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Contains fulltext : 232581.pdf (Publisher’s version ) (Closed access) BACKGROUND: In the Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial, nintedanib reduced the rate of decline in forced vital capacity (FVC) in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). Patients on stable treatment with mycophenolate for at least 6 months before randomisation could participate. The aim of this subgroup analysis was to examine the efficacy and safety of nintedanib by mycophenolate use at baseline. METHODS: The SENSCIS trial was a randomised, double-blind, placebo-controlled trial, in which patients with SSc-ILD were randomly assigned (1:1) to receive 150 mg of oral nintedanib twice daily or placebo for at least 52 weeks. In a prespecified subgroup analysis, we analysed the primary endpoint of rate of decline in FVC over 52 weeks by mycophenolate use at baseline. In a post-hoc analysis, we analysed the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted at week 52 (proposed minimal clinically important difference estimate for worsening of FVC in patients with SSc-ILD) in subgroups by mycophenolate use at baseline. Adverse events were reported in subgroups by mycophenolate use at baseline. Analyses were done in all participants who received at least one dose of study drug. We analysed the annual rate of decline in FVC using a random coefficient regression model (with random slopes and intercepts) including anti-topoisomerase I antibody status, age, height, sex, and baseline FVC as covariates and terms for baseline-by-time, treatment-by-subgroup, and treatment-by-subgroup-by-time interactions. SENSCIS is registered with ClinicalTrials.gov, NCT02597933, and is now complete. FINDINGS: Between Nov 30, 2015, and Oct 31, 2017, 819 participants were screened and 576 were enrolled, randomly assigned to, and treated with nintedanib (n=288) or placebo (n=288). 139 (48%) of 288 in the nintedanib group and 140 (49%) of 288 in the placebo group were taking mycophenolate at baseline. In patients taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was -40·2 mL per year (SE 19·8) with nintedanib and -66·5 mL per year (19·3) with placebo (difference: 26·3 mL per year [95% CI -27·9 to 80·6]). In patients not taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was -63·9 mL per year (SE 19·3) with nintedanib and -119·3 mL per year (19·0) with placebo (difference: 55·4 mL per year [95% CI 2·3 to 108·5]). We found no heterogeneity in the effect of nintedanib versus placebo on the annual rate of decline in FVC between the subgroups by mycophenolate use (p value for interaction=0·45). In a post-hoc analysis, the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted was lower with nintedanib than with placebo in both patients taking mycophenolate (40 [29%] of 138 vs 56 [40%] of 140; odds ratio 0·61 [0·37 to 1·01]) and those not taking mycophenolate (59 [40%] of 149 vs 70 [47%] of 148; 0·73 [0·46 to 1·16]) at baseline. The adverse event profile of nintedanib was similar between the subgroups. Diarrhoea, the most common adverse event, was reported in 106 (76%) of 139 patients in the nintedanib group and 48 (34%) of 140 in the placebo group among those taking mycophenolate at baseline, and in 112 (75%) of 149 in the nintedanib group and 43 (29%) of 148 in the placebo group among those not taking mycophenolate at baseline. Over the entire trial period, 19 patients died (ten in the nintedanib group and nine in the placebo group). One death in the nintedanib group was considered to be related to study drug. INTERPRETATION: Nintedanib reduced the progression of interstitial lung disease both in patients with SSc-ILD who were and were not using mycophenolate at baseline, with no heterogeneity in its treatment effect detected between the subgroups. The adverse event profile of nintedanib was similar in the subgroups by mycophenolate use. Our findings suggest that the combination of mycophenolate and nintedanib offers a safe treatment option for patients with SSc-ILD. More data are needed on the benefits of initial combination therapy versus a sequential approach to treatment of SSc-ILD. FUNDING: Boehringer Ingelheim.

Introduction: Systemic sclerosis (SSc) is a rare and complex connective tissue disease characterized by fibrosis of the skin and internal organs. Interstitial lung disease (ILD) is a common complication of SSc and the leading cause of SSc-related death. No drugs are licensed for the treatment of SSc-ILD. Areas covered: This review provides an overview of the current treatment of SSc-ILD and a perspective on investigational therapies, focusing on those studied in randomized controlled trials. Expert opinion: There is substantial room for improvement in the treatment of SSc-ILD. Current treatment focuses on immunosuppressant therapies, particularly cyclophosphamide and mycophenolate. Hematopoietic stem cell transplantation has been shown to improve long-term outcomes, but the risk of treatment-related mortality restricts its use to select patients at specialized centers. Modifying the course of disease to improve outcomes remains the goal for new therapies. Several drugs are under investigation as potential therapies for SSc-ILD, providing hope that the limited treatment armamentarium for SSc-ILD will be expanded and improved in the near future. Expert consensus is needed on how to screen for and monitor SSc-ILD and on when to initiate and escalate therapy.

Background: Guidelines are needed to aid early recognition and treatment of interstitial lung disease in systemic sclerosis (SSc-ILD). Objective: To develop expert consensus recommendations for the identification and management of SSc-ILD. Methods: Evidence-based consensus recommendations were established using a modified Delphi process based on a systematic literature analysis. An expert panel of 27 European-based pulmonologists, rheumatologists and internists participated in three rounds of online surveys, a face-to-face discussion and a WebEx meeting, to establish recommendations and define a SSc-ILD management algorithm. Results: The final evidence-based consensus included detailed recommendations for screening and risk stratification, diagnosis, assessment of severity, treatment options, monitoring, assessment of progression and treatment escalation. The consensus management algorithm is presented here in an abbreviated form for clinical use (figure). Conclusion: These evidence-based expert consensus recommendations, developed using a modified Delphi process, provide important guidance for the identification and management of SSc-ILD in clinical practice. Funding: Boehringer Ingelheim

Background: Some patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) develop progressive ILD, but disease course and outcome are unknown. Objectives: To assess frequency, disease course and mortality of progressive ILD in the European Scleroderma Trials and Research group (EUSTAR) database. Methods: Adult patients fulfilling SSc classification criteria, registered since 2010, with ILD on high- resolution computed tomography, serial lung function and disease duration recordings, were eligible. Progressive ILD was defined as: significant (forced vital capacity [FVC] decline >10% or 5-10% with diffusing capacity for carbon monoxide decline ≥15%); moderate (FVC decline 5-10%); or stable ( Results: Of 826 patients included, serial lung function data (median follow-up 5 yrs) were available in 411 (49.8%); 124/411 (30.2%) had stable lung function throughout the 5 yrs. In 128/411 (31%) with initial progressive ILD at 12±3 months, 59/128 (46.1%) showed further progression. Baseline FVC, baseline extent of skin fibrosis and disease duration were significantly associated with further ILD progression. 85/826 (10.3%) patients died, 11/124 (8.9%) with stable ILD. 10/59 (16.9%) with progressive ILD at 12±3 months and further progression during follow-up died vs 4/69 (5.8%) with stable ILD after initial progression (P=0.004). Conclusion: While not all patients with SSc-ILD show progression, prevention of further ILD progression may improve survival. Funding: Boehringer Ingelheim

Background Interstitial lung disease (ILD) represents a clinical challenge in systemic sclerosis (SSc) and associates with high mortality. The presence of severe lung fibrosis is a strong predictor for early mortality. There is substantial progress in SSc-ILD research, but precise, population-based data on cumulative incidence, range of severity and predictive value of clinical risk factors are lacking. Such data are vital for clinical decision making, and highly warranted as background information for appropriate development of screening and management strategies for SSc-ILD. Objectives To assess cumulative incidence of ILD, range of ILD severity and mortality risk predicted by baseline pulmonary function tests (PFT) and ILD extent by CT in a complete, nationwide SSc cohort. Methods The Norwegian SSc cohort study (Nor-SSc) includes all the 630 incident and 185 prevalent SSc patients from 2000-2012 meeting SSc classification criteria. A baseline PFT was recorded in 703 (86%) patients, and 650 (80%) had high resolution computed tomography (HRCT) images available for analyses. Extent of fibrosis was scored on 10 sections from every HRCT and expressed as percentage of total lung volumes. For the survival and mortality analyses, all Nor-SSc patients diagnosed from 2000-2012 (the 630 incident cases) were included and compared with 15 age- and gender matched controls per patient drawn from the national population registry. Vital status was available for all patients and controls at study end (January 2018). Descriptive statistics and standardized mortality rates (SMR) were estimated. Results Of the 815 patients in the total Nor-SSc cohort, 682 (84%) were female and 629 (77%) had limited cutaneous SSc. Mean age at SSc diagnosis was 53 yrs, with mean time from SSc onset to diagnosis of 3.8 yrs. We observed ILD on HRCT in 324/650 patients (50%), and the majority of these had 100% (Figure 1B). Proportionate distribution of FVC values in patients with no lung fibrosis, 10% lung fibrosis is shown in Figure 1C. During the mean 8.6 yrs observation period of this study, 148 of the 630 incident SSc patients died, corresponding to an overall SMR of 2.4. Separate analyses of the 650 patients with baseline HRCT data showed that the SMR correlated with presence and extent of lung fibrosis, from SMR 2.2 in patients with no fibrosis to SMR 8 in patients with >25% lung fibrosis (Figure 1D). Correspondingly, we found that the SMR changed across patient groups stratified by baseline FVC%, with increased mortality evident already in the FVC 90-100% group (Figure 1E). Conclusion The results from this population based SSc cohort study provide new, unbiased data regarding the impact of ILD. Our results indicate a dose-response relationship between lung fibrosis extent and SMR; and between FVC% and SMR. Importantly, this relationship was evident even in groups with limited lung fibrosis and groups with normal range FVC%, strongly suggesting that all SSc patients should be screened with PFT and HRCT at baseline, to diagnose ILD early and tailor further management. Disclosure of Interests Anna-Maria Hoffmann-Vold Grant/research support from: Received research funding or other remuneration from Boehringer Ingelheim, GSK, and Actelion, Consultant for: Received consulting fees or other remuneration from Boehringer Ingelheim, GSK, and Actelion, Speakers bureau: Actelion and Boehringer Ingelheim, Havard Fretheim Consultant for: Received consulting fees or other remuneration from GSK, and Actelion, Anna-Kristine H Halse: None declared, Marit Seip: None declared, Helle Bitter: None declared, Marianne Wallenius: None declared, Anne Salberg: None declared, Torhild Garen: None declared, May Brit Lund: None declared, Trond M Aalokken: None declared, Oyvind Midtvedt: None declared, Oyvind Molberg: None declared

Background Pulmonary arterial hypertension (PAH) is a frequent complication in systemic sclerosis (SSc) and a major cause of death despite the available treatments (1). Until the availability of the oral prostacyclin receptor agonist selexipag in 2016, parenteral medication targeting the prostacyclin pathway was often not feasible for patients with SSc -PAH due to practical barriers. Selexipag added to background therapy improves prognosis of PAH in the published pivotal trial (2). However, to date information on results of SSc-PAH patients treated with any combination of targeted therapies including selexipag in daily clinical practice are lacking. Objectives Evaluation of the efficacy and safety of selexipag in SSc-PAH patients in a real life case series. Methods All patients with SSc associated PAH (WHO group 1) diagnosed by right heart catheterization who started with selexipag between 09-2016 and 06-2018 from two PAH expert centres were included. Data on demographics, concurrent medication, functional class, 6 minute walking distance and NT-pro-BNP level were recorded at baseline and during follow-up. Every 12 weeks we recorded the opinion of the treating expert team, resulting in a conclusion “improvement”, “stabilization” or “deterioration”. Additionally treatment effect was assessed according to the abbreviated risk assessment described by Boucly (3). Side effects and adverse events were registered and evaluated. Results We included 13 SSc-PAH patients, all classified as limited cutaneous SSc. Ten patients were female. Median age was 68 years (IQR 58-75), median SSc disease duration 7.4 years (IQR 4.7-13.5) and median PAH duration 4 years (IQR 2.5-7.5). All patients were on double background therapy. At baseline 1 patient had two low risk criteria, 1 patient had one low risk criterion, the other patients had no low risk criteria. Two patients discontinued selexipag within 4 weeks due to side effects. The eleven patients reaching maintenance dosage had a median follow up of 48 weeks (IQR 24-72). At the end of follow up, 2/11 patients improved, 4/11 stabilized, and 5/11 deteriorated as evaluated by their expert team. Two of these deteriorated patients died due to right ventricular failure and gastro-intestinal bleeding respectively. Of the patients deteriorating, 3 initially stabilized for a period of 24 to 60 weeks. None of the patients achieved 3 low risk criteria, three patients achieved 1 low risk criterion. No unknown side effects were reported. Conclusion Adding selexipag to double background therapy in a high risk cohort stabilized symptoms in the majority of these patients with an acceptable safety profile. Sustained improvement of PAH symptoms is reached in only a minority of our SSc-PAH patients. Further research examining multiple target therapy, including selexipag, in patients with early SSc-associated PAH is warranted. References [1] Lefevre G, et al. Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: a systematic review and meta-analysis. Arthritis Rheum. 2013;65(9):2412-23. [2] Sitbon O, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2015;373(26):2522-33. [3] Boucly A, et al. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J. 2017;50(2). Disclosure of Interests Jacqueline Lemmers: None declared, Havard Fretheim Grant/research support from: Travel bursary from Actelion and GSK, Hanneke Knaapen-Hans: None declared, Frank van den Hoogen: None declared, Jolanda van Haren-Willems: None declared, Toon Duijnhouwer: None declared, C.H.M. van den Ende: None declared, Arie van Dijk Grant/research support from: Unrestricted grant for PhD student from Actelion, Consultant for: Actelion, Speakers bureau: Actelion, Anna-Maria Hoffmann-Vold Grant/research support from: Received research funding or other remuneration from Boehringer Ingelheim, GSK, and Actelion, Consultant for: Received consulting fees or other remuneration from Boehringer Ingelheim, GSK, and Actelion, Speakers bureau: Actelion and Boehringer Ingelheim, Madelon Vonk Grant/research support from: Madelon Vonk has received unrestricted research funds from Actelion and Therabel, Consultant for: Madelon Vonk was a consultant for Actelion, Boehringer-Ingelheim, Speakers bureau: Actelion, Boehringer-Ingelheim, Roche

Background Interstitial lung disease in systemic sclerosis (SSc-ILD) occurs frequently and carries a high burden of morbidity and mortality. To date, there are no existing guidelines for screening, diagnosis and management of SSc-ILD that would aid early recognition and treatment and improve the care of these patients. Objectives To develop expert consensus recommendations for the identification and management of SSc-ILD. Methods Based on the results of a comprehensive systematic literature analysis conducted in line with NICE/CRD and IQWiG guidelines and PRISMA methodology, evidence-based statements on SSc-ILD risk, screening, diagnosis, treatment and follow-up were developed. A modified Delphi process was then used to establish consensus statements for the identification and management of SSc-ILD. Briefly, an expert panel of 27 European-based pulmonologists, rheumatologists and internists with experience in treating SSc-ILD was established. Between July and November 2018, the panel took part in 3 rounds of online surveys, a face-to-face discussion and a WebEx meeting to establish consensus-based recommendations for the management of SSc-ILD. Statements were categorised by topic: risk factors (including biomarkers); screening; diagnosis; assessment of severity; treatment initiation; treatment options; disease progression; treatment escalation; other management options. Panellists indicated their level of agreement with proposed statements on a scale of 1 (strong disagreement) to 7 (strong agreement), and consensus was considered achieved when ≥80% either disagreed (score of 1–3) or agreed (score of 5–7) with a statement. Based on panel feedback, statements that did not reach consensus were modified and re-voted in later rounds. Results At the close of the Delphi process, the panel agreed on the following: Risk factors: The presence of anti–topoisomerase I antibodies, male gender and diffuse cutaneous SSc all increase risk for ILD Screening: All SSc patients should undergo screening for ILD, using HRCT and lung function testing. Frequency of screening using HRCT should be guided by risk of developing ILD, in combination with clinical symptoms and lung function Diagnosis and assessment of severity: Use of HRCT to diagnose SSc–ILD and assess severity, with supporting findings from lung function testing and clinical assessment, is also recommended Treatment initiation and options: All patients with severe or progressive SSc–ILD should be considered for pharmacotherapy, with mycophenolate mofetil and cyclophosphamide recommended as treatments. Patients not receiving treatment should be followed closely for signs of disease progression Disease progression: Indicators of progression include sustained decline in lung function, worsening of clinical symptoms, and change in extent and/or pattern of fibrosis on HRCT Treatment escalation: Patients with inadequate treatment responses should be considered for treatment escalation. Suitability for lung transplant should be evaluated early, especially for patients diagnosed with advanced disease. Autologous haematopoietic stem cell transplant may be considered in carefully selected patients Conclusion These evidence-based expert consensus recommendations, developed using a modified Delphi process, provide important guidance for the identification and management of SSc-ILD. Acknowledgement Funding: Boehringer Ingelheim Disclosure of Interests Anna-Maria Hoffmann-Vold Grant/research support from: Received research funding or other remuneration from Boehringer Ingelheim, GSK, and Actelion, Consultant for: Received consulting fees or other remuneration from Boehringer Ingelheim, GSK, and Actelion, Speakers bureau: Actelion and Boehringer Ingelheim, Toby M Maher Shareholder of: Has stock options or bond holdings in a for-profit corporation in Apellis, Grant/research support from: Received funds from BI advisory board participation and conference travel. Received research funding and/or consulting fees or other remuneration from GSK, UCB, AstraZeneca, Roche, Bayer, Biogen Idec, Cipla, Prometic, and Sanumed, Consultant for: Toby Maher has received consultancy or speakers fees from Apellis, AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Galapagos, GlaxoSmithKline RD and has received consultancy fees from Galecto, Edward E Philpot Employee of: Employee of IQVIA, Ali Ashrafzadeh Employee of: Employee of IQVIA, Oliver Distler Grant/research support from: Prof. Distler received research funding from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi Tanabe to investigate potential treatments of scleroderma and its complications, Consultant for: Prof. Distler has/had consultancy relationship within the last 3 years with Actelion, AnaMar, Bayer, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, iQvia, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Serodapharm and UCB in the area of potential treatments of scleroderma and its complications. In addition, he had/has consultancy relationship within the last 3 years with A. Menarini, Amgen, Abbvie, GSK, Mepha, MSD, Pfizer and UCB in the field of arthritides and related disorders

