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BackgroundRituximab (RTX) is associated with reduced humoral response to SARS-CoV-2 mRNA-based vaccine (1, 2). A recent study has shown that, despite their immunosuppression burden, kidney transplant recipients with previous exposure to SARS-CoV-2 showed a marked increase in antibody titer, even after a single dose of vaccine (3).ObjectivesTo describe the results of immunization after 1 to 3 doses of mRNA SARS-CoV-2 vaccine in RTX-treated patients with previous symptomatic COVID-19 infection.MethodsObservational prospective usual care study including consecutive patients with inflammatory rheumatic diseases in maintenance therapy with RTX. All patients received a 1 to 3-dose regimen of mRNA-based COVID-19 vaccination (BNT162b2 Pfizer/BioNTech or mRNA-1273, Moderna). Serum IgG antibody levels against SARS-CoV-2 spike proteins were measured at the time of the new RTX infusion. The SARS-CoV-2 S1/S2 IgG immunoassay (DiaSorin) was used for the quantitative determination of antibodies to the receptor-binding domain of the viral spike (S) protein. Seropositivity was defined by anti-S antibodies >15 UA/mL.ResultsWe included 69 patients (60 females, mean age 60±13 years) on maintenance therapy with RTX including 13 with previous symptomatic COVID-19, all proven by RT-PCR (10 females, mean age 58±12 years) (Table 1). SymptomaticCOVID-19 occurred between March 2020 and May 2021. The mean interval between the infection and vaccination was 8±3 months and the serological response was assessed after a mean of 74±58 days from the last dose of vaccination (3rd dose for 3 patients, 2nd dose for 6 patients and 1st dose for 4 patients). The 56 patients with no history of symptomatic COVID-19 infection all received 3 doses of vaccine and the serological response was assessed after a mean of 63±27 days from the 3rd dose of vaccination. The seropositivity rate was significantly higher in RTX-treated patients with previous symptomatic COVID-19 infection (11/13, 85% vs.15/56, 27%, pTable 1.Study populationPatients with previous symptomatic COVID-19 (n=13)Patients without symptomatic COVID-19 (n=56)Age (years), mean ± SD58±1260±11Females, n (%)10 (77)50 (89)Underlying disease: Rheumatoid arthritis10 (77)45 (80) Systemic sclerosis2 (15)5 (9) Systemic lupus erythematosus1 (8)1 (2) Sjögren syndrome0 (0)3 (5) Mixed connective tissue disease0 (0)2 (4)Disease duration (years), mean ± SD17±920±10Associated Methotrexate, n (%)9 (69)36 (64)Current treatment with corticosteroids, n (%)5 (38)21 (38)Corticosteroid dose >10 mg/day, n (%)0 (0)0 (0)CD19+ (/µL) (100-600), mean ± SD65±10645±51CD19 7 (54)33 (58)Figure 1.Distribution of SARS-CoV-2 spike antibody levels according to the history of proven symptomatic COVID-19. **** pConclusionRTX-treated patients with previous proven COVID-19 showed increased seropositivity and antibody titers after SARS-CoV-2 vaccination, even after a single-dose of vaccine. This response is strikingly different from that observed for SARS-CoV-2-naïve RTX treated patients who received 3 doses of SARS-CoV-2 mRNA-based vaccination. An “antigen dose phenomenon” may account for these discrepancies. A potential clinical implication might be to increase antibody response with an additional dose of vaccine following an exposure to SARS-CoV-2 in RTX-treated patients with absent or insufficient postvaccination antibody response.References[1]Avouac et al, Rheumatology 2021[2]Jyssum et al, Lancet Rheumatol 2021[3]Benotmane et al, Am J Transplant 2021Disclosure of InterestsNone declared

BackgroundCOMPACT is a non-interventional study evaluating the effectiveness and safety in patients (pts) with rheumatoid arthritis (RA), axial-spondyloarthritis (axSpA) or psoriatic arthritis (PsA) treated with GP2015 (an etanercept [ETN] biosimilar) in real-world conditions.ObjectivesWe present the effectiveness and safety data from the final analysis of the COMPACT study for all patient groups.MethodsPts aged ≥18 years on treatment with GP2015 were enrolled. Baseline visit corresponded with date of study inclusion and not with date of GP2015 treatment start. Pts were categorised based on prior treatment status: pts on clinical remission or low disease activity under treatment with reference ETN or biosimilar ETN (initial ETN: [iETN]) and switched to GP2015 (Group A) or pts who received non-ETN targeted therapies and switched to GP2015 (Group B) or biologic-naïve pts who started GP2015 after conventional therapy failure (Group C) or DMARD-naïve pts with recent diagnosis of RA considered suitable for treatment initiation with a biologic and started on treatment with GP2015 (Group D). Effectiveness assessments included Disease Activity Score 28-joint count Erythrocyte Sedimentation Rate (DAS28-ESR) or Ankylosing Spondylitis Disease Activity Score (ASDAS) until Month 12 after enrolment (baseline) in the study.ResultsOf the 1466 pts enrolled, 572 were switched from iETN (Group A), 171 were switched from other targeted therapies (Group B), 713 were biologic-naïve (Group C), and 10 were RA DMARD-naïve (Group D). Comorbidities were more frequent in pts with RA (68.7%,) followed by pts with PsA (59.4%) and axSpA (52.1%). After 12 months of treatment with GP2015, pts with RA or PsA achieved comparable DAS28-ESR scores irrespective of whether they switched from iETN, or from other targeted therapies or were biologic-naïve. At Month 12, the mean ASDAS scores were comparable between the treatment groups in pts with axSpA (Table 1). Across all pt groups, no major differences were observed in the disease activity scores between baseline and Month 12 that may be explained by the ongoing GP2015 treatment at the time of enrolment for an observed average of 138 days. Overall, the proportion of patients with at least one adverse event (AE) and serious AE (SAE) was 47.6% and 7.7% in pts who were switched from iETN, 56.7% and 9.9% in pts switched from other targeted therapies, 56% and 8.7% in biologic-naïve pts, and 60% and 0% in DMARD-naïve pts. Rate of injection site reaction was low across the groups (Figure 1).Table 1.Effectiveness outcomes in patients treated with GP2015Effectiveness outcomesGroup AGroup BGroup CGroup DOverall (A-D)RADAS28-ESR, n, mean (SD)N=295N=88N=451N=10N=844Baselinen=259n=70n=392n=8n=7292.5 (1.1)3.6 (1.3)3.3 (1.5)3.8 (1.2)3.0 (1.4)Month 12n=135n=47n=238n=2n=4222.5 (1.3)2.7 (1.0)2.8 (1.4)4.3 (2.5)2.7 (1.3)PsAN=117N=36N=135N=0N=288Baselinen=80n=30n=116-n=2262.1 (1.0)2.9 (1.6)2.9 (1.6)2.6 (1.5)Month 12n=32n=13n=60-n=1052.6 (1.9)2.6 (1.6)2.3 (1.4)2.4 (1.5)AxSpAASDAS, n, mean (SD)N=160N=47N=127N=0N=334Baselinen=77n=18n=59-n=1541.6 (0.6)1.8 (0.8)2.3 (0.9)1.9 (0.8)Month 12n=39n=8n=23-n=701.8 (0.9)1.9 (0.6)1.9 (1.0)1.8 (0.9)N, total number of patients in the treatment group; n, number of patients with available data at each time point, SD, standard deviationFigure 1.Overall safety outcomes in patients treated with GP2015Figure 1 represents the adverse events reported during GP2015 treatment.N, total number of patients in the treatment; n, number of patients in each treatment groupConclusionThe results show comparable disease activity scores between pts who were switched from iETN, pts switched from other targeted therapies and biologic-naïve pts after 12 months of treatment with GP2015. No impact on the effectiveness of ETN was observed in pts with RA, axSpA or PsA who switched to GP2015. No new safety signals were reported.Disclosure of InterestsMarc Schmalzing Speakers bureau: Novartis, AbbVie, Chugai/Roche, Janssen-Cilag, Lilly, Consultant of: AstraZeneca, Chugai/Roche, Hexal/Sandoz, Gilead, AbbVie, Janssen-Cilag, Boehringer/Ingelheim, Grant/research support from: Chugai/Roche, Boehringer/Ingelheim, Celgene, Medac, Herbert Kellner: None declared, Ayman Askari: None declared, Javier de Toro Santos: None declared, JULIO CESAR VAZQUEZ PEREZ-COLEMAN Speakers bureau: Sandoz, Abbvie, Sanofi, Fresenius, Rosario Foti Speakers bureau: Abbivie, Gilead, Lilly, Pfizer, UCB, Roche, Novartis, Pfizer, UCB, Sławomir Jeka: None declared, Boulos Haraoui Consultant of: Abbvie, Amgen, Fresenius Kabi, Lilly and Pfizer, Grant/research support from: Abbvie, Amgen, Fresenius Kabi, Lilly and Pfizer, Yannick Allanore Consultant of: Sandoz Hexal, Mylan, Astra-Zeneca, Masiur Rahman Employee of: Sandoz Hexal AG, Fabricio Furlan Employee of: Sandoz Hexal AG, Sohaib HACHAICHI Employee of: Sandoz Hexal AG, Tom Sheeran Speakers bureau: Pfizer, UCB, Roche, Consultant of: Novartis, Pfizer, Grant/research support from: Novartis, UCB, Roche

BackgroundNintedanib slows the progression of fibrosing ILDs, with a safety profile characterised predominantly by gastrointestinal events.ObjectivesAssess the safety and tolerability of nintedanib in patients with autoimmune disease-related ILDs by sex and age.MethodsThe SENSCIS trial was conducted in patients with ILD associated with systemic sclerosis. The INBUILD trial was conducted in patients with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis. Patients were randomised to receive nintedanib 150 mg bid or placebo. Dose reductions to 100 mg bid and treatment interruptions were permitted to manage adverse events (AEs). Data from all patients in SENSCIS and patients with autoimmune disease-related ILDs in INBUILD were pooled. In subgroups based on sex and age (ResultsAmong 746 patients; 70.1% were female; 29.1% were aged ≥65 years. Mean (SD) exposure to nintedanib or placebo was 10.8 (3.2) and 11.1 (2.9) months in females and males, and 11.0 (3.0) and 10.6 (3.5) months in patients aged ConclusionIn patients with autoimmune-disease related ILDs, the AE profile of nintedanib in subgroups by sex and age was generally consistent with the known safety profile, but certain types of AE and dose reductions were more frequent in female patients, while serious AEs were more common in male patients.Table 1.Adverse events in patients with autoimmune disease-related ILDs in the SENSCIS and INBUILD trials in subgroups by sex and age at baseline.FemaleMaleAge Age ≥65 yearsNintedanib(n=268)Placebo(n=255)Nintedanib(n=102)Placebo(n=121)Nintedanib(n=267)Placebo(n=262)Nintedanib(n=103)Placebo(n=114)Most frequent adverse events*Diarrhoea198 (73.9)77 (30.2)73 (71.6)38 (31.4)197 (73.8)85 (32.4)74 (71.8)30 (26.3)Nausea92 (34.3)35 (13.7)21 (20.6)14 (11.6)86 (32.2)38 (14.5)27 (26.2)11 (9.6)Vomiting73 (27.2)22 (8.6)12 (11.8)14 (11.6)61 (22.8)27 (10.3)24 (23.3)9 (7.9)Skin ulcer42 (15.7)37 (14.5)12 (11.8)13 (10.7)42 (15.7)45 (17.2)12 (11.7)5 (4.4)Nasopharyngitis34 (12.7)41 (16.1)12 (11.8)21 (17.4)33 (12.4)43 (16.4)13 (12.6)19 (16.7)Weight decreased34 (12.7)8 (3.1)10 (9.8)6 (5.0)29 (10.9)9 (3.4)15 (14.6)5 (4.4)Decreased appetite29 (10.8)9 (3.5)13 (12.7)4 (3.3)25 (9.4)10 (3.8)17 (16.5)3 (2.6)Abdominal pain32 (11.9)18 (7.1)8 (7.8)5 (4.1)27 (10.1)19 (7.3)13 (12.6)4 (3.5)Upper respiratory tract infection30 (11.2)31 (12.2)9 (8.8)8 (6.6)31 (11.6)33 (12.6)8 (7.8)6 (5.3)Cough23 (8.6)39 (15.3)13 (12.7)19 (15.7)27 (10.1)46 (17.6)9 (8.7)12 (10.5)Liver-related investigations, signs and symptoms49 (18.3)11 (4.3)13 (12.7)6 (5.0)42 (15.7)12 (4.6)20 (19.4)5 (4.4)Adverse event(s) leading to dose reduction101 (37.7)9 (3.5)18 (17.6)3 (2.5)81 (30.3)9 (3.4)38 (36.9)3 (2.6)Adverse event(s) leading to treatment discontinuation44 (16.4)21 (8.2)17 (16.7)13 (10.7)39 (14.6)18 (6.9)22 (21.4)16 (14.0)Serious adverse event(s)57 (21.3)53 (20.8)40 (39.2)37 (30.6)63 (23.6)54 (20.6)34 (33.0)36 (31.6)n (%) of patients with ≥1 such adverse event over 52 weeks. Adverse events were coded based on preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA), except for liver-related investigations, signs and symptoms, which was based on a standardised MedDRA query. *Adverse events reported in >10% of patients with autoimmune disease-related ILDs in the nintedanib or placebo group.AcknowledgementsThe SENSCIS and INBUILD trials were funded by Boehringer Ingelheim. Oliver Distler was a member of the SENSCIS trial Steering Committee.Disclosure of InterestsAnna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme, Roche, Paid instructor for: Boehringer Ingelheim, Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme, Roche, Grant/research support from: Boehringer Ingelheim, Elizabeth Volkmann Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Grant/research support from: Boehringer Ingelheim, Corbus, Forbius, Horizon, Kadmon, Yannick Allanore Consultant of: Abbvie, Astra-Zeneca, Bayer, Boehringer, Mylan, Janssen, Medsenic, Prometheus, Roche, Sanofi, Grant/research support from: Alpine Immunosciences, Medsenic, OSE immunotherapeutics, Shervin Assassi Speakers bureau: On speaker bureau for Integrity Continuing Education, Consultant of: Abbvie, AstraZeneca, Boehringer Ingelheim, CSL Behring, Novartis, Grant/research support from: Boehringer Ingelheim, Janssen, Jeska de Vries-Bouwstra Speakers bureau: Boehringer Ingelheim, Janssen, Consultant of: Abbvie, Boehringer Ingelheim, Grant/research support from: Galapagos NV, Janssen and Roche B.V., Vanessa Smith Speakers bureau: Actelion Pharmaceuticals, Boehringer-Ingelheim Pharma GmbH&Co, Janssen-Cilag NV, UCB Biopharma Sprl, Consultant of: Boehringer-Ingelheim Pharma GmbH&Co, Janssen-Cilag NV, Grant/research support from: Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer-Ingelheim Pharma GmbH&Co, Janssen-Cilag NV, Research Foundation - Flanders (FWO), Inga Tschoepe Employee of: Inga Tschoepe is an employee of Elderbrook Solutions that is contracted by Boehringer Ingelheim., Lazaro Loaiza Employee of: Lazaro Loaiza is an employee of Boehringer Ingelheim, Madhu Kanakapura Employee of: Madhu Kanakapura is an employee of Boehringer Ingelheim, Oliver Distler Speakers bureau: OD has/had relationships with the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years:Speaker fee: Bayer, Boehringer Ingelheim, Janssen, Medscape, Consultant of: OD has/had relationships with the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years:Consultancy fee: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, 4P Science, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and TopadurOD has/had relationships with the following companies in the area of potential treatments for arthritides in the last three calendar years:Consultancy fee: Abbvie, Grant/research support from: OD has/had relationships with the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years:Research Grants: Boehringer Ingelheim, Kymera, Mitsubishi Tanabe

