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.

ObjectivesThe aim was to update the 2009 EULAR recommendations for the treatment of systemic sclerosis (SSc) [1] with a distinct focus on new therapeutic aspects.MethodsRevision and update of the previous recommendations were performed according to the EULAR standard operating procedures. The task force consisted of 30 SSc experts from Europe and USA, two patients nominated by the pan-European patients association FESCA, a clinical epidemiologist and 3 fellows for systematic literature research. All centers from the EULAR Scleroderma Trials and Research (EUSTAR) group were invited to submit and select research questions concerning SSc treatment using a Delphi approach. A set of 46 research questions addressing 26 different interventions was selected for systematic literature research. The new recommendations were developed in a meeting, based on the available evidence while using a consensus procedure.ResultsSixteen recommendations were developed (instead of 14 in 2009) which address treatments of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis, and gastrointestinal involvement. Compared with the 2009 recommendations, the 2015 recommendations include phosphodiestase-5 (PDE5) inhibitors in the treatment of SSc-related RP and DUs, riociguat and new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE5 inhibitors for SSc-related PAH. The new recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressing SSc were added. In addition, the statement regarding sitaxentan for PAH was removed, because it was withdrawn from the market. A web-based internal evaluation of the new recommendations revealed high level of approval among task force members (average score >7 out of maximum 9) for all statements except the one regarding fluoxetine for RP (average score of 6,1). In addition, several comments regarding other treatments addressed in research questions and suggestions for the future SSc research agenda were formulated by the experts.ConclusionsThese updated and improved, data- and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations will also facilitate the directions for future clinical research in SSc.ReferencesKowal-Bielecka et al. Ann Rheum Dis 2009;68:620)AcknowledgementsThe project is funded by a research grant of EULAR to the EUSTAR SSc recommendation group. All contributing experts will be listed as full coauthors on the respective presentations and publications.Disclosure of InterestO. Kowal-Bielecka Speakers bureau: Abbvie, Actelion, Pfizer, Roche, J. Fransen: None declared, J. Avouac: None declared, M. Becker Consultant for: Actelion, A. Kulak: None declared, Y. Allanore Consultant for: Bayer Pharma, Actelion, Pfizer, Sanofi-Aventis, CSL Behring, Roche, O. Distler Consultant for: 4D Sc...

This article discusses points to consider when undertaking a clinical trial to test therapy for skin ulcers in SSc. A validated definition of skin ulcers should be used if available. Defining a uniform SSc patient population, including consideration of disease duration, history of digital ulcers and capillaroscopic patterns, is important. Excluding confounding factors such as infection, calcinosis and trauma should be strongly considered, or at least accounted for, in defining patients. Outcome measures such as time to healing, prevention of new ulcers, function, pain and objective measures such as US, laser Doppler and thermography can be considered as outcome measures, although their validation has not yet been achieved and efforts may be needed to validate them before use. Likewise, biomarkers should be considered or consideration should be given to storing serum, plasma or cells for possible future analysis. A pre-planned analysis is important and should include consideration of missing data.