Background Some patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) develop progressive ILD, but the prevalence is unknown and no validated algorithms for early detection exist. Objectives To assess the frequency of, and parameters associated with, progressive SSc-ILD in the EUSTAR database. Methods Patients from the EUSTAR database registered after 2010, ≥18 yrs old, fulfilling SSc classification criteria, with serial lung function, HRCT assessments and disease duration recordings were eligible. Progressive ILD, assessed as absolute changes in%predicted, was defined as: significantly progressive (FVC decline >10% or FVC decline 5−10% and DLCO decline ≥15%); moderately progressive (FVC decline 5−10%); or stable ( Results 826 SSc-ILD patients were included; 219/826 (26.5%) showed moderate/significant ILD progression at 12±3 months’ follow-up. Baseline FVC, erythrocyte sedimentation rate, modified Rodnan skin score (mRSS), GERD and disease duration were significantly associated with significant progressive fibrosis in uni- and multivariable modelling (area under curve 0.67). Serial lung function data with median follow-up of 5 yrs were available in 411/826 (49.8%) patients. In 128/411 with initial progressive ILD at 12±3 months, 59/128 (46.1%) showed further progression, while 69/128 (53.9%) were stable. Baseline FVC, mRSS and disease duration were significantly associated with further ILD progression. The incident cumulative frequency of moderate and significant ILD progression was 22.9% (n=189/826) and 28.5% (n=235/826) during the median 5-yr follow-up and time to first progressive event (Figure). Conclusion This study provides novel insights into the frequency, severity and association of progressive fibrosis in patients with SSc-ILD in the EUSTAR database. Acknowledgement Funding: Boehringer Ingelheim (Schweiz) GmbH, Switzerland Disclosure of Interests Anna-Maria Hoffmann-Vold Grant/research support from: Received research funding or other remuneration from Boehringer Ingelheim, GSK, and Actelion, Consultant for: Received consulting fees or other remuneration from Boehringer Ingelheim, GSK, and Actelion, Speakers bureau: Actelion and Boehringer Ingelheim, Yannick Allanore Grant/research support from: Inventiva, F Hoffman La-Roche, Sanofi, BMS, Pfizer, Consultant for: Actelion, Bayer, BMS, Boehringer, Roche, Sanofi, Margarida Alves Employee of: Employee of Boehringer Ingelheim, Nicole Graf Grant/research support from: Received consulting fees or other remuneration from Astellas and Biotronik, Paolo Airo: None declared, Lidia P. Ananyeva: None declared, Laszlo Czirjak: None declared, Serena Guiducci: None declared, Eric Hachulla Consultant for: Received consulting fees or other remuneration from Actelion, GSK, Pfizer, and Bayer, Mengtao Li: None declared, Carina Mihai Consultant for: Received consulting fees or other remuneration from Actelion, Geneva, Roche, and Rofarm, Consultant for: F. Hoffmann-La Roche, Actelion, Geneva Romfarm, Gabriela Riemekasten Consultant for: Chugai, F. Hoffmann-La Roche, Speakers bureau: Chugai, F. Hoffmann-La Roche, Petros Sfikakis: None declared, Gabriele Valentini Grant/research support from: Received research funding and other remuneration from AbbVie, BMS, Lilly, Pfizer, and Sanofi, Consultant for: Received consulting fees and other remuneration from AbbVie, BMS, Lilly, Pfizer, and Sanofi, Otylia Kowal-Bielecka Consultant for: Received consulting fees or other remuneration from Bayer, Boehringer Ingelheim, Inventiva, Medac, Novartis, and Roche, Oliver Distler Grant/research support from: Prof. Distler received research funding from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi Tanabe to investigate potential treatments of scleroderma and its complications, Consultant for: Prof. Distler has/had consultancy relationship within the last 3 years with Actelion, AnaMar, Bayer, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, iQvia, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Serodapharm and UCB in the area of potential treatments of scleroderma and its complications. In addition, he had/has consultancy relationship within the last 3 years with A. Menarini, Amgen, Abbvie, GSK, Mepha, MSD, Pfizer and UCB in the field of arthritides and related disorders

Background Early identification of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) at risk of progression could help tailor management and aid cohort enrichment in clinical trials to improve outcome. Objectives To assess the frequency of progressive SSc-ILD in the total ILD cohort and in subgroups enriched by risk factors in the EUSTAR database. Methods Patients from the EUSTAR database registered after 2010, ≥18 yrs old, fulfilling SSc classification criteria, with serial lung function and HRCT assessments were eligible. The following risk factors for progressive SSc-ILD available in the EUSTAR database were chosen as enrichment criteria: low forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), diffuse cutaneous SSc, anti-topoisomerase I antibody (ATA), short disease duration, older age, male sex, increased C-reactive protein, and presence of respiratory symptoms and reflux disease. Eligible patients with progressive ILD were assessed in the cohort and in subgroups enriched by the risk factors. Progressive SSc-ILD was assessed as absolute changes in%predicted and defined as: significant progressive (FVC decline >10%, or FVC decline 5−10% and DLCO decline ≥15%), moderate progressive (FVC decline 5−10%) or stable ( Results 6004 patients fulfilled the main entry criteria; of these, 1822 (30.3%) had ILD. At baseline, mean age was 57 yrs, 17.4% were male, 48.2% had diffuse SSc, 53.5% were ATA-positive, mean baseline FVC 86% and DLCO59%, mean disease duration 9.8 yrs, and follow-up was 2.5 yrs. In the total ILD cohort (30% eligible patients), 21% showed progressive ILD. Enriching with single risk factors reduced the number of eligible patients down to 6%, while the frequency of progressive ILD stayed stable (Figure). Combinations of risk factors did not result in increasing numbers of progressive ILD patients, but in further decreasing numbers of eligible patients. Conclusion There is still an unmet need to identify SSc-ILD patients at risk of progression with efficient risk factors. For clinical trials, it is a challenge to balance feasibility of recruitment and enrichment. Acknowledgement Funding: Boehringer Ingelheim (Schweiz) GmbH, Switzerland Disclosure of Interests Anna-Maria Hoffmann-Vold Grant/research support from: Received research funding or other remuneration from Boehringer Ingelheim, GSK, and Actelion, Consultant for: Received consulting fees or other remuneration from Boehringer Ingelheim, GSK, and Actelion, Speakers bureau: Actelion and Boehringer Ingelheim, Martina Gahlemann Employee of: Employee of Boehringer Ingelheim , Nicole Graf Grant/research support from: Received consulting fees or other remuneration from Astellas and Biotronik, Paolo Airo: None declared, Lidia P. Ananyeva: None declared, Laszlo Czirjak: None declared, Serena Guiducci: None declared, Eric Hachulla Consultant for: Received consulting fees or other remuneration from Actelion, GSK, Pfizer, and Bayer, Mengtao Li: None declared, Carina Mihai Consultant for: Received consulting fees or other remuneration from Actelion, Geneva, Roche, and Rofarm, Consultant for: F. Hoffmann-La Roche, Actelion, Geneva Romfarm, Gabriela Riemekasten Consultant for: Chugai, F. Hoffmann-La Roche, Speakers bureau: Chugai, F. Hoffmann-La Roche, Petros Sfikakis: None declared, Gabriele Valentini Grant/research support from: Received research funding and other remuneration from AbbVie, BMS, Lilly, Pfizer, and Sanofi, Consultant for: Received consulting fees and other remuneration from AbbVie, BMS, Lilly, Pfizer, and Sanofi, Otylia Kowal-Bielecka Consultant for: Received consulting fees or other remuneration from Bayer, Boehringer Ingelheim, Inventiva, Medac, Novartis, and Roche, Yannick Allanore Grant/research support from: Inventiva, F Hoffman La-Roche, Sanofi, BMS, Pfizer, Consultant for: Actelion, Bayer, BMS, Boehringer, Roche, Sanofi, Oliver Distler Grant/research support from: Prof. Distler received research funding from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi Tanabe to investigate potential treatments of scleroderma and its complications, Consultant for: Prof. Distler has/had consultancy relationship within the last 3 years with Actelion, AnaMar, Bayer, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, iQvia, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Serodapharm and UCB in the area of potential treatments of scleroderma and its complications. In addition, he had/has consultancy relationship within the last 3 years with A. Menarini, Amgen, Abbvie, GSK, Mepha, MSD, Pfizer and UCB in the field of arthritides and related disorders

Background Systemic sclerosis (SSc) is a progressive, multi organ, auto-immune disease marked by frequent and severe gastrointestinal (GI) afflictions and gut dysbiosis. Objectives Determine the safety and efficacy of fecal microbiota transplantation (FMT) using commercially-available anaerobic cultivated human intestinal microbiota (ACHIM) in patients with SSc. Methods The trial was a single-center, randomized, double-blind, placebo-controlled 16-week pilot of FMT by gastroduodenoscopy of ACHIM in SSc conducted at Oslo University Hospital. Primary endpoints were safety and clinical efficacy on GI symptoms assessed at weeks 4 and 16. Safety was assessed by observation, interviews and standardized safety form. Efficacy on GI symptoms was measured using the UCLA GIT 2.0 score questionnaire. Patients were defined as responders if reported symptom improvement was equivalent to the UCLA GIT definition of “minimally clinically important difference”. Secondary and explorative endpoints included changes in relative abundance of total, immunoglobulin (Ig)A- and IgM-coated fecal bacteria measured by 16s rRNA sequencing; changes in modified Rodnan skin score, lung function, CRP, ESR, and patient and physician global. Descriptive statistics were applied for clinical endpoints and linear mixed models for microbial analysis. Results Ten patients with limited cutaneous SSc randomized to ACHIM (n=5) or placebo (n=5) were included. All patients were female with clinical apparent GI symptoms, mean age of 62 years and mean time from diagnosis of 12 yrs. Two placebo controls experienced procedure-related serious adverse events; one developed laryngospasms at first gastroduodenoscopy necessitating study exclusion, one duodenal perforation at final gastroduodenoscopy. Improvement in total GIT score was reported by 3/5 FMT patients compared to 2/4 placebo controls at weeks 4 and 16 (Figure 1). FMT effects were most pronounced on lower GI symptoms, with improvement reported by 5/5 FMT patients with diarrhea, distention/bloating and/or fecal incontinence at baseline compared to 2/4 placebo controls (Figure). Clinical secondary endpoints showed no differences and other side effects (stomach discomfort, bloating and diarrhea) were mild and transient. Fecal microbiota diversity (observed number of operational taxonomic units) was increased after FMT compared to placebo treatment at week 16 (p Conclusion FMT of commercially-available ACHIM in patients with SSc appeared safe, effectively reduced lower GI symptoms, altered gut microbiota composition, richness and diversity and appeared to affect the mucosal immune system Disclosure of Interests Anna-Maria Hoffmann-Vold Grant/research support from: Received research funding or other remuneration from Boehringer Ingelheim, GSK, and Actelion, Consultant for: Received consulting fees or other remuneration from Boehringer Ingelheim, GSK, and Actelion, Speakers bureau: Actelion and Boehringer Ingelheim, Havard Fretheim Consultant for: Received consulting fees or other remuneration from GSK, and Actelion, Brian K Chung: None declared, Henriette Didriksen Consultant for: Received consulting fees or other remuneration from GSK, and Actelion, Espen S Baekkevold: None declared, Oyvind Midtvedt: None declared, Cathrine Brunborg: None declared, Torhild Garen: None declared, Tore Midtvedt Shareholder of: Owner of ACHIM, Johannes R Hov: None declared, Knut EA Lundin: None declared, Oyvind Molberg: None declared

Systemic sclerosis (SSc) is a complex autoimmune disease of unknown etiology. Genetic factors are thought to collude with various environmental triggers to induce SSc and subsequently manifest various SSc disease phenotypes. Emerging evidence suggests that the microbiota of the gastrointestinal tract (GIT) may represent a key pathogenic participant in this disease state. Recent studies have demonstrated specific alterations in the GIT microbial composition in SSc patients, and this article reviews studies that have investigated the GIT microbiota in SSc patients. The focus of this article is to highlight the modifications in the GIT microbiota observed in SSc patients belonging to different cohorts and to demonstrate how these alterations may be associated with specific SSc features. This article presents the results of these SSc microbiota studies in the context of findings from microbiotic studies in other autoimmune states to explore similarities and differences across disease states affecting the immune system. Finally, this article provides insights into potential SSc therapies that target the GIT microbiota. Given the complexity and variability of the SSc disease state, any treatment aimed at modulating GIT microbiota will likely need to be coupled with additional interventions that target other SSc disease components.

Rationale: Interstitial lung disease (ILD) represents a major challenge in systemic sclerosis (SSc), but there are no precise, population-based data on its overall impact, limiting opportunities for screening and management strategies. Objectives: Evaluate impact of ILD in a unique, nationwide, population-based SSc cohort. Methods: ILD was assessed prospectively in the Norwegian SSc (Nor-SSc) cohort, including all 815 patients with SSc resident in the country from 2000 to 2012. Lung high-resolution computed tomography (HRCT) scans were available for fibrosis quantification at baseline (n = 650, 80%) and follow-up. Pulmonary function tests were assessed at baseline (n = 703, 86%) and follow-up. Vital status and standardized mortality ratios (SMRs) were estimated at study end (2018) in the 630 incident Nor-SSc cases and 15 individually matched control subjects. Cumulative survival rates were computed. Measurements and Main Results: At baseline, 50% of the subjects with SSc (n = 324) had ILD by HRCT and 46% displayed pulmonary function declines consistent with ILD progression. Mortality correlated with extent of lung fibrosis as SMR increased from 2.2 with no fibrosis to 8.0 with greater than 25% fibrosis. SMR was inversely related to baseline FVC% and increased at all FVC levels below 100%. In patients with normal-range baseline FVC (80–100%), the 5- and 10-year survival rates correlated with presence or absence of lung fibrosis, being 83% and 80%, respectively, with no fibrosis and 69% and 56%, respectively, with lung fibrosis (P = 0.03). Conclusions: The mere presence of ILD at baseline appears to affect outcome in SSc, suggesting that all patients with SSc should undergo a baseline pulmonary function test and lung HRCT screening to diagnose ILD early and tailor further management. Supported by the Norwegian Women’s Public Health Association and the South Eastern Regional Health Authorities.