BackgroundIn the SENSCIS trial conducted in a population of subjects with SSc-ILD with a mean time since first non-Raynaud symptom of 3.5 years and 52% with diffuse cutaneous SSc (dcSSc), nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks by 44% versus placebo. Risk factors for a rapid decline in FVC in patients with SSc include early SSc, elevated inflammatory markers, significant skin involvement, and dcSSc. Patients with SSc with these risk factors for rapid progression of ILD are typically given immunosuppressants but not nintedanib.ObjectivesTo analyse the rate of decline in FVC and the effect of nintedanib on FVC decline in subjects with risk factors for a rapid decline in FVC in the SENSCIS trial.MethodsIn post-hoc analyses of data from the SENSCIS trial, we analysed the rate of decline in FVC (mL/year) over 52 weeks in all subjects and in those with early SSc (9/L), or significant skin fibrosis using two approaches (modified Rodnan skin score [mRSS] 15-40 or mRSS >18) at baseline. We also analysed the rate of decline in FVC over 52 weeks in subjects with one of these risk factors and dcSSc.ResultsOf 575 subjects analysed, 79 (13.7%) had 18. Of 299 subjects with dcSSc, 29 (9.7%) had 18. In the placebo group, the rate of decline in FVC over 52 weeks was numerically greater in subjects with these risk factors for rapid decline in FVC compared with all subjects (Figure 1). Across the subgroups, the rate of decline in FVC was numerically lower in subjects treated with nintedanib than placebo (Figure 1).Figure 1.Rate of decline in FVC (mL/year) over 52 weeks in (A) all patients and in patients with risk factors for rapid decline in FVC at baseline and (B) all patients and in patients with dcSSc and risk factors for rapid decline in FVC at baseline in the SENSCIS trial.ConclusionThe SENSCIS trial included a broad range of subjects with a fibrotic ILD complicating SSc, including those with risk factors for a rapid decline in FVC. In the placebo group, subjects with these risk factors had a more rapid decline in FVC over 52 weeks compared with the overall trial population. By targeting fibrosis with nintedanib, the rate of decline in FVC in patients with risk factors for FVC decline was reduced in patients treated with nintedanib compared with placebo.AcknowledgementsThe SENSCIS trial was funded by Boehringer Ingelheim. Toby M Maher and Masataka Kuwana were members of the SENSCIS trial Steering Committee.Disclosure of InterestsDinesh Khanna Shareholder of: Stocks - Eicos Sciences, Inc, Consultant of: AbbVie, Acceleron, Actelion, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos NV, Genentech/Roche, Gilead, GlaxoSmithKline, Horizon Therapeutics, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Prometheus, Sanofi-Aventis, Theraly, United Therapeutics, Grant/research support from: Bayer, Bristol-Myers Squibb, Horizon Therapeutics, Immune Tolerance Network, National Institutes of Health, Pfizer, Employee of: Leadership/Equity position – Chief Medical Officer - CiviBioPharma/Eicos Sciences, Inc, Toby Maher Speakers bureau: Boehringer Ingelheim, Galapagos, Genentech, Consultant of: AstraZeneca, Bayer, Blade Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Galapagos, Galecto, GlaxoSmithKline R&D, IQVIA, Pliant, Respivant, Roche, Theravance and Veracyte, Grant/research support from: AstraZeneca, GlaxoSmithKline, Elizabeth Volkmann Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Grant/research support from: Boehringer Ingelheim, Corbus, Forbius, Horizon, Kadmon, Yannick Allanore Consultant of: AbbVie, AstraZeneca, Bayer, Boehringer, Mylan, Janssen, Medsenic, Prometheus, Sanofi, Roche, Grant/research support from: Alpine Immunosciences, Medsenic, OSE Immunotherapeutics, Vanessa Smith Speakers bureau: Actelion Pharmaceuticals, Boehringer-Ingelheim Pharma GmbH&Co, Janssen-Cilag NV, UCB Biopharma Sprl, Consultant of: Boehringer-Ingelheim Pharma GmbH&Co, Janssen-Cilag NV, Grant/research support from: Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer-Ingelheim Pharma GmbH&Co, Janssen-Cilag NV, Research Foundation - Flanders (FWO), Shervin Assassi Speakers bureau: On speaker bureau for Integrity Continuing Education, Consultant of: Abbvie, AstraZeneca, Boehringer Ingelheim, CSL Behring, Novartis, Grant/research support from: Boehringer Ingelheim, Janssen, Michael Kreuter Speakers bureau: Boehringer Ingelheim and Roche, Consultant of: Boehringer Ingelheim and Roche, Grant/research support from: Boehringer Ingelheim and Roche, Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme, Roche, Paid instructor for: Boehringer Ingelheim, Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme, Roche, Grant/research support from: Boehringer Ingelheim, Masataka Kuwana Speakers bureau: AbbVie, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai, Eisai, GlaxoSmithKline, Janssen, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, Consultant of: AstraZeneca, Boehringer Ingelheim, Corbus, Kissei, Mochida, Grant/research support from: Boehringer Ingelheim, MBL, Ono Pharmaceuticals, Christian Stock Employee of: Christian Stock is an employee of Boehringer Ingelheim, Margarida Alves Employee of: Margarida Alves is an employee of Boehringer Ingelheim, Steven Sambevski Employee of: Steven Sambevski is an employee of Boehringer Ingelheim, Christopher P Denton Speakers bureau: Boehringer Ingelheim, Janssen, Consultant of: Abbvie, Acceleron, Boehringer Ingelheim, Corbus, CSL Behring, GlaxoSmithKline, Roche, Grant/research support from: ARXX Therapeutics, GlaxoSmithKline, Horizon Therapeutics, Servier

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

BackgroundSystemic sclerosis (SSc) is a heterogeneous autoimmune disease, with a high disease-related mortality and morbidity. A subset of patients show elevated CRP levels (20-35%), which has been reported as inflammatory SSc. Preliminary data suggest that this subset is characterized by a severe phenotype.ObjectivesTo analyse the phenotype and the survival of inflammatory compared with non-inflammatory SSc patient subsets.MethodsData from 8571 SSc patients with available CRP measurement from the EUSTAR cohort were analysed. Exclusion criteria included acute infection, missing follow-up and tocilizumab treatment. Patients with a CRP ≥5mg/l at ≥80% of visits were stratified as persistent inflammatory and as non-inflammatory if CRP was ≥5 mg/l at ResultsOut of 2883 patients with more than two visits, 404 (14%) showed persistent inflammation and 1032 (36%) a non-inflammatory phenotype. Out of 5619 patients with more than one visit, 1830 (33%) were stratified as inflammatory as defined by as single CRP measurement at baseline and 3789 (67%) as non-inflammatory. With both definitions, the inflammatory subset revealed a more severe phenotype than non-inflammatory patients, including more frequent diffuse-cutaneous disease, anti-Scl-70 autoantibodies, pulmonary fibrosis, pulmonary hypertension, higher modified Rodnan skin score, and lower forced vital capacity and diffusing capacity for carbon monoxide. Patients with persistent inflammation had a strongly increased risk of all-cause mortality (HR 7.1 [95%CI 3.7 to 13.5], pConclusionThe severe phenotype and decreased survival of the inflammatory SSc subset, which was most prominent in patients with persistently elevated CRP levels, suggest a distinct disease subset. Therefore both, the need for more regular monitoring of inflammatory parameters and implications for immune-modulating treatment, needs to be carefully analysed.References[1]Mitev, A., et al., Inflammatory stays inflammatory: a subgroup of systemic sclerosis characterized by high morbidity and inflammatory resistance to cyclophosphamide. Arthritis Res Ther, 2019. 21(1): p. 262. PMID: 31791379Figure 1.Overall mortality from baseline onward a. by persistent inflammatory phenotype, b. by inflammatory phenotype at baselineDisclosure of InterestsAdela-Cristina Sarbu: None declared, Sabina Guler: None declared, Odile Stadler: None declared, Yannick Allanore: None declared, Vera Bernardino: None declared, Jörg H.W. Distler: None declared, Armando Gabrielli: None declared, Anna-Maria Hoffmann-Vold: None declared, Marco Matucci-Cerinic: None declared, Ulf Müller-Ladner: None declared, Vera Ortiz-Santamaria: None declared, Simona Rednic: None declared, Valeria Riccieri: None declared, Vanessa Smith: None declared, Susanne Ullman: None declared, Ulrich Walker: None declared, Thomas Geiser: None declared, Oliver Distler: None declared, Britta Maurer Speakers bureau: Boehringer-Ingelheim, Consultant of: Novartis, Boehringer Ingelheim, Janssen-Cilag, Grant/research support from: AbbVie, Protagen, Novartis Biomedical Research, Florian Kollert Shareholder of: Roche, Consultant of: BMS, Actelion, Boehringer-Ingelheim, Pfizer, Grant/research support from: Roche, Gilead, Pfizer, Employee of: Roche

BackgroundMixed connective tissue disease (MCTD) is a rare autoimmune condition characterized by Raynaud’s phenomenon, positivity of antibodies targeting the U1 small nuclear ribonucleoprotein particle (U1 snRNP), various clinical features and potential risk of severe cardio-pulmonary involvement (interstitial lung disease, ILD, and pulmonary hypertension, PH) (1), (2).Nailfold videocapillaroscopy (NVC) is a simple, non-invasive and inexpensive imaging technique that allows a detailed assessment of skin microcirculation. NVC abnormalities have been barely described in MCTD and associations between NVC features and MCTD disease characteristics have only been partially investigated.ObjectivesTo describe the NVC patterns observed in MCTD and assess their potential association with disease characteristics.MethodsCross-sectional study based on the retrospective analysis of patients hospitalized in the department of Rheumatology, Cochin Hospital, Paris France. To be included, patients were required to fulfil at least one classification criteria used in MCTD (3). The following data were collected: demographics, clinical features, para-clinical and laboratory data, treatment, and NVC findings.Results51 patients met the inclusion criteria. Mean age was 51±12 years, 44 (86%) were women, mean disease duration was 13.8±11.1 years and 16 patients (31%) had ILD.Three different NVC patterns have been identified in our cohort (Figure 1): A) normal findings in 6 patients (11,7 %); B) non-specific organic microangiopathy in 16 patients (31,4%) and C) scleroderma pattern in 18 patients (35.3%), defined by the presence of at least 3 of the 4 following features: at least 1 giant capillary, decreased capillary density (Scleroderma pattern was associated with clinical features of systemic sclerosis: skin sclerosis (9/18 vs. 5/33; p=0.008) and digital ulcers (6/18 vs. 2/31; p=0.017). Conversely, no association was observed between the normal or the non-specific NVC pattern and disease specific characteristics.Interestingly, we observed, a significant reduction in the number of capillaries in patients with ILD (4.80±1.87 vs. 6.03±1.47; p=0.039), and patients with severe reduction of capillary density (≤4/mm) were more likely to have ILD (5/7 vs. 5/33; p=0.002). Neoangiogenesis was also more frequent in patients with ILD (6/13 vs. 4/27; p=0.034).Multivariate logistic regression analysis showed that the association between severe reduction of capillary density and ILD was observed independently of the presence of a scleroderma NVC pattern and skin fibrosis.Figure 1.ConclusionWe identified three main NVC patterns in MCTD patients. The scleroderma NVC pattern was associated with clinical scleroderma characteristics whereas non-specific microangiopathy and normal NVC were not associated with a specific phenotype. Moreover, severe capillary loss was independently associated with the presence of ILD. These data suggest that NVC may be helpful for disease risk stratification in MCTD, and that NVC findings, and particularly severe capillary loss, may be a warning for the presence of ILD.References[1]Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed connective tissue disease--an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. févr 1972;52(2):148‑59.[2]Gunnarsson R, Hetlevik SO, Lilleby V, Molberg Ø. Mixed connective tissue disease. Best Pract Res Clin Rheumatol. févr 2016;30(1):95‑111.[3]John KJ, Sadiq M, George T, Gunasekaran K, Francis N, Rajadurai E, et al. Clinical and Immunological Profile of Mixed Connective Tissue Disease and a Comparison of Four Diagnostic Criteria. Int J Rheumatol. 2020;2020:9692030.[4]Boulon C, Devos S, Mangin M, Decamps-Le Chevoir J, Senet P, Lazareth I, et al. Reproducibility of capillaroscopic classifications of systemic sclerosis: results from the SCLEROCAP study. Rheumatol Oxf Engl. 1 oct 2017;56(10):1713‑20.Disclosure of InterestsGonçalo Boleto: None declared, Camille Kasser: None declared, Yannick Allanore Speakers bureau: YA reports personal fees from Actelion, Bayer, BMS, Boehringer, Curzion, Inventiva, Roche and Sanofi and research grants from Inventiva, Sanofi and Alpine Immunosciences., Jerôme Avouac: None declared

BackgroundDigital ulcers (DU) are common in systemic sclerosis (SSc) and associated with reduced survival, high morbidity and poor quality of life. Recommendations have previously been proposed for DU management yet there remains significant unmet patient need. Therefore the World Scleroderma Foundation DU Working Group intends to develop practical evidence based recommendations for DU management.ObjectivesTo summarise data on efficacy and safety of systemic treatments for SSc DU.MethodsA systematic literature review to May 2021 was performed. PubMed, MEDLINE, Embase, Web of Science, Cochrane Library, Emcare (OVID) and Academic Search Premier databases were searched for original studies on adult patients with SSc DU treated with systemic pharmacological treatment. Based on the PICO framework, eligibility criteria were defined and references were independently screened by two reviewers. Reviewers independently assessed the full text of eligible articles. Owing to interstudy heterogeneity narrative summaries were used to present data.ResultsThe search strategy identified 1271 references of which 45 eligible articles were included. Seventeen studies were randomised placebo controlled trials (RCT) pertaining to PDE5 antagonists (PDE5i) (n=3), endothelin receptor antagonists (ERA) (n=3), prostanoids (n=7), antiplatelet agents (n=1) and other (n=3) (Table 1). No head to head RCT was retrieved. All other studies were observational studies (OBS). Studies were highly heterogeneous with application of differing definition of DU, variable study eligibility criteria, clinical endpoints and follow up periods. This limited the calculation of effect size and comparison across studies.Table 1.Characteristics of placebo controlled randomised controlled trialsAuthor YearInterventionnFollow upOutcomeFavours interventionHachulla 2016Sildenafil8312 weeksTime to DU healing-Andrigueti 2017Sildenafil4112 weeksDU healing+Shenoy 2010Tadalafil246 weeksNew DU+Khanna 2016Macitentan55416 weeksNew DU-Matucci-Cerinic 2011Bosentan18832 weeksNew DU Time to healing of DU+-Korn 2004Bosentan12212 weeksNew DU+Kawald 2008IV iloprost5012 monthsDU healing-Wigley 1992IV iloprost3510 weeksDU healing+Wigley 1994IV iloprost739 weeks50% reduction in DU score-Seibold 2017Treprostinil14820 weeksNet DU burden-Vayssairat 1999Beraprost10725 weeks% patients with new DU-Denton 2017Selexipag7412 weeksNumber of new DU DU healing-Lau 1993Cicaprost334 weeksNumber of DU-Abou-Raya 2008Atorvastatin844 monthsNumber of DU+Au 2010Cyclophosphamide15812 monthsNumber of patients with DU-Beckett 1984Dipyridamole / aspirin412 yearsChange in general SSc-Nagaraja 2019Riociguat1732 weeksNet DU burden-+ significantly superior to comparator- non significantly different from comparatorDU: digital ulcers IV: intravenous SSc: systemic sclerosisSeveral RCT found improved DU healing with treatment: two with PDE5i, one with iloprost and one showed improved DU healing and prevention with atorvastatin. Two RCT demonstrated effective prevention of new DU with bosentan. OBS studies with a total of 621 patients showed variable improvements in the healing of DU with CCB, PDE5i, ERA, statins, N-acetylcysteine, prostanoids and ketanserin and prevention of new DU with ERA.Regarding safety, all treatments were generally tolerated with few serious adverse events. Treatment was ceased in 6.25-17.5% of patients in RCT due to treatment related side effects.ConclusionDespite several studies assessing the efficacy and safety of systemic pharmacological treatment of SSc DU, it is not possible to draw solid conclusions due to study heterogeneity. Small RCT have shown treatment benefit with PDE5i, iloprost and atorvastatin. Large studies demonstrated effective prevention of new DU with bosentan. Our results highlight the urgent need for improved clinical trial design to generate more robust evidence and novel therapies to guide the management SSc DU.AcknowledgementsThis work was supported by the World Scleroderma Foundation.Disclosure of InterestsNancy Maltez: None declared, Laura Ross: None declared, Michael Hughes Speakers bureau: Actelion Pharmaceuticals, Eli Lilly and Pfizer outside of the submitted work., Jan Schoones: None declared, Murray Baron: None declared, Lorinda Chung Consultant of: Eicos, Corrado Campochiaro: None declared, Yossra A. Suliman: None declared, Dilia Giuggioli: None declared, Pia Moinzadeh Speakers bureau: Actelion Pharmaceuticals, Boehringer Ingelheim, Yannick Allanore: None declared, Christopher P Denton: None declared, Oliver Distler Speakers bureau: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur., Consultant of: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur., Grant/research support from: Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143), Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur., Tracy Frech: None declared, Daniel Furst: None declared, Dinesh Khanna Consultant of: Eicos Sciences Inc, Janssen, Thomas Krieg: None declared, Masataka Kuwana Speakers bureau: Speaker fees from AbbVie, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai, Eisai, GlaxoSmithKline, Janssen, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, and consultancy fees from AstraZeneca, Boehringer Ingelheim, Corbus, Kissei, Mochida outside of the submitted work., Marco Matucci-Cerinic: None declared, Janet Pope: None declared, Alessia Alunno: None declared

