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Objective In the SENSCIS trial, participants with systemic sclerosis-associated interstitial lung disease (SSc-ILD) were randomized to receive nintedanib or placebo until the last participant reached week 52 but for 100 weeks or less. Nintedanib reduced the rate of decline in forced vital capacity (FVC) (ml/year) over 52 weeks by 44% (41 ml [95% confidence interval (95% CI): 2.9-79.0]) versus placebo. We investigated the effect of nintedanib over the whole SENSCIS trial. Methods The annual rate of decline in FVC (ml/year) over the whole trial was assessed descriptively using 1) on-treatment data plus off-treatment data from participants who prematurely discontinued treatment (intent-to-treat analysis) and 2) only on-treatment data to assess the effect of nintedanib in participants who remained on treatment. Results In the intent-to-treat analysis, the adjusted mean (SE) annual rate of decline in FVC over 100 weeks was −54.9 (11.1) and −88.8 (10.9) ml/year in the nintedanib (n = 287) and placebo (n = 288) groups, respectively (difference 34.0 ml/year [95% CI: 3.4-64.5]). In the on-treatment analysis, the adjusted mean (SE) annual rate of decline in FVC over 100 weeks was −55.1 (12.3) and −94.0 (11.7) ml/year in the nintedanib (n = 286) and placebo (n = 288) groups, respectively (difference 38.9 ml/year [95% CI: 5.6-72.1]). The adverse event profile of nintedanib over 100 weeks was consistent with that observed over 52 weeks. Conclusion Nintedanib provides a sustained benefit on slowing the progression of SSc-ILD over 100 weeks, with adverse events that are manageable for most patients.

ObjectivesTocilizumab showed trends for improving skin fibrosis and prevented progression of lung fibrosis in systemic sclerosis (SSc) in randomised controlled clinical trials. We aimed to assess safety and effectiveness of tocilizumab in a real-life setting using the European Scleroderma Trial and Research (EUSTAR) database.MethodsPatients with SSc fulfilling the American College of Rheumatology (ACR)/EULAR 2013 classification criteria, with baseline and follow-up visits at 12±3 months, receiving tocilizumab or standard of care as the control group, were selected. Propensity score matching was applied. Primary endpoints were the modified Rodnan skin score (mRSS) and FVC at 12±3 months compared between the groups. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months.ResultsNinety-three patients with SSc treated with tocilizumab and 3180 patients with SSc with standard of care fulfilled the inclusion criteria. Comparison between groups did not show significant differences, but favoured tocilizumab across all predefined primary and secondary endpoints: mRSS was lower in the tocilizumab group (difference −1.0, 95% CI −3.7 to 1.8, p=0.48). Similarly, FVC % predicted was higher in the tocilizumab group (difference 1.5 (−6.1 to 9.1), p=0.70). The percentage of progressive/regressive patients favoured tocilizumab over controls. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles.ConclusionAlthough this large, observational, controlled, real-life EUSTAR study did not show significant effectiveness of tocilizumab on skin and lung fibrosis, the consistency of direction of all predefined endpoints generates hypothesis for potential effectiveness in a broader SSc population.

Background and purpose Genetic deletion and pharmacological studies suggest a role for lysophosphatidic acid (LPA1 ) receptor in fibrosis. We investigated the therapeutic potential in systemic sclerosis (SSc) of a new orally active selective LPA1 receptor antagonist using dermal fibroblasts from patients and an animal model of skin fibrosis. Experimental approach Dermal fibroblast and skin biopsies from systemic sclerosis patients were used. Myofibroblast differentiation, gene expression and cytokine secretion were measured following LPA and/or SAR100842 treatment. Pharmacolgical effect of SAR100842 was assessed in the tight skin 1 (Tsk1) mouse model. Key results SAR100842 is equipotent against various LPA isoforms. Dermal fibroblasts and skin biopsies from patients with systemic sclerosis expressed high levels of LPA1 receptor. The LPA functional response (Ca2+ ) in systemic sclerosis dermal fibroblasts was fully antagonized with SAR100842. LPA induced myofibroblast differentiation in systemic sclerosis dermal and idiopathic pulmonary fibrosis lung fibroblasts and the secretion of inflammatory markers and activated Wnt markers. Results from systemic sclerosis dermal fibroblasts mirror those obtained in a mouse Tsk1 model of skin fibrosis. Using a therapeutic protocol, SAR100842 consistently reversed dermal thickening, inhibited myofibroblast differentiation and reduced skin collagen content. Inflammatory and Wnt pathway markers were also inhibited by SAR100842 in the skin of Tsk1 mice. Conclusion and implications The effects of SAR100842 on LPA-induced inflammation and on mechanisms linked to fibrosis like myofibroblast differentiation and Wnt pathway activation indicate that LPA1 receptor activation plays a key role in skin fibrosis. Our results support the therapeutic potential of LPA1 receptor antagonists in systemic sclerosis.

Current available therapeutic options for Coronavirus Disease-2019 (COVID-19) are primarily focused on treating hospitalized patients, and there is a lack of oral therapeutic options to treat mild to moderate outpatient COVID-19 and prevent clinical progression. Raloxifene was found as a promising molecule to treat COVID-19 due to its activity to modulate the replication of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and act as an immunomodulator to decrease proinflammatory cytokines.This was a phase 2 multicenter, randomized, placebo-controlled trial to evaluate the efficacy and safety of raloxifene in adult patients with mild to moderate COVID-19 between October 2020 to June 2021 in five centers located in Italy. This was a planned 2/3 adaptive study, but due to operational difficulties, the study was discontinued during the phase 2 study segment. Participants were randomized 1:1:1 to receive oral placebo, raloxifene 60 mg, or raloxifene 120 mg by self-administration for a maximum of two weeks. The primary outcomes were the proportion of patients with undetectable SARS-CoV-2 via nasopharyngeal swabs at day 7 and the proportion of patients who did not require supplemental oxygen therapy or mechanical ventilation on day 14. Safety was assessed. The trial is registered (EudraCT 2021-002,476-39, and ClinicalTrials.gov: NCT05172050).A total of 68 participants were enrolled and randomized to placebo (Raloxifene showed evidence of effect in the primary virologic endpoint in the treatment of early mild to moderate COVID-19 patients shortening the time of viral shedding. The safety profile was consistent with that reported for other indications. Raloxifene may represent a promising pharmacological option to prevent or mitigate COVID-19 disease progression.The study was funded by Dompé Farmaceutici SpA and supported by the funds from the European Commission - Health and Consumers Directorate General, for the Action under the Emergency Support Instrument- Grant to support clinical testing of repurposed medicines to treat SARS-COV-2 patients (PPPA-ESI-CTRM-2020-SI2.837140), and by the COVID-2020-12,371,675 Ricerca finalizzata and line 1 Ricerca Corrente COVID both funded by Italian Ministry of Health.

Quantitative high resolution computed tomography (HRCT) may objectively assess systemic sclerosis (SSc)-interstitial lung disease (ILD) extent, using three basic densitometric measures: mean lung attenuation (MLA), skewness, and kurtosis. This prospective study aimed to develop a composite index - computerized integrated index (CII) – that accounted for MLA, skewness, and kurtosis by means of Principal Component Analysis over HRCTs of 83 consecutive SSc subjects, thus eliminating redundancies. Correlations among CII, cardiopulmonary function and immune-inflammatory biomarkers (e.g. sIL-2Rα and CCL18 serum levels) were explored. ILD was detected in 47% of patients at visual HRCT assessment. These patients had worse CII values than patients without ILD. The CII correlated with lung function at both baseline and follow-up, and with sIL-2Rα and CCL18 serum levels. The best discriminating CII value for ILD was 0.1966 (AUC = 0.77; sensitivity = 0.81 [95%CI:0.68–0.92]; specificity = 0.66 [95%CI:0.52–0.80]). Thirty-four percent of patients without visual trace of ILD had a CII lower than 0.1966, and 67% of them had a diffusing lung capacity for CO