Background:Coronavirus disease-19 (COVID-19) has been a major clinical challenge worldwide. Sex, age and comorbidities have been associated with worse outcome in the general population. Systemic sclerosis (SSc) is a severe, autoimmune disease with frequent multi-organ involvement.Objectives:To assess the impact of COVID-19 and to determine factors associated with worse outcome in SSc patients from the European Scleroderma Trial and Research (EUSTAR) database.Methods:SSc patients from the EUSTAR database with COVID-19 were prospectively collected between 15.03.-31.12.2020. Two outcomes were chosen: (1) hospitalization; and (2) severe outcome defined as either non-invasive ventilation, mechanical ventilation/extracorporeal membrane oxygenation (ECMO) or death. General risk factors assessed were sex, age and number of comorbidities. SSc related risk factors were SSc subtype, autoantibodies, disease duration, SSc associated organ manifestations including interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), cardiac, gastrointestinal (GI), and musculoskeletal involvement; digital ulcers (DU), CRP at last visit, renal disease (scleroderma renal crisis and SSc associated renal insufficiency), modified Rodnan skin score (mRSS) and immunosuppressive treatment. Descriptive statistics and logistic regression models were applied.Results:In total, 178 European SSc patients with COVID-19 were registered with a median observation time of 5.5 weeks (Table 1). 95 patients (53%) could recall SAR-Cov-2 contact, while 47 (26%) had no contact. 156 (88%) were symptomatic at COVID-19 onset with fever, cough, malaise and dyspnea being most prevalent. Over the disease course, 63 (36%) developed pneumonia. In total, 67/176 (38%) were hospitalized which were in 84% due to COVID-19. 41/170 (24%) had a severe outcome including 21 (12%) deaths. 128 (72%) recovered completely, while 14 (8%) complained of sequela, with 7 (50%) stating respiratory complications. Age, non-SSc comorbidities, presence of ILD, PAH and SSc associated renal or cardiac disease were numerically associated with hospitalization and severe outcome (Table 1). Univariable logistic analyses for hospitalization and severe outcome are shown in Figure 1. In multivariable logistic regression, age (OR 1.03, 95%CI 1.01-1.07, p=0.019), presence of non-SSc comorbidities (OR 2.52, 95%CI 1.16-5.47, p=0.019) and SSc-related renal disease (predicting success perfectly) were associated with hospitalization and for severe outcome age (OR 1.05, 95%CI 1.01-1.08).Conclusion:SSc patients at older age, with non-SSc comorbidities, SSc related renal disease or ILD are at risk of a more severe outcome and should follow precautions to avoid COVID-19 infections and need careful monitoring in case of COVID-19.Table 1.SSc disease characteristics of COVID-19 patientsAll(n=172)Hospitalized(n=67)Severe outcome(n=41)Age at COVID-19, yrs (SD)57 (14.0)63 (13.8)65 (12.2)Male sex, n (%)38 (21)18 (27)12 (29)≥1 comorbidity, n (%)63/176 (36)37 (55)30 (58)SSc disease duration at COVID, yrs (SD)11.5 (8.8)13.3 (9.7)12.7 (10.2)Diffuse cutaneous SSc, n (%)74 (42)29 (43)19 (46)mRSS, median (IQR)5 (8)5 (9)5 (7)ILD, n (%)90/175 (51)36/65 (55)26/40 (65)PAH, n (%)21/175 (12)11/65 (17)8/40 (20)GI disease, n (%)112/176 (64)45 (67)30 (73)Cardiac disease, n (%)37/166 (22)19/59 (32)16/36 (44)Musculoskeletal disease, n (%)40/175 (23)15/65 (23)6/40 (15)Renal disease, n (%)8/175 (5)7/65 (11)5/40 (13)Ever DU, n (%)69/175 (39)27/65 (42)14/40 (35)CRP, ng/ml (SD)35/177 (20)14 (21)9 (22)Immunosuppressive treatment, n (%)104/177 (59)41/66 (62)26 (63)Figure 1.Univariable logistic analyses for hospitalization and severe outcomeDisclosure of Interests:Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, ARXX, Lilly and Medscape, Consultant of: Actelion, Boehringer Ingelheim, Bayer, ARXX, and Medscape, Grant/research support from: Boehringer Ingelheim, Cathrine Brunborg: None declared, Francesca Tirelli: None declared, Patricia Carreira: None declared, Nicoletta Del Papa: None declared, Arsene Mekinian: None declared, Madelon Vonk: None declared, Alessandro Giollo: None declared, Giacomo De Luca: None declared, Maria De Santis: None declared, Corrado Campochiaro: None declared, Carina Mihai: None declared, Paolo Airò Speakers bureau: Bristol Myers Squibb, Bohringer Ingelheim, Consultant of: Bristol Myers Squibb, Bohringer Ingelheim, non-financial support from CSL Behring, SOBI, Janssen, Roche, Sanofi, Pfizer, Maria Grazia Lazzaroni: None declared, Elisabetta Zanatta: None declared, Rosario Foti: None declared, Yannick Allanore: None declared, Daniel Furst: None declared, Marco Matucci-Cerinic: None declared, Armando Gabrielli: None declared, Oliver Distler Speakers bureau: Actelion, Kymera Therapeutics, Mitsubishi Tanabe Pharma, Abbvie, Acceleron, Alexion, Amgen, AnaMar, Arxx Therapeutics, Baecon, Discovery, Blade Therapeutics, Corbus Pharmaceuticals, Drug Development International, Ltd, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Kymera Therapeutics, Lilly, Novartis, Pfizer, Topadur and UCB, Consultant of: Actelion, Kymera Therapeutics, Mitsubishi Tanabe Pharma, Abbvie, Acceleron, Alexion, Amgen, AnaMar, Arxx Therapeutics, Baecon, Discovery, Blade Therapeutics, Corbus Pharmaceuticals, Drug Development International, Ltd, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Kymera Therapeutics, Lilly, Novartis, Pfizer, Topadur and UCB, Grant/research support from: Boehringer Ingelheim.

Background:High-resolution computed tomography (HRCT) is the gold standard diagnostic test for Interstitial lung disease (ILD), a significant cause of morbidity and mortality in systemic sclerosis (SSc). Different algorithms have been proposed for the screening of SSc-ILD, including the use of pulmonary function tests (Forced Vital Capacity - FVC, Lung Diffusion of Carbone Monoxyde - DLCO). A prior survey reported that 50-66% of general rheumatologists and SSc experts ordered HRCT for ILD screening in newly diagnosed SSc patients (1).Objectives:Given the recent availability of on-label treatment for SSc-ILD (2), the publication of consensus recommendations for the identification of SSc-ILD (3) and recent awareness programs for the use of HRCT to detect SSc-ILD, we aimed to re-evaluate the use of HRCT for screening, re-screening and follow-up of SSc-ILD.Methods:An invitation was sent to the European Scleroderma Trials and Research (EUSTAR) and Scleroderma Clinical Trials Consortium (SCTC) members, also advertised through social media. Answers were recorded between Nov 25th and Dec 31st 2020. Questions were asked on the use of chest HRCT at baseline, the re-screening of patients with a negative baseline HRCT and the follow-up of HRCT positive SSc-ILD patients. When HRCT was not routinely requested, additional details were collected about the parameters guiding its use. The results of the survey were tested for association with geographical origin, medical specialty, working environment, SSc referral institute and scientific group membership of the responders, using Chi-squared test.Results:205/630 (32.5%) physicians replied to the survey. Participants were widely distributed in terms of geographical origin (130 Europe, 23 Asia, 23 North America, 31 other continents), medical specialty (156 rheumatology, 21 internal medicine, 14 clinical immunology, 14 other), working environment (176 University Hospital, 12 community hospital, 17 other), SSc dedicated clinic (179 referral and 26 non-referral) and scientific group membership (98 EUSTAR, 42 SCTC, 42 EUSTAR and SCTC, 23 not declared).At SSc diagnosis, 95.7% of responders would perform HRCT: 66.7% as routine screening for ILD (67,4% of SSc referral and 62% for non-referral physicians) and 29% for diagnostic purposes (among the latter, if crackles on auscultation – 92.5%, FVCDuring follow-up, 78.8% of responders would repeat an HRCT in baseline negative cases: 20.3% as a yearly routine screening and 64.5% for diagnostic aims (decision on the latter group was more frequently driven by FVC±DLCO relative decline indicative of ILD progression– 90.6%, new onset or worsening of dyspnoea at rest/exercise – 80.5/86.6%, new onset or worsening of lung crackles on auscultation – 82.6%).Finally, 94.5% of responders would repeat a chest HRCT after SSc-ILD diagnosis: 36.8% as a yearly routine and 56.7% according to clinical evaluation (driven by new FVC±DLCO relative decline based ILD progression – 90.8%, new onset or worsening of dyspnoea at rest/exercise – 83.2/81.7%; 5.2% to evaluate treatment effects). We found no difference in the distribution of answers among groups.Conclusion:The use of baseline HRCT for the screening of SSc-ILD has slightly increased in non-referral and remained stable in referral centers compared to previous surveys, indicating that the implementation of guidelines might be successful and awareness programs should be continued. In addition, we provide new data on use of HRCT in re-screening and follow-up. The development of validated algorithms to further support the appropriate application of HRCT at follow-up is highly needed.References:[1]Bernstein EJ et al. Arthritis Rheumatol. 2018 Jun;70(6):971-972.[2]Distler O et al. N Engl J Med. 2019 Jun 27;380(26):2518-2528.[3]Hoffmann-Vold AM et al. The Lancet Rheumatology, Volume 2, Issue 2, e71 - e83.Disclosure of Interests:Cosimo Bruni Speakers bureau: Actelion, Consultant of: Eli Lilly, Grant/research support from: Foundation for Research in Rheumatology (FOREUM), Gruppo Italiano Lotta alla Sclerodermia (GILS), Fondazione Italiana per la Ricerca sull’Artrite (FIRA), New Horizon Fellowship, European Sclerodermia Trial and Reserach (EUSTAR) Group., Lorinda Chung Consultant of: Boehringer Ingelheim, Eicos, Mitsubishi Tanabe, Reata., Anna-Maria Hoffmann-Vold Consultant of: Actelion, ARXX therapeutics, Bayer, Boehringer-Ingelheim, Medscape, MSD, Lilly, Roche, Shervin Assassi Speakers bureau: Integrity Continuing Education, Consultant of: Boehringer Ingelheim, Novartis, and Corbus, Armando Gabrielli: None declared, Dinesh Khanna Consultant of: Acceleron, Actelion, Abbvie, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, Corbus, Gilead, Galapagos, Genentech/Roche, GSK, Horizon, Merck, Mitsubishi Tanabe Pharma, Sanofi-Aventis, and United Therapeutics Leadership, Grant/research support from: NIH, Immune Tolerance Network, Bayer, BMS, Horizon, Pfizer, Employee of: Equity position – Chief Medical Officer, Eicos Sciences, Inc., Elana Bernstein Consultant of: Boehringer Ingelheim, Oliver Distler Consultant of: 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., Grant/research support from: 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).

Background:SSc is a heterogeneous autoimmune disease characterised by fibrosis of the skin and internal organs. In most patients with SSc-ILD, organs other than the lungs are also affected. In the SENSCIS trial in patients with SSc-ILD, nintedanib reduced the rate of decline in forced vital capacity (FVC) (mL/year) over 52 weeks by 44% versus placebo.Objectives:We investigated the extent of organ involvement related to SSc at baseline in patients in the SENSCIS trial and the effect of nintedanib versus placebo on the rate of FVC decline in subgroups by internal organ involvement.Methods:The SENSCIS trial enrolled patients with SSc-ILD with first non-Raynaud symptom ≤7 years before screening, extent of fibrotic ILD ≥10% on high-resolution computed tomography (HRCT) and FVC ≥40% predicted. Patients with clinically significant pulmonary hypertension were excluded. Patients were randomised to receive nintedanib or placebo until the last patient reached week 52 but for ≤100 weeks. In post-hoc analyses, we analysed the rate of decline in FVC (mL/year) over 52 weeks in subgroups with and without different types of SSc-related internal organ involvement (upper gastrointestinal; lower gastrointestinal; cardiovascular [CV]; peripheral vascular; muscular; joint). These subgroups were defined based on patients’ SSc-related medical history as reported in the case report form. A random slope and intercept model was used to assess the rate of decline in FVC (mL/year) and an interaction test applied to assess potential heterogeneity in the treatment effect of nintedanib between the subgroups.Results:Of 576 patients, 96.9% had peripheral vascular involvement, 75.5% had upper gastrointestinal and 39.8% lower gastrointestinal involvement, 45.7% had CV involvement, 40.6% had joint involvement, and 27.1% had muscular involvement at baseline. In the placebo group, the rate of decline in FVC (mL/year) was numerically greater in patients with than without upper gastrointestinal involvement and in patients without than with joint involvement or muscular involvement (Figure). The exploratory interaction p-values did not indicate heterogeneity in the treatment effect of nintedanib versus placebo on reducing the rate of decline in FVC (mL/year) between the subgroups based on organ involvement (p>0.05 for all treatment-by-time-by-subgroup interactions) (Figure).Conclusion:Patients in the SENSCIS trial had diverse complications related to SSc. There was no evidence of a differential treatment effect of nintedanib on reducing the rate of decline in FVC based on gastrointestinal, CV, joint, or muscular involvement at baseline.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:Yannick Allanore Consultant of: Boehringer Ingelheim, Medsenic, Menarini and Sanofi, Grant/research support from: Alpine Pharmaceuticals, Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Lilly, MSD and Roche, Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Lilly, Medscape, MSD and Roche, Grant/research support from: Boehringer Ingelheim, Maureen Mayes Consultant of: Paid consultant or member of Advisory Board/Steering Committee for Boehringer Ingelheim, Eicos, Galapagos and Mitsubishi Tanabe Pharma, Grant/research support from: Clinical trial research support from Boehringer Ingelheim, Corbus, Eicos and Galapagos, Madelon Vonk Speakers bureau: Boehringer Ingelheim, GlaxoSmithKline, Janssen and Roche, Consultant of: Boehringer Ingelheim and Janssen, Grant/research support from: Boehringer Ingelheim, Ferrer, Galapagos and Janssen, Corinna Miede Employee of: Currently an employee of mainanalytics GmbH, contracted by Boehringer Ingelheim, Margarida Alves Employee of: Currently an employee of Boehringer Ingelheim, Gabriela Riemekasten Speakers bureau: Actelion, Boehringer Ingelheim, Cellgene, GlaxoSmithKline, Janssen, Novartis and Roche, Consultant of: Actelion, Boehringer Ingelheim and Janssen, Grant/research support from: Janssen

Background:Gastro-intestinal tract (GIT) symptoms is highly prevalent in patients with systemic sclerosis (SSc). The GIT-symptoms impact on the quality of life is significant, and available treatment alternatives are limited. Recently published articles show associations between gut microbiota changes and GIT-symptoms in SSc. We, therefore, performed a successful feasibility trial on faecal microbiota transplantation (FMT) in SSc patients using the single-donor bacterial culture “Anaerobic Cultivated Human Intestinal Microbiome (ACHIM)”. Based on the promising results from the feasibility trial, we aim to evaluate the safety and efficacy of FMT by ACHIM in SSc patients. (NCT04300426)Objectives:To design a clinical trial that explores the safety and efficacy of FMT in SSc patients.Methods:The ReSScue trial is a phase II, placebo-controlled, randomised 20-week, multicentre trial. The trial comprises three parts. In the induction phase (A1) lasting from week 0 to week 12, participants are randomised 1:1 to repeat infusions of 30 ml ACHIM or placebo at week 0 and 2 by gastro-duodenoscopy. In the maintenance phase (A2), all study participants will receive 30 ml ACHIM at week 12 and are followed continued blinded until week 20.For longer-term data on intervention effects and safety, the participant will be followed for a maximum extended monitoring period of 16 weeks (part B).The primary endpoint is change from baseline to week 12 in UCLA GIT scores on bloating or diarrhoea, depending on the worst symptom at baseline evaluated separately for each patient. Secondary endpoints are changes in UCLA GIT scores (bloating, diarrhoea and total) and safety measures.Results:We aim to enrol 70 SSc patients based on the power calculations for the primary endpoint “change in worst symptom from baseline to week 12”, with a considered drop out rate of 10%. This number of patients is expected to give a power of 80% of detecting a change in mean (p=0.05, two-sided) of -5.0 (or higher) if the relating standard deviation is 0.70 or lower. The patient screening started in September 2020, and we expect the study to be completed in May 2022.Conclusion:The ReSScue-study is to our knowledge the first FMT-study in SSc. This trial will assess the safety and efficacy of FMT in SSc patients with lower GI-symptoms, possibly leading to a novel treatment approach in SSc patients.Disclosure of Interests:Håvard Fretheim Grant/research support from: Received travel bursaries from Actelion, and remuneration from Bayer., Imon Barua: None declared, Vikas Sarna: None declared, Maylen N Carstens: None declared, Oliver Distler Speakers bureau: Below, Consultant of: Below, Grant/research support from: OD 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, Baecon Discovery, Blade, Bayer, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos NV, Glenmark, GSK, Horizon (Curzion), Inventiva, iQvia, Italfarmaco, iQone, Kymera, 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)., Dinesh Khanna Consultant of: Abbvie, Actelion/Janssen, Acceleron Pharma, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, GSK, Horizon Pharmaceuticals, Mitsubishi Tanabe Pharma, Pfizer, Roche, Sanofi, United Therapeutics. DK is chief medical officer of Eicos Sciences, Inc., Grant/research support from: Abbvie, Actelion/Janssen, Acceleron Pharma, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, GSK, Horizon Pharmaceuticals, Mitsubishi Tanabe Pharma, Pfizer, Roche, Sanofi, United Therapeutics. DK is chief medical officer of Eicos Sciences, Inc., Elizabeth Volkmann Consultant of: Boehringer Ingelheim, Grant/research support from: Corbus, Forbius, Boehringer Ingelheim, Øyvind Midtvedt Shareholder of: Son of owner of ACHIM., Henriette Didriksen Speakers bureau: Travel bursary - GSK, Alvilde Dhainaut: None declared, Anna-Kristine H Halse: None declared, Gunnstein Bakland: None declared, Inge Christoffer Olsen: None declared, Maiju E Pesonen: None declared, Øyvind Molberg: None declared, Anna-Maria Hoffmann-Vold Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Medscape, Merck Sharp & Dohme, Lilly and Roche., Grant/research support from: Actelion, ARXX, Bayer, Boehringer Ingelheim, Medscape, Merck Sharp & Dohme, Lilly and Roche.