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BackgroundEnrichment strategies from clinical trials for progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD) have been partly successful but have not been tested in a real life cohort.ObjectivesAnalyse the efficacy, representativeness and feasibility of enrichment strategies in SSc-ILD patients from the EUSTAR cohort.MethodsWe applied the inclusion criteria of major recent SSc-ILD trials (focuSSced, SLS II and SENSCIS) in SSc-ILD patients and assessed progressive ILD, defined as absolute change in forced vital capacity (FVC) and as significant progression (FVC decline >10%) over time. Data were compared to all patients and patients not fulfilling any inclusion criteria.ResultsIn total, 2258 SSc-ILD patients were included, with 31.2% meeting SENSCIS, 5.8% SLS II, 1.6% focuSSced criteria and 1529 (67.7%) not meeting any criteria (Table 1). In the first 12+/-3 months, a slow FVC% decline of –0.1% was seen in the total, unselected cohort and in patients fulfilling SENSCIS criteria. Patients fulfilling criteria from focuSSced showed a strong FVC decline of –3.7%. Notably, patients enriched for SLS II criteria showed FVC improvement of +2.3% (Figure 1). Similarly, compared to the total unselected cohort, the number of significant progressive events was numerically higher in patients fulfilling focuSSced criteria, the same for SENSCIS criteria and even slightly lower for patients fulfilling the SLS2 criteria.Table 1.Demographics and baseline clinical characteristics of EUSTAR patientsNot fulfilling any criteria (n=1529)focuSSced (n=36)SLS II (n=132)SENSCIS (n=704)Age, years (SD)58.4 (2.9)51.5 (12.2)†51.2 (12.7) †54.2 (13.8) †Male, n (%)231 (15.1)7 (19)35 (27)**156 (21)*Disease duration, months (SD)156.3 (99.4)16.1 (13.9)†40.7 (25.2) †39.4 (23.9) †DcSSc, n (%)597 (43.8)36 (100) †85 (65) †35 (52) †ATA, n (%)735 (51.1)24 (67)*85 (69) †370 (56)mRSS, mean (SD)9.5 (8.3)21 (6.5)*13 (9.6)*11 (9.2)GERD, n (%)1002 (65.9)25 (69)92 (70)430 (62)ESR, mean (SD)27 (20.5)43.1 (23) †29.6 (19.6) †24.7 (20.7)MMF, n (%)75 (16.5)0 (0) †0 (0) †52 (22) †MTX, n (%)42 (9.2)0 (0) †2 (5)20 (9)FVC % predicted, mean (SD)85.7 (22.5)88 (13.6)*66 (9.1) †88 (19.8)DLCO% predicted, mean (SD)58.9 (21.5)61 (12.7)49(14.6)†59 (14.2)NYHA class, n (%)3261 (17.8)6 (19)28 (21)72 (10)*440 (2.7)0 (0)3 (2)4 (1)**P-value: 0.001–0.05; †P<0.001, between focuSSced, SENSCIS or SLS compared with not fulfilling any study criteria.In the second 12 months period, SENSCIS enriched patients had a further absolute FVC% decline as described for the total cohort. In contrast, patients fulfilling the focuSSced and SLS II inclusion criteria showed numerical improvement of lung function in the second period (Figure 1). There were no significant associations of enrichment criteria and ILD progression in the second period.Over the mean observation period of 2.3 years, patients not fulfilling any inclusion criteria showed the same FVC decline of –0.9 (12.1) as observed for the total cohort (–0.9% (12.6)). There were numerical differences in FVC changes in the enriched patient cohorts, varying from –2.8% FVC decline in patients fulfilling the focuSSced criteria to +3.4% FVC improvement with SLS II criteria.ConclusionApplication of enrichment criteria from previous clinical trials showed enrichment for progression with variable success but led to selected patient populations reducing feasibility of recruitment. These findings are important for future clinical trial design and interpretation of the results of published trials.AcknowledgementsWe thank all EUSTAR collaborators.Disclosure of InterestsAnna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Grant/research support from: Boehringer Ingelheim, Cathrine Brunborg: None declared, Paolo Airò Speakers bureau: Bristol-Myers-Squibb, Boehringer Ingelheim, Consultant of: Bristol-Myers-Squibb, Grant/research support from: Bristol-Myers-Squibb, Roche, Jannsen, CSL Behring, Lidia P. Ananyeva Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, László Czirják Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Actelion (now GSK), MSD, Novartis, Pfizer, Roche, Lilly, Grant/research support from: Boehringer Ingelheim, Actelion (now GSK), MSD, Novartis, Pfizer, Serena Guiducci: None declared, Eric Hachulla Speakers bureau: GSK, Roche-Chugai, Johnson & Johnson, Boehringer Ingelheim, Consultant of: CSL Behring, GSK, Roche-Chugai, Johnson & Johnson, Boehringer Ingelheim, Grant/research support from: CSL Behring, Boehringer Ingelheim, GSK, Roche-Chugai, Sanofi Genzyme, Mengtao Li: None declared, Carina Mihai Speakers bureau: MEDtalks Switzerland, Mepha, Grant/research support from: Roche, Boehringer Ingelheim, Janssen, Gabriela Riemekasten Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Petros Sfikakis Consultant of: Boehringer Ingelheim, Gabriele Valentini Consultant of: Boehringer Ingelheim, Sanofi, Grant/research support from: BMS, Otylia Kowal-Bielecka Speakers bureau: Boehringer Ingelheim, Novartis, Pfizer, Gilead Sciences, Janssen-Cilag, MEDAC, MSD, Abbvie, Sandoz, Consultant of: Boehringer Ingelheim, Health Care system Navigator, CSL Behring, MSD, Novartis, Grant/research support from: CSL Behring, Boehringer Ingelheim, Abbvie, Roche, MEDAC, Yannick Allanore Speakers bureau: Boehringer, Abbvie, Consultant of: Boehringer, Bayer, Astra-Zeneca, Prometheus, Sanofi, Genentech/Roche, Boehringer, Grant/research support from: Alpine Immunosciences, OSE Immunotherapeutics, Medsenic, Oliver Distler Speakers bureau: Bayer, Boehringer Ingelheim, Janssen, Medscape, Consultant of: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, 4P Science, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur, Grant/research support from: Kymera, Mitsubishi Tanabe, Boehringer Ingelheim