BackgroundShort disease duration is a predictor for progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD), but studies assessing ILD progression in later disease stages are lacking. To individually tailor management of ILD in SSc patients in clinical practice it is, however, of high importance to understand disease behaviour also in patients with late disease.ObjectivesAnalyse ILD progression in SSc-ILD patients from the EUSTAR cohort segregated by subgroups of disease duration.MethodsWe segregated SSc-ILD patients into four categories of disease duration (≤3 years, >3- ≤7 years, >7- ≤15 years and >15 years after onset of Raynaud’s phenomenon). We assessed progressive ILD, defined as forced vital capacity (FVC) decline >10% or FVC decline ≥10% and FVC decline 5–10% and diffusing capacity of the lungs for carbon monoxide (DLCO) decline ≥15% (composite decline) over the first and second 12+/-3 months period after first registration (baseline) into EUSTAR. Clinical characteristics, pulmonary involvement, treatment at first registration and ILD progression were evaluated by descriptive statistics.ResultsIn total, 2258 SSc-ILD patients were included, with 469 (20.8%) having a disease duration ≤3 years, 550 (24.4%) between >3- ≤7 years, 752 (33.3%) between >7- ≤15 years and 488 (21.6%) of >15 years (Table 1). Baseline characteristics and treatment patterns differed between the four subgroups, with more younger male patients with diffuse cutaneous SSc, anti-topoisomerase I antibody and higher Rodnan skin score having ≤3 years disease duration. Lung function with FVC and DLCO were similar between the four groups (Table 1). Notably, in the first and second 12+/-3 months periods after first registration in the EUSTAR database, there were no significant difference in FVC decline >10% or composite FVC and DLCO decline within the four subgroups. For example, patients with disease duration >7- ≤15 years and >15 years frequently showed disease progression of FVC >10%: 41/347 (11.8%) and 32/228 (14%) compared to 38/244 (15.6%) and 33/273 (15.6%) for disease duration ≤3 years and >3- ≤7 years (P=0.529), respectively (Figure 1).Table 1.Demographics and baseline clinical characteristics of EUSTAR patientsDisease duration≤ years(n=460)>3- ≤7 years(n=550)>7- ≤15 years(n=752)>15 years(n=488)p-valueAge, years (SD)55 (13.5)55 (14.1)57 (13.1)61 (11.5)Male, n (%)123 (26.2)115 (20.9)112 (14.9)38 (7.8)DcSSc, n (%)228 (56.4)262 (45.8)311 (45.4)163 (31.2)ATA, n (%)236 (53.4)293 (55.9)374 (52.8)218 (48.0)0.099mRSS, mean (SD)12.3(10.1)10.4 (8.3)9.4 (8.1)8.7 (7.7)GERD, n/N (%)273 (58.7)353 (64.4)482 (64.4)344 (71.2)0.001ESR, mean (SD)26.9(21.7)24.2 (19.5)26.2 (19.9)28.3 (21.2)0.022MMF, n/N (%)33 (16.6)43 (25.2)37 (20.4)14 (9.3)0.002MTX, n/N (%)19 (10)17 (10.1)19 (10.6)8 (5.2)0.296Any IS, n/N (%)81 (38.6)89 (47.1)82 (40.8)46 (28.7)0.006FVC % pred, mean (SD)86 (20.9)87 (21.6)86 (21.4)87 (22.8)0.770DLCO % pred, mean (SD)58 (19.3)59 (19.3)59 (19.9)58 (19.7)0.405NYHA class 3&4, n (%)84 (18.6)78 (14.6)125 (17.5)22.6 (7.0)0.090Figure 1.FVC decline >10% and composite FVC and DLCO decline in the first and second 12+/-3 months within the four subgroups segregated by disease durationConclusionIt was long believed that ILD burned out in late disease stages. In our analysis of ILD progression by four disease duration categories, we showed that ILD frequently progressed also in late disease stages. This has important implications for clinical practise, as SSc patients need to be regularly monitored for ILD progression independent of disease duration.Disclosure of InterestsAnna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Grant/research support from: Boehringer Ingelheim, Cathrine Brunborg: None declared, Paolo Airò Speakers bureau: Bristol-Myers-Squibb, Boehringer Ingelheim, Consultant of: Bristol-Myers-Squibb, Grant/research support from: Bristol-Myers-Squibb, Roche, Jannsen, CSL Behring, Lidia P. Ananyeva Speakers bureau: Boehringer Ingelheim, Grant/research support from: Boehringer Ingelheim, László Czirják Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Actelion (now GSK), MSD, Novartis, Pfizer, Roche, Lilly, Grant/research support from: Boehringer Ingelheim, Actelion (now GSK), MSD, Novartis, Pfizer, Serena Guiducci: None declared, Eric Hachulla Speakers bureau: GSK, Roche-Chugai, Johnson & Johnson, Boehringer Ingelheim, Consultant of: CSL Behring, GSK, Roche-Chugai, Johnson & Johnson, Boehringer Ingelheim, Grant/research support from: CSL Behring, Boehringer Ingelheim, GSK, Roche-Chugai, Sanofi Genzyme, Mengtao Li: None declared, Carina Mihai Speakers bureau: MEDtalks Switzerland, Mepha, Grant/research support from: Roche, Boehringer Ingelheim, Janssen, Gabriela Riemekasten Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Petros Sfikakis Consultant of: Boehringer Ingelheim, Gabriele Valentini Consultant of: Boehringer Ingelheim, Grant/research support from: Sanofi/BMS, Otylia Kowal-Bielecka Speakers bureau: Boehringer Ingelheim, Novartis, Pfizer, Gilead Sciences, Janssen-Cilag, MEDAC, MSD, Abbvie, Sandoz, Consultant of: Boehringer Ingelheim, Health Care system Navigator, CSL Behring, MSD, Novartis, Grant/research support from: CSL Behring, Boehringer Ingelheim, Abbvie, Roche, MEDAC, Yannick Allanore Speakers bureau: Boehringer, Abbvie, Consultant of: Boehringer, Bayer, Astra-Zeneca, Prometheus, Sanofi, Genentech/Roche, Boehringer, Grant/research support from: Alpine Immunosciences, OSE Immunotherapeutics, Medsenic, Oliver Distler Speakers bureau: Bayer, Boehringer Ingelheim, Janssen, Medscape, Consultant of: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, 4P Science, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur, Grant/research support from: Kymera, Mitsubishi Tanabe, Boehringer Ingelheim

BackgroundThe sudden emergence of SARS-CoV-2 onto the world stage has accelerated a major change in the management of patients with chronic rheumatic diseases and has catalyzed the rapid emergence of telemedicine.ObjectivesOur aim was to describe which parameters were used by rheumatologists to monitor patients with rheumatoid arthritis (RA) in teleconsultation during the first wave of the pandemic and identify the most relevant for decision making.MethodsRetrospective monocentric routine care cross-sectional study including RA patients seen in teleconsultation between March and September 2020. Available parameters assessing disease status were collected in teleconsultation files. Clinician intervention was defined by treatment escalation and/or the need for a rapid face-to-face consultation or day hospitalization.Results143 RA patients were included (117 females, mean age of 58±16 years, mean disease duration of 14±11 years). The presence or absence of patient self-reported RA flares was mentioned in all medical files, followed by the presence and/or the number of tender joints (76%), the duration of morning stiffness (66%), the number of pain-related nocturnal awakenings (66%) and the CRP value (54%).Patient self-reported RA flares concerned 43/143 patients (30%). The presence of self-reported RA flares was associated with a more detailed evaluation of patient in teleconsultation: The presence (or number) of tender joints and swollen joints were more significantly reported in patients who presented a flare (39/43, 91% vs. 70/100, 70%, p=0.008 and 25/43, 58% vs. 23/100, 23%, pTeleconsultation led to a clinician intervention in 22/143 patients (14%), representing 51% of patients with self-reported flares (22/43 patients). Therapeutic escalation was necessary in 13 patients: introduction or dose increase of corticosteroids in 8 patients, introduction or dose increase of methotrexate in 4 patients and introduction of hydroxychloroquine in 1 patient. Face-to-face consultation or day hospitalization were organized for 10 patients. Active disease was confirmed during this next face-to-face visit in 9 patients, with DAS28 ranging from 3.35 to 5.62, leading to therapeutic modification. The 133 other patients were seen in face-to-face consultation 6±2 months after the teleconsultation. No DMARD modification was recorded during this next face-to-face consultation.The following variables were associated with clinician intervention during the teleconsultation in univariate analysis: patient self-reported RA flares since the last visit (p10 mg/mL (p=0.012) and a morning stiffness > 30 minutes (p10 mg/L (OR: 3.32, 95% CI % 1.12-13.27) as the variables independently associated with clinician intervention.ConclusionOur study identified patient reported RA flares and increased CRP values as 2 red flags in teleconsultation, independently associated with therapeutic modification and/or the need for a rapid face-to-face consultation. These indicators may help clinician’s decision making in teleconsultation.Disclosure of InterestsJerôme Avouac Speakers bureau: Bristol Myers Squibb, SANOFI, galapagos, Lilly, Abbvie, Pfizer, Novartis, Biogen, Fresenius Kabi, Janssen, MSD, Roche-Chugai, Medac, Consultant of: galapagos, Abbvie, Pfizer, Bristol Myers Squibb, SANOFI, Nordic-Pharma, Grant/research support from: Bristol-Myers Squibb, Pfizer (Passerelle), Novartis (Dreamer), Fresenius Kabi, Anna Moltó: None declared, CAMELIA FRANTZ: None declared, Sarah Wanono: None declared, Elise Descamps: None declared, Olivier Fogel: None declared, Alice Combier: None declared, Lucile Poiroux: None declared, Corinne Miceli Richard: None declared, Yannick Allanore: None declared

BackgroundɣGT has been identified as a maker of systemic inflammation and cardiovascular (CV) risk. The composite index DAS28-ɣGT has been developed to allow an evaluation of both joint disease activity and CV risk.ObjectivesTo assess the value of the DAS28-ɣGT in a population of patients with rheumatoid arthritis (RA) requesting cardiologic assessment.MethodsRetrospective analysis of RA patients referred to cardio-metabolic day hospitalization in the Rheumatology department of Cochin hospital between February 2021 and January 2022. Criteria for referral were age > 50 years and presence of at least one CV risk factor. DAS28-GGT index was calculated as follows: 0,56 * √TJ-28 + 0,28 * √SJ-28 + 2 * ln (γGT) + 0,14 * GH. This index was analysed according to disease activity measured with the DAS28-CRP, CV risk assessed by the Framingham score and the decision taken by the cardiologist (requirement of complementary explorations and/or therapeutic intervention).ResultsWe included 22 RA patients (17 women), with a mean age of 66±10 years, a disease duration of 21±12 years. Rheumatoid factor was positive in 15 patients, anti-CCP antibodies in 17, and bone erosions in 16. 15 patients received methotrexate, 13 corticosteroids (dose < 10 mg per day), 15 targeted biologic therapies and 3 JAK inhibitors. The mean DAS28-CRP was 2.5±0.9 and the mean DAS28-ɣGT was 7.90±1.90.2 patients had a DAS28-ɣGT < 5.5, defined in our previous study as high probability of RA remission and low probability of CV risk. These two patients were in remission and their Framingham score was < 10% (low CV risk). No complementary exploration was requested by the cardiologist.8 patients (6 women, 2 men) had a DAS28-ɣGT index between 5,5 and 7,5, defined in our previous study as high probability of RA remission or low disease activity (LDA) and increased probability of CV risk. As expected, all patients were in remission or in LDA. This population were at higher CV risk: 2 patients had a Framingham score > 20% (high risk), 3 patients a score ranging from 10 to 20% (intermediate risk), and 3 patients a score < 10%. One patient presented carotid atheroma. 4 patients required additional CV explorations and 3 patients necessitated escalation of blood hypertension therapy.Twelve patients (9 women, 3 men) had a DAS28-ɣGT index > 7,5, defined in our previous study as high probability of active RA and/or increased probability of CV risk. 4 patients were in remission, 3 were in LDA and 5 presented moderate disease activity. One patient had a Framingham score > 20%, 4 had a score ranging between 10 and 20% and 6 had a score < 10%. The score was not applicable in an 80-year-old patient. Three other patients had coronary artery disease, including a patient who presented both coronary artery disease and carotid atheroma. 5 patients requested additional CV explorations and 4 required CV therapy escalation (introduction of statin and aspirin in 2 patients and increased blood hypertension therapy in 2 patients). Among these 12 patients, 3 with the highest DAS28-ɣGT values presented CV complications: a 64-year-old woman with a DAS28-ɣGT of 12.8 (DAS28-CRP: 2.89) had carotid atheroma and intermediate lesion of the right artery on coroscanner justifying a coronarography; a 81-year-old woman with a DAS28-ɣGT of 10.67 (DAS29-CRP: 4.62) had atrial fibrillation and aortic stenosis requiring Transcatheter Aortic Valve Implantation; and a 77-year-old woman with a DAS28-ɣGT of 10.35 (DAS28-CRP: 3.89) had ischemic chest pain necessitating rapid explorations in cardiology.ConclusionThe DAS28-ɣGT allowed a reliable classification of patients according to the RA activity disease and CV risk. This index may be relevant for CV risk stratification decision making to refer RA patients to a cardiologist. Its validation is in progress in a prospective cohort.References[1]Vergneault H, vandebeuque E, Codullo V, et al, J rheumatol 2020;47(12):1738-1745Disclosure of InterestsNone declared