Background:Hydroxychloroquine (HCQ) is a well-tolerated drug that contributes to downregulating the immune response against autoantigens and it has been used in several autoimmune diseases. In systemic sclerosis (SSc) it is used to treat inflammatory arthritis without proof of efficacy.Objectives:Our aim was to evaluate the use of HCQ and its impact on Health Assessment Questionnaire disability index (HAQ-DI) and the Cochin Hand Function Status (CHFS). in a large SSc cohort compared to a propensity matched group of SSc patients not using HCQ.Methods:SSc patients from the European Scleroderma Trials and Research (EUSTAR) data base treated with HCQ for at least 6 months were evaluated. Demographic and clinical data, concomitant drugs, duration of HCQ treatment and reasons for its discontinuation, HAQ-DI and CHFS (at least 2 evaluation) were recorded and were the outcome variables of interest. Statistical analysis was performed using propensity score matching for age, gender, disease duration, corticosteroids, immunosuppressives, vasoactive drugs, DMARDs in a 3:1 control:HCQ ratio. Standard descriptive statistics and Student’s t-test and Chi-square test were used to assess the propensity-matched groups.Results:1,636 of 17,805 SSc patients (9.2%) were treated with HCQ for at least 6 months; out of these 3% (50/1636). had at least a baseline and follow-up HAQ-DI evaluation, (and 44/1636 (2.7%) had at least a baseline and follow-up CHFS evaluation. Propensity matching assured that pts were matched for demographic variables such as gender (mean on HCQ vs no HCQ:femals:92.0 vs 85.3), age(49.8 vs 49.97yrs) disease duration(8.3 vs 9.1 yrs), limited disease(55.3 vs 62.6%) as well as background medications (P>0.1-0.9). We did not find any significant changes in HAQ or CHFS (difference in slope) over 365 days of treatment, comparing the HCQ-treated group to the non-HCQ treated patients (p=0.240 for both (Figure 1).Conclusion:Results from the EUSTAR registry showed that HCQ was used by 9.2% of SSc patients. HCQ use did not improve the HAQ or CHFS, comparing HCQ users to non-HCQ users.Disclosure of Interests:Silvia Bellando Randone: None declared, Holly Wilhalme: None declared, Cosimo Bruni: None declared, Elise Siegert: None declared, Paolo Airò: None declared, Rosaria Irace: None declared, Oliver Distler: None declared, Andrea Doria: None declared, Lidia P. Ananieva: None declared, László Czirják: None declared, Christopher Denton: None declared, Yannick Allanore: None declared, Valeria Riccieri: None declared, ALESSANDRA VACCA: None declared, Ivan Foeldvari Consultant of: Gilead, Novartis, Pfizer, Hexal, BMS, Sanofi, MEDAC, Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Lilly and Medscape, Consultant of: Actelion, Boehringer Ingelheim, Roche, Bayer, ARXX, and Medscape, Grant/research support from: Boehringer Ingelheim, Armando Gabrielli: None declared, Marco Matucci-Cerinic: None declared, Daniel Furst: None declared

Background:Some patients with SSc-ILD develop dyspnoea secondary to parenchymal lung disease, while others do not report dyspnoea even when their lung function is impaired. It is unclear whether the presence of dyspnoea is associated with a worse course of SSc-ILD or with response to therapy.Objectives:To investigate the rate of decline in FVC in patients with SSc-ILD in the SENSCIS trial in subgroups by patient-reported dyspnoea at baseline.Methods:The SENSCIS trial enrolled patients with SSc-ILD with first non-Raynaud symptom within ≤7 years before screening, extent of fibrotic ILD ≥10% on HRCT and FVC ≥40% predicted. Patients were randomised to receive nintedanib or placebo until the last patient reached week 52. In post-hoc analyses, we analysed the rate of decline in FVC (mL/year) over 52 weeks in patients with and without dyspnoea at baseline based on the question about dyspnoea in the St. George’s Respiratory Questionnaire (SGRQ). Patients who reported having shortness of breath “most days a week”, “several days a week” or “a few days a month” (rather than “only with chest infection” or “not at all”) over the last month were considered to have dyspnoea at baseline. A random slope and intercept model was used to assess the rate of decline in FVC (mL/year) and an interaction test was applied to assess potential heterogeneity in the treatment effect of nintedanib between the subgroups.Results:Of 576 patients, 69.8% had dyspnoea at baseline. At baseline, in patients with and without dyspnoea, respectively, mean (SD) extent of fibrotic ILD on HRCT was 37.7 (21.7)% and 31.6 (19.4)%; mean (SD) FVC was 71.0 (16.3) and 76.5 (16.8) % predicted; 50.7% and 44.8% were taking mycophenolate; 53.5% and 41.9% were taking corticosteroids. In the placebo group, the rate of decline in FVC (mL/year) was similar in patients with and without dyspnoea at baseline (Figure). The effect of nintedanib versus placebo on reducing the rate of decline in FVC (mL/year) was numerically more pronounced in patients without dyspnoea (difference: 79.8 [95% CI: 9.8, 149.7]) than with dyspnoea (difference: 25.7 [-19.9, 71.3]), but the exploratory interaction p-value did not indicate heterogeneity in the treatment effect between subgroups (p=0.20).Conclusion:In the SENSCIS trial, patients with SSc-ILD who had dyspnoea at baseline had a numerically greater extent of fibrotic ILD on HRCT and numerically lower FVC % predicted at baseline. The rate of decline in FVC in the placebo group was similar in patients with and without dyspnoea. Nintedanib had a numerically greater treatment effect in patients without dyspnoea. These data suggest that the presence of dyspnoea should not be used as a criterion for starting nintedanib in patients with SSc-ILD.Acknowledgements:The SENSCIS trial was funded by Boehringer Ingelheim. Medical writing support was provided by Fleishman Hillard Fishburn, London, UK. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE).Disclosure of Interests:Elizabeth Volkmann Consultant of: Boehringer Ingelheim, Grant/research support from: Corbus and Forbius, Michael Kreuter Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Grant/research support from: Boehringer Ingelheim and Roche, Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Lilly, Merck Sharp & Dohme and Roche, Consultant of: Actelion, Arxx Therapeutics, Bayer, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme and Roche, Grant/research support from: Boehringer Ingelheim, Marlies Wijsenbeek Speakers bureau: Boehringer Ingelheim (fees paid to institution) and Hoffmann-La Roche (fees paid to institution), Consultant of: Boehringer Ingelheim (fees paid to institution), Bristol-Myers Squibb (fees paid to institution), Galapagos NV (fees paid to institution), Hoffmann-La Roche (fees paid to institution), NeRRe Therapeutics (fees paid to institution), OncoArendi Therapeutics (fees paid to institution), Respivant Sciences (fees paid to institution) and Savara (fees paid to institution), Grant/research support from: Boehringer Ingelheim (fees paid to institution) and Hoffmann-La Roche (fees paid to institution), Vanessa Smith Speakers bureau: Boehringer Ingelheim and Janssen-Cilag NV, Consultant of: Boehringer Ingelheim, Grant/research support from: Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim, Janssen-Cilag NV and Research Foundation - Flanders (FWO), Dinesh Khanna Shareholder of: Eicos Sciences, Inc. (less than 5%), Consultant of: Acceleron Pharma, Actelion, AbbVie, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, Corbus, Gilead Sciences, Galapagos NV, Genentech/Roche, GlaxoSmithKline, Horizon Therapeutics, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Sanofi-Aventis and United Therapeutics, Grant/research support from: Bayer, Bristol-Myers Squibb, Horizon Therapeutics, Immune Tolerance Network, National Institutes of Health and Pfizer, Employee of: Chief Medical Officer- CiviBioPharma/Eicos Sciences, Inc., Christopher Denton Speakers bureau: Boehringer Ingelheim, Corbus, Janssen, and Mallinckrodt Pharmaceuticals, Consultant of: Acceleron Pharma, Arxx Therapeutics, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos NV, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mallinckrodt Pharmaceuticals, Roche, Sanofi and UCB, Grant/research support from: Arxx Therapeutics, GlaxoSmithKline and Servier, Wim Wuyts: None declared, Corinna Miede Employee of: Currently an employee of mainanalytics GmbH, contracted by Boehringer Ingelheim, Margarida Alves Employee of: Currently an employee of Boehringer Ingelheim, Steven Sambevski Employee of: Currently an employee of Boehringer Ingelheim, Yannick Allanore Consultant of: Boehringer Ingelheim, Medsenic, Menarini and Sanofi, Grant/research support from: Alpine Pharmaceuticals

Background:The interstitial lung disease (ILD) associated with connective tissue diseases including systemic sclerosis (SSc) is heterogenous disease characterized by reduced survival of approximately 3 years (1). “Radiomics’’ is a field of research which describes the in-depth analysis of tissues by computational retrieval of high-dimensional quantitative features from medical images (2). Our previous study suggested capacity of radiomics features to differentiate between “high” and “low” risk groups for lung function decline in two independent cohorts (3).Objectives: •bTo develop robust, machine learning (ML) workflow for “radiomics” data in SSc-ILD to select optimal methods for prediction. •oTo predict the time to individual lung function decline defined as defined by the time to a relative decline of ≥ 15% in Forced Vital Capacity (FVC)% as previously (3), using workflow.Methods:We investigated two cohorts of SSc-ILD: 90 patients (76.7% female, median age 57.5 years) from the University Hospital Zurich and 66 patients (75.8% female, median age 61.0 years) from Oslo University Hospital’s. Patients were retrospectively selected if (3): a) diagnosed with early/mild SSc according to the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) criteria, b) presence of ILD on HRCT as determined by a senior radiologist. For every subject, we defined 1,355 robust radiomic features from HRCT images. The follow-up period was defined as the time interval between baseline visit and the last available follow-up visit.We have developed a systematic computational workflow to build predictive ML models. To reduce the number of redundant radiomic features, we applied correlation thresholds. We applied distinct methods including 1) Lasso Penalized Regression for feature selection, and 2) Random Forest (RF) for modeling using the R package ‘caret’. To select the optimal ML model, we randomly divided derivation cohort into Training (70%) and Holdout (30%) sets and applied fivefold cross-validation (5kCV) for feature and classifier selection on Training set only.Results:We have investigated various methods to select the optimal set of predictive radiomic features. Since the ML model performance is affected by both, feature, and classifier selection, we assessed these factors first.Results from feature filtering and selection, suggested that the combination of correlation threshold of 0.9 with Lasso regression proved best. As we perform feature selection in 5k CV workflow, features present in at least 2 sets entered model optimization step.During model selection, we selected RF classifier. We detected positive correlation between actual and predicted values with Spearman’s rho = 0.313, p = 0.167 and Spearman’s rho = 0.341, p = 0.015 in Oslo and Holdout sets respectively, as shown on Figure 1. The percentage of variance remained modest for both Holdout (Rsq = 0.104) and Oslo (Rsq = 0.126) datasets.Figure 1.Performance of the best, RF classifier shown as scatterplot between actual and predicted values of individual time to lung decline.Conclusion:In summary, we: (1) developed ML workflow that allowed to select o optimal methodology for modeling (i.e., feature and classifier selection), and (2) provide models that predicted time to individual lung function decline, characterized by significant correlation between predicted and actual values.References:[1]Hansell DM, Goldin JG, King TE, Jr., Lynch DA, Richeldi L, Wells AU. CT staging and monitoring of fibrotic interstitial lung diseases in clinical practice and treatment trials: a position paper from the Fleischner Society. Lancet Respir Med. 2015;3(6):483-96.[2]Lambin, P. et al. Radiomics: extracting more information from medical images using advanced feature analysis. Eur. J. Cancer 48, 441–446 (2012).[3]Schniering J. et al. Resolving phenotypic and prognostic differences in interstitial lung disease related to systemic sclerosis by computed tomography-based radiomics. https://www.medrxiv.org/content/10.1101/2020.06.09.20124800v1Disclosure of Interests:None declared

Background:Digital ulcers (DUs) affect half of the patients with systemic sclerosis (SSc) and can be complicated by gangrene and amputation. The direct involvement of platelets in the development of DUs has been suggested by in vitro studies, which encouraged physicians to consider platelet inhibitors as a therapeutic option in the management of DUs. However, until now, there is no clinical study to assess the efficacy of platelet inhibitors for DUs in SSc patients.Objectives:To demonstrate a possible relationship between treatment with platelet inhibitors and the occurrence of DUs at the next follow-up visit in patients with SSc.Methods:This study used prospectively collected data from the European Scleroderma Trials and Research group (EUSTAR) registry. Patients fulfilling the 2013 ACR/EULAR SSc classification criteria with complete longitudinal data on the presence of DUs and platelet inhibitors were included in the analysis. Multiple imputation using a random forest algorithm was implemented to handle missing values.The dataset was split into a derivation and validation cohort. To investigate the response for the binary dependent variable of DUs, a generalized linear mixed model (GLMM) was developed in the derivation cohort and validated using ROC analysis and Brier scores to address discrimination and calibration, respectively.Results:Of 3,463 patients (2,961 in the derivation cohort, 722 in the validation cohort), 453 had current DUs at the baseline and 245 were exposed to platelet inhibitors (table 1).Our GLMM revealed that the exposure to platelet inhibitors is associated with a reduced risk of DUs at the next follow up visit (OR = 0.33, 95% CI = [0.13 to 0.82]). Further factors associated with absence or presence of DUs at the next follow-up visit are shown in figure 1. This confirmed the previously identified risk factors for the presence of DUs, supporting the overall robustness and the validity of our model.The performance was evaluated by ROC curve analysis and showed an AUC = 97.97% (95% CI = [96.93% to 97.67%]) for the derivation cohort and AUC = 77.3% (95% CI = [74.01% to 81.39%]) for the validation cohort, respectively, showing an acceptable discrimination. The Brier score was 0.05 in the derivation cohort and 0.07 in the validation cohort, suggesting a good calibration of the model.Conclusion:Our model, with acceptable discrimination and good calibration, suggests a positive treatment effect of platelet inhibitors on DUs in clinical practice.Table 1.Baseline characteristics of patients before imputationCharacteristicsOverallDerivation setValidation setn3,4632,691772Age (median [IQR])56.00 [47.00, 66.00]56.00 [47.00, 65.00] 57.00 [48.00, 67.00]Disease duration (median [IQR]) 9.00 [4.00, 16.00] 9.00 [4.00, 16.00] 8.00 [4.00, 15.00]Disease subset = Limited cutaneous SSc (%) 1562 (65.2) 1164 (64.6) 398 (66.9)DUs (%): Current 453 (13.1) 378 (14.0) 75 (9.7)DUs (%): Never 1783 (51.5) 1326 (49.3) 457 (59.2)DUs (%): Previously 1227 (35.4) 987 (36.7) 240 (31.1)mRSS (median [IQR]) 5.00 [2.00, 11.00] 6.00 [2.00, 12.00] 4.00 [1.00, 11.00]Joint Contractures = Yes (%) 881 (26.8) 770 (29.4) 111 (16.5)LVEF (median [IQR])62.00 [60.00, 65.00]60.00 [60.00, 65.00] 65.00 [60.00, 67.00]Dyspnea NYHA III and IV (%)300 (9.5)214 (8.6)86 (12.7)Pulmonary hypertension = Yes (%) 244 (10.7) 200 (11.3) 44 (8.4)Lung fibrosis on HRCT = Yes (%) 685 (46.6) 600 (47.7) 85 (39.7)FVC % predicted (median [IQR])97.00 [82.00, 111.00]95.00 [81.00, 110.00]101.00 [85.00, 115.00]Serum creatinine mg/dl (median [IQR]) 0.70 [0.60, 0.90] 0.70 [0.60, 0.90] 0.70 [0.70, 0.90]Anti-Scl-70 positive = Yes (%) 1147 (33.1) 958 (35.6) 189 (24.5)CRP elevation = Yes (%) 639 (21.1) 490 (20.8) 149 (22.1)Platelet inhibitors therapy = Yes (%) 245 (7.1) 206 (7.7) 39 (5.1)Oral anti-coagulants therapy = Yes (%) 53 (1.5) 50 (1.9) 3 (0.4)Disclosure of Interests:None declared