DeSScipher is the first European multicentre study on management of systemic sclerosis (SSc), and its observational trial 1 (OT1) evaluated the efficacy of different drugs for digital ulcer (DU) prevention and healing. The aim of this study was to assess current use of vasoactive/vasodilating agents for SSc-related DU in the expert centres by analysing the baseline data of the DeSScipher OT1.Baseline characteristics of patients enrolled in the OT1 and data regarding DU were analysed.The most commonly used drugs, in both patients with and without DU, were calcium channel blockers (CCBs) (71.6%), followed by intravenous iloprost (20.8%), endothelin receptor antagonists (ERAs) (20.4%) and phosphodiesterase 5 (PDE-5) inhibitors (16.5%). Of patients, 32.6% with DU and 12.8% without DU received two drugs (p 0.001), while 11.5% with DU and 1.9% without DU were treated with a combination of three or more agents (p 0.001). Sixty-five percent of the patients with recurrent DU were treated with bosentan and/or sildenafil. However, 64 out of 277 patients with current DU (23.1%) and 101 (23.6%) patients with recurrent DU were on CCBs alone.Our study shows that CCBs are still the most commonly used agents for DU management in SSc. The proportion of patients on combination therapy was low, even in patients with recurrent DU: almost one out of four patients with current and recurrent DU was on CCBs alone. Prospective analysis is planned to investigate the efficacy of different drugs/drug combinations on DU healing and prevention. Key Points • The analysis of DeSScipher, the first European multicentre study on management of SSc, has shown that the most commonly used vasoactive/vasodilating drugs for DU were CCBs, followed by intravenous Iloprost, ERAs and PDE-5 inhibitors. • More than half of the patients with recurrent DU received bosentan and/or sildenafil. • However, the proportion of patients on combination therapy of more than one vasoactive/vasodilating drug was low and almost one out of four patients with current and recurrent DU was on CCBs alone.

Background:Tocilizumab (TCZ) showed trends for improving skin fibrosis and prevented progression of lung fibrosis in patients with systemic sclerosis (SSc) in placebo-controlled randomised clinical trials (RCTs). However, safety and effectiveness of TCZ beyond these selected and enriched clinical trial populations in SSc is still unknown.Objectives:To assess safety and effectiveness of TCZ treatment compared to standard of care in SSc patients from the large, multicentre, observational, real-life EUSTAR network/database using propensity score matching.Methods:SSc patients from the EUSTAR network/database, who fulfilled the ACR/EULAR 2013 classification criteria, with a baseline and a follow-up visit at 12±3 months, receiving TCZ or standard of care (controls), were selected. The following variables were used for the propensity score matching (1:1): age at diagnosis, gender, disease subtype, baseline modified Rodnan skin score (mRSS), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO), co-therapy with immunosuppressives, disease duration, and year of treatment. Primary endpoints were mRSS and FVC at 12±3 months follow-up compared between the groups, using paired t-tests. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months follow-up according to standard definitions (1,2). Sensitivity analyses assessed pre-processing decisions (selection of most recent vs. random observation for control patients with multiple suitable time intervals), as well as the matching method (optimal vs. exact matching). Missing values were addressed with 100-fold multiple imputation using chained equations. Safety data were analysed in all patients. The study including the statistical analysis plan was pre-registered at www.drks.de (DRKS-ID: DRKS00015537).Results:We identified 93 SSc patients treated with TCZ and 2370 SSc patients with standard of care who fulfilled the inclusion criteria. Forty nine (57.7%) of the TCZ treated patients were diffuse, eight patients were not classified, disease duration was (mean±SD) 6.35±5.40 years, their baseline mRSS was 15.05±10.85, and 76 (81.7%) received immunosuppressive therapy in addition to TCZ.Through multiple imputation and propensity score matching, 100 imputed sets of 93 pairs of TCZ/controls were generated. Comparison between groups showed consistent effects of TCZ across all pre-defined primary and secondary endpoints: mRSS was lower in the TCZ group (mean difference (95% confidence interval (CI)) -1.8 (-4.79 to 1.19), p=0.24, Figure 1A). Similarly, FVC % predicted was higher in the TCZ group mean difference (2.25, 95% CI -4.57 to 9.06), p=0.51, Figure 1B). Considering secondary endpoints, the percentage of skin progressors as well as lung progressors at follow up was lower in the TCZ group (odds ratio OR 0.67 (95% CI 0.07 to 6.41), p=0.74 and OR 0.53 (95% CI 0.16 to 1.7); p=0.2, respectively. Consistently, the percentage of regressors for skin (OR 1.6 (95% CI 0.56 to 4.54), p=0.38) and for lung (OR 1.74 (95% CI 0.66 to 4.58), p=0.26) was higher in TCZ. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles.Conclusion:In this large, observational, controlled, real-life EUSTAR study, effectiveness of TCZ did not reach statistical significance compared to standard of care treatment but showed consistent positive effects of TCZ on skin and lung fibrosis across all pre-defined primary and secondary endpoints confirming data from recent RCTs.References:[1]Prediction of improvement in skin fibrosis in diffuse cutaneous systemic sclerosis: a EUSTAR analysis. Ann Rheum Dis 2016:1743-8.[2]Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Ann Rheum Dis 2021:219-227.Disclosure of Interests:Simon Kuster: None declared, Suzana Jordan: None declared, Muriel Daniele Elhai: None declared, Ulrike Held: None declared, Klaus Steigmiller: None declared, Cosimo Bruni: None declared, Florenzo Iannone: None declared, Serena Vettori: None declared, Elise Siegert: None declared, Simona Rednic: None declared, Veronica Codullo: None declared, Paolo Airò Consultant of: Dr. Airo’ reports personal fees (consultancies) from Bristol Myers Squibb, Bohringer Ingelheim, non-financial support from CSL Behring, SOBI, Janssen, Roche, Sanofi, Pfizer, Yolanda Braun-Moscovici: None declared, Nicolas Hunzelmann: None declared, Maria Joao Salvador: None declared, Valeria Riccieri: None declared, Ana Maria Gheorghiu: None declared, Juan Jose Alegre Sancho: None declared, Katarzyna Romanowska-Prochnicka: None declared, Ivan Castellví: None declared, Ina Koetter: None declared, Marie-Elise Truchetet Consultant of: Marie-Elise Truchetet has had consultancy relationships and/or has received research funding from Boehringer Ingelheim, Genentech/Roche, and Sanofi in the area of potential treatments of scleroderma and its complications., Grant/research support from: Marie-Elise Truchetet has had consultancy relationships and/or has received research funding from Boehringer Ingelheim, Genentech/Roche, and Sanofi in the area of potential treatments of scleroderma and its complications., Francisco J López-Longo: None declared, Pavel Novikov: None declared, Alessandro Giollo: None declared, Yuichiro Shirai: None declared, Laura Belloli: None declared, Elisabetta Zanatta: None declared, Eric Hachulla: None declared, Vanessa Smith: None declared, Christopher Denton: None declared, Ruxandra Ionescu: None declared, Tim Schmeiser: None declared, Jörg H.W. Distler: None declared, Armando Gabrielli: None declared, Anna-Maria Hoffmann-Vold Consultant of: AMHV has received research funding and/or consulting fees and/or other remuneration from Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly and Medscape, Grant/research support from: AMHV has received research funding and/or consulting fees and/or other remuneration from Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly and Medscape. Masataka Kuwana: None declared, Yannick Allanore: None declared, Oliver Distler Speakers bureau: Oliver Distler has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years): Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Consultant of: Oliver Distler has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years): Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Grant/research support from: The study was partially supported by a grant from Roche. Roche was not involved in analysis or interpretation of the results.

