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ObjectivesTo assess the reliability and the minimal clinically important differences (MCID) for FVC% predicted in the Scleroderma Lung Study I and II.MethodsUsing 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.ResultsReliability 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.ConclusionFVC% 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.

Introduction: Treprostinil diethanolamine is an innovative salt form of the prostacyclin analogue, treprostinil sodium, developed as an oral sustained release (SR) osmotic tablet. The availability of a formulation permitting convenient systemic delivery mi

OBJECTIVE: To assess the impact of cyclophosphamide (CYC) on the health-related quality of life (HRQOL) of patients with scleroderma after 12 months of treatment. METHODS: One hundred fifty-eight subjects participated in the Scleroderma Lung Study, with 79 each randomized to CYC and placebo arms. The study evaluated the results of 3 measures of health status: the Short Form 36 (SF-36), the Health Assessment Questionnaire (HAQ) disability index (DI), and Mahler's dyspnea index, and the results of 1 preference-based measure, the SF-6D. The differences in the HRQOL between the 2 groups at 12 months were calculated using a linear mixed model. Responsiveness was evaluated using the effect size. The proportion of subjects in each treatment group whose scores improved at least as much as or more than the minimum clinically important difference (MCID) in HRQOL measures was assessed. RESULTS: After adjustment for baseline scores, differences in the HAQ DI, SF-36 role physical, general health, vitality, role emotional, mental health scales, and SF-36 mental component summary (MCS) score were statistically significant for CYC versus placebo (P < 0.05). Effect sizes were negligible (<0.20) for all of the scales of the SF-36, HAQ DI, and SF-6D at 12 months. In contrast, a higher proportion of patients who received CYC achieved the MCID compared with placebo in the HAQ DI score (30.9% versus 14.8%), transitional dyspnea index score (46.4% versus 12.7%), SF-36 MCS score (33.3% versus 18.5%), and SF-6D score (21.3% versus 3.8%). CONCLUSION: One year of treatment with CYC leads to an improvement in HRQOL in patients with scleroderma lung disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate CAT-192, a recombinant human antibody that neutralizes transforming growth factor beta1 (TGFbeta1), in the treatment of early-stage diffuse cutaneous systemic sclerosis (dcSSc). METHODS: Patients with SSc duration of <18 months were randomly assigned to the placebo group or to 1 of 3 CAT-192 treatment groups: 10 mg/kg, 5 mg/kg, 0.5 mg/kg. Infusions were given on day 0 and weeks 6, 12, and 18. The primary objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of CAT-192. Secondary outcomes included the modified Rodnan skin thickness score (MRSS), the Scleroderma Health Assessment Questionnaire, assessment of organ-based disease, serum levels of soluble interleukin-2 receptor, collagen propeptides (N propeptide of type I [PINP] and type III collagen), and tissue levels of messenger RNA for procollagens I and III and for TGFbeta1 and TGFbeta2. RESULTS: Forty-five patients were enrolled. There was significant morbidity and mortality, including 1 death in the group receiving 0.5 mg/kg of CAT-192 and 3 deaths in the group receiving 5 mg/kg of CAT-192. There were more adverse events and more serious adverse events in patients receiving CAT-192 than in those receiving placebo, although these events were not more frequent in the high-dose treatment group. The MRSS improved in all groups during the study, but there was no evidence of a treatment effect for CAT-192. Improvement in the MRSS correlated with the disease duration (r = -0.54, P = 0.0008). Changes in the PINP level from baseline correlated with changes in the MRSS (r = 0.37, P = 0.027). CONCLUSION: We report the first evaluation of a systemically administered and repeatedly dosed anti-TGFbeta1 drug. In this pilot study, CAT-192, in doses up to 10 mg/kg, showed no evidence of efficacy. The utility of clinical and biochemical outcome measures and the feasibility of multicenter trials of early dcSSc were confirmed. [ABSTRACT FROM AUTHOR]

Objectives: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD)., Methods: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification., Results: Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration., Conclusions: Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: Competing interests: JRS reports personal fees from Atlantic, Bayer, Blade, Boehringer Ingelheim, Camurus, Corbus, DRG, Eicos, Eiger Pharmaceuticals, EMD Serono, Guidepoint, Indalo, Mitsubishi and Xenikos; and stock ownership or options in BriaCell and Pacific Therapeutics. VK and MA are employees of Boehringer Ingelheim. OD reports grants and personal fees from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi; personal fees from AbbVie, Acceleron Pharma, Anamar, Amgen, Baecon Discovery, Blade Therapeutics, Catenion, CSL Behring, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, Glenmark Pharma, GlaxoSmithKline, Inventiva, Italfarmaco, IQVIA, Lilly, Medac, Medscape, Menarini, Mepha, Merck Sharp & Dohme, Novartis, Roche, Sanofi, Target BioScience and UCB; personal fees and non-financial support from Pfizer; and patent US8247389; and was a member of the SENSCIS trial steering committee.