Background:Current treatments for systemic sclerosis-associated interstitial lung disease (SSc-ILD) are characterised by different attributes such as mode of administration, adverse events (AE) and efficacy. Physicians and patients often have different perspectives on treatments, thus shared decision-making between patients and physicians is essential. An understanding of patients’ decision processes when weighing treatment attributes and the trade-offs they are willing to make is important for shared decision-making.Objectives:The study aimed to 1) identify relevant treatment attributes, 2) elicit patient preferences for these attributes and 3) quantify preference as relative attribute importance (RAI; a higher RAI indicates that more of the variability in patients’ responses may be explained by changes in the attribute); and maximum acceptable risk (MAR) of diarrhoea, nausea and/or vomiting (MAR is a trade-off measure that evaluates attributes in risk-equivalences as a unit of measurement).Methods:A discrete choice experiment (DCE) was created, based on a literature review, a patient advisory board, qualitative patient interviews, and a workshop involving SSc-ILD expert physicians. Seven SSc-ILD treatment attributes were identified: 1) mode of administration; 2) shortness of breath; 3) skin tightness; 4) cough; 5) tiredness; 6) risk of gastrointestinal tract (GIT) AEs; and 7) risk of serious and non-serious infections. The levels of AE risk were informed by frequencies observed in clinical trials and patient input during the interviews. The DCE was integrated into an online survey, which asked patients to make repeated choices between two alternatives described by varying levels of included attributes. Patients with SSc-ILD were recruited by physician referral from Switzerland, Norway, France, Germany and the USA. DCE data were analysed using a logit model, and RAI and MAR measures were calculated.Results:A total of 231 patients with physician-confirmed SSc-ILD (mean age 52.6±13.2 years; 54% diagnosed for >5 years) completed the survey. Patients with SSc-ILD mostly preferred twice-daily oral treatments (pPatients accepted an additional 21% risk (95% CI 13–29%) of GIT AEs if they could reduce the frequency of infusions from monthly to 6–12 monthly, or accepted an extra 15% (95% CI 7–23%) increase in risk if changing to an oral treatment twice daily. Among symptoms, an additional 28% (95% CI 20–36%) risk of GIT AEs was considered acceptable if the severity of patients’ persistent cough was reduced to a level that was easier to tolerate, even if it remained persistent. Similarly, a 37% (95% CI 28–46%) increase in the risk of GIT AEs was acceptable if it resulted in breathlessness during routine activities rather than breathlessness at rest. Finally, patients were willing to accept an additional 36% risk (95% CI 27–45%) of GIT AEs if it reduced their risk of non-serious infections from 30% to 15% and of serious infections from 10% to 5%.Conclusion:This is the first study to quantitatively elicit patients’ preferences for attributes of SSc-ILD treatments. Preferences were driven by safety, efficacy and technical considerations. Patients showed willingness to make trade-offs, providing a firm basis for shared decision-making in routine clinical practice.Disclosure of Interests:Cosimo Bruni Speakers bureau: Actelion, Consultant of: Eli Lilly, Grant/research support from: Gruppo Italiano Lotta alla Scleroderma (GILS), Fondazione Italiana per la Ricerca sull’Artrite (FIRA), New Horizon Fellowship, European Scleroderma Trial and Research (EUSTAR), Foundation for Research in Rheumatology (FOREUM)., Sebastian Heidenreich Consultant of: Sebastian Heidenreich, PhD is employed by Evidera Inc, a business unit of PPD. Evidera is a CRO that offers paid research services to pharmaceutical companies., Ashley Duenas Consultant of: Yes. I am an employee of Evidera which received funding from Boehringer Ingelheim for work related to this study., Anna-Maria Hoffmann-Vold Speakers bureau: Boehringer Ingelheim, Actelion, Roche, Merck Sharp & Dohme, Lilly, Consultant of: Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly and Medscape, Grant/research support from: Boehringer Ingelheim, Armando Gabrielli Grant/research support from: Pfizer Bhering, Yannick Allanore Consultant of: Honorarium received from Boehringer, Medsenic,Sanofi, Menarini, Grant/research support from: Grants received from Alpine, Ose Immunogenetics, Emmanuel Chatelus: None declared, Jörg H.W. Distler Shareholder of: JHWD is stock owner of 4D Science, Consultant of: JHWD has consultancy relationships with Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Grant/research support from: JHWD has received research funding from Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB, Eric Hachulla: None declared, Vivian Hsu Speakers bureau: I am a speaker for Boehringer Ingelheim Pharmaceuticals, Consultant of: with Boehringer Ingelheim Pharmaceuticals, Grant/research support from: Principal Investigator for several clinical trials, currently with Genentech, Corbus Pharmaceutical, and EICOS, Nicolas Hunzelmann Speakers bureau: Boehringer, Roche, Sanofi, Dinesh Khanna Shareholder of: Eicos Sciences, Inc (less than 5%), Consultant of: Paid Consultant for: Acceleron, Actelion, Abbvie, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, Corbus, Gilead, Galapagos, Genentech/Roche, GSK, Horizon, Merck, Mitsubishi Tanabe Pharma, Sanofi-Aventis, and United Therapeutics, Grant/research support from: Research Grant support from: Immune Tolerance Network, Bayer, BMS, Horizon, Pfizer, Employee of: Leadership/Equity position – Chief Medical Officer, CiviBioPharma/Eicos Sciences, Inc – recieves a stipend for role as Chief Medical Officer, which would technically qualify as emplyoment., Marie-Elise Truchetet Speakers bureau: Abbvie, Lilly, Sobi, Boehringer, Paid instructor for: Lilly, Consultant of: UCB, Sobi, Abbvie, Grant/research support from: UCB, Gilead, Ulrich Walker Shareholder of: Bayer, NASDAQ, MSCI-World ETF’s, Speakers bureau: All companies producing pharmaceuticals used in AIDS, Paid instructor for: Roche, Abbvie, Novartis, Consultant of: All companies producing pharmaceuticals used in AIDS, Grant/research support from: Gilead, Abbvie, (in the last two years). Other companies in previous years., Margarida Alves Employee of: Boehringer Ingelheim, Nils Schoof Employee of: Employee of Boehringer Ingelheim International GmbH, Lesley Ann Saketkoo Speakers bureau: Boehringer Ingelheim, Actelion, Janssen, Mallinckrodt, United Therapeutics, Consultant of: Actelion, Boehringer Ingelheim, Bayer, Bristol Meyer Squibb, Corbus, EICOS, Janssen, Horizon, United Therapeutics, Inc, Grant/research support from: Mallinckrodt, United Therapeutics, Oliver Distler Speakers bureau: Boehringer Ingelheim, Medscape, IQone, Roche, Consultant of: OD 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: Kymera Therapeutics, Mitsubishi Tanabe

Background:Based on the argument that symptoms define disease, physicians commonly apply the terms “preclinical” or “subclinical” disease to describe patients with disease-related findings but no accompanying symptoms for connective tissue disease associated interstitial lung disease (CTD-ILD). The term subclinical frequently applies to patients with mild ILD changes on high resolution chest tomography (HRCT), normal forced vital capacity (FVC), and without respiratory symptoms. Previous work in systemic sclerosis (SSc)-ILD did show that patients with even minor extent of ILD at baseline often progressed and had increased mortality risk, suggesting that it is not appropriate to define these patients as “subclinical.”Objectives:To identify the prevalence of subclinical ILD across CTD diagnoses, and assess the rate of progression of lung fibrosis compared to CTD without ILD and with clinical ILD.Methods:All CTD patients, including SSc, anti-synthetase syndrome (ASS) and mixed connective tissue disease (MCTD) from the Oslo University Hospital diagnosed before 2015 and assessed for the presence of ILD by HRCT were included. The year 2015 was chosen to secure an observation time of at least five years from ILD diagnosis to study end on 01.01.2021 or time of death. All patients fulfilled the respective CTD classification criteria. Subclinical ILD was defined as an ILD extent 80% predicted and without respiratory symptoms. Clinical ILD was defined as >5% extent of ILD or Results:We identified 525 CTD patients, including 296 with SSc, 135 with MCTD and 94 with ASS who had conducted a baseline HRCT. Of these, 227 (43%) had no ILD, 67 (13%) subclinical and 231 (44%) clinical ILD (Table). Of the 67 subclinical ILD patients, 45 (15%) had SSc, 13 (10%) MCTD and 9 (10%) ASS of thespecific cohorts. Over a median time of 4.5 years between baseline and follow-up HRCT, 95/395 (24%) showed progression of ILD, including 72 (26%) SSc and 23 (19%) MCTD patients. Disease progression frequently occurred in both subclinical ILD (38%) and clinical ILD (51%) patients (Figure). Age, gender, underlying CTD, and baseline lung function were not predictive for the progression of lung fibrosis. Progression was too infrequent to allow for meaningful multivariable regression analyses. After a median observation period of 12 years, 153 (29%) of the patients died. The 1-, 5- and 10-year survival rates in those without ILD, subclinical and clinical ILD were 97%/97%/99%, 88%/91%/82%, and 82%/85%/68% (pTable 1.Clinical characteristics, demographics and outcomeNo ILD (n=227)Subclinical ILD (n=67)Clinical ILD (n=231)Age, y (SD)50 (15.4)51 (14.4)52 (15.3)Male sex, n (%)89 (39)22 (33)111 (48)Deceased, n (%)50 (22)12 (18)91 (39)Observation period, y median (range)13.7 (18.6)13.9 (17.9)11.5 (17.1)FVC% (SD)97 (18.6)99 (17.9)81 (20.9)FVC decline% (SD)-0.70 (11.1)-0.81 (16.5)-1.61 (15.9)DLCO% (SD)73 (19.4)73 (16.9)55 (17.4)Extent of ILD% (SD)0 (0)2.3 (1.5)19.3 (16.8)ILD progression% (SD)0.08 (1.0)3.1 (6.2)3.6 (9.9)ILD progressors, n (%)3 (2)20 (38)72 (51)Figure 1.Time to ILD progression in CTD without ILD, with subclinical and clinical ILDConclusion:Subclinical ILD is frequently present across CTDs and progresses over time in a substantial subgroup of patients, comparable to patients with clinical ILD. Our findings question the terms sub- and preclinical ILD, which may potentially lead to a suboptimal “watchful waiting management strategy”. Monitoring all CTD patients with any ILD is of high importance to identify disease progression early.Disclosure of Interests:Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Lilly and Medscape, Consultant of: Actelion, Boehringer Ingelheim, Bayer, ARXX, and Medscape, Grant/research support from: Boehringer Ingelheim, Helena Andersson: None declared, Silje Reiseter: None declared, Håvard Fretheim Consultant of: Actelion, Bayer., Imon Barua: None declared, Torhild Garen: None declared, Øyvind Midtvedt: None declared, Ragnar Gunnarsson: None declared, Mike Durheim Speakers bureau: Boehringer Ingelheim and Roche, Consultant of: Boehringer Ingelheim, Grant/research support from: Boehringer Ingelheim, Trond M Aaløkken: None declared, Øyvind Molberg: None declared

Interstitial lung disease (ILD) is a relatively frequent manifestation of systemic autoimmune rheumatic disorders (SARDs), including systemic sclerosis (SSc), rheumatoid arthritis (RA), idiopathic inflammatory myopathies (IIM), systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS), and anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis. Interstitial pneumonia with autoimmune features (IPAF) has been proposed to describe patients with ILD who have clinical or serological findings compatible with SARDs but they are not sufficient for a definite diagnosis. ILD may present with different patterns among patients with SARDs, but most commonly as nonspecific interstitial pneumonia (NSIP), with the exception of RA and ANCA vasculitis that more often present with usual interstitial pneumonia (UIP). The natural history of ILD is quite variable, even among patients with the same SARD. It may present with subclinical features following a slow progressively course or with acute manifestations and clinically significant rapid progression leading to severe deterioration of pulmonary function and respiratory failure. The radiographic pattern of ILD, the extent of the disease, the baseline pulmonary function, the pulmonary function deterioration rate over time and clinical variables related to the primary SARD, such as age, sex and the clinical phenotype, are considered prognostic factors for SARDs-ILD associated with adverse outcomes and increased mortality. Different modalities can be employed for ILD detection including clinical evaluation, pulmonary function tests, high resolution computed tomography and novel techniques such as lung ultrasound and serum biomarkers. ILD may determine the clinical outcome of SARDs, since it is associated with significant morbidity and mortality and therefore screening of patients with SARDs for ILD is of great clinical importance.

Interstitial lung disease (ILD) is the major determinant of morbidity and mortality in systemic sclerosis (SSc). In highly selected SSc patients, it was recently shown that stem cell therapy early in the disease course improved survival and reduced the extent of ILD, providing a rationale for early ILD detection strategies in this disease. Here, we review recent progress on ILD screening and early diagnosis in SSc.Two studies showed that over 60% of unselected SSc cases with ILD by high-resolution computer tomography (HRCT) had normal range pulmonary function tests (PFTs); indicating poor performance of PFTs for ILD screening purposes. Serial, paired HRCT and PFT analyses indicated that screening by HRCT at baseline predicted risk for lung fibrosis development, progression rate of fibrosis and PFT decline. Analyses of circulating biomarkers, like CCL18, and nonradiating lung imaging modalities, like ultrasound and MRI, showed promise as tools for early ILD detection; but further work is needed.Prospective cohort data indicated poor performance of PFT as a stand-alone method for ILD screening. Lung HRCT appeared promising, but radiation is an issue. Promising biomarker data indicate the possibility of new ILD screening algorithms in SSc.

Markers for early identification of progressive interstitial lung disease (ILD) in systemic sclerosis (SSc) are in demand. Chemokine CCL18, which has been linked to pulmonary inflammation, is an interesting candidate, but data have not been consistent. We aimed to assess CCL18 levels in a large, prospective, unselected SSc cohort with longitudinal, paired data sets on pulmonary function and lung fibrosis.Sera from the Oslo University Hospital SSc cohort (n = 298) and healthy control subjects (n = 100) were analyzed for CCL18 by enzyme immunoassay. High CCL18 (53 ng/mL) was defined using the mean value plus 2 SD in sera obtained from healthy control subjects as the cutoff.High serum CCL18 was identified in 35% (105 of 298). Annual decline in FVC differed significantly between high and low CCL18 subsets (13.3% and 4.7%; P = .016), as did the annual progression rate of lung fibrosis (0.9% [SD, 2.9] and 0.2% [SD, 1.9]). Highest rates of annual FVC decline10% (21%) and annual fibrosis progression (1.2%) were seen in patients with high CCL18 and early disease (3 years). In multivariate analyses, CCL18 was associated with annual FVC decline10% (OR, 1.1; 95% CI, 1.01-1.11) and FVC 70% at follow-up (OR, 3.1; 95% CI, 1.08-8.83). Survival analyses showed that patients with high CCL18 had reduced 5- and 10-year cumulative survival compared with patients with low CCL18 (85% and 74%, compared with 97% and 89%, respectively; P = .001).The results from this prospective cohort reinforce the notion that high CCL18 may serve as a marker for early identification of progressive ILD in SSc.