Background:In the randomized SENSCIS trial in subjects with SSc-ILD, nintedanib reduced the rate of decline in FVC over 52 weeks (mL/year) by 44% compared to placebo. Healthy individuals have varied FVC depending on age, sex, ethnicity and height; expected values can be determined using internationally recognised reference equations.Objectives:To provide further context to the FVC declines observed in the SENSCIS trial, we compared the decline in FVC observed in subjects with SSc-ILD in the SENSCIS trial with the decline in FVC that would be expected in hypothetical subjects without ILD matched for age, sex, ethnicity and height.Methods:The SENSCIS trial enrolled subjects with SSc-ILD aged ≥18 years with first non-Raynaud symptom ≤7 years before screening, extent of fibrotic ILD ≥10% on HRCT, FVC ≥40% predicted and DLco 30–89% predicted. Baseline FVC (mL) and changes in FVC (mL) at week 52 were assessed in the nintedanib and placebo groups, with missing values at week 52 imputed using predictions from the primary analysis model (random slope and intercept model). Changes in FVC in the SENSCIS trial were compared to values in hypothetical healthy reference subjects matched to the SENSCIS subjects for age, sex, ethnicity and height. FVC values in these healthy reference subjects were derived from the equations published by the European Respiratory Society Global Lung Function Initiative in 2012, which were derived from data from over 70,000 subjects.1Results:In the nintedanib and placebo groups of the SENSCIS trial, respectively, mean (SD) time since onset of first non-Raynaud symptom was 3.5 (1.6) and 3.5 (1.8) years. In the nintedanib group, mean (SD) FVC at baseline was 2460 (737) mL, compared with 3403 (787) mL in the healthy reference subjects. In the placebo group, mean (SD) FVC at baseline was 2544 (817) mL compared with 3516 (887) mL in the healthy reference subjects. The difference in the change from baseline in FVC at week 52 between the nintedanib-treated subjects in the SENSCIS trial (n=287) and the healthy reference subjects was 26.6 mL ([95% CI: 1.2, 52.0]; p=0.04). The difference in the change from baseline in FVC at week 52 between the placebo-treated subjects in the SENSCIS trial (n=286) and the reference subjects was 77.5 mL ([95% CI: 51.4, 103.7]; pConclusion:Subjects with SSc-ILD who participated in the SENSCIS trial had marked lung function impairment at baseline compared with healthy matched reference subjects, despite a mean duration of SSc of 3.5 years. Over 52 weeks, the decline in FVC in subjects with SSc-ILD who received placebo was 4-fold greater than in healthy reference subjects. Subjects with SSc-ILD who were treated with nintedanib had a decline in FVC that was only slightly greater than the decline observed in the matched healthy subjects. These data support the clinical relevance of the reduction in the rate of FVC decline provided by nintedanib in patients with SSc-ILD.References:[1]Quanjer et al. Eur Respir J 2012;40:1324−43.Acknowledgements:The SENSCIS trial was funded by Boehringer Ingelheim. Medical writing support was provided by FleishmanHillard Fishburn, London, UK. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE).Disclosure of Interests:Toby Maher Speakers bureau: Boehringer Ingelheim and Roche/Genentech, Consultant of: Acelleron Pharma, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline and Roche/Genentech, Arnaud Bourdin Speakers bureau: Actelion/Janssen (personal fees and other), AstraZeneca (personal fees and other), Boeringher Ingelheim (personal fees and other), Chiesi (personal fees and other), GlaxoSmithKline (personal fees and other), Novartis (personal fees and other), Pulsar Therapeutics (other), Roche (personal fees and other), Sanofi Regeneron (personal fees and other), Teva (other) and United Therapeutics (other), Consultant of: Actelion/Janssen (personal fees and other), AstraZeneca (personal fees and other), Boeringher Ingelheim (personal fees and other), Chiesi (personal fees and other), GlaxoSmithKline (personal fees and other), Novartis (personal fees and other), Pulsar Therapeutics (other), Roche (personal fees and other), Sanofi Regeneron (personal fees and other), Teva (other) and United Therapeutics (other), Grant/research support from: Actelion/Janssen (grants and other), AstraZeneca (grants and other), Boeringher Ingelheim (grants and other), Chiesi (other), GlaxoSmithKline (grants and other), Novartis (other), Pulsar Therapeutics (other), Roche (other), Sanofi Regeneron (other), Teva (other) and United Therapeutics (other), Elizabeth Volkmann Consultant of: Boehringer Ingelheim, Grant/research support from: Corbus and Forbius, Serena Vettori Paid instructor for: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Jörg H.W. Distler Speakers bureau: Actelion, Active Biotech, AnaMar, Arxx Therapeutics, Bayer, Boehringer Ingelheim, Celgene, Galapagos NV, GlaxoSmithKline, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Consultant of: AnaMar, Arxx Therapeutics, Bayer, Boehringer Ingelheim, Galapagos NV, Inventiva, JB Therapeutics and UCB, Grant/research support from: Active Biotech, AnaMar, Array BioPharma, Arxx Therapeutics, aTyr, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Galapagos NV, GlaxoSmithKline, Inventiva, Novartis, Sanofi-Aventis, Redx and UCB, Margarida Alves Employee of: Currently an employee of Boehringer Ingelheim, Christian Stock Employee of: Currently an employee of Boehringer Ingelheim, Oliver Distler Consultant of: AbbVie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Bayer, Blade Therapeutics, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos NV, GlaxoSmithKline, Glenmark Pharmaceuticals, Horizon (Curzion) Pharmaceuticals, Inventiva, IQVIA, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Target Bioscience, Topadur Pharma and UCB, Grant/research support from: Kymera Therapeutics and Mitsubishi Tanabe Pharma

Background: Idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-interstitial lung disease (SSc-ILD) are chronic fibrotic disorders that, despite sharing common profibrotic pathways, display differences in epidemilogy and clinical presentation. Objective: To investigate features of IPF and SSc-ILD patients admitted to a tertiary pulmonology unit for a recent onset/worsening dyspnea. Methods: Fourty-one IPF and 39 SSc-ILD patients visited over 1 year were investigated for lung function and comorbidities frequently associated with both conditions. Results: As expected, SSc-ILD were predominantly females and younger (median 61 vs 73 years old, p Conclusion: Despite differences in epidemilogical and clinical features, patients with SSc-ILD and IPF share common functional features at presentation.

Introduction Dans l’etude SENSCIS, des patients atteints d’une ScS-PID ont ete randomises pour recevoir le nintedanib ou le placebo jusqu’a ce que le dernier patient ait atteint la semaine 52 mais sans depasser 100 semaines. Les patients ayant arrete prematurement le traitement devaient venir aux visites jusqu’a la semaine 100 (S100) ou la fin de l’etude. Le nintedanib a reduit le taux de declin de la CVF sur 52 semaines vs placebo (−52,4 vs −93,3 mL/an ; difference 41,0 mL/an [IC a 95 % : 2,9 ; 79,0]). L’effet du nintedanib sur le declin de la CVF a ete etudie sur l’ensemble de l’etude. Methodes Le declin de la CVF (mL/an) jusqu’a 100 semaines a ete evalue au moyen de 3 approches : – en utilisant toutes les donnees disponibles, y compris celles recueillies apres l’arret du traitement ; – en incluant les donnees apres traitement seulement pour les patients ayant arrete prematurement le traitement ; – en utilisant uniquement les donnees sous traitement (entre la randomisation et la date de la derniere prise du medicament [ou la S100, selon la premiere de ces dates]). La tolerance a ete evaluee sur la base des evenements indesirables (EI) rapportes jusqu’a la derniere prise du medicament plus 28 jours. Les analyses etaient descriptives. Resultats A l’inclusion, la CVF moyenne (ecart-type) etait de 2459 (736) mL dans le groupe nintedanib (n = 288) et de 2541 (816) mL dans le groupe placebo (n = 288). L’exposition mediane au medicament sur l’ensemble de l’etude etait de 15,4 mois dans le groupe nintedanib et de 15,6 mois dans le groupe placebo. Les taux annuels moyens (erreur standard) ajustes de declin de la CVF sur 100 semaines, bases sur les trois approches, sont presentes dans le Tableau 1. Conclusion Les donnees de cette etude suggerent que l’effet du nintedanib sur le ralentissement de la progression de la ScS-PID persiste au-dela de 52 semaines. Le profil d’EI du nintedanib sur l’ensemble de l’etude (jusqu’a 100 semaines) a ete coherent avec celui rapporte sur 52 semaines. Resultats presentes a l’ATS 2020.