BackgroundRecently, EULAR has proposed a definition of difficult-to-treat rheumatoid arthritis (D2TRA). However, descriptive data on D2TRA are scarce and only one Japanese publication details the D2TRA encountered in routine practice, no similar work has been done in Europe so far.ObjectivesTo describe D2TRA patients encountered in France according to two definitions and evaluate their therapeutic responses to different targeted therapies.MethodsWe reviewed all patients with RA treated in day hospital at Cochin University Hospital between 2020 and 2021. We divided our population into two groups of patients, a D2TRA group and a non-D2TRA group. This division was made on the same population according to two different definitions of D2TRA, resulting in four patient groups. The first definition is the one proposed by EULAR (EULAR D2TRA) defining D2TRAs as RAs with failure of ≥2 b/tsDMARDs (with different mechanisms of action) after failing csDMARD therapy. The second defined as D2TRA patients who have failed at least two targeted therapies, without prejudging the mechanism of action (non-EULAR D2TRA). We analyzed clinical characteristics and evaluated their response to different targeted therapies. Disease activity was assessed using the DAS for 28 joints (DAS28) at the latest visit.ResultsIn total, we included 320 patients, we identified 76 EULAR D2TRA patients (mean age 59 years, 87% female) with 244 of corresponding non-DTRA patients (mean age 60 years, 85% female) and 120 non-EULAR D2TRA patients (mean age 58.7 years, 87% female) with 200 of corresponding non-DTRA (mean age 61 years, 85% female). Compared to non-D2TRA patients, there were significantly more D2TRA patients from low socioeconomic backgrounds in both D2TRA groups. In the EULAR-D2TRA group, compared to the non-D2TRA, there were significantly more patients with diabetes (14% vs 6%, p=0.024). D2TRA patients in both groups had significantly more rheumatoid factor (RF), interstitial lung disease (ILD) and a higher DAS28 than non-D2TRA patients. No difference was noted regarding ACPA and erosions. We observed a lower proportion of remission in both D2TRA groups than in non-D2TRA group (21% in EULAR-D2TRA vs 34% in non-D2TRA, p=0.034 and 23% in non-EULAR D2TRA vs 36% in non-D2TRA, p=0.024). There were significantly fewer patients on Methotrexate in the non-EULAR D2TRA group compared to the non-D2TRA group (53% vs 64%, p=0.046). In the non-EULAR D2TRA group, there were significantly more patients in remission on Rituximab than on TNF inhibitors (41% vs 5%, p=0.0032). We did not observe a significant difference in achieving remission in patients on JAK inhibitors or IL-6 inhibitors in the two groups of D2TRA.Table 1.Clinical data of patients with D2TRANON D2T RA n=200NON-EULAR D2T RA n=120p-valueNON D2T RA n=244EULAR D2T RA n=76p-valueLow socioeconomic level69 (35)61 (51)0.00591 (37)39 (51)0.032TJC (0-28), mean (SD)3.4 (4.6)4.9 (5.8)0.01673.5 (4.5)5.6 (6.5)0.001SJC (0-28), mean (SD)2.4 (3.1)3.5 (4.3)0.00672.6 (3.3)3.5 (4.3)0.0503CRP in mg/dl, mean (SD)6 (9.5)7 .5 (12.1)0.21286.1 (9.9)7.9 (12.3)0.2060DAS28CRP, mean (SD)3.2 (1.2)3.6 (1.4)0.00443.2 (1.3)3.6 (1.4)0.0052Remission71 (36)28 (23)0.02483 (34)16 (21)0.034RF positive, n (%)156 (78)105 (88)0.037193 (79)68 (89)0.043Anti-CCP positive, n (%)152 (76)101 (84)0.099188 (77)66 (87)0.075Erosion, n (%)114 (57)69 (58)1138 (56)46 (60)0.596Interstitial Lung Disease, n (%)16 (8)19 (16)0.04117 (7)18 (24)Corticosteroids, n (%)84 (42)64 (53)0.064101 (41)46 (61)0.004 Dose (mg), mean ± SD6 (4.9)5.5 (3.4)0.4166 (4.6)5.3 (3.6)0.374Methotrexate, n (%)128 (64)63 (53)0.046149 (61)42 (55)0.422 Dose (mg), mean ± SD17.3 (4.25)17.5 (5.3)0.78617.2 (4.5)18.1 (5.1)0.291ConclusionThe complexity of managing RA patients can be explained by socio-economic status and the presence of comorbidities such as diabetes and ILD. Our work suggests that D2TRA patients have less Methotrexate and better response to Rituximab. These data need to be confirmed in prospective studies to allow personalized management of D2TRA.Disclosure of InterestsNone declared

BackgroundThe lack of validated tools to predict rheumatoid arthritis (RA) disease course warrants the development of new reliable biomarkers. We have previously detected increased SEMA4A expression in endothelial cells, synovial tissue, and serum of patients with RA. In addition, SEMA4A serum levels correlated with multiple clinical, biological, and power doppler ultrasound markers of disease activity and angiogenesis (1).ObjectivesTo evaluate the merit of circulating semaphorin 4A (SEMA4A) for the prediction of disease progression in RA patients.MethodsProspective monocentric observational study including consecutive RA patients between May 2016 and February 2018 with available SEMA4A concentrations, measured by quantitative ELISAs (Coud-Clone Corp, Katy, TX). Increased SEMA4A concentrations were defined as values >94 ng/mL, as previously reported (1). Patients were followed up on an annual basis until August 2021. Primary endpoints were the occurrence of patient-reported flares with swollen joints and the necessity to initiate or change a targeted biologic or synthetic disease-modifying anti-rheumatic drugs.ResultsA total of 101 patients (85 females, 84%) were included, with a mean age of 58±13 years and a mean disease duration of 14±11 years. During a follow-up period of 41±15 months, disease flares occurred in 38 patients and targeted therapy was added or modified in 26 patients because of insufficient disease control. Increased baseline SEMA4A levels were predictive of flares and treatment escalation (hazard ratio, HR: 2.43, 95% confidence interval, CI 1.27-4.68 and 2.73, 95%CI 1.24-5.96, respectively) (Figure 1A-B). Multivariate Cox analyses confirmed that SEMA4A was an independent predictors of flares and treatment escalation (HR: 2.12, 95%CI 1.04-4.32 and 2.71, 95%CI1.14-6.43, respectively), and revealed that DAS28-CRP and synovial hyperhemia were independent predictors of flares. Baseline age, disease duration, ACPA or RF positivity, smoking status, presence of erosions, line of targeted DMARDs, treatment with corticosteroids and CRP levels were not predictive of these outcomes. SEMA4A remained predictive of flares and treatment escalation in the 58 patients with a DAS28 C). The highest predictive value of flares and treatment escalation was obtained with the combination of increased circulating SEMA4A and/or DAS28-CRP>3.2 and/or the presence of synovial hyperemia on power-doppler ultrasound (HR:4.88, 95%CI 1.50-15.89 and 10.42, 95%CI 1.41-76.94, respectively).Figure 1.A-C: Predictive value of SEMA4A for the progression of rheumatoid arthritis. A, Disease flare-free survival according to circulating SEMA4A concentrations (≤ or > 94 ng/mL). B, Time to treatment escalation according to circulating SEMA4A concentrations (≤ or > 94 ng/mL). C, Course of the DAS28-CRP during the follow-up period according to baseline SEMA4A concentrations (≤ or > 94 ng/mL). All data are shown as the mean ± SEM. * pConclusionCirculating SEMA4A was a robust biomarker of disease progression in this cohort, complementary of the DAS28 and synovial hyperemia on power-doppler ultrasound. These results need to be confirmed in replication cohorts.References[1]Avouac et al, Arthritis Rheumatol 2021Disclosure of InterestsNone declared.

BackgroundManagement of digital ulcers (DUs) in systemic sclerosis (SSc) is a major clinical challenge. To date, systemic therapy is generally considered as the ‘standard of care’ for significant SSc-DUs. However, there is a strong rationale to develop local approaches to DUs, to avoid side effects from systemic therapies. World Scleroderma Foundation DU Working Group intends to develop practical, evidence-based recommendations for DU management including local, Surgical Treatment (L-ST).ObjectivesTo summarize the literature on the safety and efficacy of L-ST for SSc-DUs.MethodsA systematic literature review (SLR) was conducted up to May 2021. According to the PICO framework, eligibility criteria were defined and original research articles about surgical treatment of SSc DUs in adult patients were included. References were independently screened by 2 reviewers who assessed the full text of eligible articles and extracted data.ResultsThirteen eligible articles out of 790 total publications were identified (Table 1). Due to the paucity of randomized controlled trials of surgical treatments for SSc-DU, we included retrospective studies and case series with at least 4 patients. Autologous fat (adipose tissue AT) grafting was the surgical modality mostly identified (7 studies of which 1 RCT and 6 prospective open label single arm). The healing rate (HR) with autologous fat grafting (4 studies) ranged from 66-100 %. In the RCT, two age and sex matched groups were included, adipose tissue (AT)group (n=25 pts) and sham procedure (SP) group (n=13), DU healing was reported in 23/25 in AT group versus 1/13 in the SP group in 8 wks, (pTable 1.Characteristics of the extracted studies.StudydesignPatients (n)Baseline DU (n)Background therapy (%)Follow-upOutcomeHealed ulcers(%) Adipose tissue graftAutologous fat graftp9.15PG, CCB—100ETA 26PDE-5i 138-12 wks66Adipose tissue graftingRCT25 case13- Ctr25-case13- CtrPG- 100CCB 1008 wks92-case7-CtrAdipose tissue implantp1515no therapy7 wks100Adipose tissue graftp129PG,CCB-100ETA6 month88adipose derived SVFp1215PDE-5i, ccb, PG allowed22m6Adipose derived SVFp1215CCB 50ETA166 m63 Adipose derived SVFp1819CCB 50PG 27ETA 5IS 7124 wks32SympathectomySympathectomyR611CCB-10020 m81SympathectomyR1335PGCCBAPA35Sympathectomy, vascular bypass (+vein graftR1726Ccb 35APA 47PDE-i5 589 m100Bone marrow derived cells transplantation)p88PG-6236 m87Direct microsurgical revascularizationR44m100Limited microsurgical arteriolysisR61712 m100SVF =stromal vascular fraction P = prospective. R = retrospective. RCT= double blind randomized-controlled trial. ETA = endothelin antagonist. CCB= calcium channel blockers. APA= anti-platelet agents. PG= prostaglandins. ARB= angiotensin receptor antagonist. ACEi= ACE inhibitors. PDE-5i= PDE-5 inhibitors. IS= immunosuppression. M=median. SoC= standard of care. HR= healing rateConclusionOur SLR has identified several surgical modalities for SSc-DUs. L-STseemed generally effective and safe for DU healing, thus Significant methodological issues emerged including small numbers of pts, lack of comparator, failure to report confounders such as background therapies and variable follow up. Future research is warranted to rigorously investigate surgical interventions for Dus.Disclosure of InterestsYossra A. Suliman: None declared, Corrado Campochiaro: None declared, Michael Hughes Speakers bureau: speaking fees from Actelion pharmaceuticals, Eli Lilly, and Pfizer, outside of the submitted work, Jan Schoones: None declared, Dilia Giuggioli: None declared, Nancy Maltez: None declared, Pia Moinzadeh Speakers bureau:: speaking fees from Actelion pharmaceuticals and Boehringer Ingelheim, Laura Ross: None declared, Lorinda Chung: None declared, Yannick Allanore: None declared, Murray Baron: None declared, Christopher P Denton: None declared, Oliver Distler Shareholder of: Consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Speakers bureau: Consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Consultant of: Consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Grant/research support from: Consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Tracy Frech: None declared, Daniel Furst: None declared, Dinesh Khanna Speakers bureau: Janssen and Eicos Sciences, Inc., Paid instructor for: Janssen and Eicos Sciences, Inc., Consultant of: Janssen and Eicos Sciences, Inc., Thomas Krieg: None declared, Masataka KUWANA Speakers bureau: Speakers fees from AbbVie, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai, Eisai, GlaxoSmithKline, Janssen, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, and Consultant fees from AstraZeneca, Boehringer Ingelheim, Corbus, Kissei, Mochida, outside of the submitted work., Paid instructor for: Speakers fees from AbbVie, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai, Eisai, GlaxoSmithKline, Janssen, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, and Consultant fees from AstraZeneca, Boehringer Ingelheim, Corbus, Kissei, Mochida, outside of the submitted work., Consultant of: Speakers fees from AbbVie, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai, Eisai, GlaxoSmithKline, Janssen, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, and Consultant fees from AstraZeneca, Boehringer Ingelheim, Corbus, Kissei, Mochida, outside of the submitted work., Marco Matucci-Cerinic: None declared, Janet Pope: None declared, Alessia Alunno: None declared