Background:Systemic sclerosis-associated interstitial lung disease (SSc-ILD) has traditionally been treated with therapies such as cyclophosphamide, mycophenolate mofetil, and hematopoietic stem cell transplantation. However, these therapies are limited by potential toxicity, as well as duration and magnitude of effect. Clinicians need awareness of emerging therapies in late-stage clinical trials that may address these limitations.Objectives:This study was conducted to determine whether online independent medical education could improve rheumatologists’ and pulmonologists’ knowledge of emerging therapies for the management of SSc-ILD.Methods:Physicians (N = 2,076) participated in a 30-minute, 2-faculty, video-based, online CME with synchronized slides.1The majority of participants were rheumatologists (n = 522) or pulmonologists (n = 557), but the cohort also included clinical immunologists (n = 132) and other physicians with an interest in the topic (n = 865). This study focuses on the 120 rheumatologists and 111 pulmonologists who completed all pre- and post-questions. The effects of the education on knowledge was assessed using a 3-question, repeated pairs, pre-assessment/post-assessment study design. For all questions combined, the chi-square test assessed differences from pre- to post-assessment. P values Results:Overall significant improvements were seen after participation for both rheumatologists (average correct response rate of 55% at pre-assessment vs 75% at post-assessment; PFigure.Clinicians from APAC (n = 67) and Europe (n = 79) made up the majority of the cohort, and had similar rates of correct responses without significant differences, indicating consistent effects, independent of the region of origin. After participating in the activity, 48% of pulmonologists and rheumatologists had measurable improved confidence related to their knowledge of emerging therapies for patients with SSc-ILD.Despite the increases in knowledge and confidence observed, the rates of correct responses suggest there is still room for improvement; therefore, ongoing education will be needed to reinforce knowledge of the latest data evaluating new therapies for SSc-ILD and what they will mean for future practice.Conclusion:This study demonstrates the success of online, video-based education in improving rheumatologists’ and pulmonologists’ knowledge of the latest clinical data on emerging therapies for SSc-ILD. This could lead to earlier adoption of new, efficacious therapies that may slow disease progression and improve overall outcomes for these patients.References:[1]Distler O, Hoffmann-Vold A-M. How Can We Meet the Treatment Needs of Patients With Systemic Sclerosis-Interstitial Lung Disease? Launched: 9/17/2019. Data as of 11/5/2019. Available atwww.medscape.org/viewarticle/917034Disclosure of Interests:Christy Rohani-Montez: None declared, Marinella Calle: None declared, Chris Allen: None declared, Anna-Maria Hoffmann-Vold Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Actelion, Bayer, GlaxoSmithKline, Speakers bureau: Boehringer Ingelheim, Actelion, Roche, Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche

Background:In the SENSCIS trial in patients with SSc-ILD, nintedanib reduced the rate of decline in FVC over 52 weeks vs placebo, with no difference between groups in change in mRSS.Objectives:Analyse correlation between progression of skin fibrosis and progression of SSc-ILD in the SENSCIS trial.Methods:Patients with SSc-ILD were randomised to receive nintedanib or placebo until the last patient reached week 52 but for ≤100 weeks. We calculated Spearman correlation coefficients between FVC (mL) at baseline and change from baseline in mRSS, mRSS at baseline and change from baseline in FVC (mL), and changes from baseline in mRSS and FVC at weeks 52 and 100 in all patients. We analysed the rate of decline in FVC (mL/year) in patients who did and did not have progression of skin fibrosis (relative change from baseline in mRSS >25% and absolute change from baseline >5 points) at week 52.Results:In the nintedanib (n=288) and placebo (n=288) groups, respectively, mean (SD) baseline FVC (mL) was 2459 (736) and 2541 (816) and mRSS was 11.3 (9.2) and 10.9 (8.8); 53.1% and 50.7% had dcSSc;18.4% and 16.0% had progression of mRSS at week 52. No meaningful correlations were observed in analyses between mRSS and FVC (Table). The mean (SE) annual rate of decline in FVC in the placebo group was similar in patients who did and did not have progression of mRSS (-95.2 [27.1] and -91.4 [15.7] mL/year, respectively). The effect of nintedanib vs placebo on reducing the rate of decline in FVC was numerically more pronounced in patients who did not have progression of mRSS vs those who did (difference [95% CI] 44.3 mL/year [0.6, 88.1] vs 24.6 [-53.7, 102.9]), but the interaction p-value (0.66) did not indicate heterogeneity in treatment effect between subgroups.Conclusion:In the SENSCIS trial, the proportion of patients who had progression of skin fibrosis over 52 weeks was low, without significant differences between placebo and nintedanib. No meaningful correlations were observed between skin fibrosis at baseline or progression of skin fibrosis and progression of SSc-ILD. The rate of decline in FVC was similar between patients who did and did not have progression of mRSS. These findings suggest that in the overall patient population in the SENSCIS trial, progression of skin fibrosis and progression of ILD were distinct manifestations of disease progression.Table:FVC at baseline and change from baseline in mRSSmRSS at baseline and change from baseline in FVCChanges from baseline in mRSS and FVCNCorrelation*NCorrelation*NCorrelation*Week 52Nintedanib2470.11 (-0.01, 0.23)241-0.08 (-0.20, 0.05)238-0.07 (-0.19, 0.06)Placebo2540.12 (-0.00, 0.24)257-0.15 (-0.27, -0.03)2520.03 (-0.09, 0.15)Week 100Nintedanib730.21 (-0.02, 0.42)73-0.06 (-0.29, 0.17)700.06 (-0.17, 0.30)Placebo660.28 (0.04, 0.49)730.04 (-0.19, 0.27)66-0.14 (-0.37, 0.10)*Spearman correlation coefficient (95% CI)Disclosure of Interests:Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Kristin Highland Grant/research support from: Boehringer Ingelheim - PI for SENSCIS and SENSCIS-ON trials (paid to my institution), Consultant of: Kristin Highland has acted as a consultant to Boehringer Ingelheim. She was a member of the SENSCIS trial Steering Committee (Boehringer Ingelheim), Speakers bureau: Kristin Highland reports speaker fees from Boehringer Ingelheim, Anna-Maria Hoffmann-Vold Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Actelion, Bayer, GlaxoSmithKline, Speakers bureau: Boehringer Ingelheim, Actelion, Roche, Otylia Kowal-Bielecka Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Inventiva, MSD, Novartis, Speakers bureau: Boehringer Ingelheim, Medac, Novartis, Roche, Sandoz, Ulrich Walker Grant/research support from: Ulrich Walker has received an unrestricted research grant from Abbvie, Consultant of: Ulrich Walker has act as a consultant for Abbvie, Actelion, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, MSD, Novartis, Pfizer, Phadia, Roche, Sandoz, Sanofi, and ThermoFisher, Paid instructor for: Abbvie, Novartis, and Roche, Speakers bureau: Abbvie, Actelion, Bristol-Myers Squibb, Celgene, MSD, Novartis, Pfizer, Phadia, Roche, Sandoz, and ThermoFisher, Francesco Del Galdo: None declared, Madelon Vonk Grant/research support from: Janssen and Ferrer, Consultant of: Boehringer Ingelheim, Janssen and GSK, Speakers bureau: Boehringer Ingelheim, BMS and Roche, Laura Hummers Grant/research support from: Boehringer Ingleheim, Corbus pharmaceuticals, CSL Behring, Cumberland Pharmaceuticals, and GlaxoSmithKline, Consultant of: Boehringer Ingleheim, Corbus pharmaceuticals, and CSL Behring, Elvira Erhardt Employee of: Employee of Boehringer Ingelheim, Manuel Quaresma Employee of: Employee of Boehringer Ingelheim, Margarida Alves Employee of: Employee of Boehringer Ingelheim, Vanessa Smith Grant/research support from: The affiliated company received grants from Research Foundation - Flanders (FWO), Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim Pharma GmbH & Co and Janssen-Cilag NV, Consultant of: Boehringer-Ingelheim Pharma GmbH & Co, Speakers bureau: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH & Co and UCB Biopharma Sprl

Background:Gastrointestinal tract (GIT) involvement is associated with high morbidity in systemic sclerosis (SSc) but the data on its impact from unselected and well characterized SSc cohorts are scarce. Currently, the effect of immunosuppressive (IS) treatment on GIT involvement is largely unknown.Objectives:To evaluate the severity and worsening of GIT involvement in two prospective SSc cohorts. To assess factors associated with severity of GIT involvement, stratified for disease duration. To evaluate effect of IS treatment on worsening of GIT involvement.Methods:All SSc patients fulfilling the 2013 SSc classification criteria from two SSc cohorts were evaluated. Incident SSc was defined as disease duration since first symptom non-Raynaud < 24 months at first presentation. GIT involvement was assessed by the UCLA GIT 2.0 score at baseline and after one year to assess worsening of GIT involvement. Worsening was defined as change > minimal clinical important difference for total score and for each of the seven subdomains. GIT involvement was defined as present if the patients reported symptoms resulting in a score of ≥0.01 and was segregated into mild ≥0.01 ( 1.01 or for distension/bloating > 1.61 or for fecal soiling > 2.01). Logistic regression was applied to identify risk factors associated with GIT involvement at baseline. The effect of IS treatment on worsening on each of the subdomains after one year was evaluated with logistic regression, with adjustment for baseline disease duration and severity.Results:In total, 834 SSc patients were included; 236 (28%) had incident disease (table 1). Incident cases (IC) showed comparable severity of GIT involvement compared to non-incident cases (NIC) except for significantly less severe reflux and distension/bloating (figure 1). Logistic regression showed female sex (OR 8.5(1.1-36.01)) and smoking (OR 2.9(1.2-7.3)) to be associated with GIT severity at baseline in IC; in NIC anti-centromere antibody (OR 1.7(1.3-2.2)) was additionally associated with GIT severity. The use of IS at baseline did not associate with GI severity at baseline. In total n = 685 (82% never had IS treatment (83% NIC, 81% IC); of these 258 (38%) started with IS after baseline assessment (52% IC, 32% NIC, p =0.02). When comparing change of GIT involvement after one year between those who started IS and those who did not, worsening of GI symptoms occurred more frequently in patients who started IS treatment (figure 2), but notably, patients in this group were also more frequently anti-topoisomerase positive, had ILD, and diffuse disease subset compared to the patients without IS treatment; age and sex were comparable. In the logistic regression with adjustment for disease duration and severity, there were no significant associations between IS treatment and worsening on GIT involvement.Conclusion:Regardless disease duration, about 1/3 of all SSc patients had moderate-severe GIT involvement. Disease duration and treatment initiation with IS did not have a significant influence on worsening of GIT involvement.Table:Baseline characteristicsNon-inception cohort(n=598)Inception cohort(n=236)Female, n(%)504 (85)180 (76)Age, mean(SD)55 (13)56 (14)Disease duration non Raynaud-Phenomenon, median (IQR)8.8 (4.8-14.4)0.7 (0.3-1.2)Diffuse cutaneous subset, n(%)119 (20)67 (28)Interstitial lung disease, n(%)233 (39)71 (30)Anti-centromere, n(%)296 (50)96 (41)Immunosuppresive treatment at baseline, n(%)102 (17)44 (19))Duration of treatment at baseline in years, mean (SD)4.1 (4.8)1.2 (2.9)Methotrexate, n(%)54 (9)24 (10)Mycophenolate mofetil, n(%)25 (4)13 (6)Hydroxycholoquine, n(%)20 (3)7 (3)Cyclofosfamide, n(%)1 (1)10 (4)Azathioprine, n(%)11 (2)2 (1)Corticosteroids, n(%)58 (10)27 (11)Acknowledgments:NADisclosure of Interests:Nina van Leeuwen: None declared, Håvard Fretheim: None declared, Øyvind Molberg: None declared, Thomas Huizinga Grant/research support from: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Consultant of: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Jeska de Vries-Bouwstra: None declared, Anna-Maria Hoffmann-Vold Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Actelion, Bayer, GlaxoSmithKline, Speakers bureau: Boehringer Ingelheim, Actelion, Roche

Background:Presence of anti-centromere antibodies (ACA) generally associates with a better prognosis than many other systemic sclerosis (SSc) associated autoantibodies. However, presentation of the disease can be very heterogeneous and prediction of the disease course is challenging. Some older studies suggest a possible association between clinical characteristics and isotypes of ACA in patients with SSc. It is unknown whether ACA can serve as biomarker for future SSc development.Objectives:To evaluate the clinical course of very early SSc and to assess whether ACA isotype levels can identify subjects that will progress to definite SSc.Methods:ACA IgG+ patients with very early SSc (defined as presence of ACA IgG AND Raynaud and/or puffy fingers and/or abnormal nailfold capillaroscopy but not fulfilling ACR 2013 criteria) from five prospective SSc cohorts (Leiden, Zurich, Oslo, Bordeaux, Ghent) were included. Presence and levels of ACA IgG, IgM and IgA were determined at first clinical assessment and clinical course was evaluated annually. Disease progression to definite SSc, which was defined as fulfillment of the ACR 2013 criteria for SSc, and included any development of: digital ulcers (DU), interstitial lung disease (ILD) assessed by high resolution chest tomography, pulmonary arterial hypertension assessed by right heart catheterization, gastro-intestinal involvement, renal crisis or myocardial involvement was determined. ACA response characteristics were compared between very early SSc patients that progressed to definite SSc and those who did not. Logistic regression was performed to determine whether ACA response characteristics can predict progression to definite SSc, with adjustment for age and follow-up duration.Results:In total 92 subjects were included with median follow-up (FU) of 3 years (table 1); 39% progressed to definite SSc, mostly based on the development of skin involvement (77%). Twenty-three percent of patients developed lung involvement, 11% DU, 17% gastro-intestinal involvement and 4% myocardial involvement. Progression on more than one organ system was present in 31% of the very early SSc patients. In the multivariable logistic regression, with adjustment for age and follow-up duration, ACA IgG levels at baseline were significantly associated with progression to definite SSc (OR 3.0 (1.1-8.8)). Likewise, a trend was observed for higher ACA IgM levels (OR 1.8 (0.9-3.5)) in the very early SSc patients progressing to definite SSc (figure 1).Table 1.Baseline characteristics and ACA isotype levels in patients with very early SSc, and between progressors and non-progressors. * p value < 0.05.Progressors(n=35)Non-progressors(n=57)Female, n(%)32 (91)50 (91)Age, mean (SD)56 (14)53 (13)Disease duration since non Raynaud phenomenon, median(IQR) in years3 (0.8-10)2 (0.6-7)Follow-up duration in years, median (IQR)4 (2-6)2 (1-3)*Abnormal Nailfold videocapillaroscopy, n(%)17 (65)27 (60)IgA level [aU/mL], median (IQR)63 (34-120)75 (35-144)IgM level [aU/mL], median (IQR)131 (32-585)79 (18-391)IgG level [U/mL], median (IQR)342 (162-720)195 (93-488)*Conclusion:In this study we illustrate that 39% of the ACA positive very early SSc subjects progress to definite SSc within median 4 years. We identified higher ACA IgG level as a predictive biomarker for progression to definite SSc indicating that it might be a useful biomarker for risk stratification in clinical practice.Disclosure of Interests:Nina van Leeuwen: None declared, Jaap Bakker: None declared, Annette Grummels: None declared, Corrie Wortel: None declared, Suzana Jordan: None declared, Sophie Liem: None declared, Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Anna-Maria Hoffmann-Vold Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Actelion, Bayer, GlaxoSmithKline, Speakers bureau: Boehringer Ingelheim, Actelion, Roche, Karin Melsens: None declared, Vanessa Smith Grant/research support from: The affiliated company received grants from Research Foundation - Flanders (FWO), Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim Pharma GmbH & Co and Janssen-Cilag NV, Consultant of: Boehringer-Ingelheim Pharma GmbH & Co, Speakers bureau: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH & Co and UCB Biopharma Sprl, Marie-Elise Truchetet: None declared, Hans Ulrich Scherer Grant/research support from: Bristol Myers Squibb, Sanofi, Pfizer, Speakers bureau: Pfizer, Lilly, Roche, Abbvie, Rene Toes: None declared, Thomas Huizinga Grant/research support from: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Consultant of: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Jeska de Vries-Bouwstra: None declared