Michele Iudici, Rosaria Irace, Antonella Riccardi, Giovanna Cuomo, Serena Vettori, Gabriele Valentini Rheumatology Section, Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy Introduction/objectives: To prospectively assess the quality of life (QoL) of patients affected by undifferentiated connective tissue diseases (UCTDs) and to identify factors associated with changes over time.Patients and methods: A total of 46 consecutive UCTD patients completed the Short-Form 36 (SF-36) questionnaire at presentation and then yearly. At each 6-month visit, all patients underwent a detailed history taking and a laboratory and physical assessment, in order to follow the evolution of the disease over time and to assess the the co-existence of fibromyalgia.Results: At presentation, scores lower than the average of the general population were detected in 34 (74%) and 41 (89%) patients in the physical and mental domains, respectively. No difference between patients with and without Raynaud’s phenomenon was detected. Fibromyalgia was the only independent variable associated with an impaired physical component summary score (p=0.0009). No patient feature was found to be associated with the basal mental component summary score. During 24months of follow-up, a significant improvement (ie, a change ≥5 from baseline) in physical component summary and mental component summary scores was observed in 14 (33.3%) and 20 (43.4%) patients, respectively. Patients who significantly improved in the physical domain more frequently had a history of glucocorticoids intake (p&nbsp

Background:Previous studies suggested that male sex may be associated with a greater rate of decline in FVC in patients with SSc-ILD. In the SENSCIS trial, nintedanib reduced the rate of FVC decline over 52 weeks vs placebo.Objectives:Analyse the rate of decline in FVC and the efficacy and safety of nintedanib in the SENSCIS trial in subgroups by sex.Methods:Patients with SSc-ILD with first non-Raynaud symptom Results:Of 576 patients, 433 (75.2%) were female. Compared with males, the female subgroup included a smaller proportion of White patients (64.7% vs 74.8%), a smaller proportion on mycophenolate at baseline (46.9% vs 53.1%), a greater proportion of ATA positive patients (63.3% vs 53.1%), and had a lower mean weight at baseline (66.6 vs 79.1 kg). FVC % predicted (72.8% vs 71.7%) and mRSS (11.2 vs 10.8) were similar in females and males. The adjusted annual rate of decline in FVC in the placebo group was numerically greater in male than female patients (-126.8 [SE 29.0] vs -82.0 [16.2] mL/year). The estimated effect of nintedanib vs placebo on reducing the rate of decline in FVC was numerically more pronounced in males than females (difference: 58.6 [95% CI -18.0, 135.1] vs 34.6 [-9.3, 78.4] mL/year), but the interaction p-value did not indicate heterogeneity in the treatment effect between subgroups (p=0.59). Among nintedanib-treated patients, diarrhoea was reported in similar proportions of females and males (74.7% vs 79.1%); nausea, vomiting and liver test abnormalities were reported in greater proportions of females vs males (35.3% vs 19.4%, 28.1% vs 13.4%, and 15.4% vs 9.0%), while serious adverse events were more frequent in males (32.8% vs 21.3%). In the nintedanib and placebo groups, respectively, adverse events leading to treatment discontinuation were reported in 16.7% and 8.5% of females and 13.4% and 9.2% of males.Conclusion:In the SENSCIS trial in patients with SSc-ILD, the annual rate of decline in FVC in the placebo group was numerically greater in male than female patients. The rate of FVC decline was lower with nintedanib than placebo both in males and females. The safety profile of nintedanib was similar between males and females.Disclosure of Interests:Elizabeth Volkmann Grant/research support from: Forbius, Corbus Pharmaceuticals, Consultant of: Boehringer Ingelheim, Forbius, Speakers bureau: Boehringer Ingelheim, Serena Vettori Consultant of: Boehringer Ingelheim, John Varga Grant/research support from: John Varga is awaiting grants from Boehringer Ingelheim and has received grants from Bristol-Myers Squibb, Pfizer, Takeda, and TeneoBio, Consultant of: John Varga has acted as a consultant for Boehringer Ingelheim, Bristol-Myers Squibb, Emerald Health, and TeneoBio, Ariane Herrick: None declared, Maurizio Cutolo Grant/research support from: Bristol-Myers Squibb, Actelion, Celgene, Consultant of: Bristol-Myers Squibb, Speakers bureau: Sigma-Alpha, Ana Cordeiro Consultant of: Ana Cordeiro has acted as a consultant for Roche, Speakers bureau: Ana Cordeiro has received speaker fees from Boehringer Ingelheim, Lilly, and Vitoria, Valderilio F Azevedo Grant/research support from: Abbvie, Janssen, Bristol-Myers Squibb, Boehringer-Ingelheim, Lilly and Novartis, Consultant of: Lilly, Novartis, Janssen, Boehringer-Ingelheim, Amgen, Pfizer and Abbvie, Speakers bureau: Sandoz, Celltrion, Lilly, Novartis, Janssen, Boehringer-Ingelheim, Amgen, Pfizer and Abbvie, Sindhu Johnson Grant/research support from: Boehringer Ingelheim, Corbus Pharmaceuticals, GlaxoSmithKline, Roche, Merck, Bayer, Consultant of: Boehringer Ingelheim, Ikaria, Christian Stock Employee of: Employee of Boehringer Ingelheim, Martina Gahlemann Employee of: Employee of Boehringer Ingelheim, Lizette Moros Employee of: Lizette Moros is an employee of Boehringer Ingelheim, Margarida Alves Employee of: Employee of Boehringer Ingelheim, Maureen Mayes Grant/research support from: Maureen Mayes has received grants from Boehringer Ingelheim, Corbus, CSL Behring, Eicos, and Galapagos, Consultant of: Maureen Mayes has acted as a consultant for Boehringer Ingelheim, Eicos, and Galapagos. She was a member of the SENSCIS trial Steering Committee (Boehringer Ingelheim)

Background Mycophenolate mofetil (MMF) has been increasingly used in the treatment of early diffuse cutaneous Systemic Sclerosis (dcSSc) and SSc-associated interstitial lung disease (SSc-ILD), and a recent Randomized Controlled Trial confirmed its efficacy and safety in SSc-ILD. However, the safety of this drug in the long term use has not been assessed in a real life setting. Objectives We aimed to analyze the period prevalence and the type of adverse events (AEs) associated to MMF treatment in a single center large cohort. Methods Charts of all SSc patients meeting the 2013 ACR/EULAR classification criteria consecutively visited at our outpatient clinic from January 1st 2017 to December 31st 2017 were retrospectively analyzed. Demographics, clinical, serological, functional, imaging data, treatments, and AEs were recorded. Patients were subgrouped according to the immunosuppressant (IS) taken during the observation period (e.g. MMF, azathiprine- AZA, or cyclophosphamide- CYC, no IS). The period prevalence of AEs was calculated and correlations of between AEs and patient features were investigated by univariate and multivariate analyses. Results Two-hundred and thirty-seven patients were included (92.4% were females, aged 56.4±11.3 years, with a median disease duration of 17 years, range 1-60). Among them, 85 (35.9%) were taking MMF, 34 (14.3%) AZA or CYC, 118 (49.8%) had no current IS treatment. Prevalence of the dcSSc subset was higher in the MMF group (34.1% versus 17.6% in the AZA/CYC group and 5.9% in the no IS group; p Conclusion The period prevalence of AEs recorded during MMF treatment appeared as high as 71.7% in our real life setting. Even though we did not record any serious AE, our analysis suggests a close monitoring of this therapy in SSc. Disclosure of Interests Rossella Chieffo: None declared, Maria Sofia Ciliento: None declared, Veronica Giacco: None declared, GIUSEPPE SCALISE: None declared, Serena Vettori Consultant for: Boehringer Ingelheim Italia SpA

Autoimmune rheumatic diseases are characterised by an abnormal immune system response, complement activation, cytokines dysregulation and inflammation. In last years, despite many progresses in managing these patients, it has been shown that clinical remission is reached in less than 50% of patients and a personalised and tailored therapeutic approach is still lacking resulting in a significant gap between guidelines and real-world practice. In this context, the need for biomarkers facilitating early diagnosis and profiling those individuals at the highest risk for a poor outcome has become of crucial interest. A biomarker generally refers to a measured characteristic which may be used as an indicator of some biological state or condition. Three different types of medical biomarkers has been suggested: i. mechanistic markers; ii. clinical disease markers; iii. therapeutic markers. A combination of biomarkers from these different groups could be used for an ideal more accurate diagnosis and treatment. However, although a growing body of evidence is focused on improving biomarkers, a significant amount of this information is not integrated on standard clinical care. The overarching aim of this work was to clarify the meaning of specific biomarkers during autoimmune diseases; their possible role in confirming diagnosis, predicting outcome and suggesting specific treatments.