BackgroundGastrointestinal (GI) involvement is a common manifestation of systemic sclerosis (SSc) and a frequent side-effect of drugs used to treat SSc. In the SENSCIS trial, nintedanib reduced the rate of decline in forced vital capacity (FVC) in patients with SSc-associated interstitial lung disease (SSc-ILD), with an adverse event profile characterised predominantly by GI events.ObjectivesTo assess the severity and impact of GI symptoms on quality of life in patients treated with nintedanib in the open-label extension trial, SENSCIS-ON.MethodsPatients with SSc-ILD who completed the SENSCIS trial or a drug–drug interaction (DDI) study of nintedanib and oral contraceptive were eligible to enter SENSCIS-ON. Patients who received nintedanib in SENSCIS (up to 100 weeks) and continued nintedanib in SENSCIS-ON comprised the “continued nintedanib” group. Patients who received placebo in SENSCIS and initiated nintedanib in SENSCIS-ON, or who received nintedanib for a short time in the DDI study, comprised the “initiated nintedanib” group. We assessed changes in scores on the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA SCTC GIT) questionnaire v2.0 from baseline to week 52. This questionnaire comprises 7 scales measuring the severity and impact of GI symptoms: reflux, distension or bloating, faecal soilage, diarrhoea, constipation, emotional well-being, social functioning. Each scale is scored from 0 to 3 except for the diarrhoea scale (0 to 2) and constipation scale (0 to 2.5). The total score, the mean of the scores for the scales except constipation, ranges from 0 to 2.83, with higher scores indicating worse symptoms.ResultsThe “continued nintedanib” group comprised 197 patients and the “initiated nintedanib” group comprised 247 patients (231 from SENSCIS). Of these, 178 and 218 patients, respectively, provided a total UCLA SCTC GIT score at baseline. At baseline, mean (SD) total scores were 0.33 (0.33) and 0.33 (0.34) in the continued nintedanib and initiated nintedanib groups, respectively. Mean (SD) scores on the 7 scales ranged from 0.16 (0.52) to 0.70 (0.73) in the continued nintedanib group and from 0.13 (0.43) to 0.64 (0.68) in the initiated nintedanib group. Increases (worsening) in scores were observed in both groups from baseline to week 52, except for on the constipation scale (Figure 1). Based on the total score, between baseline and week 52, the proportion of patients with moderate or severe or very severe GI symptoms increased, but 45.7% and 39.7% of patients in the continued nintedanib and initiated nintedanib groups, respectively, had no or mild GI symptoms at week 52 (Table 1).Table 1.Changes in severity and impact of gastrointestinal symptoms based on UCLA SCTC GIT total score between baseline and week 52 of SENSCIS-ONBaselineWeek 52None or mildModerateSevere or very severeMissingTotalContinued nintedanibNone or mild81 (41.1)5 (2.5)04 (2.0)90 (45.7)Moderate38 (19.3)10 (5.1)01 (0.5)49 (24.9)Severe or very severe13 (6.6)14 (7.1)7 (3.6)1 (0.5)35 (17.8)Missing6 (3.0)3 (1.5)1 (0.5)13 (6.6)23 (11.7)Total138 (70.1)32 (16.2)8 (4.1)19 (9.6)197 (100)Initiated nintedanibNone or mild87 (35.2)6 (2.4)1 (0.4)4 (1.6)98 (39.7)Moderate35 (14.2)12 (4.9)2 (0.8)3 (1.2)52 (21.1)Severe or very severe8 (3.2)7 (2.8)4 (1.6)1 (0.4)20 (8.1)Missing37 (15.0)15 (6.1)4 (1.6)21 (8.5)77 (31.2)Total167 (67.6)40 (16.2)11 (4.5)29 (11.7)247 (100)Data are n (%) of patients. None or mild=scores of 0 to 0.49; moderate=scores of 0.5 to 1; severe or very severe=scores of 1.01 to 3.Figure 1.Changes in UCLA SCTC GIT scores from baseline to week 52 of SENSCIS-ONConclusionIn the SENSCIS-ON trial, the majority of patients with SSc-ILD treated with nintedanib had no or mild GI symptoms at baseline. A small worsening in GI symptoms was observed over 52 weeks. Diarrhoea had the greatest impact, reflecting the adverse event profile of nintedanib. Recommendations for the management of diarrhoea in patients treated with nintedanib should be implemented in clinical practice.AcknowledgementsThe SENSCIS-ON trial was funded by Boehringer Ingelheim.Disclosure of InterestsDinesh Khanna Shareholder of: Eicos Sciences, Inc - stocks, Consultant of: AbbVie, Acceleron, Actelion, Amgen, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos NV, Genentech/Roche, Gilead, GlaxoSmithKline, Horizon Therapeutics, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Sanofi-Aventis, United Therapeutics, Prometheus, Theraly, AstraZeneca, Grant/research support from: Bayer, Bristol-Myers Squibb, Horizon Therapeutics, Immune Tolerance Network, National Institutes of Health, Pfizer, Employee of: CiviBioPharma/Eicos Sciences, Inc - Leadership/Equity position – Chief Medical Officer, Elizabeth Volkmann Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Grant/research support from: Boehringer Ingelheim, Corbus, Forbius, Horizon, Kadmon, Kristin Highland Speakers bureau: Actelion Pharmaceuticals (Jansen), Bayer Healthcare, Boehringer Ingelheim, United Therapeutics, Paid instructor for: Acceleron Pharmaceuticals, Actelion Pharmaceuticals, Bayer Healthcare, Boehringer Ingelheim, Gilead Sciences, United Therapeutics, Consultant of: Boehringer Ingelheim, United Therapeutics, Genentech, Forsee Pharmaceuticals, Grant/research support from: Acceleron Pharmaceuticals, Actelion Pharmaceuticals, Bayer Healthcare, Boehringer Ingelheim, Genentech, Gossamer Bio, Eiger Pharmaceuticlas, Lilly Pharmaceuticals, Reata Pharmaceuticals, United Therapeutics, Viela Bio (Horizon Pharmaceuticals), Yannick Allanore Consultant of: Abbvie, AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, Medsenic, Mylan, Prometheus, Roche, Sanofi, Grant/research support from: Alpine Immunosciences, Medsenic, OSE Immunotherapeutics, Stéphane Jouneau Paid instructor for: Cours, formations - Actelion, AIRB, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, LVL, Mundipharma, Novartis, Pfizer, Roche, Consultant of: Advisory Boards, consultancy - AIRB, Boehringer Ingelheim, Roche, Grant/research support from: Recherche Clinique - AIRB, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Galactic, Gilead, LVL, Roche, SavaraAides pour des recherches - AIRB, Boehringer Ingelheim, LVL, Novartis, Roche, James Seibold Shareholder of: Prometheus Biosciences, Speakers bureau: Boehringer Ingelheim, Consultant of: Alexion, Blade, Camurus AB, GlaxoSmithKline, Prometheus Biosciences, Sironax, Sojournix, Xenikos, Employee of: Prometheus Biosciences, Alexandra James Employee of: Alexandra James is an employee of Elderbrook solutions GmbH that is contracted by Boehringer Ingelheim, Margarida Alves Employee of: Margarida Alves is an employee of Boehringer Ingelheim, Oliver Distler Speakers bureau: OD has/had relationships with the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years:Speaker fee: Bayer, Boehringer Ingelheim, Janssen, Medscape, Consultant of: OD has/had relationships with the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years:Consultancy fee: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, 4P Science, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and TopadurOD has/had relationships with the following companies in the area of potential treatments for arthritides in the last three calendar years:Consultancy fee: Abbvie, Grant/research support from: OD has/had relationships with the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years:Research Grants: Boehringer Ingelheim, Kymera, Mitsubishi Tanabe

BackgroundInterstitial lung disease (ILD) has become the leading cause of mortality in systemic sclerosis (SSc) patients (1). The presence of anti-U1RNP antibodies is primarily associated with mixed connective tissue disease (MCTD), however these autoantibodies may be found in up to 10% of SSc patients (2). A recent large multicenter study showed that the presence of anti-U1RNP antibodies was independently associated with more severe disease in SSc patients. However, so far, little is known about the influence of anti-U1RNP antibodies specifically on lung outcomes in SSc-ILD patients.ObjectivesTo describe the clinical features, outcomes and prognosis of anti-U1RNP SSc-ILD patients.MethodsSSc patients with available data on their autoantibody profile were identified from the EUSTAR database. Those with ILD identified by high-resolution chest tomography (HRCT) were included for analysis. Baseline demographic and disease features were compared between anti-U1RNP positive and anti-U1RNP negative patients. For the longitudinal part in patients with repeated lung function tests, the mean annual decline in %predicted forced vital capacity (%pFVC) was compared between the two groups. Predictors associated with death of any cause or severe ILD progression, defined as a drop >10% in %pFVC/year, were evaluated in SSc-ILD patients with or without U1RNP. Mild progression was defined as a loss of 5-10% in %pFVC/year. Demographic and clinical parameters were compared between patients positive and negative for anti-U1RNP antibodies in univariate analysis. Associations between anti-U1RNP status and lung involvement were tested in multivariate logistic regression models.ResultsA total of 5676 SSc-ILD patients were included for the analysis, among which 320 (5.6%) were positive for anti-U1RNP antibodies. Mean age was 56.4±13.5 years and 4645 (81.8%) were women.Anti-U1RNP+ SSc-ILD patients had more frequently limited cutaneous SSc (52.5% vs 39.8%, pAnti-U1RNP+ patients had a baseline lower mean %pFVC (81.1% vs 85.3%, p=0.002) and lower mean %predicted diffusing capacity for carbon monoxide (%pDLCO) (58.9% vs 60.2%, p=0.004) than anti-U1RNP- SSc-ILD patients. No significant differences were found at baseline HRCT, including lung involvement >20% (4.4 vs 4.2%%, p=0.39), or the presence of ground glass opacities (38.1% vs 33.6%, p=0.14).A total of 2697 (50.3%) patients with SSc-ILD had at least one FVC measurement available during a mean follow-up of 20.8±20.5 months. Mean expected decline in %FVC per year was not different between U1RNP positive and negative patients (-0.21% vs -0.68%, p=0.70). Mortality or severe ILD progression was not statistically different between the two groups (35 (21.6%) vs 677 deaths (26.7%), p=0.43, and 23 (14.0%) vs 283 severe progressors (11.0%), p=0.25, respectively). Mild ILD progression was also not statistically different between the two groups (11.0% vs 10.0%, p=0.20). The proportion of patients with FVCConclusionOur results from the EUSTAR database show that SSc patients positive for anti-U1RNP antibodies have more impaired baseline lung function but similar rate of progression during follow-up. This suggests that early stages might be important in RNP+ SSc-ILD patients who may require specific management and follow-up.References[1]Hoffmann-Vold A-M, Allanore Y, Alves M, Brunborg C, Airó P, Ananieva LP, et al. Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Ann Rheum Dis. 28 sept 2020;[2]Asano Y, Ihn H, Yamane K, Kubo M, Tamaki K. The Prevalence and Clinical Significance of Anti-U1 RNA Antibodies in Patients with Systemic Sclerosis. Journal of Investigative Dermatology. fevereiro 2003;120(2):204‑10.Disclosure of InterestsGonçalo Boleto: None declared, Corrado Campochiaro: None declared, Anna-Maria Hoffmann-Vold: None declared, Armando Gabrielli: None declared, Oliver Distler Consultant of: OD has/had consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Jerôme Avouac: None declared, Yannick Allanore Paid instructor for: YA reports personal fees from Actelion, Bayer, BMS, Boehringer, Curzion, Inventiva, Roche and Sanofi and research grants from Inventiva, Sanofi and Alpine Immunosciences.

BackgroundRisk-stratification is key in a heterogeneous disease like systemic sclerosis (SSc). Until now, SSc patients are stratified according to the extent of skin involvement into limited cutaneous, diffuse cutaneous and sine scleroderma subtypes. However, this classification remains inaccurate to capture disease heterogeneity. Autoantibodies are found in more than 90% of the patients and can be detected before onset of the disease. Among them, three predominant and specific antibodies are used: anti-centromere, anti-Scl70 and RNA polymerase III antibodies.ObjectivesTo compare the performances of stratification into LeRoy’s cutaneous subtypes versus autoantibody status in SSc versus combination of cutaneous subtypes and autoantibodies status.MethodsPatients from the EUSTAR database were classified either as (i) limited cutaneous, diffuse cutaneous or sine scleroderma (based on the recording made by the treating physician) or (ii) according to autoantibodies with the following subclassifications: (1) no specific autoantibodies, (2) isolated ANA, (3) anti-centromere antibodies, (4) anti-Scl70 antibodies and (5) anti-RNA polymerase III antibodies or (iii) according to combination of cutaneous subset and auto-antibodies. The respective performance of each model to predict overall survival (OS), progression-free survival (PFS), disease progression and different organ involvements was assessed and the three models were compared by the area under the receiver operating characteristic curve (AUC 95%CI) and the net reclassification improvement (NRI). Missing data were imputed through multiple imputation using chain equations.ResultsIn all, 10’711 patients were included: 84.6% females, mean age: 54.4±13.8 years, mean disease duration: 7.9±8.2 years. In the prospective analysis (n= 6’467 to 7’829 according to the outcome), after a mean follow-up of 56 months and a mean of three visits per patient, we did not identify any difference in AUC between the cutaneous-based model and the antibody-based model for prediction of OS and disease progression. However, the NRI showed a significant improvement in prediction of OS (0.57 [0.46-0.71] vs. 0.29 [0.19-0.39]) and disease progression (0.36 [0.29-0.46] vs. 0.21 [0.14-0.28]) at 4 years using the antibody-based model. Regarding prediction of each organ involvement in longitudinal analyses, the antibody-based model showed better performance than the cutaneous-one for renal crisis (AUC: 0.719 [0.696-0.742] vs. 0.664 [0.643-0.685]), with the highest association observed with anti-RNA polymerase III (OR: 7.47 [1.63-34.24], p= 0.010). Similarly, the antibody-based model was better than the cutaneous model in predicting lung fibrosis (AUC 0.719 [0.715-724] vs. 0.653 [0.647-0.659]) and restrictive lung fibrosis (AUC 0.759 [0.749-0.766] vs. 0.711 [0.701-0.721]) which were both associated with anti-Scl70 antibodies (OR: 9.29 [8.17-10.55] and 7.92 [5.37-11.69], respectively, pConclusionAuto-antibody status outperforms the common cutaneous subsetting to risk-stratify SSc patients in the EUSTAR cohort. This easily performed subclassification using autoantibodies specific status can be used by the clinicians to risk-stratify their patients and to adapt disease monitoring in routine practice.Disclosure of InterestsMuriel Elhai Speakers bureau: BMS outside of the submitted work, Marouane Boubaya: None declared, Nanthara Sritharan: None declared, Alexandra Balbir-Gurman: None declared, Elise Siegert: None declared, Eric Hachulla: None declared, Jeska de Vries-Bouwstra: None declared, Gabriela Riemekasten: None declared, Jörg H.W. Distler: None declared, Douglas Veale: None declared, Edoardo Rosato: None declared, Francesco Del Galdo: None declared, Fabian A Mendoza: None declared, Daniel Furst Consultant of: Abbvie, Novartis, Pfizer, R-Pharm, Grant/research support from: Emerald, Kadmon, PICORI, Pfizer,Prometheus, Talaris, Mitsubishi, Carlos De la Puente Bujidos: None declared, Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Grant/research support from: Boehringer Ingelheim, Armando Gabrielli: None declared, Oliver Distler Speakers bureau: Bayer, Boehringer Ingelheim, Janssen, Medscape, Consultant of: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, 4P Science, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur, Grant/research support from: Kymera, Mitsubishi Tanabe, Boehringer Ingelheim, Coralie Bloch-Queyrat: None declared, Yannick Allanore Consultant of: Actelion, Bayer, BMS, Boehringer-Ingelheim, Inventiva, Roche, Sanofi-Aventis, Grant/research support from: Actelion, Bayer, BMS, Boehringer-Ingelheim, Inventiva, Roche, Sanofi-Aventis

BackgroundLeRoy’s classification defines two main subsets of Systemic Sclerosis (SSc) based on the extent of skin fibrosis: limited cutaneous SSc (lcSSc) with skin thickening sparing the trunk and distal to the elbow and knees, and diffuse cutaneous SSc (dcSSc) with proximal and distal skin thickening. These two subsets notably differ in terms of survival and frequency of visceral involvement, dcSSc being less prevalent but having a higher mortality rate with more frequent visceral manifestations. SSc sine scleroderma (ssSSc) is a third subset initially described by Rodnan et al. and characterized by the absence of skin fibrosis but with the existence of SSc-associated visceral manifestations.ObjectivesThis study aimed to characterise the main clinical features of patients with ssSSc in comparison with the lcSSc and dcSSc subsets within the international EUSTAR database.MethodsAll patients from the EUSTAR database fulfilling the ACR2013 or 1980 classification criteria for SSc assessed by the modified Rodnan Skin score (mRSS) at inclusion and with at least one follow-up visit were eligible. Sine scleroderma (ssSSc) was defined by the absence of skin thickening (mRSS=0 and no sclerodactyly) at all available visits. The clinical characteristics of these ssSSc patients were compared to those of patients with lcSSc and dcSSc with similar disease duration at last follow-up visit. Descriptive statistics were applied.ResultsAmong the 4263 patients fulfilling the inclusion criteria, 376 (8.8%) were classified as ssSSc. Among them, 40.3% had puffy fingers, 39.4% had interstitial lung disease (ILD), 1.6% had a history of scleroderma renal crisis at inclusion visit. At last available visit, in comparison with 708 lcSSc and 708 dcSSc with the same disease duration, ssSSc patients had a lower prevalence of previous or current digital ulcers (28.2% versus 53.1% in lcSSc (PConclusionThis study highlights that ssSSc patients account for almost 10% of SSc patients with milder disease severity compared to both lcSSc and dcSSc.AcknowledgementsThe authors thank all EUSTAR collaboratorsDisclosure of InterestsAlain LESCOAT: None declared, Suiyuan Huang: None declared, Patricia Carreira: None declared, Elise Siegert: None declared, Jeska de Vries-Bouwstra: None declared, Jörg H.W. Distler: None declared, Vanessa Smith: None declared, Francesco Del Galdo: None declared, Branimir Anic: None declared, Nemanja Damjanov: None declared, Simona Rednic: None declared, Camillo Ribi: None declared, DOMNIQUE FARGE: None declared, Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Grant/research support from: Boehringer Ingelheim, Armando Gabrielli: None declared, Oliver Distler: None declared, Dinesh Khanna: None declared, Yannick Allanore: None declared