Objective: To analyze the efficacy and safety of nintedanib in patients with fibrosing autoimmune disease-related interstitial lung diseases (ILDs) with a progressive phenotype., Methods: The INBUILD trial enrolled patients with a fibrosing ILD other than idiopathic pulmonary fibrosis, with diffuse fibrosing lung disease of >10% extent on high-resolution computed tomography, forced vital capacity percent predicted (FVC%) ≥45%, and diffusing capacity of the lungs for carbon monoxide percent predicted ≥30% to <80%. Patients fulfilled protocol-defined criteria for progression of ILD within the 24 months before screening, despite management deemed appropriate in clinical practice. Subjects were randomized to receive nintedanib or placebo. We assessed the rate of decline in FVC (ml/year) and adverse events (AEs) over 52 weeks in the subgroup with autoimmune disease-related ILDs., Results: Among 170 patients with autoimmune disease-related ILDs, the rate of decline in FVC over 52 weeks was -75.9 ml/year with nintedanib versus -178.6 ml/year with placebo (difference 102.7 ml/year [95% confidence interval 23.2, 182.2]; nominal P = 0.012). No heterogeneity was detected in the effect of nintedanib versus placebo across subgroups based on ILD diagnosis (P = 0.91). The most frequent AE was diarrhea, reported in 63.4% and 27.3% of subjects in the nintedanib and placebo groups, respectively. AEs led to permanent discontinuation of trial drug in 17.1% and 10.2% of subjects in the nintedanib and placebo groups, respectively., Conclusion: In the INBUILD trial, nintedanib slowed the rate of decline in FVC in patients with progressive fibrosing autoimmune disease-related ILDs, with AEs that were manageable for most patients., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Many therapies have been investigated for systemic sclerosis-associated interstitial lung disease (SSc-ILD), including immunosuppressive therapies, antifibrotic agents, immunomodulators and monoclonal antibodies. There is a high unmet medical need to better understand the current evidence for treatment efficacy and safety. This systematic review aims to present the existing literature on different drug treatments investigated for SSc-ILD and to critically assess the level of evidence for these drugs. A systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A structured literature search was performed for clinical trials and observational studies on the treatment of SSc-ILD with pharmaceutical interventions from 1 January 1990 to 15 December 2020. The quality of each reference was assessed using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) criteria. A total of 77 references were reviewed and 13 different treatments were identified. We found high-quality evidence for the use of cyclophosphamide, nintedanib, mycophenolate and tocilizumab. Therefore, we would posit that the clinical community has four valid options for treatment of SSc-ILD. Further research is mandatory to provide more evidence for the optimal treatment strategy in SSc-ILD, including the optimal time to initiate treatment, selection of patients for treatment and upfront combination therapy., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the effects of abituzumab in systemic sclerosis-associated interstitial lung disease (SSc-ILD)., Methods: STRATUS was a phase II, double-blind, parallel-group, multicenter trial (ClinicalTrials.gov: NCT02745145). Adults (≤ 75 yrs) with SSc-ILD on stable mycophenolate were randomized (2:2:1) to receive intravenous abituzumab 1500 mg, abituzumab 500 mg, or placebo every 4 weeks for 104 weeks. The primary endpoint was the annual rate of change in absolute forced vital capacity., Results: STRATUS was terminated prematurely due to slow enrollment (n = 75 screened, n = 24 randomized), precluding robust analysis of efficacy. Abituzumab was well tolerated; no new safety signals were detected., Conclusion: Further investigation of abituzumab for treatment of SSc-ILD is required., (© 2021 The Journal of Rheumatology.)

