24 months derived from the joint model showed that the % FVC improved significantly in both the mycophenolate mofetil and cyclophosphamide groups. 16 (11%) patients died (five [7%] mycophenolate mofetil and 11 [15%] cyclophosphamide), with most due to progressive interstitial lung disease. Leucopenia (30 patients vs four patients) and thrombocytopenia (four vs zero) occurred more often in patients given cyclophosphamide than mycophenolate mofetil. Fewer patients on mycophenolate mofetil than on cyclophosphamide prematurely withdrew from study drug (20 vs 32) or met prespecified criteria for treatment failure (zero vs two). The time to stopping treatment was shorter in the cyclophosphamide group (p=0·019)., Interpretation: Treatment of scleroderma-related interstitial lung disease with mycophenolate mofetil for 2 years or cyclophosphamide for 1 year both resulted in significant improvements in prespecified measures of lung function over the 2 year course of the study. Although mycophenolate mofetil was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than cyclophosphamide was not confirmed. These findings support the potential clinical effectiveness of both cyclophosphamide and mycophenolate mofetil for progressive scleroderma-related interstitial lung disease, and the present preference for mycophenolate mofetil because of its better tolerability and toxicity profile., Funding: National Heart, Lung and Blood Institute, National Institutes of Health; with drug supply provided by Hoffmann-La Roche and Genentech., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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.

Skin thickening is one of the early organ manifestations of systemic sclerosis (SSc) and has a great impact on quality of life (QOL) as well as overall daily living in patients with SSc. The dynamic changes that occur as the disease progresses and as other organs become further involved present the treating physician with therapeutic challenges. Hence, when considering drug therapy for skin disease, the treating physician should consider a number of factors including disease duration, the rate of skin thickening, the extent of disease progression, organ involvements, and patient-related outcome measures, all of which impact the type of treatments considered. For early diffuse skin disease, we prefer the use of methotrexate (MTX). And when there is evidence of lung involvement or tendon friction rubs (given its association with ILD development), we tend to shift to the use of mycophenolate or cyclophosphamide because these agents have been shown efficacious for the specific indication of lung disease in SSc. We have managed joint disease, on the other hand when present, with MTX or other DMARDs, as well as the use of biologics when there is evidence of inflammatory polyarthritis or rheumatoid arthritis overlap. While the treatment of myositis in the setting of SSc can present a therapeutic dilemma, reluctantly, we may use steroids along with MTX, mycophenolate, intravenous immunoglobulin (IV-Ig), or rituximab. Ongoing clinical trials investigating the use of tocilizumab, abatacept, and other agents offer promising potential therapies. Great strides have been made in treating skin disease in SSc. And with recent trials focusing on early SSc disease, this will allow for a greater insight into the mechanisms underlying SSc especially as it relates to skin, and the expansion of future treatment options in this field.

Objective: Changes in appearance are common in patients with systemic sclerosis (SSc) and can significantly affect well-being. The Satisfaction with Appearance Scale (SWAP) measures body image dissatisfaction in persons with visible disfigurement; the Brief-Satisfaction with Appearance Scale (Brief-SWAP) is its short form. The present study evaluated the reliability and validity of SWAP and Brief-SWAP scores in SSc., Methods: A sample of 207 patients with SSc participating in the University of California, Los Angeles Scleroderma Quality of Life Study completed the SWAP. Brief-SWAP scores were derived from the SWAP. The structural validity of both measures was investigated using confirmatory factor analysis. Internal consistency reliability of total and subscale scores was assessed with Cronbach's alpha coefficients. Convergent and divergent validity was evaluated using the Center for Epidemiological Studies Depression Scale, the Health Assessment Questionnaire-Disability Index, and the Medical Outcomes Study Short Form-36 questionnaire., Results: SWAP and Brief-SWAP total scores were highly correlated (r = 0.97). The 4-factor structure of the SWAP fit well descriptively; the 2-factor structure of the Brief-SWAP fit well descriptively and statistically. Internal consistencies for total and subscale scores were good, and results supported convergent and divergent validity., Conclusion: Both versions are suitable for use in patients with SSc. The Brief-SWAP is most efficient; the full SWAP yields additional subscales that may be informative in understanding body image issues in patients with SSc.

Objective: Dyspnoea is a common, multifactorial source of functional impairment among patients with dcSSc. Our objective was to assess the reliability, construct validity and responsiveness to change of the Saint George's Respiratory Questionnaire (SGRQ) in patients with early dcSSc participating in a multicentre prospective study., Methods: At enrolment and 1 year, patients completed the SGRQ (a multi-item instrument with four scales: symptoms, activity, impact and total), a visual analogue scale (VAS) for breathing and the HAQ Disability Index (HAQ-DI) and underwent 6 min walk distance and pulmonary function tests, physician and patient global health assessments and high-resolution CT (HRCT). We assessed internal consistency reliability using Cronbach's α. For validity we examined the ability of the SGRQ to differentiate the presence vs absence of interstitial lung disease (ILD) on HRCT or restrictive lung disease and evaluated the 1 year responsiveness to change using pulmonary function tests and patient- and physician-reported anchors. Correlation coefficients of 0.24-0.36 were considered moderate and >0.37 was considered large., Results: A total of 177 patients were evaluated. Reliability was satisfactory for all SGRQ scales (0.70-0.93). All scales showed large correlations with the VAS for breathing and diffusing capacity of the lung for carbon monoxide in the overall cohort and in the subgroup with ILD. Three of the four scales in the overall cohort and the total scale in the ILD subgroup showed moderate to large correlation with the HAQ-DI and the predicted forced vital capacity (r = 0.33-0.44). Each scale discriminated between the presence and absence of ILD and restrictive lung disease (P ≤ 0.0001-0.03). At follow-up, all scales were responsive to change using different anchors., Conclusion: The SGRQ has acceptable reliability, construct validity and responsiveness to change for use in a dcSSc population and differentiates between patients with and without ILD., (© 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.)