BackgroundJuvenile systemic sclerosis (jSSc) is an orphan autoimmune disease with a prevalence of 3 in 1 000 000 children. Information on long-term development of organ involvement and clinical characteristics of jSSc patients in adulthood are lacking. It was believed that patients in adult cohorts may represent a survival biased population.ObjectivesTo assess differences in clinical characteristics of jSSc-onset patients from the pediatric age group, with a mean disease duration of 3 years, compared to the adult age jSSc-onset group, with a mean disease duration of 18.5 years.MethodsWe extracted clinical data at time of inclusion into the cohorts from the Juvenile Scleroderma Inception Cohort (jSScC) and data from juvenile-onset adult SSc patients from the European Trials and Research Group (EUSTAR) cohort. We compared the clinical characteristics of the patients by descriptive statistics.ResultsWe extracted data of 187 jSSc patients from the jSScC and 236 patients from EUSTAR. The mean age at time of assessment was 13.4 years old in the jSScC and 32.4 years old in EUSTAR. The mean disease duration since first non-Raynaud was 3.0 years in jSScC and 18.5 years in the EUSTAR (Table 1).We found significant differences between the cohorts. There were more female patients in EUSTAR (87.7% versus 80.2%, p=0.04). More patients had diffuse subtype in jSScC (72.2% versus 40%, pTable 1.Clinical characteristics of juvenile onset SSc patients at time point of the inclusion into the juvenile scleroderma inception (jSScC) cohort and in the adult EUSTAR- cohortjSScCEUSTAR CohortP valueNumber of patients1872360.04Age in years, mean (SD)13.4 (3.6)32.4 (15.4)Female patients, n (%)150 (80.2%)207 (87.7%)jSSC Subtype, n (%)diffuse135 (72.2%)87 (38.1%)limited52 (27.8%)121 (53.3%)Age at Raynaud onset in years, mean (SD)10.0 (3.9)13.7 (9.1)Age at non-Raynaud onset in years, mean (SD)10.3 (3.9)11.7 (3.7)Duration since first Raynaud symptoms in years, mean (SD)3.4 (2.7)20.6 (15.9)Duration since first non-Raynaud symptoms in years, mean (SD)3.0 (2.7)18.5 (15.6)Raynaud´s, n (%)170 (90.9%)222 (94.9%)ANA positive, n (%)166 (91.7%)210 (92.9%)0.99Anti-Scl 70 positive, n (%)62 (34.4%)73 (33.3%)0.68Modified Rodnan Skin Score, mean (SD)5%Data missingModified Rodnan Skin Score, mean (SD)14.2 (11.7)12.1 (14.5)0.02Digital ulceration, n (%)At the time of inclusion33 (17.8)21 (26.6%)0.01In the past history100 (54.1%)34 (43%)Telangiectasia62 (37.4%)42 (53.2%)0.04FVC, mean (SD)84.1 (18.6)84 (22.4)0.96DLCO, mean (SD)75.4 (19.2)86.3 (19.9)Arterial hypertension, n (%)10 (5.4%)20 (8.5%)0.26Renal crisis, n (%)03 (1.3%)0.26Esophageal involvement, n (%)63 (33.7%)149 (63.7%)Intestinal involvement, n (%)62 (33.2%)56 (23.8%)0.04Articular involvement, n (%)34 (18.3%)27 (11.6%)0.06Muscular involvement, n (%)31 (19.3%)46 (19.8%)0.45ConclusionPatients with jSSc-onset who are currently adult age (defined as >18 years of age) are less frequently male and from the diffuse subset, have lower mRSS, less digital ulcers and intestinal involvement. This might represent a combination of both survival bias and/or be explained by the longer observation time with less active disease (i.e. natural progression decreased mRSS over time). Further long-term observational studies with jSSc patients are required to address this issue.Disclosure of InterestsNone declared

BackgroundPatient Reported Outcomes (PROs) are central to measure how patients feel and function especially when determining the effect of disease modifying agents. In patients with Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD), dyspnea is the main driver of HAQ decline but the effect of reduced lung function on both generic and specific measures of functional impairment is not well defined, and there are many potential confounding biases that could distort the apparent extent and direction of this relationship. Moreover, collider biases potentially induced by selection into the cohort and in clinical trials can also play a role.ObjectivesTo define within the EUSTAR database, the correlation of Forced Vital Capacity (FVC) and functional impairment PROs and identify potential confounders to be considered in casual inference studies.MethodsA cross-sectional analysis included for each patient with SSc-ILD (by X-ray and/or HRCT) in the EUSTAR registry the last visit with at least one PRO (Health Assessment Questionnaire Disability Index [HAQ-DI], Cochin hand function scale [CHFS] and/or dyspnoea visual analogue scale [VAS]) and % predicted FVC (%pFVC), if available. Patients with LVEF≤50% or pulmonary arterial hypertension at RHC were excluded. SSc-ILD with restricted lung volume was defined as %pFVC≤70 [1]. Spearman’s correlation analysis was performed. Results of this analysis and literature review were integrated to design a directed acyclic graph (DAG) and identify the appropriate confounder adjustment set for the total causal effect of FVC on functional impairment PROs.ResultsAmong 17.338 SSc patients in the EUSTAR registry (extracted in November 2019), 727 SSc-ILD patients fulfilled the inclusion criteria (median %pFVC 90 (IQR 74-104), median %pDLCO 60 (IQR 47-52)). Patients with %pFVCTable 1.Results are reported as number/number available (%) for dichotomic variables, or as median (IQR) (n available) for continuous variables.%pFVC≥70 (n=578)%pFVC)Age at disease onset (years)60.6 (52.3-69.3) (546)52.5 (45.6-63-7) (137)Disease duration (months)134.4 (77.5-212.2) (546)110.3 (66.3-199.7) (137)Male sex84/578 (14.5)32/149 (21.5)Anti-Scl70+231/468 (40.7)81/122 (66.4)Smoker ever52/389 (13.4)17/107 (15.9)Caucasian ethnicity545/569 (95.8)131/145 (90.3)dcSSc167/559 (29.9)74/147 (50.3)Oesophageal symptoms319/571 (55.9)93/147 (63.3)Muscle weakness78/565 (13.8)37/149 (24.8)CRP elevation141/540 (26.1)53/134 (39.6)Elevated sPAP (ECHO)45/456 (9.9)21/121 (17.2)Pericardial effusion2/448 (0.4)4/110 (3.6)Diastolic function abnormality151/431 (35.0)31/102 (30.4)Conduction blocks78/480 (16.3)35/120 (29.2)%pDLCO62 (52-74) (527)42 (35-53) (118)CHFS7 (1-23) (493)16 (2-34.8) (114)HAQ-DI0.63 (0.13-1.13) (578)1.25 (0.38-2) (139)VAS dyspnoea (0-100)15 (10-45) (391)40 (20-70) (109)NYHA stage 3/447/561 (8.4)37/143 (25.9)Subsequently, we created a DAG showing the proposed causal pathway considered relevant to the relationship between FVC and HAQ (Figure 1).ConclusionLung function as measured by FVC appears to correlate with worse patient-reported function in our unadjusted analysis of the large multicentre EUSTAR dataset. However, to estimate the total causal effect we must consider a multitude of potentially confounding factors, which need to be integrated and analysed in a causal inference framework. The proposed DAG will inform the development of simulations of the potential impact of bias (confounding, collider and omitted variable) on effect estimates we could obtain from EUSTAR cohort.References[1]Goh NS, et al. Am J Respir Crit Care Med, 2008.Disclosure of InterestsMaria Grazia Lazzaroni Grant/research support from: Research grant from Boehringer-Ingelheim, Michelle Wilson Grant/research support from: Research grant from Boehringer-Ingelheim, Elizabeth Hensor: None declared, Jörg H.W. Distler: None declared, Giovanna Cuomo: None declared, Elise Siegert: None declared, Ulf Müller-Ladner: None declared, Yannick Allanore: None declared, Maria Joao Salvador: None declared, Branimir Anic: None declared, Ulrich Walker: None declared, László Czirják: None declared, Camillo Ribi: None declared, Cristina-Mihaela Tanaseanu: None declared, Armando Gabrielli: None declared, Anna-Maria Hoffmann-Vold: None declared, Oliver Distler: None declared, Francesco Del Galdo: None declared

BackgroundDigital ulcers(DUs) in systemic sclerosis(SSc) represent a major clinical challenge. There are no recommendations for the local management of SSc-DUs. Systemic therapy is considered the standard of care. However, there is a strong rationale for local approaches to DU by avoiding side effects from systemic therapies. The World Scleroderma Foundation DU Working Group intends to develop evidence-based recommendations for DU management including local, non-surgical treatment(ln-sT).ObjectivesTo summarise the literature on the safety and efficacy of ln-sT for SSc-DUs.MethodsA systematic literature review(SLR) of papers describing the use of ln-sT for DU in SSc was performed up to May 2021 according to the PICO framework. References were independently screened by two reviewers who independently assessed the full text of eligible articles and extracted data.ResultsAmong 790 retrieved references, 12 were included. Median(range) number of patients per study was 9(7–84), mean age ranging from 37 to 62.5 years. In 5(41%) studies a control group was included. Background systemic therapies are summarized in Table 1. The most studied treatment was botulin toxin A(BTA). It was used as hand injection in 3 studies (median dose ranging from 90 to 150 U) and as 50 U single finger injection in 1 study. Healing rate after a median time of 8-49 weeks ranged from 71% to 100%. In 2 studies a reduction in VAS pain was observed from 20% to 100%. Transient muscle weakness was the most common side effect in 10% of patients. Amniotic(Am) and hydrocolloid membranes(HyM) were used in 1 study each. They were associated with a good healing rate, statistically significant for the HyM. Tadalafil 2% cream was studied in 1 study and was associated with a reduction in the median DU number from 1.6 to 1 per patient after a median time of 4 weeks and a reduction by 1.4 point in the 10-mm VAS scale. Vitamin E gel was shown to be associated with a statistically significant reduction in the healing time compared to SoC alone in 1 RCT(13.2 ± 2.7 versus 20.9 ± 3.6 weeks, P=Table 1.Characteristics of the studies.TreatmentType of studyPatientsBaseline DUBackground therapy (%) ETA CCB APA PG ARB ACE-I PDE-5i ISFollow-up (weeks)Healing rate(%)*Pain Reduction (VAS/10)ComparatorHydrodissection and corticosteroid injectionP1202334.4Rheumatoid ArthritisTadalafil 2% Vitamin E gelRRCT15131.6(1)3.5±2.30462700130704 241(1)Reduced time to heal**1.4SoCAmHyMRP67310001002800002817033143810090**SoCBTAMedian 90 U per handHigh-concentration hand100 U non-dominant handSingle finger 50 URRPP772010314571140718558551008514201001414718 4981277717510020%100%Untreated CHLow-level light therapyP8102537025378100ESWP9493355661144441**1.31Dimethyl sulfoxideDBRCT84No change, skin toxicity with 70% formulation*Unless otherwise stated. **Statistically significant. ARB= angiotensin receptor antagonist. ACEi= ACE inhibitors. APA= anti-platelet agents. CCB= calcium channel blockers. CH= contralateral hand. DBRCT= double blind randomized-controlled trial. ETA = endothelin antagonist. IS= immunosuppression. PG= prostaglandins. PDE-5i= Phosphodiesterase type-5 inhibitors. P = prospective. R = retrospective. SoC= standard of care (as per local protocol).ConclusionOur SLR supports interest to develop ln-sTs for SSc-DUs. The number of studies is limited and mainly case reports and small single studies are present. Treatments were well tolerated and there was evidence of efficacy for BTA, vitamin E, ESW and HyM in refractory DUs. The evidence is not robust and confounding factors (vasodilators background therapies) could impact on the findings. Future research is indicated to conduct larger, well-designed studies.Disclosure of InterestsCorrado Campochiaro: None declared, Yossra A. Suliman: None declared, Michael Hughes Speakers bureau: Actelion pharmaceuticals, Eli Lilly, and Pfizer, outside of the submitted work., Jan Schoones: None declared, Dilia Giuggioli: None declared, Pia Moinzadeh Speakers bureau: speaking fees from Actelion pharmaceuticals and Boehringer Ingelheim, Nancy Maltez: None declared, Laura Ross: None declared, Murray Baron: None declared, Lorinda Chung: None declared, Yannick Allanore: None declared, Christopher P Denton: None declared, Oliver Distler Speakers bureau: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur, Tracy Frech: None declared, Daniel Furst: None declared, Dinesh Khanna Speakers bureau: Janssen and Eicos Sciences, Inc., Thomas Krieg: None declared, Masataka Kuwana Speakers bureau: Speakers fees from AbbVie, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai, Eisai, GlaxoSmithKline, Janssen, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, and Consultant fees from AstraZeneca, Boehringer Ingelheim, Corbus, Kissei, Mochida, outside of the submitted work., Marco Matucci-Cerinic: None declared, Janet Pope: None declared, Alessia Alunno: None declared