Objectives: To characterise the safety and tolerability of nintedanib and the dose adjustments used to manage adverse events in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD)., Methods: In the SENSCIS trial, patients with SSc-ILD were randomised to receive nintedanib 150 mg two times per day or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg two times per day. We assessed adverse events and dose adjustments over 52 weeks., Results: A total of 576 patients received nintedanib (n=288) or placebo (n=288). The most common adverse event was diarrhoea, reported in 75.7% of patients in the nintedanib group and 31.6% in the placebo group; diarrhoea led to permanent treatment discontinuation in 6.9% and 0.3% of patients in the nintedanib and placebo groups, respectively. In the nintedanib and placebo groups, respectively, 48.3% and 12.2% of patients had ≥1 dose reduction and/or treatment interruption, and adverse events led to permanent discontinuation of the trial drug in 16.0% and 8.7% of patients. The adverse events associated with nintedanib were similar across subgroups defined by age, sex, race and weight. The rate of decline in forced vital capacity in patients treated with nintedanib was similar irrespective of dose adjustments., Conclusions: The adverse event profile of nintedanib in patients with SSc-ILD is consistent with its established safety and tolerability profile in patients with idiopathic pulmonary fibrosis. Dose adjustment is important to minimise the impact of adverse events and help patients remain on therapy., Competing Interests: Competing interests: JRS reports personal fees from Atlantic, Bayer, Blade, Boehringer Ingelheim, Camurus, Corbus, DRG, Eicos, Eiger Pharmaceuticals, EMD Serono, Guidepoint, Indalo, Mitsubishi and Xenikos; and stock ownership or options in BriaCell and Pacific Therapeutics. TMM reports grants and personal fees from GlaxoSmithKline and UCB, and personal fees from Apellis, Bayer, Biogen Idec, Blade, Boehringer Ingelheim, Bristol-Myers Squibb, Galapagos, Galecto, Indalo, Novartis, Respivent, Roche and Trevi. KBH reports grants and personal fees from Actelion Pharmaceuticals, Boehringer Ingelheim and United Therapeutics; personal fees from Bayer; and grants from Genentech, Eiger BioPharmaceuticals and Reata Pharmaceuticals. SA reports grants, personal fees and other remuneration from Boehringer Ingelheim; grants from Bayer, Biogen Idec and Momenta; and personal fees from Medscape, Integrity Continuing Education and Corbus. AA reports personal fees and other remuneration from Boehringer Ingelheim, Taiho Pharmaceutical and Toray; personal fees from Asahi Kasei Pharma; and other remuneration from Shionogi & Co., Ltd, and aTyr Pharma. LKH reports other remuneration from Boehringer Ingelheim (investigator of SENSCIS trial). UC reports personal fees and non-financial support from Boehringer Ingelheim and Roche; and personal fees from AstraZeneca, Fibrogen, Novartis and Pliant Therapeutics. UvW, VK, MG and MA are employees of Boehringer Ingelheim. OD reports grants and personal fees from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi; personal fees from AbbVie, Acceleron Pharma, Anamar, Amgen, Baecon Discovery, Blade Therapeutics, Catenion, CSL Behring, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, Glenmark Pharma, GlaxoSmithKline, Inventiva, Italfarmaco, IQVIA, Lilly, Medac, Medscape, Menarini, Mepha, Merck Sharp & Dohme, Novartis, Roche, Sanofi, Target BioScience and UCB; personal fees and non-financial support from Pfizer; and patent US8247389. TMM, KBH, AA and OD were members of the SENSCIS trial steering committee., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Systemic sclerosis (SSc) is an autoimmune rheumatic disease with heterogeneous clinical manifestations and a variable course in which the severity of the pathology dictates the disease prognosis and course. Among autoimmune rheumatic diseases, SSc has the highest mortality rate among all rheumatic diseases, though there are exciting new therapeutic targets that appear to halt the progression of SSc manifestations such as skin or lung fibrosis. In selected patients, high-intensity regimens with autologous stem cell transplantation can favorably modify the course. In what was once thought to be an untreatable disease, targeted therapies have now changed the outlook of SSc to a treatable disorder. Herein, we discuss the targeted therapies modifying the outlook on selected organ involvement and creating opportunities for future treatment. We also present a framework for defining low disease activity in SSc., (© 2020, 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 .).

Objective: Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc). In this longitudinal study, we aimed to identify factors associated with an unfavourable outcome in patients with SSc with early PAH (SSc-PAH) from the DETECT cohort., Methods: Patients with SSc-PAH enrolled in DETECT were observed for up to 3 years. Associations between cross-sectional variables and disease progression (defined as the occurrence of any of the following events: WHO Functional Class worsening, combination therapy for PAH, hospitalisation or death) were analysed by univariable logistic regression., Results: Of 57 patients with PAH (median observation time 12.6 months), 25 (43.9%) had disease progression. The following factors (OR (95% CI)) were associated with disease progression: male gender (4.1 (1.2 to 14.1)), high forced vital capacity % predicted/carbon monoxide lung diffusion capacity (DLCO)% predicted ratio (3.6 (1.2 to 10.7)), high Borg Dyspnoea Index (1.7 (1.1 to 2.6)) and low DLCO% predicted (non-linear relationship)., Conclusion: More than 40% of early-diagnosed patients with SSc-PAH had disease progression during a short follow-up time, with male gender, functional capacity and pulmonary function tests at PAH diagnosis being associated with progression. This suggests that even mild PAH should be considered a high-risk complication of SSc., Competing Interests: Competing interests: CM has/had consultancy relationship and/or has received honoraria from Actelion Pharmaceuticals, AbbVie, Roche and Geneva Romfarm in the area of systemic sclerosis and its complications. MA: no disclosures. RD has received research funding from Actelion Pharmaceuticals and Pfizer (Articulum fellowship). DB has/had consultancy relationship and/or has received research funding from Actelion Pharmaceuticals, GlaxoSmithKline, Merck Sharp & Dohme, Bayer, Pfizer, AOP Orphan and United Therapeutics. JGC has/had consultancy relationship and/or has received research funding from Actelion Pharmaceuticals, GlaxoSmithKline, United Therapeutics, Bayer and Endotronix. CPD has/had consultancy relationships, received lecture honoraria and/or has received research funding from Actelion Pharmaceuticals, Pfizer, GlaxoSmithKline, Sanofi-Aventis and Novartis. EG received speaker honoraria/advisory board fees and has taken part in clinical trials from Actelion Pharmaceuticals, GlaxoSmithKline, Merck Sharp & Dohme, Bayer, United Therapeutics, Pfizer, OMT, AOP Orphan and Novartis. DK has/had consultancy relationship and/or has received research funding from Actelion Pharmaceuticals, Bayer, Bristol-Myers Squibb, Covis, Cytori, EMD Serono, Genentech/Roche, Gilead, GSK, Sanofi-Aventis and NIH K24AR063120. VVM has acted as a consultant and/or received honoraria/lecture fees from Actelion Pharmaceuticals, Bayer, Gilead and United Therapeutics. She has received research funding (to the University of Michigan) from Actelion Pharmaceuticals, Bayer, Novartis and United Therapeutics. UM-L has acted as a consultant and lecturer for Actelion Pharmaceuticals, Pfizer and GlaxoSmithKline. JEP consults for Actelion Pharmaceuticals, Bayer, Bristol-Myers Squibb, Merck and Roche with respect to potential SSc treatment. JRS has/had consultancy relationships with Acer, Anthera, arGen-X, aTyr, Bayer, Blade, Boehringer Ingelheim, Bristol Myers Squibb, Biogen Idec, Covis, Eiger, EMD Serono, Genkyotex, Gilead, Ironwood, Medac, MedImmune, Mitsubishi, Octapharma, Roche-Genentech, Sanofi, Teva and United Therapeutics. MCV has/had consultancy relationship and/or has received research funding from Actelion Pharmaceuticals, Therabel and United Therapeutics. HC-B, MD and DMR are employees of Actelion Pharmaceuticals. OD has/had consultancy relationship and/or has received research funding from 4D Science, Actelion Pharmaceuticals, Active Biotec, Bayer, Biogen Idec, Boehringer Ingelheim Pharma, Bristol-Myers Squibb, ChemomAb, EpiPharm, Ergonex, espeRare Foundation, GlaxoSmithKline, Roche-Genentech, Inventiva, Lilly, Medac, MedImmune, Mitsubishi Tanabe, Pharmacyclics, Pfizer, Sanofi, Serodapharm and Sinoxa in the area of potential treatments of scleroderma and its complications. He has a patent on mir-29 for the treatment of systemic sclerosis licensed., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