Background:In the INBUILD trial in patients with progressive fibrosing ILDs, nintedanib reduced the rate of decline in forced vital capacity (FVC) versus placebo over 52 weeks both in the overall population and in the subgroup with autoimmune disease-related ILDs. Patients continued blinded randomised treatment until the end of the trial.Objectives:Assess the effects of nintedanib on the risks of death, acute exacerbation of ILD or death, and disease progression or death over the whole INBUILD trial in patients with autoimmune disease-related ILDs and a progressive phenotype.Methods:Patients with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF) were randomised to receive nintedanib 150 mg bid or placebo. Time to i) death, ii) first acute exacerbation of ILD or death, and iii) disease progression (absolute decline in FVC ≥10% predicted) or death, over the whole trial were analysed in patients with autoimmune disease-related ILDs. Incidence rates of adverse events per 100 patient–years were calculated based on events with onset between the first trial drug intake and the last intake plus 28 days. Analyses were descriptive.Results:Of 663 patients, 170 (82 nintedanib, 88 placebo) had autoimmune disease-related ILDs (89 RA-ILD, 39 SSc-ILD, 19 MCTD-ILD, 23 other autoimmune ILDs including Sjogren’s disease-related ILD [n=7], interstitial pneumonia with autoimmune features [n=5] and undifferentiated CTD-ILD [n=3]). Over the whole trial, in the nintedanib and placebo groups, respectively, mean (SD) exposure to drug was 15.4 (7.4) and 16.9 (6.1) months and maximum exposure was 26.0 and 25.2 months; 62 (75.6%) and 68 (77.3%) patients in these groups, respectively, completed the planned observation time. Over the whole trial, in the nintedanib and placebo groups, respectively, 9.8% and 12.5% of patients died, 12.2% and 20.5% of patients had ≥1 acute exacerbation of ILD or died, and 40.2% and 53.4% of patients had disease progression or died (Table). Diarrhoea was the most common adverse event, with incidence rates of 139.2 and 26.3 events per 100 patient–years in the nintedanib and placebo groups, respectively. Adverse events led to treatment discontinuation in 20.7% of patients in the nintedanib group and 13.6% of patients in the placebo group.Conclusion:Data from the INBUILD trial suggest that nintedanib has a clinically meaningful effect on slowing the progression of ILD in patients with progressive fibrosing autoimmune disease-related ILDs, with adverse events that can be tolerated by most patients.Table.Nintedanib (n=82)Placebo (n=88)HR (95% CI)*Death8 (9.8)11 (12.5)0.80 (0.32, 1.98)≥1 acute exacerbation of ILD or death10 (12.2)18 (20.5)0.58 (0.27, 1.27)Disease progression (absolute decline in FVC ≥10% predicted) or death33 (40.2)47 (53.4)0.72 (0.46, 1.13)n (%) with event over the whole trial (mean [SD] exposure: 15.4 [7.4] and 16.9 [6.1] months in nintedanib and placebo groups, respectively). *Based on time to first event.Disclosure of Interests:Eric Matteson Grant/research support from: Pfizer, Consultant of: Boehringer Ingelheim, Gilead, TympoBio, Arena Pharmaceuticals, Speakers bureau: Simply Speaking, Clive Kelly Consultant of: Boehringer Ingelheim, Speakers bureau: Boehringer Ingelheim, Jörg Distler Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Paid instructor for: Boehringer Ingelheim, Speakers bureau: Boehringer Ingelheim, Anna-Maria Hoffmann-Vold Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Actelion, Bayer, GlaxoSmithKline, Speakers bureau: Boehringer Ingelheim, Actelion, Roche, James Seibold Shareholder of: BriaCell, Pacific Therapeutics, Consultant of: Atlantic, Blade Therapeutics, Eicos Sciences, Eiger Biopharmaceuticals, Indalo Therapeutics, Mitsubishi Tanabe Pharma, Bayer, Xenikos, Boehringer Ingelheim, Camurus, Corbus Pharmaceuticals, EMD Serono, Speakers bureau: Boehringer Ingelheim, Shikha Mittoo Grant/research support from: Pfizer, Consultant of: Novartis, Abbvie, Pfizer, Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Paul F. Dellaripa Grant/research support from: Paul Dellaripa has received institutional grants from Genentech, Consultant of: Paul Dellaripa participated in advisory boards for Boehringer Ingelheim, Alexandra James Employee of: Employee of Boehringer Ingelheim, Rozsa Schlenker-Herceg Employee of: Employee of Boehringer Ingelheim, Susanne Stowasser Employee of: Employee of Boehringer Ingelheim, Manuel Quaresma Employee of: Employee of Boehringer Ingelheim, Kevin R. Flaherty Grant/research support from: Kevin Flaherty has received grants from Boehringer Ingelheim, Consultant of: Kevin Flaherty has acted as a consultant for Boehringer Ingelheim, Bellerophon, Blade Therapeutics, Roche/Genentech, and VeracyteHe was a member of the INBUILD trial Steering Committee

Background:In systemic sclerosis (SSc) patients with interstitial lung disease (ILD) approximately 30% show progressive ILD. It is unknown whether a progressive ILD period is followed by further lung function decline. In clinical practice, treatment is frequently initiated after observation of lung function decline over 6-12 months and lung function stabilization at follow up is often interpreted as treatment effect.Objectives:Assess the predictive ability of lung function decline over 12 months for further deterioration adjusted for known risk factors for ILD and treatment in two large and well characterized SSc cohorts.Methods:Patients with SSc-ILD by HRCT, fulfilling SSc classification criteria, from the Oslo and Zurich University Hospital were included. The first period with three consecutive annual forced vital capacity (FVC) measurements (i.e. at 0, 12 and 24 months, +/- 3 months) was used. Lung function decline was assessed by absolute changes in FVC% predicted. Moderately progressive ILD was defined as FVC decline of >5-Results:In total, 240 SSc-ILD patients met the inclusion criteria (table). Of these 69 (29%) SSc-ILD patients showed progressive ILD in the first 12 months period; 34 (14%) with moderate (5-10%) and 35 (15%) with significant FVC decline (≥10%). Independent of FVC changes in the first period, 77 (32%) showed progressive ILD in the second period; 44 (18%) moderate and 33 (14%) significant FVC decline. Only 21 (9%) SSc-ILD patients had two progressive periods, and 115 (48%) were stable in the two 12 month’s periods; all independent of treatment. In multivariable logistic regression, progressive ILD in the first period (moderate, significant or combined FVC decline) was not predictive for progression in the following period. Of all applied risk factors, only mRSS was significantly predictive for further FVC decline, also when adjusted for age, gender and treatment (OR 1.03, 95%CI 1.00-1.08, p=0.035).Conclusion:Decline of FVC in one 12 months period did not predict further ILD progression in the following 12 months independent of treatment. These results have important clinical implications. Firstly, a decline of lung function in one period seems not to be the right indicator for initiating treatment. Secondly, stabilization of lung function under treatment initiated after ILD progression cannot necessarily be interpreted as a treatment response on the individual patient level.Table:First periodBoth periodsSSc-ILD (n=240)ILD progression (n=69)ILD progression (n=21)Stable ILD (n=115)Age, years (SD)48 (14.7)49 (13.8)50 (14.3)46 (15.3)Male, n (%)57 (24)18 (26)5 (24)27 (24)Disease duration yrs, mean (SD)10.2 (11.4)9.8 (10.2)8.8 (11.0)10.8 (12.3)Disease duration 68 (28)22 (32)8 (38)29 (25)Diffuse cutaneous SSc, n (%)95 (40)30 (44)11 (52)43 (27)Anti-topoisomerase I Ab, n (%)84 (35)27 (40)9 (43)42 (37)mRSS, mean (SD)10 (9.3)11 (10.2)16 (13.0)8 (8.3)CRPml, mean (SD)3.6 (7.2)3.3 (6.2)4.4 (9.1)3.1 (5.1)GERD, n (%)148 (62)44 (64)15 (74)70 (61)FVC % predicted90 (20.3)90 (21.9)92 (21.7)89 (19.3)DLCO% predicted64 (17.9)64 (16.6)70 (11.3)65 (17.5)Lung fibrosis >20%, n (%)55 (23)16 (23)4 (19)27 (24)Mycophenolate Mofetil, n (%)47 (20)15 (22)5 (24)23 (20)Other immunosuppression, n (%)79 (33)22 (32)9 (43)42 (37)Corticosteroids, n (%)62 (26)18 (26)8 (38)28 (24)Disclosure of Interests:Anna-Maria Hoffmann-Vold Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Actelion, Bayer, GlaxoSmithKline, Speakers bureau: Boehringer Ingelheim, Actelion, Roche, Håvard Fretheim: None declared, Britta Maurer Grant/research support from: AbbVie, Protagen, Novartis, congress support from Pfizer, Roche, Actelion, and MSD, Speakers bureau: Novartis, Mike Durheim Grant/research support from: BI, Consultant of: BI, Speakers bureau: BI, Øyvind Midtvedt: None declared, Mike O. Becker: None declared, Rucsandra Dobrota: None declared, Øyvind Molberg: None declared, Suzana Jordan: None declared, Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche

Background:In previous studies, we showed that in patients with diffuse cutaneous systemic sclerosis (dcSSc), worsening of skin fibrosis predicts later decline in lung function and worse survival. However, in many patients, an improvement of skin fibrosis is the natural course of dcSSc, and many current clinical trials are designed to show improvement of skin fibrosis rather than prevention of skin fibrosis progression.Objectives:To investigate whether an improvement in skin fibrosis is associated with less progression of visceral organ involvement and better overall-survival during follow-up.Methods:We evaluated patients from the European Scleroderma Trials and Research Group (EUSTAR) database with diffuse cutaneous systemic (dcSSc), baseline modified Rodnan skin score (mRSS) ≥7, valid mRSS at 12±3 months after baseline and ≥1 follow-up visit. Regression of skin fibrosis was defined as a decrease in mRSS >5 and ≥25% and progression as increase by the respective numbers from baseline to 12±3 months. Outcomes were pulmonary progression, cardiac progression, intestinal progression, new onset of scleroderma renal crisis and all-cause death using recently specified definitions (1). Associations between skin changes and outcomes were evaluated by Kaplan-Meier analysis and multivariable Cox regression.Results:Of 1257 included patients, 282 (22.4%) showed a regression of skin fibrosis, 883 (70.2%) were categorized as stable patients and 92 (7.3%) showed progression of skin fibrosis at 12±3 months. Median long-term follow-up for organ involvement/death was 4.2 years. Cox regression analyses indicated that skin fibrosis regression had a significantly lower probability of later FVC decline ≥10% than non-regressive (stable and progressive) patients when controlled for baseline mRSS (p=0.013). No significant association of skin fibrosis regression was found with other organ manifestations or all-cause death. Conversely, associations of skin fibrosis progression were found for later FVC decline ≥10% with a more significant p-value (pConclusion:Progression of skin fibrosis is stronger associated with organ changes and all-cause death at follow up than improvement of skin fibrosis. These data suggest a prevention of progression paradigm for clinical practice. They also suggest that clinical trials designed for prevention of skin fibrosis progression are more meaningful for long-term outcome of SSc patients than trials designed to show improvement of skin fibrosisReferences:[1]Progressive skin fibrosis is associated with a decline in lung function and worse survival in patients with diffuse cutaneous systemic sclerosis in the European Scleroderma Trials and Research (EUSTAR) cohort. Wu W, Jordan S, Graf N, de Oliveira Pena J, Curram J, Allanore Y, Matucci-Cerinic M, Pope JE, Denton CP, Khanna D, Distler O; EUSTAR Collaborators. Ann Rheum Dis. 2019 May;78(5):648-656Disclosure of Interests:Anja Wyss: None declared, Suzana Jordan: None declared, Nicole Graf: None declared, Elise Siegert Grant/research support from: Actelion, Consultant of: AEC, Speakers bureau: NA, László Czirják Consultant of: Actelion, BI, Roche-Genentech, Lilly, Medac, Novartis, Pfizer, Bayer AG, Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS, Alessandro Giollo: None declared, Edoardo Rosato: None declared, Anna-Maria Hoffmann-Vold Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Actelion, Bayer, GlaxoSmithKline, Speakers bureau: Boehringer Ingelheim, Actelion, Roche, Armando Gabrielli: None declared, Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche

Objectives Systemic sclerosis (SSc) is an auto-immune, multi organ disease marked by severe gastrointestinal (GI) involvement and gut dysbiosis. Here, we aimed to determine the safety and efficacy of fecal microbiota transplantation (FMT) using commercially-available anaerobic cultivated human intestinal microbiota (ACHIM) in SSc. Methods Ten patients with SSc were randomized to ACHIM (n = 5) or placebo (n = 5) in a double-blind, placebo-controlled 16-week pilot. All patients had mild to severe upper and lower GI symptoms including diarrhea, distention/bloating and/or fecal incontinence at baseline. Gastroduodenoscopy transfer of ACHIM or placebo was performed at weeks 0 and 2. Primary endpoints were safety and clinical efficacy on GI symptoms assessed at weeks 4 and 16. Secondary endpoints included changes in relative abundance of total, immunoglobulin (Ig) A- and IgM-coated fecal bacteria measured by 16s rRNA sequencing. Results ACHIM side effects were mild and transient. Two placebo controls experienced procedure-related serious adverse events; one developed laryngospasms at week 0 gastroduodenoscopy necessitating study exclusion whilst one encountered duodenal perforation during gastroduodenoscopy at the last study visit (week 16). Decreased bloating, diarrhea and/or fecal incontinence was observed in four of five patients in the FMT group (week 4 or/and 16) and in two of four in the placebo group (week 4 or 16). Relative abundance, richness and diversity of total and IgA-coated and IgM-coated bacteria fluctuated more after FMT, than after placebo. Conclusions FMT of commercially-available ACHIM is associated with gastroduodenoscopy complications but reduces lower GI symptoms by possibly altering the gut microbiota in patients with SSc.

Systemic sclerosis (SSc) is a systemic autoimmune disease affecting multiple organ systems, including the lungs. Interstitial lung disease (ILD) is the leading cause of death in SSc. There are no valid biomarkers to predict the occurrence of SSc-ILD, although auto-antibodies against anti-topoisomerase I and several inflammatory markers are candidate biomarkers that need further evaluation. Chest auscultation, presence of shortness of breath and pulmonary function testing are important diagnostic tools, but lack sensitivity to detect early ILD. Baseline screening with high-resolution computed tomography (HRCT) is therefore necessary to confirm an SSc-ILD diagnosis. Once diagnosed with SSc-ILD, patients' clinical courses are variable and difficult to predict, although certain patient characteristics and biomarkers are associated with disease progression. It is important to monitor patients with SSc-ILD for signs of disease progression, although there is no consensus about which diagnostic tools to use or how often monitoring should occur. In this article, we review methods used to define and predict disease progression in SSc-ILD. There is no valid definition of SSc-ILD disease progression, but we suggest that either a decline in forced vital capacity (FVC) from baseline of ≥10%, or a decline in FVC of 5–9% in association with a decline in diffusing capacity of the lung for carbon monoxide of ≥15% represents progression. An increase in the radiographic extent of ILD on HRCT imaging would also signify progression. A time period of 1–2 years is generally used for this definition, but a decline over a longer time period may also reflect clinically relevant disease progression., Lung function tests and chest imaging help predict who has SSc-associated ILD and whether it will progress. In the absence of standardised methods for doctors, we recommend a strategy that combines both lung function tests and chest imaging. http://bit.ly/2uK9ZD2

Objective.To compare safety and efficacy outcomes between the cyclophosphamide (CYC) arms of Scleroderma Lung Study (SLS) I and II.Methods.Participants enrolled in the CYC arms of SLS I (n = 79) and II (n = 69) were included. SLS I and II randomized participants to oral CYC for 1 year and followed patients for an additional year off therapy (in SLS II, patients received placebo in Year 2). Eligibility criteria for SLS I and II were nearly identical. Outcomes included the forced vital capacity (FVC%)-predicted and DLCO%-predicted (measured every 3 mos) and quantitative radiographic extent of interstitial lung disease (measured at 1 and 2 yrs for SLS I and SLS II, respectively). Joint models were created to evaluate the treatment effect on the course of the FVC/DLCO over 2 years while controlling for baseline disease severity.Results.SLS I and II CYC participants had similar baseline characteristics. After adjusting for baseline disease severity, there was no difference in the course of the FVC%-predicted (p = 0.535) nor the DLCO%-predicted (p = 0.172) between the SLS I and II CYC arms. In both groups, treatment with CYC led to a significant improvement in the FVC%-predicted from 3 to 12 months, but no significant improvement beyond this point. Treatment with CYC had no effect on the DLCO for either group.Conclusion.Treatment with 1 year of oral CYC led to similar improvements in lung function in both SLS I and II, although the effects were not sustained following cessation of CYC. These results suggest that increasing the duration of ILD therapy may improve outcomes for patients with systemic sclerosis–ILD.