Background Digital ulcers (DUs) affect about half of systemic sclerosis (SSc) patients during disease course. In some patients, peripheral vasculopathy can promote critical ischemia and gangrene, severe complications with potential life threatening consequences. Recently the DUO registry suggested a 18% prevalence of gangrene in DU-SSc patients, with smoking and a high number of DUs being predictive factors. However, little is known about gangrene in unselected SSc patients. Objectives To investigate the prevalence, incidence and risk factors for gangrene in the EUSTAR cohort. Methods We included patients from the EUSTAR database satisfying the ACR 1980 or the ACR/EULAR 2013 classification criteria for SSc, with at least one visit recording data on gangrene. We extracted from this database data regarding the reporting of DUs, DUs history and digital gangrene. Centres were asked for supplementary data on traditional cardiovascular (CV) risk factors. We analysed by uni- and multivariable logistic regression the cross-sectional relationship between gangrene and its potential risk factors such as history of DUs, cutaneous subset, disease duration, autoantibodies, traditional CV risk factors. Furthermore, longitudinal data were analysed by Cox proportional hazards regression. Results 1757 patients matched the inclusion criteria (age at inclusion 55.9±14.5 years, disease duration since first non-Raynaud’s symptom 7.9±10.3 years and from onset of Raynaud’s phenomenon (RP) 11.1±11.0 years, male sex 16.7%, 24.6% diffuse cutaneous subset (DcSSc)). At inclusion, 8.9% of patients had either current or previous digital gangrene, 15.7% had current DUs and a further 25.8% had previously had DUs. Among the potential risk factors, older age, a history of DUs and the DcSSc subset were statistically significant risk factors in the cross-sectional multivariable model. For the longitudinal part, during the entire follow-up (median [Q1,Q3] 13.1 [9.6, 19.3] months), 16/771 patients had incident gangrene (2.1%), accounting for an incidence of 1.73/100 patient-years. All 16 patients who developed incident gangrene had previously had DUs and gangrene. Further risk factors for incident gangrene were the DcSSc subset and longer disease duration: hazard ratio [95% confidence interval]: 8.97 [2.90–27.71] and 1.08 [1.04–1.13] respectively, both p Conclusions In unselected SSc patients, gangrene still occurs in about 9% of SSc patients. Of the most importance, a history of DUs and, to a lesser extent, the DcSSc subset are strongly and independently associated with gangrene, while traditional CV risk factors were not identified as risk factors. Our results confirm that gangrene is still a concern in SSc. They emphasise the importance of microvascular SSc-associated disease in the pathogenesis of gangrene and suggest that the DcSSc subset should be prioritised for risk-stratification of the patients. Acknowledgements The authors thank all the contributing EUSTAR investigators and patients. Disclosure of Interest C. Mihai Grant/research support from: Actelion Pharmaceuticals Ltd, Abbvie, Speakers bureau: Roche, Geneva Romfarm, O. Distler Grant/research support from: Actelion, Bayer, Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Roche, Consultant for: Actelion, Bayer, BiogenIdec, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Sinoxa, A. M. Gheorghiu Grant/research support from: Geneva Romfarm, Abbvie, P. Constantin: None declared, R. Dobrota Grant/research support from: Actelion Pharmaceuticals Ltd, Pfizer, S. Jordan: None declared, V. Smith Grant/research support from: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH, Bayer AG, Roche NV/SA, Fund for Scientific Research Flanders, E. Hachulla: None declared, J. Henes: None declared, E. Siegert: None declared, S. Vettori: None declared, U. Muller-Ladner: None declared, M. Matucci-Cerinic: None declared, Y. Allanore Grant/research support from: BMS, Genentech-Roche, Inventiva, Pfizer, Sanofi, Consultant for: Actelion, Bayer, Biogen, Genentech-Roche, Galapagos, Medac, Pfizer, Sanofi, Servier, UCB

Background Several studies have consistently showed that the extent of skin involvement has a major impact on disease prognosis in the diffuse cutaneous subtype of systemic sclerosis. The large majority of the ongoing clinical trials aim at identifying efficient drug in this subset. By contrast, little is known about the limited cutaneous subset (LcSSc) and the translation of the data coming for DcSSc to LcSSc is uncertain. Objectives Therefore, our aim was to investigate skin and lung involvement trajectories of LcSSc patients using the large EUSTAR registry. Methods We analysed the longitudinal data extracted from the EUSTAR cohort collected before February 2017. Worsening of skin fibrosis was defined by an increase in modified Rodnan skin score (mRSS) >3.5 points from baseline to 2nd visit. Interstitial lung disease (ILD) was defined by any fibrosis on imaging (X-ray/computed tomography). Worsening of ILD was defined by a decrease of FVC >10% from baseline to 2nd visit. For predicting models, predictors with p Results 8013 LcSSc were included with a mean follow-up of about 3.3±3.7 years. At baseline, mean ±SD mRSS was 6±5 and ILD was present in 28.4% of all patients. Worsening of skin fibrosis was observed in 6.4% (19/298), 7.8% (97/1248) and 9.8% (289/2957) of LcSSc patients at 6, 12 and 24 months follow-up respectively. In multivariate analysis, variables predicting skin fibrosis progression were elevated European Scleroderma Study Group activity index (EScSG-AI) (OR [95 IC]: 1.22 [1.05–1.4], p=0.007) for 12 months progression and EScSG-AI (1.24 [1.13–1.38], p Worsening of ILD was observed in 11.7% (23/196) and 19.9% (65/326) of LcSSc patients with ILD at baseline, at 12 and 24 months follow-up respectively. In multivariate analysis, variables predicting ILD progression at 24 months were EScSG-AI >3 (OR [95 IC]: 3.8 [1.51–9.56], p=0.005), FVC (1.03 [1.01–1.04], p Conclusions It appears that only few LcSSc patients progress for skin fibrosis ; this limits the use of mRSS in this subset and the potential of anti-fibrotic drugs of skin disease. However, a substantial rate of ILD progression was identified as well as relevant predictors. These results support the inclusion of LcSSc patients in SSc-ILD trials evaluating anti-fibrotic drugs. Our predictive models will be helpful to define enriched population in future clinical trials. Acknowledgements: This work was supported by an unrestricted grant from INVENTIVA Disclosure of Interest None declared

Background Few small-sized observational studies have suggested that rituximab might be a promising treatment in systemic sclerosis (SSc) Objectives To evaluate the outcomes of SSc-patients receiving in routine care Rituximab Methods Retrospective longitudinal multicenter observational study which included SSc-patients treated with rituximab upon the decision of their physician within the framework of EUSTAR. We interrogated the participating centres and EUSTAR database to determine epidemiological and clinical characteristics, the indication for initiating the treatment, and the following parameters at baseline and at the last visit under treatment: modified Rodnan Skin Score (mRSS), joint, lung and gastrointestinal involvements, treatment, laboratory tests and safety events. Results 248 patients were included: 70 (28%) men, mean age: 51±13 years, mean disease duration: 7±7 years; 150 (65%) had diffuse cutaneous-SSc, 54% were positive for anti-topoisomerase and 71% had lung fibrosis. Overlap disease was noticed in 62 patients (26%) including 23 with rheumatoid arthritis. The indication for the treatment was lung involvement (56%) followed by articular (42%) and skin involvements (30%). At baseline, 175 patients were treated with steroids and 132 with DMARDs. Mean follow-up was 2.4 (±1.9) years. In the whole sample, mRSS decreased from 15±11 to 10±8 (p For SSc-patients treated for lung with baseline FVC In the whole population, 45 patients could stop steroids and mean dose decreased from 10 mg to 7 mg in the other. During the follow-up, 78 (31%) patients had side effects including 35 (14%) with severe side effects leading to discontinuation of the treatment in 10%. Six deaths were recorded (1 heart failure, 1 sepsis, 2 respiratory insufficiencies, 2 sudden deaths). 76 patients had infection, requiring hospitalisation in 20 patients. Conclusions In this study, skin, lung and joint involvement appeared to improve under rituximab. Infections and other severe adverse events were frequently reported. A comparative study including control patients from EUSTAR centres is ongoing. Disclosure of Interest M. Elhai: None declared, O. Distler Grant/research support from: Actelion, Bayer, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Sanofi, Sinoxa and UCB in the area of potential treatments of scleroderma and its complications, V. Smith : None declared, M. Matucci-Cerinic: None declared, J. J. Alegre-Sancho : None declared, M.-E. Truchetet: None declared, Y. Braun-Moscovici: None declared, F. Iannone: None declared, F. Chotchaeva: None declared, A. Lescoat : None declared, E. Siegert : None declared, I. Castellvi: None declared, P. Airo : None declared, S. Vettori: None declared, E. Hachulla: None declared, A. Erler : None declared, L. Ananieva : None declared, M. Krusche: None declared, F. Lopez-Longo : None declared, J. Distler : None declared, N. Hunzelmann : None declared, A.-M. Hoffmann-Vold : None declared, V. Riccieri: None declared, V. Hsu: None declared, M. Pozzi: None declared, C. Ancuta : None declared, E. Rosato : None declared, C. Mihai: None declared, M. Kuwana: None declared, Y. Allanore Grant/research support from: Actelion, Bayer, Boehringer Ingelheim, ChemomAb, Genentech/Roche, Inventiva, Pfizer, Sanofi, Servier, in the area of potential treatments of scleroderma and its complications.