There are proven successful approaches to clinical trial design in pulmonary arterial hypertension (PAH), which in turn have led to the licensing of a number of effective therapies. SSc has been included in trials of World Health Organization Group 1 PAH but has been under-represented. Responses in outcomes as diverse as exercise capacity, quality of life, durability of drug effect and survival have been reduced in comparison with those seen in idiopathic PAH. The PAH community has achieved international and interdisciplinary consensus guidelines for future studies. We consider the diverse outcome measures used in trials in the context of the complexities of scleroderma. An argument is advanced in favour of future trials focused exclusively on SSc but with adaptations of the core outcome measures and trial design templates applicable to more general studies of PAH., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The modified Rodnan skin score (mRSS) is a measure of skin thickness and is used as a primary or secondary outcome measure in clinical trials of systemic sclerosis (scleroderma). This state-of-art review provides a historical perspective of the development of the mRSS, summarizes the performance of mRSS as an outcome measure, provides guidance on assessing mRSS, and makes recommendations for incorporation of the mRSS into clinical trials., Competing Interests: CONFLICTS Dr. Khanna has consultancy relationships with Actelion, Bayer, Bristol-Myers Squibb, ChemomAb, Corbus, Cytori, Eicos, EMD Serono, Genentech/Roche, Gilead, Glaxo SmithKline, MedImmune, Medac, and Sanofi-Aventis/Genzyme. He has received research funding from Astra-Zeneca, Bayer, Bristol-Myers Squibb, and Pfizer. This work was funded in part by the NIH/NIAMS K24 AR06312 grant. Dr. Furst has consultancy relationships and/or has received research funding in relationship grant/research from Amgen, BMS, NIH, Novartis, Pfizer, Roche/Genentech, AbbVie, Amgen, BMS, Cytori, Janssen, NIH, Novartis, Pfizer, Roche/Genentech, and UCB. Dr. Clements has no relevant conflicts. Dr. Allanore has consultancy relationships and/or has received research funding in relationship with the treatment of systemic sclerosis from Actelion, Bayer, Biogen Idec, Bristol-Myers Squibb, Genentech/Roche, Inventiva, Medac, Pfizer, Sanofi/Genzyme, Servier and UCB. Dr. Baron has no relevant conflicts. Dr. Czirjak has consultancy relationships with the treatment of systemic sclerosis from Actelion, Bayer, Genentech/Roche, Inventiva, Medac, and Pfizer. Dr. Distler has/had consulting relationships from 4 D Science, Actelion, Active Biotec, Chemom AG, Bayer, BiogenIdec, BMS, Boehringer Ingelheim, ChemomAb, EpiPharm, espeRare foundation, Genentech/Roche, GSK, Inventiva, Lilly, medac, Mepha, MedImmune, Pharmacyclics, Pfizer, Sanofi, Serodapharm, and Sinoxa; and grants from Actelion, Bayer, Boehringer Ingelheim, Pfizer, and Sanofi. Patent licensed: mir-29 for the treatment of systemic sclerosis. Speaker fees from AbbVie, iQone Healthcare, Mepha Dr. Foeldvari has consultancy relationships with Bayer, Roche-Genentech, Novartis, Abbive, Chugai. Speakers fee: Pfizer, Abbvie, and Medac Dr. Kuwana has consultancy or speaker fees from Bayer, Boehringer Ingelheim, Chugai, Actelion, and Glaxo SmithKline, and/or has received research funding from Chugai, Actelion, and Bayer. Dr. Matucci-Cerinic has active consultancies or has received grant support from Amgen, BMS, Pfizer, Bruno farma, and Actelion. Consultant: BMS, Actelion, Pfizer, Inventiva, Chemomab Dr. Mayes has consultancy relationship with and/or has received research funding from Bayer, Boehringer-Ingelheim, Corbus, Cytori, Genentech/Roche. Dr. Medsger has consultancy relationship with iBio. Dr. Merkel has consultancy relationship with and/or has received research funding from Actelion, Bristol-Myers Squibb, ChemoCentryx, Genentech/Roche, Glaxo SmithKline, Kypha, MedImmune/AztraZeneca, PrincipoBio, Sanofi-Aventis/Genzyme. Dr. Pope has consultancy relationship with AbbVie, Actelion, Amgen, Bayer, BMS, Hospira, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, UCB. Dr. Seibold has consultancy relationship with Anthera, Bayer, BioGen IDEC, Blade Therapeutics, Boehringer Ingelheim, Covis Pharma, Cytori, Eiger, EMD Serono, Milestone, Mitsubishi, Sanofi-Aventis, Teva and Xenikos. There are no speaker’s bureaus or stock holdings. Dr. Steen has consultancy fees from Bristol Myers Squibb, Cytori, Bayer, Gilead, and research grant funding from CSL Behring, United Therapeutics and Gilead, and Clinical Trial research funding from Cytori, Roche, Boehringer Ingelheim, EMD Serono, Covis, and Reata Dr. Stevens has consultancy relationship or received research funding form Actelion, GSK, Bayer and Pfizer and has received speakers fees from Actelion and GSK Dr. Denton has consultancy relationships with or speaker fees from Actelion, Bristol-Myers Squibb, GlaxoSmithKline, Bayer, Sanofi-Aventis, Boehringer Ingelheim, Genentech-Roche, and CSL Behring, and research grant funding from GlaxoSmithKline, Actelion, Novartis, CSL Behring.