We thank Zhou and co-workers for their interest regarding our newly published manuscript on the role of CCL21 in pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc). Here, we want to respond to their concerns. Genome-wide association studies (GWASs) have been foreshadowed to be a major advance in biomedical discovery, with many robust associations to complex diseases. However, although there are found polymorphisms with SSc, there are, to date, no existing genetic loci for SSc-PAH. Secondly, despite this success, GWAS studies have met considerable skepticism regarding their clinical applicability; mainly arising from their unclear functional consequences. This article is protected by copyright. All rights reserved.

Background Systemic sclerosis (SSc) is a severe multi-organ disease associated with substantial morbidity and mortality. Lung and heart involvement are currently the major causes of disease-related deaths. Skin, gastrointestinal and musculoskeletal involvement, digital ulcers and Raynaud’s phenomenon have shown to be associated with high morbidity, reduced quality of life and lower social functioning. SSc is progressive and many of the disease features aggravate over time, while other features may commence during the disease course. However, to date, there are no established standardised international guidelines for follow-up of SSc patients. Objectives The aim was to establish an expert consensus regarding the longitudinal systemic assessment of organ involvement in SSc to improve the standard-of-care for SSc patients. Methods All experts in SSc from the European Scleroderma Trials and Research Group (EUSTAR) network and the scleroderma clinical trial consortium (SCTC) were invited to participate. The final expert panel consisted of a multidisciplinary team including rheumatologists, dermatologists, pulmonologists, cardiologists and nephrologists. The Delphi method was Internet based and completed from December 2016 until October 2017. The method entailed the entire group of experts who anonymously replied to in total 5 online questionnaires. The experts were asked to score each item in the survey to answer the following question: “Which domains and tools do you strongly suggest for the minimum annual systemic investigation of SSc patients”. Every item in every questionnaire was asked to be rated between 0% and 100%, with 100% as ‘very important/appropriate’ and 0% as ‘not important/appropriate at all’. Parameters rated >80% by more than 80% of the experts were rated as acceptable in all steps. Results Of the 269 invited centres, physicians from 132 (49.1%) centres participated in the DELPHI survey of 5 steps. Of the included participants, 71.3% were seeing >50 SSc patients annually and 48.3% of the centres seeing >100 patients on an annual basis. Of all, 98 of the centres were located in Europe (74.2%), 18 in North America (13.6%), 7 in Asia (5.3%), 5 in South America (3.8%) and 4 in Oceania (3.0%). In the first round, 23 domains were suggested by the expert panel. After the second Delphi step, 10 domains were included (figure 1). In the third round, tools for each domain were received. The tools were included in the fourth step and rated by all participating experts. The tools for each of the 10 domains that were rated appropriately by all experts were included in the last step of the DELPHI survey and were re-rated. The final tools for each domain are shown in figure 1 and can be seen as the collective opinions of the convened expert panel. Conclusions Through five Delphi rounds with world leading experts in SSc, an expert consensus was established on strongly suggested tools for a minimum longitudinal systemic assessment of organ involvement in SSc to improve the standard-of-care for patients with SSc. Disclosure of Interest None declared

Background In systemic sclerosis (SSc), previous GWASs have identified several loci associated with the disease, but their rate of discovery has been limited due to modest sample sizes. Extensive collaborative efforts have enabled us to gather the largest cohort of SSc patients. In the present study, we have performed a large meta-GWAS taking advantage of our well-powered cohort. Objectives To continue unravelling the complex genetic component of SSc. Methods The complete set of individuals enrolled for this study comprised a total of 26 679 genome-wide genotyped individuals of European ancestry. PLINK and EIGENSTRAT were used for quality control and population stratification adjustments. Genotype imputation was performed with IMPUTE2 and the 1000 Genome Project Phase 3 as reference panel. Results Twenty-three loci reached the genome-wide significance level (p-value Conclusions Using a large meta-GWAS, we have identified twelve novel associations for SSc susceptibility and confirmed several previously reported risk loci. These results considerably increase our understanding of the genetic basis of SSc and shed light on the pathogenesis of the disease providing important information to discover new therapeutic targets genetically validated. Disclosure of Interest None declared

Background Pulmonary arterial hypertension (PAH) continues to be a major complication in systemic sclerosis (SSc); indicating an unmet need for rational therapeutic targets. Recently, we found that chemokine CCL21 was upregulated in SSc and associated with PAH. CCL21 appears to be a key regulator of the expression and secretion of vascular endothelial growth factor-C (VEGF-C); a critical growth factor for lymphatic vessels. This is interesting as SSc is marked by lymphatic vessel abnormalities; and high blood levels of Angiopoietin-2, which is a known regulator of VEGF-C. Moreover, it was recently shown that VEGFR3, the cognate receptor for VEGF-C, is down-regulated in pulmonary arterial endothelial cells from human idiopathic PAH subjects with BMPR2 gene defects. Based on these observations, we reasoned that the observed upregulation of CCL21 in SSc-PAH could be linked to VEGF-C and Ang-2 dysregulation. Objectives Assess serum concentrations of CCL21, the VEGF family and Ang-2 in right heart catheterization (RHC) verified SSc-PAH patients and compare these to patients with borderline PAH, no PH and to healthy controls. Methods Sera from the prospective Oslo University Hospital SSc cohort (n=372) and healthy controls (n=100) were analysed for VEGF-A,C,D, CCL21 and Ang2 using Luminex kits from Millipore. Patients with an incident RHC (n=167) were included in the present study. PAH was defined as precapillary PH (mean pulmonary arterial pressure, mPAP ≥25 mmHg) in the absence of significant interstitial lung disease (ILD), based on high resolution computed tomography and lung function tests. Borderline PAH was defined as mPAP of 20–24 mmHg in in the absence of significant ILD. Patients with pulmonary hypertension (PH) due to other causes were excluded. Descriptive statistics and logistic regression analyses were performed and tested by the goodness-of-fit test with area under the curve (AUC). Results Mean age at onset was 54±14.1, at RHC 61±10.9 years. The time from sera to RHC was 0.9±3.1 years. In total, 73.7% (123) patients had limited cutaneous SSc, 46.7%48 were positive for anti-centromere antibody and 80.2% (134) were females. Of these, 123 (73.7%) patients were included in the study, 28 patients with PAH, 45 borderline PAH and 50 patients with no PH. Mean VEGF-A,C,D, CCL21 and Ang2 levels are shown in figure 1A. VEGF-A was significantly higher in SSc patients compared to healthy controls (p=0.001), no significant differences between PAH and no PH patients were found. VEGF-D was decreased in SSc-PAH but not significantly. CCL21 and Ang2 levels were increased in patients with PAH, whereas in VEGF-C was significantly decreased in patients with PAH (figure 1 B-D). In univariable logistic regression analyses, VEGF-C (OR 0.99, 95% CI 0.997–0.998,p=0.001, AUC=0.79), CCL21 (OR 1, 95% CI 1–1.003,p=0.050, AUC=0.69) and Ang2 (OR 1, 95% CI 1–1.0001,p=0.49, AUC=0.67) were associated with PAH compared to no PH patients. Due to few event numbers, no multivariable analyses were performed. Conclusions The present study is the first to demonstrate dysregulation of lymphangiogenetic factor expression of multiple targets in sera of SSc-PAH patients. 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 In systemic sclerosis (SSc) it is well-documented that severe interstitial lung disease (ILD), defined as an extent of lung fibrosis >20% on high resolution computed tomography (HRCT) is strongly associated with male gender, anti-topoisomerase antibody (ATA), diffuse cutaneous (dc) form of disease and decreased survival. Much less is, however, known about the disease characteristics and impact of less lung involvement. A possible explanation might be the selected nature of many hitherto investigated SSc cohorts. In an era with novel treatment options, and multiple ongoing clinical trials, it is important to gain natural history knowledge on the whole spectre of lung involvement in systemic sclerosis. Objectives Characterise the SSc patients with mild to moderate ILD, defined as 1%–10% extent of lung fibrosis on HRCT in the population based nationwide Norwegian SSc cohort and assess the impact of this ILD form on survival. Methods The Norwegian, nationwide SSc (Nor-SSc) study cohort included all adult SSc patients who were resident in Norway between 01.01.2000–01.01.2013 and met the classification criteria for SSc. Detailed electronic patient journal review was performed in all patients to assess demographic, clinical and ILD features at baseline. Pulmonary function tests (PFTs) and lung HRCT images were analysed and the extent of lung fibrosis was expressed as percentage of total lung volumes. We defined mild-moderate ILD as 1%–10% fibrosis on HRCT and severe disease as >20% fibrosis. Ground glass opacities, bronchiectasis and honeycombing were registered if present. Vital status and causes of deaths were available in all patients at study end (January 2018). Descriptive statistics and regression analysis were applied. Results The Nor-SSc cohort included 815 patients. Baseline lung HRCT images were available in 416 patients (51%), whereof 226 (54.3%) had signs compatible with ILD. Mild to moderate ILD, defined as 1%–10% lung fibrosis were present in 149 (65.9%), while 48 (21.2%) had extensive lung fibrosis defined as >20%. Patients with mild-moderate ILD were 55.2 years at SSc onset and characterised by female gender (81.9%) and limited cutaneous SSc (70.5%). Their antibody profile was dominated by anti-centromere Ab (ACA) in 48.3%, followed by anti-polymerase III, ATA, and anti-RNP, in 14.1%, 13.4% and 5.4%, respectively. The mean modified Rodnan skin score (mRSS) was 9.3 (9.3%), baseline FVC was 93.4% and DLCO 66.5%. Univariable associations of clinical characteristics and mild-moderate ILD are shown in figure 1. After a mean observation time of 8.2 years, 49 (32.9%) of patients with mild-moderate ILD had died. The 5- and 10 year survival was 76% and 62% compared to 83% and 76% in patients with no ILD (p=0.03). In univariable cox regression analyses, mild-moderate ILD was associated with mortality (HR 1.6, 95% CI 1.03–2.40, p=0.034). Conclusions In this population based, nationwide study, mild-moderate ILD was frequent and had a considerably impact on survival in SSc patients. Disclosure of Interest None declared

Objective Interstitial lung disease (ILD ) in systemic sclerosis (SS c) runs a highly variable course, and prediction tools are highly desired. The aim of this study was to assess the diagnostic and prognostic performance of 4 candidate serum biomarkers for SS c‐associated ILD . Methods Serum samples from a combined cohort of SS c patients (from Paris, France and Oslo, Norway; n = 427) were analyzed by enzyme‐linked immunosorbent assay for concentrations of lung epithelial–derived surfactant protein D (SP ‐D), Krebs von den Lungen 6 glycoprotein (KL ‐6), CCL 18, and OX 40 ligand (OX 40L). Lung fibrosis was measured by high‐resolution computed tomography and pulmonary function tests. Associations of these candidate biomarkers with baseline disease involvement and prediction of disease progression over time (mean ± SD follow‐up 3.2 ± 4.4 years) were investigated. Results In SS c patients at baseline, serum levels of KL ‐6 correlated with the forced vital capacity (FVC ) (r = −0.317, P < 0.001), diffusing capacity for carbon monoxide (r = −0.335, P < 0.001), and extent of lung fibrosis (r = 0.551, P < 0.001). In multivariate analyses, serum levels of KL ‐6 and SP ‐D, but not CCL 18 and OX 40L, were associated with lung fibrosis (odds ratio [OR ] 2.41, 95% confidence interval [95% CI ] 1.43–4.07 [P = 0.001] and OR 3.15, 95% CI 1.81–5.48 [P < 0.001], respectively). In SS c patients with ILD at baseline, longitudinal, multivariate analyses showed that CCL 18 serum levels were an independent predictor of a >10% decrease in the FVC (hazard ratio [HR ] 2.90, 95% CI 1.25–6.73; P = 0.014) and de novo development of extensive disease (HR 3.71, 95% CI 1.02–13.52; P = 0.048). Matrix‐based logistic regression models for the diagnosis and prognosis of SS c‐associated ILD were constructed, and these models discriminated 3 groups of risk (mild, moderate, or high) for the diagnosis or worsening of lung fibrosis according to the serum levels of SP ‐D (for diagnosis) and serum levels of CCL 18 (for progression of disease). Conclusion These results show that SP ‐D is a relevant diagnostic biomarker for SS c‐associated ILD , whereas KL ‐6 could be used to assess the severity of lung fibrosis. CCL 18 appears to be a potential predictive marker for progression of ILD in SS c.

Background Dysregulation of Fractalkine (CX3CL1) and its receptor CX3CR1 has been linked to the pathobiology of chronic inflammatory conditions. We explored CX3CL1 in systemic sclerosis (SSc) related progressive interstitial lung disease (ILD) and pulmonary hypertension (PH) in two different but complementary sources of biomaterial. Methods We collected lung tissue at the time of lung transplantation at UCLA from SSc-ILD patients (n = 12) and healthy donors (n = 12); and serum samples from the prospective Oslo University Hospital SSc cohort (n = 292) and healthy donors (n = 100). CX3CL1 was measured by ELISA. Cellular sources of CX3CL1/CX3CR1 in lung tissues were determined by immunohistochemistry and immunofluorescence. ILD progression and new onset PH endpoints were analysed. Results CX3CL1 concentrations were increased in SSc in lung tissue as well as in sera. In the UCLA cohort, CX3CL1 was highly correlated with DLCO. In the SSc-ILD lungs, CX3CL1 was identified in reactive type II pneumocytes and airway epithelial cells. CX3CR1 stained infiltrating interstitial mononuclear cells, especially plasma cells. In the Oslo cohort, CX3CL1 correlated with anti-Topoisomerase-I-antibody and lung fibrosis. CX3CL1 was associated with ILD progression in multivariable regression analysis but not PH. Conclusion CX3CL1 is associated with progressive SSc-ILD but not SSc-PH. The CX3CR1/CX3CL1-biological axis may be involved in recruiting antibody secreting plasma cells to SSc lungs, thereby contributing to the immune-mediated pathobiology of SSc-ILD.

Objective Systemic sclerosis (SSc) carries a high risk of progressive interstitial lung disease (ILD), but tools for stratifying individual risk are scarce. The purpose of this study was to assess detailed data from serial lung fibrosis measurements and paired pulmonary function tests (PFTs) as outcome prediction tools in a prospective cohort of SSc patients. Methods Paired PFTs and high-resolution computed tomography (HRCT) scans were obtained at baseline and at followup in 305 SSc patients who met the American College of Rheumatology/European League Against Rheumatism 2013 classification criteria. The extent of fibrosis was scored on 10 sections from every HRCT scan and expressed as the percentage of the total lung volume. Results Baseline HRCT analyses revealed 3 SSc subgroups: those with >20% lung fibrosis (n = 40), those with 1–20% fibrosis (n = 157), and those with no fibrosis (n = 108). At followup HRCT (mean of 3.1 years later), all 108 group 3 patients were still free of fibrosis. In group 2 patients, 146 continued to have 1–20% fibrosis (group 2a), whereas 11 (marked by short disease duration of 1.3 years) had experienced progression to >20% fibrosis (group 2b). The annual fibrosis progression rate differed across the 4 groups: 0.9% in group 1, 0.7% in group 2a, 5.9% in group 2b, and 0% in group 3. The annual fibrosis progression rate correlated with the total decline in the forced vital capacity (FVC) (7.1%, 5.7%, 8.7%, and 2.9% in groups 1, 2a, 2b, and 3, respectively), but not the diffusing capacity for carbon monoxide (DLco) (8.4%, 7.7%, 7.7%, and 8.6%, respectively). Multivariate analyses identified anticentromere antibodies (odds ratio [OR] 4.7) and baseline DLco (OR 1.04) as predictors of no fibrosis at followup and baseline fibrosis (OR 1.3) and FVC (OR 0.96) as predictors of >20% fibrosis at followup. Conclusion These prospective cohort data suggest that HRCT performed at baseline predicts the development of fibrosis, the rate of progression of fibrosis, and the decline in pulmonary function in SSc.