Background Systemic sclerosis (SSc) is a chronic autoimmune disease characterised by vascular changes and progressive fibrosis of skin and various internal organs. In SSc a variety of autoantibodies have been detected which are useful for the diagnosis and management of the disease. Some of these autoantibodies are well-established tools strongly associated with SSc (e.g. anti-centromere, anti-topoisomerase I, anti-RNA polymerase III). Other autoantibodies are less frequent and/or less-specific for SSc even if potentially useful to better assess disease subsets and prognosis. Objectives Our goal was to assess the frequency of SSc-related autoantibodies detected using a novel technology as well as to study the associations between these antibodies and clinical features in an Italian SSc cross sectional cohort. Methods Serum samples from 218 consecutive patients with SSc collected at three Italian sites were tested for a variety of autoantibodies (see table 1) using a novel fully automated system utilising bead-based immunoassays (research use only, Inova Diagnostics, San Diego, CA). The Italian cohort included: women 200 (92%), limited cutaneous SSc (lc-SSc) 166 (76%), patients with history of digital ulcers 91 (42%), calcinosis 46 (21%), lung fibrosis 84 (39%), heart involvement 38 (17.4%), pulmonary arterial hypertension 20 (9%), and esophageal involvement 138 (63.3%). Results The prevalence of antibodies is summarised in the table 1 below. Of note, anti-BICD2, anti-CENP-B, and anti-nucleosome antibodies were significantly associated with lc-SSc subtype (p=0.0237, p Conclusions Autoantibodies identified via the novel system in this SSc cohort were found in the expected frequencies and also correlated to clinical features of the patients. The multiparameter approach combined with cluster analysis holds promise for a molecular and more precise stratification of SSc subsets. Disclosure of Interest None declared

Background New computer-assisted methods for the objective quantification of interstitial lung disease (ILD) at computed tomography (CT), based on the evaluation of mean lung attenuation (MLA), skewness and kurtosis have been recently investigated in Systemic Sclerosis (SSc). We developed a computerised integrated index (CII) based on a weighted evaluation of MLA, skewness and kurtosis and investigated its reliability for the quantitative assessment of SSc-ILD and its associations with lung function parameters in a cross-sectional study. Objectives To identify the CII cut off value with the highest sensitivity and specificity for CT-detected ILD and to investigate its impact on lung function parameters over-time of baseline assessed CII. Methods SSc patients meeting the new ACR/EULAR classification criteria, who had undergone a volumetric lung CT study from July 1 st 2014 to June 30th 2015, had been evaluated at baseline for ILD quantification by Goh et al. method and the previously referred dedicated software and had their CII calculated, were enrolled in a prospective study including complete clinical, serological, and functional assessment at baseline and at 1 year follow-up (FU). Results Thirty-nine out of 83 (47%) SSc patients (79 females, 4 males; mean age 56.4±11.3 years; median disease duration 12 years;2–54 18 diffuse cutaneous and 65 limited cutaneous SSc) had evidence of ILD as assessed by volumetric CT of the lungs at baseline. CII in patients with ILD was significantly lower than in those without ILD (−0.4929±0.9933 versus 0.4145±0.8059 HU; p Conclusions Here we confirm that quantitative computer-assisted CT of the lungs could be a reliable method for SSc-ILD evaluation and found that it could also be useful in predicting the evolution of lung function in the short-term FU. Disclosure of Interest None declared

Fibrotic tissue remodelling and vascular alterations cause high morbidity and mortality in patients with systemic sclerosis (SSc).1 2 While the pathogenesis of SSc is only partially understood, recent evidence demonstrates a fundamental role of hedgehog signalling in fibrotic disease manifestations. Hedgehog signalling is activated in fibrotic SSc skin, and it induces an SSc-like phenotype in resting fibroblasts.3 Overexpression of sonic hedgehog (SHH) induces skin fibrosis, whereas inhibition of hedgehog signalling ameliorates experimental fibrosis.4 Based on these experimental findings, this European Scleroderma Trials and Research group (EUSTAR) multicentre cooperative study investigates whether circulating SHH may serve as a surrogate marker for a more severe disease phenotype in patients with SSc. We decided to evaluate SHH serum levels rather than total circulating SHH. Measurements of SHH serum levels are easy and robust but may not assess particulated SHH in various different extracellular vesicles. …

Objective: The aim of this study was to analyse differences in clinical presentation in patients with early (< 3 years’ duration) systemic sclerosis (SSc), comparing three age groups according to disease subsets. Method: Cross-sectional analysis of the prospective EULAR Scleroderma Trials and Research database (EUSTAR) was performed. Patients fulfilling preliminary American College of Rheumatology 1980 classification criteria for SSc, with < 3 years from the first non-Raynaud’s SSc symptom at first entry, were selected. Patients with < 3 years from the first SSc symptom, including Raynaud’s phenomenon, were also analysed. SSc-related variables, including antibodies, SSc subsets, and organ involvement, were examined. Age was categorized into ≤ 30, 31–59, and ≥ 60 years. We performed descriptive and bivariate analyses. Results: The study included 1027 patients: 90% Caucasian, 80% women, and 40% with diffuse disease. In early stages of SSc, younger patients had significantly more anti-Scl-70 antibodies and diffuse disease. With increasing age, we observed more elevation of estimated pulmonary systolic pressure on echocardiography (5%, 13%, and 30%, respectively, in the three age groups), cardiac conduction blocks (6%, 6%, and 15%), and left ventricular diastolic dysfunction (4%, 12%, and 27%). The results were similar for 650 patients with < 3 years from first SSc symptom, including Raynaud’s. Conclusion: In early stages of SSc, older patients showed data indicating more severe disease with greater cardiac involvement. The diffuse subset was more frequent in the younger subgroup. The identification of such differences may help in selecting appropriate management for individual patients in clinical practice. (Less)

Carbamylation is a post-translational modification that mostly affects proteins with low turnover, such as dermal proteins. Carbamylated proteins accumulate in skin in an age-dependent manner, contributing to tissue alterations. As dermis is affected by systemic sclerosis (SSc) and anti-carbamylated protein antibodies (anti-CarP Ab) are found in SSc patients, we sought to evaluate the specificity of anti-CarP Ab and their relationship with clinical parameters reflecting skin involvement in SSc. This study investigated serum samples and clinical data from 124 patients with SSc. Anti-CarP Ab were affinity purified from pooled SSc sera, and their specificity was assessed by western blotting and ELISA with carbamylated proteins from two species (human and bovine albumin; human fibrinogen). Anti-CarP Ab were measured in SSc serum samples and in 41 healthy aged-matched individuals. Affinity-purified anti-CarP Ab recognized carbamylated epitopes irrespective of the protein type or species origin. Anti-CarP Ab levels inversely correlated with the modified Rodnan skin score (mRss) (Spearman’s R = -0.32, p