Objective: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) shares a number of clinical features and pathogenic mechanisms with idiopathic pulmonary fibrosis (IPF). This study was designed to evaluate the tolerability of the IPF treatment pirfenidone in SSc-ILD. The known gastrointestinal, skin, and liver adverse events (AE) of pirfenidone are of importance given the involvement of these organs in SSc., Methods: All patients received pirfenidone and were randomized 1:1 to either a 2- or 4-week titration starting at 801 mg/day and finishing at a maintenance dose of 2403 mg/day. Patients received pirfenidone for 16 weeks in total. Assessments included treatment-emergent AE (TEAE) and exploratory disease outcomes., Results: Sixty-three patients were randomized; 96.8% experienced a TEAE and more patients reported TEAE during the titration versus the maintenance period. The most commonly reported TEAE were consistent with those observed for pirfenidone in IPF (nausea, headache, fatigue) and were similar regardless of titration schedule. More patients discontinued treatment because of TEAE in the 2- versus 4-week titration group (5 vs 1, respectively); all discontinuation events occurred > 3 weeks after reaching the full dose of pirfenidone. Mycophenolate mofetil (MMF), taken by 63.5% of patients in addition to pirfenidone, did not appear to affect tolerability. Exploratory disease outcomes remained largely unchanged., Conclusion: Pirfenidone showed an acceptable tolerability profile in SSc-ILD, although a longer titration may be associated with better tolerability. Tolerability was not affected by concomitant MMF. The present findings support further investigation of pirfenidone in future clinical trials in patients with SSc-ILD., Trial Registration: ClinicalTrials.gov; www.clinicaltrials.gov NCT01933334.

Objective: Early diffuse cutaneous systemic sclerosis (dcSSc) is characterized by rapid changes in the skin and internal organs. The objective of this study was to develop a composite response index in dcSSc (CRISS) for use in randomized controlled trials (RCTs)., Methods: We developed 150 paper patient profiles with standardized clinical outcome elements (core set items) using patients with dcSSc. Forty scleroderma experts rated 20 patient profiles each and assessed whether each patient had improved or not improved over a period of 1 year. Using the profiles for which raters had reached a consensus on whether the patients were improved versus not improved (79% of the profiles examined), we fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to followup were entered as covariates. We tested the final index in a previously completed RCT., Results: Sixteen of 31 core items were included in the patient profiles after a consensus meeting and review of test characteristics of patient-level data. In the logistic regression model in which the included core set items were change over 1 year in the modified Rodnan skin thickness score, the forced vital capacity, the patient and physician global assessments, and the Health Assessment Questionnaire disability index, sensitivity was 0.982 (95% confidence interval 0.982-0.983) and specificity was 0.931 (95% confidence interval 0.930-0.932), and the model with these 5 items had the highest face validity. Subjects with a significant worsening of renal or cardiopulmonary involvement were classified as not improved, regardless of improvements in other core items. With use of the index, the effect of methotrexate could be differentiated from the effect of placebo in a 1-year RCT (P = 0.02)., Conclusion: We have developed a CRISS that is appropriate for use as an outcome assessment in RCTs of early dcSSc., (© 2016, American College of Rheumatology.)