BackgroundFew data are available on the progression and management of ILD, or the management of adverse events associated with drug treatment, in patients with lcSSc. SENSCIS-ON is an open-label extension trial that is collecting data on decline in forced vital capacity (FVC) and adverse events in patients treated with nintedanib over the long term.ObjectivesTo assess decline in FVC and adverse events in patients with lcSSc and ILD treated with nintedanib in SENSCIS-ON.MethodsPatients with SSc-ILD were eligible to enter SENSCIS-ON if they completed the randomized placebo-controlled SENSCIS trial (in which patients received trial drug until the last patient reached week 52 but for ≤100 weeks) or a drug–drug interaction (DDI) study of nintedanib and oral contraceptive (in which female patients received nintedanib for ≤28 days). Among patients with lcSSc, we analysed changes from baseline in FVC and adverse events over 52 weeks of SENSCIS-ON in patients who received nintedanib in SENSCIS and continued it in SENSCIS-ON (“continued nintedanib” group) and in patients who received placebo in SENSCIS and initiated nintedanib in SENSCIS-ON or who received nintedanib for a short time in the DDI study (“initiated nintedanib” group). Analyses were descriptive.ResultsThere were 98 patients with lcSSc in the continued nintedanib group and 127 patients with lcSSc (114 from SENSCIS, 13 from the DDI study) in the initiated nintedanib group. In these groups, respectively, mean (SD) FVC values at inclusion in SENSCIS-ON were 2449 (662) mL and 72.7(16.7) % predicted and 2508 (771) mL and 74.1 (17.4) % predicted. Mean (SE) changes in FVC from baseline to week 52 of SENSCIS-ON were −45.1 (19.1) mL in the continued nintedanib group, −41.5 (24.0) mL in the initiated nintedanib group, and −43.3 (15.3) mL in all patients with lcSSc, similar to the change in FVC in patients with lcSSc at week 52 of the SENSCIS trial (−39.1 [22.2] mL). The adverse event profile of nintedanib in SENSCIS-ON was consistent with that reported over 52 weeks of the SENSCIS trial (Table 1). Over 52 weeks, adverse events led to discontinuation of nintedanib in 3.1% of patients with lcSSc who continued nintedanib in SENSCIS-ON and 16.5% who initiated nintedanib in SENSCIS-ON.Table 1.Adverse events (irrespective of causality) reported over 52 weeks in patients with lcSSc and ILD in SENSCIS and SENSCIS-ON.SENSCISSENSCIS-ONNintedanib(n=135)Placebo(n=142)Continued nintedanib(n=98)Initiated nintedanib(n=127)Most frequent adverse events*Diarrhoea104 (77.0)43 (30.3)70 (71.4)89 (70.1)Nausea45 (33.3)20 (14.1)19 (19.4)32 (25.2)Vomiting33 (24.4)16 (11.3)15 (15.3)31 (24.4)Nasopharyngitis21 (15.6)29 (20.4)18 (18.4)23 (18.1)Upper respiratory tract infection18 (13.3)19 (13.4)13 (13.3)18 (14.2)Skin ulcer11 (8.1)18 (12.7)11 (11.2)14 (11.0)Cough17 (12.6)25 (17.6)13 (13.3)8 (6.3)Adverse event(s) leading to permanent treatment discontinuation25 (18.5)12 (8.5)3 (3.1)21 (16.5)Adverse event(s) leading to dose reduction47 (34.8)5 (3.5)17 (17.3)62 (48.8)Serious adverse event(s)30 (22.2)26 (18.3)22 (22.4)31 (24.4)n (%) of patients with lcSSc with ≥1 such event reported over 52 weeks (or until 28 days after last drug intake if earlier in SENSCIS or until 7 days after last trial drug intake if earlier in SENSCIS-ON). *Adverse events reported in >10% of patients with lcSSc in either group in SENSCIS-ON. Adverse events were coded according to preferred terms in the Medical Dictionary for Regulatory Activities.ConclusionThe change in FVC in patients with lcSSc and ILD who received nintedanib over 52 weeks, and the safety profile of nintedanib, in SENSCIS-ON were similar to that observed in patients with lcSSc and ILD who received nintedanib in SENSCIS. These analyses support a continued effect of nintedanib on slowing decline in FVC and the ability to manage adverse events of nintedanib in patients with lcSSc and ILD over the longer term.AcknowledgementsThe SENSCIS-ON trial was funded by Boehringer Ingelheim.Disclosure of InterestsYannick Allanore Consultant of: Abbvie, AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, Medsenic, Mylan, Prometheus, Roche, Sanofi, Grant/research support from: Alpine Immunosciences, Medsenic, OSE immunotherapeutics, Dinesh Khanna Shareholder of: Stocks - Eicos Sciences, Inc., Consultant of: AbbVie, Acceleron, Actelion, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos NV, Genentech/Roche, Gilead, GlaxoSmithKline, Horizon Therapeutics, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Prometheus, Sanofi-Aventis, Theraly, United Therapeutics, Grant/research support from: Bayer, Bristol-Myers Squibb, Horizon Therapeutics, Immune Tolerance Network, National Institutes of Health, Pfizer, Employee of: Leadership/Equity position – Chief Medical Officer - CiviBioPharma/Eicos Sciences, Inc, Vanessa Smith Speakers bureau: Actelion Pharmaceuticals, Boehringer-Ingelheim Pharma GmbH&Co, Janssen-Cilag NV, UCB Biopharma Sprl, Consultant of: Boehringer-Ingelheim Pharma GmbH&Co, Janssen-Cilag NV, Grant/research support from: Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer-Ingelheim Pharma GmbH&Co, Janssen-Cilag NV, Research Foundation - Flanders (FWO), Martin Aringer Speakers bureau: AbbVie, AstraZeneca, Boehringer Ingelheim, BristolMyersSquibb, Chugai, Galapagos, GlaxoSmithKline, Lilly, MSD, Novartis, Otsuka, Pfizer, Roche, Sanofi, UCB, Consultant of: AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Galapagos, GlaxoSmithKline, Lilly, Pfizer, Roche, Sanofi, Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme, Roche, Paid instructor for: Boehringer Ingelheim, Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme, Roche, Grant/research support from: Boehringer Ingelheim, Masataka Kuwana Speakers bureau: AbbVie, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai, Eisai, GlaxoSmithKline, Janssen, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, Consultant of: AstraZeneca, Boehringer Ingelheim, Corbus, MochidaKissei, Grant/research support from: Boehringer Ingelheim, MBL, Ono Pharmaceuticals, Peter A Merkel Consultant of: AbbVie, AstraZeneca, Boeringher Ingelheim, Bristol-Myers Squibb, ChemoCentryx, CSL Behring, Dynacure, EMDSerono, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, Immagene, InflaRx, Jannsen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, Pfizer, Regeneron, Sparrow, Takeda, Talaris, Grant/research support from: AbbVie, AstraZeneca, Boeringher Ingelheim, Bristol-Myers Squibb, ChemoCentryx, Eicos, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Sanofi, Takeda, Alexandra James Employee of: Alexandra James is an employee of Elderbrook solutions GmbH that is contracted by Boehringer Ingelheim, Steven Sambevski Employee of: Steven Sambevski is an employee of Boehringer Ingelheim, Margarida Alves Employee of: Margarida Alves is an employee of Boehringer Ingelheim, Christopher P Denton Speakers bureau: Boehringer Ingelheim, Janssen, Consultant of: Abbvie, Acceleron, Boehringer Ingelheim, Corbus, CSL Behring, GlaxoSmithKline, Roche, Grant/research support from: ARXX Therapeutics, GlaxoSmithKline, Horizon Therapeutics, Servier

BackgroundMixed connective tissue disease (MCTD) is a rare autoimmune condition characterized by Raynaud’s phenomenon, positivity of autoantibodies targeting the U1 small nuclear ribonucleoprotein particle (U1RNP), and various clinical features of other connective tissue diseases (1-2). Interstitial lung disease (ILD) is an established complication of the disease that is suspected to affect morbidity and mortality (3). However, little is known about MCTD-associated ILD (MTCD-ILD) phenotype including first presentation, outcomes and predictive factors for progression.ObjectivesTo compare two distinct populations of MCTD patients with and without associated ILD and to identify predictive factors for lung progression and severity.MethodsInternational multicenter retrospective study (12 tertiary hospitals). To be included, patients were required to fulfill at least one MCTD international classification criteria (4). ILD was defined by the presence of typical chest high-resolution computed tomography (HRCT) abnormalities. Patients were divided into two groups: with or without ILD, at a ratio of 1:1 and matching on disease duration (+/- 2 years).Results300 patients were included. Mean age at MCTD diagnosis was 39.7±15.4 years and 191 (63.7%) were women.At baseline, we identified several variables associated with the presence of ILD: older age (42.2 vs 37.5 years, p=0.01), scleroderma-like phenotype (38.7 vs 27.3%, p=0.03), upper gastro-intestinal (GI) symptoms (54.7 vs 30.7%, p5mg/L (54.7 vs 28.7%, p5mg/L (OR 8.77, 95% CI 2.94 to 26.22) remained significantly associated with the presence of ILD by multivariate analysis.Patients with MTCD-ILD were more likely to be treated with synthetic immunosuppressant agents (68.7 vs 49.3%, pMean follow-up was 7.8±5.5 years. In longitudinal analyses, mortality was higher in the MTCD-ILD group (8 vs 0 deaths, p10% in 33 (55%) patients. With regards to the risk of progression, we identified that history of digital ulcers (DU) was a risk factor for FVC decline >10% (OR 6.75, 95% CI 1.7-26.4, p=0.006).ConclusionIn this large international cohort of patients with MTCD, we identified several factors associated with ILD development. Our findings highlight a high risk of mortality in MCTD-ILD patients and that digital ulceration seems to be at risk of more progressive ILD.References[1]Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed connective tissue disease--an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. févr 1972;52(2):148‑59.[2]Gunnarsson R, Hetlevik SO, Lilleby V, Molberg Ø. Mixed connective tissue disease. Best Pract Res Clin Rheumatol. févr 2016;30(1):95‑111.[3]Gunnarsson R, Aaløkken TM, Molberg Ø, Lund MB, Mynarek GK, Lexberg AS, et al. Prevalence and severity of interstitial lung disease in mixed connective tissue disease: a nationwide, cross-sectional study. Ann Rheum Dis. déc 2012;71(12):1966‑72.[4]Cappelli S, Bellando Randone S, Martinović D, Tamas M-M, Pasalić K, Allanore Y, et al. « To be or not to be, » ten years after: evidence for mixed connective tissue disease as a distinct entity. Semin Arthritis Rheum. févr 2012;41(4):589‑98.Disclosure of InterestsNone declared

Background:Nintedanib has shown to slow FVC decline by 41ml over 52 weeks in systemic sclerosis-associated interstitial lung disease (SSc-ILD). However, the long-term effect of nintedanib treatment on ILD progression and mortality in SSc patients is so far unknown.Objectives:Here, the 52-week treatment efficacy of nintedanib was modeled and extrapolated on the long-term FVC course and survival in SSc-ILD patients from the European Scleroderma Trial and Research (EUSTAR) database.Methods:SSc patients from the EUSTAR database fulfilling the inclusion criteria of the SENSCIS trial (SSc classification criteria, ILD confirmed by imaging, disease duration of Results:Of the 236 included patients, 75% were females, 65% had diffuse cutaneous SSc. Mean age was 50.6 years, mean FVC 78.2%pred and DLCO 56.3%pred at time of inclusion. Mean FVC change after 12±3 months was -2.3 ±6.9%pred. These parameters were largely similar to the characteristics of the SENSCIS population.In the longitudinal follow up of this population, the natural course of FVC showed a total FVC decline of -16.3%pred over 5 years. With assumed SENSCIS effects (effects of nintedanib treatment reported in SENSCIS), the 5-year FVC decline was reduced to -10.3%pred (Figure 1).The reduced FVC progression translated into an improved survival. The natural 5-year survival of this SSc-ILD population was 88.2%. When extrapolating also a severe FVC decline early in the course, frequently terminated by early mortality of SSc patients excluding them from long-term outcome assessment, the estimated 5-year survival was reduced to 81.6%. When the SENSCIS effects on FVC were considered, the 5-year extrapolated survival was increased to 86.3% (Figure 2).Conclusion:Long-term experience of nintedanib treatment in SSc-ILD patients is lacking so far, therefore we modeled and extrapolated the 52-week treatment efficacy of nintedanib on the long-term FVC course and survival in SSc-ILD patients from the EUSTAR database. We could demonstrate a significant reduction of FVC decline by extrapolating the annual treatment effects of nintedanib from the SENSCIS trial from 1 to 5 years in EUSTAR. Translating these reductions of FVC decline into survival, the 5-year mortality rate was reduced from 18% to 13%.Disclosure of Interests: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, Dörte Huscher: None declared, Paolo Airò Speakers bureau: Boehringer Ingelheim, Consultant of: Bristol-Myers-Squibb, Novartis, Elisabetta Zanatta Speakers bureau: Boehringer Ingelheim, Actelion, GSK, Paid instructor for: GSK, Consultant of: Boehringer Ingelheim, GSK, Patricia Carreira Speakers bureau: Actelion, Boehringer Ingellheim, Janssen, GSK, Paid instructor for: Boehringer Ingelheim, Consultant of: AbbVie, Boehringer Ingelheim, VivaCell, Emerald Health Pharmaceuticals, Gesynta Pharma, Sanofi Genzyme, Grant/research support from: Roche, GSK, Yannick Allanore Consultant of: Honorarium received from Boehringer, MedsenicSanofi, Menarini, Grant/research support from: Grants received from Alpine, Ose Immunogenetics, Ulf Müller-Ladner Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Alessandro Giollo: None declared, Maria Rosa Pozzi: None declared, CAROLINA SOUZA MULLER Speakers bureau: Boehinger Ingelheim, Janssen, Roche, LIBBS, Bristol-Myers-Squib, Radim Bečvář Consultant of: Actelion, Boehringer Ingelheim, Michele Iudici: None declared, Dominik Majewski Speakers bureau: Boehringer Ingelheim - 2 x paid as a speaker, Armando Gabrielli Grant/research support from: Pfizer, CSL Behring, Margarida Alves Employee of: Boehringer Ingelheim, Nils Schoof Employee of: Boehringer Ingelheim International GmbH, Oliver Distler Speakers bureau: Boehringer Ingelheim, Medscape, IQone, Roche, 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, Kymera Therapeutics, Lilly, Medac, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB, Grant/research support from: Kymera Therapeutics, Mitsubishi Tanabe

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

Background:There is renewed interest in the role of autoantibodies to predict outcomes in systemic sclerosis (SSc). Among the newly identified subsets, patients with limited cutaneous form (lcSSc) but anti-topoisomerase I antibodies (Scl70) positivity draw particular attention, and namely, assessing the risk of developing interstitial lung disease (ILD) —the main cause of death in SSc—to improve the management of Scl70-lcSSc patients.Objectives:We aimed to characterize patients with Scl70-lcSSc in the large multicenter European Scleroderma Trial and Research (EUSTAR) cohort.Methods:The EUSTAR database was locked in July 2019. We included all patients fulfilling 1980 ACR and/or 2013 ACR/EULAR criteria for SSc, with disease duration at database entry ≤3 yrs and known and stable skin form during the first 3 yrs. Patients with lcSSc were compared: Scl70-lcSSc (target group) vs. ACA-lcSSc and ANA-lcSSc (Step 1); and Scl70-lcSSc vs. Scl70-dcSSc (Step 2). In the ANA subgroup we included ANA+ patients with negative SSc-specific antibodies (Scl70, ACA, RNA polymerase III). In each step, we performed 5 generalized mixed models (GMM) for the risk of the new onset of ILD (defined by imaging), primary myocardial involvement (PMI), pulmonary hypertension (PH), “any severe” (ILD+PMI+PH+scleroderma renal crisis) and all-cause-mortality. An additional GMM assessed the risk of forced vital capacity (FVC) decline ≥10% vs. FVC value at ILD onset. Each GMM was adjusted for age, sex and confounders.Results:Overall, 1285 SSc patients were included: 1068 (83%) females, 860 (67%) lcSSc and 425 (33%) dcSSc. Among patients with lcSSc, 537 (62%) had ACA+, 194 (23%) Scl70+ and 129 (15%) ANA+; 425 patients had dcSSc and Scl70+. Median follow-up was similar in all 4 groups: 7.2 to 8.1 yrs.Step 1: At baseline, Scl70-lcSSc patients had significantly shorter time from Raynaud’s phenomenon (RP) to SSc onset, higher mRSS (5.8±4.8 vs. 4.3±4, p=0.001), and higher rate of articular and muscular involvement vs. ACA-lcSSc patients (Figure 1). No differences were found between Scl70-lcSSc and ANA-lcSSc comparing the aforementioned variables. ILD was more frequent in Scl70-lcSSc (46%) than in ACA-lcSSc (10%) and ANA-lcSSc (25%), as well as restrictive lung disease. GMM showed that Scl70-lcSSc carries a higher risk of ILD than both ACA-lcSSc (HR 4.55, 95%CI 3.23-6.67) and ANA-lcSSc (HR 2.17, 95%CI 1.39-3.45), with a rate of FVC decline ≥10% over time similar to the other limited forms. In Scl70-lcSSc patients the risk of “any severe” organ involvement was similar to ANA-lcSSc and higher than ACA-lcSSc (HR 1.89, 95%CI 1.40-2.50). In particular, Scl70-lcSSc shows a risk of PMI similar to ANA-lcSSc and lower than ACA-lcSSc; no differences regarding PH risk. The mortality risk in patients with Scl70-lcSSc was similar to the other limited forms’.Step 2: At baseline, time from RP to SSc onset was longer in patients with Scl70-lcSSc, with less frequent joint synovitis and tendon friction rubs vs. patients with Scl70-dcSSc. Conversely, the frequency of muscular, cardiac and pulmonary involvement was similar. The risk of ILD in Scl70-lcSSc patients was similar to Scl70-dcSSc, with a lower risk of FVC decline ≥10% over time. The risk of “any severe” involvement (HR 0.66, 95%CI 0.49-0.83), PMI and PH was lower and the mortality risk tended to be lower (HR 0.57, 95%CI 0.33-1.01, p=0.053) vs. Scl70-dcSSc.Conclusion:In our large multicenter EUSTAR cohort one quarter of lcSSc patients were Scl70+. We show a ranking for major organ involvement within lcSSc: Scl70 the most severe, ANA+ intermediate and ACA the milder form. Scl70-dcSSc patients present the most severe phenotype, and Scl70 positivity, more than the cutaneous subset, is strongly predictive of ILD, whereas other variables may influence progression. These results may provide new insight to improve the management of Scl70-lcSSc patients.Disclosure of Interests:Elisabetta Zanatta: None declared, Dörte Huscher: None declared, Paolo Airò: None declared, Alexandra Balbir-Gurman: None declared, Elise Siegert: None declared, Augusta Ortolan: None declared, Marco Matucci-Cerinic: None declared, Franco Cozzi: None declared, Gabriela Riemekasten: None declared, Anna-Maria Hoffmann-Vold: None declared, Oliver Distler Speakers bureau: has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years): Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Consultant of: 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, Armando Gabrielli: None declared, Stefan Heitmann: None declared, Nicolas Hunzelmann: None declared, Carlomaurizio Montecucco: None declared, Jadranka Morovic-Vergles: None declared, Camillo Ribi: None declared, Andrea Doria: None declared, Yannick Allanore: None declared