This study aims to investigate pre-clinical esophageal involvement in systemic sclerosis (SSc) by high-resolution impedance manometry (HRiM), its associations with disease features including lung involvement, and its predictivity of esophageal symptoms overtime. Charts of 45 asymptomatic (no heartburn/regurgitation/dysphagia) SSc patients (96% females; mean age 46 years) with at least one follow-up (FU) visit and complete clinical, serological, functional, and radiological assessment, including high-resolution computed tomography (HRCT) of the chest and lung function tests, that had undergone esophageal HRiM were retrospectively evaluated. Esophagogastric junction-contractile integral (EGJ-CI) and esophageal body motility, as evaluated by mean distal contractile integral (DCI), were assessed. SSc patients had a normal esophageal motility in 7/45 cases, a defective EGJ-CI in 28, an ineffective esophageal motility (IEM) in 17, and aperistalsis in 12. Defective EGJ-CI was associated with IEM/aperistalsis in 20 cases, while 9 patients had isolated IEM. Defective EGJ-CI and/or IEM/aperistalsis were associated with a diffusing lung capacity for CO < 80% of predicted value (all p < 0.05), while defective EGJ-CI was also associated with interstitial lung disease on HRCT (p = 0.03). Prevalence of any HRiM abnormality was higher in anti-centromere antibody negative patients (all p < 0.05). IEM/aperistalsis independently increased the risk of esophageal symptoms by 2.3-fold (95% CI 1.1–5.7) and was associated with their higher cumulative incidence with respect to patients with other HRiM patterns at FU (χ2= 4.63; p = 0.03). SSc patients asymptomatic for esophageal involvement can have HRiM abnormalities in up to 84% of cases. A baseline-impaired motility is a risk factor for symptomatic esophageal disease.

Background Systemic sclerosis (SSc), one of the most complex connective tissue disease, is characterized by three pathogenic events namely, vascular damage, autoimmunity and fibroblast activation, leading to a widespread fibrosis of skin and internal organs (1,2). Previous studies showed that 1) carbamylation mainly affects structural proteins undergoing to a low turn-over rate, namely dermal skin and tendons-associated proteins; and that 2) carbamylated proteins accumulate in skin in an age-dependent manner, contributing to tissue alteration (3). Objectives As dermis is a disease target and anti-carbamylated protein antibodies (anti-CarP Ab) have been reported in patients with SSc (4), we sought to evaluate any relationship between anti-CarP Ab and clinical parameters reflecting skin involvement in SSc. Methods Serum samples and clinical data from 123 patients with SSc were collected. Anti-CarP Ab were detected by indirect ELISA, using carbamylated bovine serum albumin as the antigen. Serum Anti-CarP Ab levels were also measured in 41 healthy aged-matched individuals. Clinical data were retrieved as previously reported (5). Results The mean serum levels of anti-CarP Ab did not statistically differ between healthy and SSc group. In SSc, Spearman analysis showed that anti-CarP inversely correlated with the modified Rodnan skin score (RSS) (R= -0.325, p Conclusions The study shows that anti-CarP Ab serum level inversely associates to the severity of skin involvement in SSc patients. One possible mechanism to explain the inverse association is that the disease-dependent accumulation of carbamylated proteins in the skin may neutralize circulating anti-CarP Ab, thus contributing to their serum levels decrease. However, further investigation is needed to clarify this issue and to assess whether the levels anti-CarP Ab can be useful in the clinical setting of SSc. References Varga J, Abraham D. J Clin Invest 117:557–67, 2007. Guy S, Kong J, Cheema GS, Keen CL, Wick G, Gershwin ME. Semin Arthritis Rheum 38:132–60, 2008. Gorisse L, Pietrement C, Vuiblet V, Schmelzer CEH, Kohler M, $ Duca L, Debelle L, Fornes P, S Jaisson, $and Gillery P. Proc Natl Acad Sci U S A 113(5): 1191–1196, 2016. Pecani A, Alessandri C, Spinelli FR, Priori R, Riccieri V, Di Franco M, Ceccarelli F, Colasanti T, Pendolino M, Mancini R, Truglia S, Barbati C, Vomero M, Sabatinelli D, Morello F, Valesini G, Conti F. Arthritis Res Ther 18(1):276, 2016. Perosa F, Favoino E, Favia IE, Vettori S, Prete M, Corrado A, Cantatore FP, Valentini G. Medicine (Baltimore) 95(25), 2016. Disclosure of Interest None declared

Background IL-17A has been implicated in the pathogenesis of systemic sclerosis (SSc) (1). We previously showed that skewed peripheral blood mononuclear cells (PBMCs) from SSc patients can induce Fas-mediated apoptosis in co-cultured autologous skin fibrobalsts (2). Objectives We therefore aimed to investigate IL-17A expression and effects in these co-cultures. Methods PBMCs and skin fibroblasts from 5 dcSSc patients with disease duration Results IL17A mRNA in co-cultured PBMCs was increased by 11.5 fold (p Conclusions Our results support the role of IL-17A in the pathogenesis of SSc. Furthermore, here we first show that IL-17A up-regulation in co-cultured PBMCs might play antifibrotic effects in autologous skin fibroblasts and might be implicated in fibroblast apoptosis, interphering with the FAS/FASL pathway. References Brembilla NC, Chizzolini C. T cell abnormalities in systemic sclerosis with a focus on Th17 cells. Eur Cytokine Netw 2012; 23: 128–39. De Palma R et al. Peripheral T cells from patients with early systemic sclerosis kill autologous fibroblasts in co-culture: is T-cell response aimed to play a protective role? Rheumatology (Oxford) 2010; 49: 1257–66. Disclosure of Interest None declared

Background A consensus on DU definition in SSc has been recently reached (1),while for their evaluation,classification and categorisation it is still missing. Objectives To identify in SSc a set of essential items for DU evaluation, to assess if the existing DU classification (2) was useful and feasible in clinical practice, and to investigate if the DU categorisation (3) was preferred to the simple division of DU in recurrent and not recurrent. Methods The DU Desscipher items that reached >60% of completion rate were administered to EUSTAR centres via online survey.These items were: DU distal to the proximal interphalangeal joints, recurrent DU, DU history, infection, gangrene, amputation, total number of DU, number of new DU, number of healed DU, number of DU defined as loss of tissue, number of DU due to calcinosis and number of DU due to digital pitting scars (DPS).Questions about feasibility and usefulness of the existing DU classification (DU due to DPS, to loss of tissue, derived from calcinosis and gangrene) (2) and newly proposed DU categorisation (episodic, recurrent and chronic) (3) were also administered. Results All Desscipher and 82/194 EUSTAR centres (42.3%) completed the questionnaire.Out of 27 items selected for the Desscipher study, those scored by>70% of participants as essential and feasible for DU evaluation in clinical practice were only the following: number of DU defined as a loss of tissue (level of agreement 91.1%), recurrent DU (84%) and number of new DU (74.4%).For 64.6% of the centres,the classification of DU was considered useful and feasible in clinical practice.Moreover, 80.3% of the centres preferred the categorization of DU in episodic,recurrent and chronic. Conclusions For clinical practice, EUSTAR centres identified only three essential items for DU evaluation and considered useful and feasible the proposed classification and categorisation of DU.The set of items needs to be further validated by Delphi voting in order to implement its use in clinical practice while further implementation of DU classification and categorisation is warranted. References Suliman Y et al.Preliminary musculoskeletal ultrasound (MSUS) ulcer definition does not correlate with visual observation in systemic sclerosis (SSc) patients. J. Scleroderma Relat. Disord.2017(in press). Amanzi L et al.Digital ulcers in scleroderma: staging, characteristics and sub-setting through observation of 1614 digital lesions. Rheumatology (Oxford) 2010;49:1374–82. Matucci-Cerinic M et al.Elucidating the burden of recurrent and chronic digital ulcers in systemic sclerosis: long-term results from the DUO Registry. Ann Rheum Dis. 2016;75:1770–6. Disclosure of Interest None declared

BackgroundValidity of European Scleroderma Study Group (EScSG) activity indexes currently used to assess disease activity in systemic sclerosis (SSc) has been criticised.MethodsThree investigators assigned an activity score on a 0–10 scale for 97 clinical charts. The median score served as gold standard. Two other investigators labelled the disease as inactive/moderately active or active/very active. Univariate–multivariate linear regression analyses were used to define variables predicting the ‘gold standard’, their weight and derive an activity index. The cut-off point of the index best separating active/very active from inactive/moderately active disease was identified by a receiver-operating curve analysis. The index was validated on a second set of 60 charts assessed by three different investigators on a 0–10 scale and defined as inactive/moderately active or active/very active by other two investigators. One hundred and twenty-three were investigated for changes over time in the index and their relationships with those in the summed Medsger severity score (MSS).ResultsA weighted 10-point activity index was identified and validated: Δ-skin=1.5 (Δ=patient assessed worsening during the previous month), modified Rodnan skin score (mRss) >18=1.5, digital ulcers=1.5, tendon friction rubs=2.25, C-reactive protein >1 mg/dL=2.25 and diffusing capacity of the lung for CO (DLCO) % predicted ConclusionsA preliminarily revised SSc activity index has been developed and validated, providing a valuable tool for clinical practice and observational studies.