Objective: Interstitial lung disease (ILD) is common in connective tissue disease (CTD) and is the leading cause of mortality. Investigators have used certain outcome measures in randomized controlled trials (RCT) in CTD-ILD, but the lack of a systematically developed, CTD-specific index that captures all measures relevant and meaningful to patients with CTD-ILD has left a large and conspicuous gap in CTD-ILD research., Methods: The CTD-ILD working group, under the aegis of the Outcome Measures in Rheumatology (OMERACT) initiative, has completed a consensus group exercise to reach harmony on core domains and items for inclusion in RCT in CTD-ILD. During the OMERACT 12 meeting, consensus was sought on domains and core items for inclusion in RCT. In addition, consensus was pursued on a definition of response in RCT. Consensus was defined as ≥ 75% agreement among the participants., Results: OMERACT 12 participants endorsed the domains with minimal modifications. Clinically meaningful progression for CTD-ILD was proposed as ≥ 10% relative decline in forced vital capacity (FVC) or ≥ 5% to < 10% relative decline in FVC and ≥ 15% relative decline in DLCO., Conclusion: There is consensus on domains for inclusion in RCT in CTD-ILD and on a definition of clinically meaningful progression. Data-driven approaches to validate these results in different cohorts and RCT are needed.

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.)

Objective: SSc is clinically and aetiopathogenically heterogeneous. Consensus standards for more uniform trial design and selection of outcome measures are needed. The objective of this study was to develop evidence-based points to consider (PTCs) for future clinical trials in SSc., Methods: Thirteen international SSc experts experienced in SSc clinical trial design were invited to participate. One researcher with experience in systematic literature review and three trainees were also included. A systematic review using PubMed and the Cochrane Central Register of Controlled Trials was conducted and PTCs when designing clinical trials in SSc were developed. As part of that development we conducted an Internet-based Delphi exercise regarding the main points to be made in the consensus statement. Consensus was defined as achieving a median score of ≥7 of 9., Results: By consensus, the experts decided to develop PTCs for each individual organ system. The current document provides a unifying outline on PTCs regarding general trial design, inclusion/exclusion criteria and analysis. Consensus was achieved regarding all the main points of the PTCs., Conclusion: Using European League Against Rheumatism suggestions for PTCs, a general outline for PTCs for controlled clinical trials in SSc was developed. Specific outlines for individual organ systems are to be published separately. This general outline should lead to more uniform and higher-quality trials and clearly delineate areas where further research is needed., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: Patients with mean pulmonary artery pressures (mPAP) of 21 to 24 mm Hg have a so-called borderline elevation of mPAP (BoPAP)--a condition thought to represent early-stage pulmonary arterial vasculopathy. Based on the DETECT study, this post-hoc analysis examined patient characteristics of systemic sclerosis (SSc) patients with normal mPAP, BoPAP and elevated mPAP, fulfilling pulmonary arterial hypertension (PAH) criteria., Methods: Adult patients with a duration of SSc more than 3 years, a diffusing capacity of the lung for carbon monoxide less than 60% predicted, and no previous diagnosis of any form of pulmonary hypertension (PH) underwent screening tests followed by right heart catheterization. Subjects were divided into three groups: normal mPAP, BoPAP, and PAH. Exploratory comparative and binary logistic regression analyses were performed for the BoPAP versus normal mPAP and PAH versus BoPAP groups., Results: Of 244 patients evaluated, 148 (60%) had normal mPAP, 36 (15%) had BoPAP, and 60 (25%) had definite PAH. Univariable logistic regression (ULR) showed the mean tricuspid regurgitation velocity in patients with BoPAP to be intermediate between normal mPAP and PAH. In the ULR analyses BoPAP versus normal mPAP and PAH versus BoPAP, the statistically significant predictors were, amongst others: demographic, clinical, pulmonary function, echocardiographic and hemodynamic variables., Conclusions: In this exploratory post-hoc analysis of the DETECT study population patients with BoPAP could be distinguished from patients with normal mPAP and PAH, and it appears that BoPAP may be an intermediate stage on the continuum between normal PA pressures and PAH.

Objectives: The aim of this study was to utilise the Quality Enhancement Research Initiative in Systemic Sclerosis (QuERI-SSc) to measure and reduce a perceived gap in the diagnosis of pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc)., Methods: Rheumatologists enrolled patients with SSc (aged ≥ 18 years) and provided data on a panel of diagnostic tests over 3 years. Pulmonary function testing, echocardiography, 6-minute walk distance, N-terminal pro-brain natriuretic peptide assays, high-resolution computed tomography of the lungs, and ventilation/perfusion scan plus right heart catheterisation (RHC; when appropriate) were emphasised. Exclusion criteria included previously documented PAH, interstitial lung disease, and SSc overlapping with other connective tissue disease., Results: Participating rheumatologists enrolled 207 patients with SSc (90% female; 80% white), with a median age of 57 years and median disease duration of 5 years. A total of 82% of patients were classified as New York Heart Association functional class I and II; of these patients, 177 had an echocardiogram at enrolment and 191 at any time during the study. Of those who met study-specified criteria for RHC at enrolment, only 3 of 7 patients underwent RHC., Conclusions: The screening algorithm was successful in identifying patients with mild impairment. Although specific tools were recommended for screening PAH in patients with SSc, results indicate that significant diagnostic care gaps still exist in the general rheumatology community. Better understanding and adherence to guidelines could improve the care and, ideally, outcomes of these high-risk patients.

Objective: Skin and musculoskeletal involvement are frequently present early in diffuse cutaneous systemic sclerosis (dcSSc). The current study examined the correlates for skin and musculoskeletal measures in a 1-year longitudinal observational study., Methods: Patients with dcSSc were recruited at 4 US centers and enrolled in a 1-year study. Prespecified and standardized measures included physician and patient assessments of skin involvement, modified Rodnan skin score (MRSS), durometer score, Health Assessment Questionnaire disability index, serum creatine phosphokinase, tender joint counts, and presence/absence of tendon friction rubs, small joint contractures, and large joint contractures. Additionally, physician and patient global health assessments and health-related quality of life assessments were recorded. Correlations were computed among the baseline global assessments, skin variables, and musculoskeletal variables. Using the followup physician and patient anchors, effect sizes were calculated., Results: A total of 200 patients were studied: 75% were women, mean ± SD age was 50.0 ± 11.9 years, and mean ± SD disease duration from first non-Raynaud's phenomenon symptom was 1.6 ± 1.4 years. Physician global health assessment had large correlations with MRSS (r = 0.60) and physician-reported skin involvement visual analog scale in the last month (r = 0.74), whereas patient global assessment had large correlations with MRSS, the Short Form 36 health survey physical component scale, skin interference, and skin involvement in the last month (r = 0.37-0.72). Four of 9 skin variables had moderate to large effect sizes (0.51-1.09)., Conclusion: Physician and patient global assessments have larger correlations with skin measures compared to musculoskeletal measures. From a clinical trial perspective, skin variables were more responsive to change than musculoskeletal variables over a 1-year period, although both provide complementary information., (Copyright © 2014 by the American College of Rheumatology.)

Objective: Earlier detection of pulmonary arterial hypertension (PAH), a leading cause of death in systemic sclerosis (SSc), facilitates earlier treatment. The objective of this study was to develop the first evidence-based detection algorithm for PAH in SSc., Methods: In this cross-sectional, international study conducted in 62 experienced centres from North America, Europe and Asia, adults with SSc at increased risk of PAH (SSc for >3 years and predicted pulmonary diffusing capacity for carbon monoxide <60%) underwent a broad panel of non-invasive assessments followed by diagnostic right heart catheterisation (RHC). Univariable and multivariable analyses selected the best discriminatory variables for identifying PAH. After assessment for clinical plausibility and feasibility, these were incorporated into a two-step, internally validated detection algorithm. Nomograms for clinical practice use were developed., Results: Of 466 SSc patients at increased risk of PAH, 87 (19%) had RHC-confirmed PAH. PAH was mild (64% in WHO functional class I/II). Six simple assessments in Step 1 of the algorithm determined referral to echocardiography. In Step 2, the Step 1 prediction score and two echocardiographic variables determined referral to RHC. The DETECT algorithm recommended RHC in 62% of patients (referral rate) and missed 4% of PAH patients (false negatives). By comparison, applying European Society of Cardiology/European Respiratory Society guidelines to these patients, 29% of diagnoses were missed while requiring an RHC referral rate of 40%., Conclusions: The novel, evidence-based DETECT algorithm for PAH detection in SSc is a sensitive, non-invasive tool which minimises missed diagnoses, identifies milder disease and addresses resource usage., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objectives: Classification criteria for systemic sclerosis (SSc) are being developed. The objectives were to develop an instrument for collating case data and evaluate its sensibility; use forced-choice methods to reduce and weight criteria; and explore agreement among experts on the probability that cases were classified as SSc., Study Design and Setting: A standardized instrument was tested for sensibility. The instrument was applied to 20 cases covering a range of probabilities that each had SSc. Experts rank ordered cases from highest to lowest probability; reduced and weighted the criteria using forced-choice methods; and reranked the cases. Consistency in rankings was evaluated using intraclass correlation coefficients (ICCs)., Results: Experts endorsed clarity (83%), comprehensibility (100%), face and content validity (100%). Criteria were weighted (points): finger skin thickening (14-22), fingertip lesions (9-21), friction rubs (21), finger flexion contractures (16), pulmonary fibrosis (14), SSc-related antibodies (15), Raynaud phenomenon (13), calcinosis (12), pulmonary hypertension (11), renal crisis (11), telangiectasia (10), abnormal nailfold capillaries (10), esophageal dilation (7), and puffy fingers (5). The ICC across experts was 0.73 [95% confidence interval (CI): 0.58, 0.86] and improved to 0.80 (95% CI: 0.68, 0.90)., Conclusions: Using a sensible instrument and forced-choice methods, the number of criteria were reduced by 39% (range, 23-14) and weighted. Our methods reflect the rigors of measurement science and serve as a template for developing classification criteria., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Rationale: Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities., Methods: The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF)., Results: A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed., Conclusion: Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.