Autoimmune diseases are a complex set of diseases characterized by immune system activation and, although many progresses have been done in the last 15 years, several unmet needs in the management of these patients may be still identified. Recently, a panel of international Experts, divided in different working groups according to their clinical and scientific expertise, were asked to identify, debate and formulate a list of key unmet needs within the field of rheumatology, serving as a roadmap for research as well as support for clinicians. After a systematic review of the literature, the results and the discussions from each working group were summarised in different statements. Due to the differences among the diseases and their heterogeneity, a large number of statements was produced and voted by the Experts to reach a consensus in a plenary session. At all the steps of this process, including the initial discussions by the steering committee, the identification of the unmet needs, the expansion of the working group and finally the development of statements, a large agreement was attained. This work confirmed that several unmet needs may be identified and despite the development of new therapeutic strategies as well as a better understanding of the effects of existing therapies, many open questions still remain in this field, suggesting a research agenda for the future and specific clinical suggestions which may allow physicians to better manage those clinical conditions still lacking of scientific clarity.

Objectives: The multisystem manifestations of SSc can greatly impact patients' quality of life. The aim of this study was to identify factors associated with disability in SSc. Methods: SSc patients from the prospective DeSScipher cohort who had completed the scleroderma health assessment questionnaire (SHAQ), a disability score that combines the health assessment questionnaire and five visual analogue scales, were included in this analysis. The effect of factors possibly associated with disability was analysed with multiple linear regressions. Results: The mean SHAQ and HAQ scores of the 944 patients included were 0.87 ( s . d . = 0.66) and 0.92 ( s . d . = 0.78); 59% of the patients were in the mild to moderate difficulty SHAQ category (0 ⩽ SHAQ < 1), 34% in the moderate to severe disability category (1 ⩽ SHAQ < 2) and 7% in the severe to very severe disability category (2 ⩽ SHAQ ⩽ 3). The means of the visual analogue scales scores were in order of magnitude: overall disease severity (37 mm), RP (31 mm), pulmonary symptoms (24 mm), gastrointestinal symptoms (20 mm) and digital ulcers (19 mm). In multiple regression, the main factors associated with high SHAQ scores were the presence of dyspnoea [modified New York Heart Association (NYHA) class IV (regression coefficient B = 0.62), modified NYHA class III (B = 0.53) and modified NYHA class II (B = 0.21; all vs modified NYHA class I)], FM (B = 0.37), muscle weakness (B = 0.27), digital ulcers (B = 0.20) and gastrointestinal symptoms (oesophageal symptoms, B = 0.16; stomach symptoms, B = 0.15; intestinal symptoms, B = 0.15). Conclusion: SSc patients perceive dyspnoea, pain, digital ulcers, muscle weakness and gastrointestinal symptoms as the main factors driving their level of disability, unlike physicians who emphasize objective measures of disability.

Background Some abnormalities in nailfold videocapillaroscopy (NVC), such as the presence of micro-haemorrhages (MHEs), micro-thromboses (MTs), giant capillaries (GCs) and reduction in the number of capillaries (nCs), suggest a disease activity (DA) phase in systemic sclerosis (SSc). In a previous paper, we showed that the number of micro-haemorrhages and micro-thromboses (the so-called NEMO score) was the NVC feature more closely associated with DA. The present study was aimed at validating the NEMO score as a measure of DA in patients with SSc. Methods Two cohorts of 122 and 97 patients with SSc who were referred to two different rheumatology units, one in Milan and one in Naples, respectively, constituted the validation cohorts. The NEMO score, the total number of GCs and the mean nCs per digit were the parameters defined in each patient by eight-finger NVC. An expert operator analysed the NVCs in each of the participating units. The European Scleroderma Study Group (ESSG) index was used to define the DA level in each patient at the time of NVC examination. Results The NEMO score was the NVC parameter more strictly correlated with the ESSG score in both the Milan and Naples cohorts (p

ObjectivesTo determine the causes of death and risk factors in systemic sclerosis (SSc).MethodsBetween 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation.ResultsWe identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile.ConclusionCombining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients’ survival.

Objective To investigate whether patients affected by 1 of the 3 subsets of early systemic sclerosis (SSc; scleroderma), i.e., subset I, Raynaud's phenomenon with SSc marker autoantibodies and typical capillaroscopic findings; subset II, autoantibody positive only; and subset III, capillaroscopy positive only and not satisfying the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for SSc at admission, differ from each other in the time to satisfy the criteria. Methods Early SSc patients subdivided into the 3 subsets indicated above consecutively admitted to a rheumatology/angiology center were monitored for 12–102 months (median 36 months). Patients were reevaluated twice yearly to assess whether and when each patient satisfied the new ACR/EULAR classification criteria for SSc. Patients with undifferentiated connective tissue disease (UCTD) served as the comparator group. Results During followup, 11 (52.3%) of 21 subset I, 10 (66.6%) of 15 subset II, 0 of 24 subset III, and 0 of 44 UCTD patients satisfied the criteria (P = 0.0001). The difference was significant between early SSc and UCTD patients (P = 0.0001) and, within the group of early SSc patients, between each of the 2 autoantibody-positive subsets (subsets I and II) and the capillaroscopic-positive/autoantibody-negative subset (subset I versus III: P = 0.0001; subset II versus III: P = 0.0009). There was no difference between the 2 autoantibody-positive subsets (P = 0.454). In addition to marker autoantibody positivity, preclinical lung or heart involvement was associated with an increased risk to satisfy the criteria during followup. Conclusion Our data demonstrated faster progression of SSc in autoantibody-positive patients, particularly in those with preclinical internal organ involvement at baseline, than in autoantibody-negative patients.

The aim of the study was to evaluate CXCL4 levels in undifferentiated connective tissue disease at risk for SSc (UCTD-SSc-risk) and confirm its increase and investigate its prognostic value. Serum CXCL4 levels were measured in 45 patients and 24 controls. CXCL4 was significantly higher in UCTD-SSc-risk patients than in controls. It resulted higher in patients with a shorter disease duration and in those lacking capillaroscopic alterations. We confirm that CXCL4 levels are increased in UCTD-risk-SSc patients. Further studies are needed to investigate the role of CXCL4 assessment in UCTD-risk-SSc.

Objectives Cardiovascular involvement is a major contributor to mortality in systemic sclerosis (SSc). We examined whether N-terminal pro-brain natriuretic peptide (NT-proBNP) is a reliable predictor of mortality in SSc. Methods and results This multicentre prospective cohort study included 523 patients presenting with SSc, whose mean age was 54 ± 13 years, mean disease duration 8 ± 9 years, and diffuse cutaneous form in 168. Plasma NT-proBNP was measured at baseline and the patients were followed yearly. Overall mortality was measured at 3 years. At baseline, cardiovascular involvement was present in 37 patients, including 17 with pulmonary artery hypertension (PAH) and 20 with a left ventricular ejection fraction (LVEF)

CXCL4 is an antiangiogenic and immunomodulatory chemokine. We aimed to investigate serum levels of CXCL4 in primary Sjögren’s syndrome (pSS), looking for associations with disease features. Thirty-nine consecutive pSS patients underwent clinical-serological assessment and nailfold videocapillaroscopy (NVC). Thirty-six patients and 30 controls affected by osteoarthritis were also investigated for serum levels of CXCL4 and soluble E-selectin (sE-selectin). CXCL4 was higher in pSS patients than in controls (1.79 [0.2–11.18] vs 1.023 ng/ml [0.02–14.45], pÂ