Objective: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc., Methods: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc., Results: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc., Conclusion: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease., (Copyright © 2013 by the American College of Rheumatology.)

Background: The impact of modern therapy on survival in pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc) is not clear. We sought to determine associations among commonly used clinical and hemodynamic variables, treatment, and long-term survival in PAH associated with SSc compared with PAH defined as idiopathic, familial, or associated with anorexigens., Methods: The observation period (1996-2010) included the option for epoprostenol and the availability of oral agents in 2002 (modern era of endothelin antagonists and phosphodiesterase-5 inhibitors). Primary outcome was all-cause mortality., Results: Eighty-three patients had SSc (mean age, 59 years), and 120 had PAH (mean age, 51 years) (P &lt; .0001, &gt; 80% were functional class III or IV in both groups). Compared with PAH, SSc had a lower mean pulmonary artery pressure (48 mm Hg vs 58 mm Hg, P &lt; .0001) and pulmonary vascular resistance (10 resistance units vs 15 resistance units, P &lt; .0001), and a higher cardiac index (2.3 L/min/m2 vs 1.8 L/min/m2, P &lt; .0001). PAH was more often treated with prostacyclin (71% vs 44%, P &lt; .0001), but there were no differences in the use of monotherapy or combination oral therapy. SSc had a twofold-higher mortality over the 14 years. The 5-year survival in the modern era for PAH was 87%, compared with 51% for SSc (P &lt; .001)., Conclusions: Despite an improvement in clinical status, unlike in PAH, mortality in SSc has not improved since the introduction of epoprostenol.

Introduction: Treprostinil diethanolamine is an innovative salt form of the prostacyclin analogue, treprostinil sodium, developed as an oral sustained release (SR) osmotic tablet. The availability of a formulation permitting convenient systemic delivery might have applicability to scleroderma vascular complications. We evaluated pharmacokinetics and perfusion in scleroderma patients with digital ischemia following escalating twice-daily doses of treprostinil diethanolamine SR., Methods: Scleroderma patients with digital ulcers were enrolled in this dual-center, open-label, phase I pharmacokinetic study. Drug concentrations and perfusion, quantified by laser Doppler imaging, were measured over 12 hours at the 2 mg and 4 mg (or maximally tolerated) doses. Pharmacokinetic parameters were determined from individual plasma concentration versus time profiles using non-compartmental analysis methods. Digital perfusion and skin temperature were modeled as a function of log-transformed drug concentration and other covariates by performing repeated measures analyses using random effects models., Results: Nineteen scleroderma patients (84% female, 53% limited scleroderma) received treprostinil diethanolamine SR with dose titration up to 4 mg twice daily as tolerated. Peak concentrations (mean maximum plasma concentration (Cmax) = 1,176 and 2,107 pg/mL) occurred approximately 3.6 hours after dose administration, and overall exposure (under the plasma concentration-time curve from time 0 to 12 hours post dose (AUC0-12) = 7,187 and 12,992 hr*pg/mL) was linear between the 2 mg and 4 mg doses. Perfusion and digital skin temperature were positively associated with log-transformed plasma concentration at the 4 mg dose (P = 0.015 and P = 0.013, respectively). The most frequent adverse events were similar to those seen with prostacyclin analogues., Conclusions: Oral treprostinil diethanolamine was effectively absorbed in patients with scleroderma. Drug administration was temporally associated with improved cutaneous perfusion and temperature. Treprostinil diethanolamine may provide a new therapeutic option for Raynaud's phenomenon and the peripheral vascular disease of scleroderma., Trial Registration: ClinicalTrials.gov NCT00848939.

Objective: To describe the prevalence and clinical correlates of endoscopic gastric antral vascular ectasia (GAVE; "watermelon stomach") in early diffuse systemic sclerosis (SSc)., Methods: Subjects with early, diffuse SSc and evidence of specific internal organ involvement were considered for the Scleroderma: Cyclophosphamide Or Transplant (SCOT) trial. In the screening procedures, all patients underwent upper gastrointestinal endoscopy. Patients were then categorized into those with or without endoscopic evidence of GAVE. Demographic data, clinical disease characteristics, and autoantibody data were compared using Pearson chi-square or Student t tests., Results: Twenty-three of 103 (22.3%) individuals were found to have GAVE on endoscopy. Although not statistically significant, anti-topoisomerase I (anti-Scl70) was detected less frequently among those with GAVE (18.8% vs 44.7%; p = 0.071). Similarly, anti-RNP antibodies (anti-U1 RNP) showed a trend to a negative association with GAVE (0 vs 18.4%; p = 0.066). There was no association between anti-RNA polymerase III and GAVE. Patients with GAVE had significantly more erythema or vascular ectasias in other parts of the stomach (26.1% vs 5.0%; p = 0.003)., Conclusion: Endoscopic GAVE was present on screening in almost one-fourth of these highly selected patients with early and severe diffuse SSc. While anti-Scl70 and anti-U1 RNP trended toward a negative association with GAVE, there was no correlation between anti-RNA Pol III and GAVE. Patients with GAVE had a higher frequency of other gastric vascular ectasias outside the antrum, suggesting that GAVE may represent part of the spectrum of the vasculopathy in SSc.