Background:In SSc, ILD is a major cause of morbidity and mortality. High resolution computed tomography (HRCT) is the gold standard for the diagnosis. Predictors of ILD onset are eagerly awaited to improve SSc-ILD management. Pulmonary function test (PFTs) are routinely performed to measure lung function changes.Objectives:Our aim was to investigate the performance of DLCO (diffusing capacity of lung carbon monoxide) and FVC (forced vital capacity) in predicting the development of SSc-ILD.Methods:The longitudinal data of DLCO, FVC and ILD on HRCT of SSc patients from the EUSTAR database were evaluated at baseline (t0), after 12 (±4) (t1) and 24 (±4) (t2) months. Patients with negative HRCT for any sign of ILD both at t0 and t1 were included. Patients who presented or developed pulmonary hypertension during the study period were excluded. At baseline, demographic data, disease duration from Raynaud’s onset, disease subsets, autoantibodies and other laboratory and instrumental data were recorded.Results:474/17805 patients were eligible for the study (403 females, 71 males): 26.0% dcSSc, 58.3% lcSSc, 220 (48.0%) patients with positive anticentromere antibodies (ACA) and 117 (25.4%) with positive antitopoisomerase I antibodies (Topo-I abs). Among all enrolled patients, 46 (9.7%) developed HRCT signs of ILD at t2. Patients with Topo-I abs showed an association with ILD development at t2 (16.7% vs 7.8%, p=0.0031), contrarily ACA positive patients were negatively associated with ILD appearance after 2 years of follow-up (4.4% vs 14.4%, p=0.0001). Positive t2 HRCT patients had a significant lower value of DLCO and FVC at all three assessments when compared to patients with a negative HRCT at t2 (Table 1) and both t0 DLCO and FVC values negatively correlated with ILD development (Table 1). The mean t0 to t1 change (Δ) of DLCO in patients with negative t2 HRTC and positive t2 HRCT were -0.5 (±12.6) and -1.0 (±15.1), respectively. The mean t0 to t1 ΔFVC in patients with negative t2 HRTC and positive t2 HRCT were -0.2 (±10.6) and 0.1 (±11.5), respectively. None of them predicted the appearance of ILD at t2 (ΔDLCO: OR (IC) 0.997 (0.97-1.02), p=0.8024; ΔFVC OR (IC) 1.002 (0.97-1.03), p=0.8664). The data showed an association between t0 DLCO value0 FVC value0 DLCOConclusion:Our data suggest that an impaired baseline DLCO (Table 1.DLCO and FVC values at t0, t1 and t2 values in patients with positive or negative HRCT for ILD at t2 and their statistical differences.Patients without ILD at t2 (mean±SD)Patients with ILD at t2 (mean±SD)OR (95%CL)p-valueDLCO at t079.0 ± 16.669.9 ± 17.40.97 (0.95 - 0.99)0.0006DLCO at t178.4 ± 16.868.9 ± 18.60.97 (0.95 - 0.98)0.0005DLCO at t278.0 ± 17.065.1 ± 19.10.95 (0.93 - 0.97)FVC at t0102.2 ± 17.394.6 ± 16.20.97 (0.96 - 0.99)0.0052FVC at t1101.9 ± 17.994.7 ± 16.50.98 (0.96 - 0.99)0.0092FVC at t2101.6 ± 17.694.5 ± 20.00.98 (0.96 - 1)0.0126Disclosure of Interests:Gemma Lepri: None declared, Cosimo Bruni Speakers bureau: CB reports personal fees from Actelion, personal fees from Eli Lilly, Grant/research support from: CB reports personal fees from Actelion, personal fees from Eli Lilly, grants from European Scleroderma Trial and Research (EUSTAR) group, grants from New Horizon Fellowship, grants from Foundation for Research in Rheumatology (FOREUM), grants from Fondazione Italiana per la Ricerca sull’Artrite (FIRA), outside the submitted work, Lorenzo Tofani: None declared, Alberto Moggi Pignone: None declared, Martina Orlandi: None declared, Tomasetti Sara Speakers bureau: Speaker’s fees for Roche and Boehringer Ingelheim, Mike Hughes: None declared, Francesco Del Galdo: None declared, Rosaria Irace: None declared, Oliver Distler Grant/research support from: OD (last three years) 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)., Valeria Riccieri: None declared, Yannick Allanore Speakers bureau: YA received personal fees from Boehringer, Sanofi, Menarini and Medsenic and grants from Alpine with regards to the management of systemic sclerosis, Grant/research support from: YA received personal fees from Boehringer, Sanofi, Menarini and Medsenic and grants from Alpine with regards to the management of systemic sclerosis, Ana Maria Gheorghiu: None declared, Elise Siegert: None declared, Jeska de Vries-Bouwstra: None declared, Eric Hachulla: None declared, Mohammed Tikly: None declared, Nemanja Damjanov: None declared, Francois Spertini: None declared, Luc Mouthon: None declared, Anna-Maria Hoffmann-Vold Speakers bureau: AMHV: received consulting fees from Actelion, ARXX, Bayer, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme and Roche; and grants from Boehringer Ingelheim., Consultant of: AMHV: received consulting fees from Actelion, ARXX, Bayer, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme and Roche; and grants from Boehringer Ingelheim., Grant/research support from: AMHV: received consulting fees from Actelion, ARXX, Bayer, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme and Roche; and grants from Boehringer Ingelheim., Armando Gabrielli: None declared, Serena Guiducci: None declared, Marco Matucci-Cerinic Speakers bureau: has received consulting fees or honorarium from Actelion, Janssen, Inventiva, Bayer, Biogen, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, Roche, Grant/research support from: has received consulting fees or honorarium from Actelion, Janssen, Inventiva, Bayer, Biogen, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, Roche, Daniel Furst: None declared, Silvia Bellando Randone: None declared

Background:In the SENSCIS trial, nintedanib reduced the progression of SSc-ILD compared with placebo, as shown by a significantly lower rate of decline in forced vital capacity (FVC) over 52 weeks. There was no significant difference between treatment groups in change in modified Rodnan skin score (mRSS) at week 52. An mRSS of 18–25 has been proposed as an upper cut-off to enrich a cohort for skin-progressive patients. Progression of skin fibrosis has been associated with later progression of ILD.Objectives:To assess the effects of nintedanib on the rate of FVC decline and change in mRSS in the SENSCIS trial in subgroups by mRSS Methods:Patients with SSc-ILD with onset of first non-Raynaud symptom Results:In the nintedanib and placebo groups, respectively, 219/288 (76.0%) and 226/288 (78.5%) patients had mRSS Conclusion:In the placebo group of the SENSCIS trial, the rate of decline in FVC over 52 weeks was numerically greater in patients with mRSS ≥18 than Acknowledgments:The SENSCIS trial was funded by Boehringer IngelheimDisclosure of Interests:Yannick Allanore Grant/research support from: Yannick Allanore has received grants from Inventiva, Roche and Sanofi, Consultant of: Yannick Allanore has received fees from Actelion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Curzion, Inventiva, Roche, Sanofi, Viginia Steen Grant/research support from: The associated affiliation has received grants/research from Boehringer Ingelheim, Corbus Pharmaceuticals, CSL Behring, Eicos, Galapagos, Immune Tolerance Network, Reata, Consultant of: Virginia Steen has acted as a consultant for Boehringer Ingelheim, Corbus, CSL Behring, Eicos, Forbius, Masataka Kuwana Grant/research support from: Acetelion, Consultant of: Acetelion, Bayer, Chugai, Corbus Pharmaceuticals, CSL Behring and Reata Pharmaceuticals. He was a member of the SENSCIS trial Steering Committee (Boehringer Ingelheim), Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Bristol-Myers Squibb, Speakers bureau: Acetelion, Lilly, Boehringer Ingelheim, Elizabeth Volkmann Grant/research support from: Forbius, Corbus Pharmaceuticals, Consultant of: Boehringer Ingelheim, Forbius, Speakers bureau: Boehringer Ingelheim, Dinesh Khanna Shareholder of: Eicos Sciences, Inc./Civi Biopharma, Inc., Grant/research support from: Dr Khanna was supported by NIH/NIAMS K24AR063120, Consultant of: Acceleron, Actelion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Corbus Pharmaceuticals, Horizon Therapeutic, Galapagos, Roche/Genentech, GlaxoSmithKline, Mitsubishi Tanabe, Sanofi-Aventis/Genzyme, UCB, Daniel Wachtlin Employee of: Employee of Boehringer Ingelheim, Martina Gahlemann Employee of: Employee of Boehringer Ingelheim, Manuel Quaresma Employee of: Employee of Boehringer Ingelheim, Margarida Alves Employee of: Employee of Boehringer Ingelheim, 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:Patient reported outcome measures (PROM) are important for clinical practice and research. Given the unmet need for a comprehensive PROM for systemic sclerosis (SSc), the ScleroID questionnaire was developed by a joint team of patients with SSc and medical experts. This is intended as a brief, specific, patient-derived, disease impact score for research and clinical use in SSc.Objectives:Here, we present the validation and final version of the ScleroID.Methods:This EULAR-endorsed project involves 9 European expert SSc centers. Patients fulfilling the ACR/EULAR 2013 criteria were prospectively included since 05/16 in a large observational cohort study. Patients completed the ScleroID and comparators SHAQ, EQ5D, SF36. They also weighted the 10 dimensions of the ScleroID by distributing 100 points according to the perceived impact on their health. The final score calculation is based on the ranking of the weights. The validation study included a reliability arm and a longitudinal arm, looking at sensitivity to change at follow-up.Results:Of the 472 patients included at baseline, 109 patients also had a reliability visit and 113 patients a follow-up visit. 84.5% of patients were female, 29.8% had diffuse SSc, mean age was 54.6 years, and mean disease duration 9.5 years. The highest weights were assigned by the patients to Raynaud`s phenomenon, fatigue, hand function and pain, confirming our previous results. The total ScleroID score showed good Spearman correlation coefficients with the comparators (SHAQ, 0.73; EQ5D -0.48; Patient’s global assessment, VAS 0.77; HAQ-DI 0.62; SF36 physical score -0.62; each pFigure 1.Conclusion:The EULAR ScleroID is a novel PROM designed for use in clinical practice and clinical trials to reflect the disease impact of SSc, showing good performance in the validation study. Importantly, Raynaud syndrome, impaired hand function, pain and fatigue were the main patient reported drivers of disease impact.Disclosure of Interests:Mike O. Becker: None declared, Rucsandra Dobrota: None declared, Kim Fligelstone: None declared, Annelise Roennow: None declared, Yannick Allanore Grant/research support from: BMS, Inventiva, Roche, Sanofi, Consultant of: Actelion, Bayer AG, BMS, BI, Patricia Carreira Grant/research support from: Actelion, Roche, MSD, Consultant of: GlaxoSmithKline, VivaCell Biotechnology, Emerald Health Pharmaceuticals, Boehringer Ingelheim, Roche, Speakers bureau: Actelion, GlaxoSmithKline, Roche, László Czirják Consultant of: Actelion, BI, Roche-Genentech, Lilly, Medac, Novartis, Pfizer, Bayer AG, Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer, Roger Hesselstrand: None declared, Gunnel Sandqvist: None declared, Otylia Kowal-Bielecka Consultant of: Bayer, Boehringer Ingelheim, Inventiva, MSD, Medac, Novartis, Roche and Sandoz, Speakers bureau: Bayer, Boehringer Ingelheim, Inventiva, MSD, Medac, Novartis, Roche and Sandoz, Cosimo Bruni Speakers bureau: Actelion, Eli Lilly, Marco Matucci Cerinic: None declared, Carina Mihai: None declared, Ana Maria Gheorghiu: None declared, Ulf Müller-Ladner Speakers bureau: Biogen, Joe Sexton: None declared, Turid Heiberg: 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:Systemic sclerosis (SSc) is a progressive, multi-organ disease with limited treatment options. Interleukin-4 (IL-4) and IL-13 have been implicated in the fibrotic pathway and pathogenesis of SSc and are promising targets. Romilkimab (RKB) is an engineered humanized bispecific Ig-G4 antibody that binds and neutralizes both IL-4/IL-13. We report a Phase IIa randomized, double-blind, placebo-controlled trial (NCT02921971, Sanofi funded) employing RKB in SSc.Objectives:To evaluate the efficacy and safety of RKB in dcSSc.Methods:Patients with dcSSc duration ≤36 months, mRSS 10-35, with or without immunosuppressive background therapy were randomized (1:1) to subcutaneous RKB 200mg or placebo (PBO) for 24 weeks and stratified on history of SSc-ILD. Primary endpoint was mean change in mRSS at Week 24 and FVC/DLco and HAQ-DI were secondary endpoints. All analyses used a 1-sided p-value Results:Ninety-seven patients with similar baseline characteristics between arms, including use of background therapy (RKB 59.2% vs. PBO 52.1%) were randomized. Six (12.2%) and 4 (8.3%) patients discontinued study treatment early in the PBO and RKB arms, respectively. Primary endpoint showed an absolute change in mRSS of -2.45 (0.85) and -4.76 (0.86) for PBO and RKB groups, respectively with a difference of -2.31 (1.21) favoring RKB (p=0.029). Subgroup analysis based on background therapy showed a similar treatment effect with a PBO subtracted difference in mRSS of -2.69 (1.83) and -2.38 (1.59), suggesting an additive effect between background therapy and RKB. Secondary endpoints did not show a statistically significant difference between RKB vs. PBO arms, although there was numerically less decline in FVC with RKB with a PBO subtracted difference of 70ml (p=0.06). Exploratory endpoints suggested possible effect of RKB on overall pain, Raynaud’s, digital ulcers, and EQ-5D-5L. Post-hoc analysis was undertaken to determine time to progression (first event defined as death, ≥10% relative decline in % predicted FVC, ≥15% relative decline in % predicted DLCO, ≥20% increase or +5 in mRSS, or other events: cardiac, SRC, PAH development) and showed a benefit for RKB (HR: 0.47 p=0.04). Adverse events were balanced between the two groups (RKB 83.3% vs. PBO 83.7%). There were 5 and 4 SAEs in the PBO and RKB arms, respectively. One death occurred in each arm (SRC – RKB, cardiomyopathy – PBO).Conclusion:Patients with dcSSc who were treated with RKB showed a statistically significant reduction in mRSS compared to those receiving PBO. Secondary outcomes were not met, although RKB was associated with a smaller decline in FVC than PBO. Post-hoc analysis showed a possible reduction on time to progression with RKB. RKB was well tolerated with no major safety concerns.References:None.Disclosure of Interests:Yannick Allanore Grant/research support from: Yannick Allanore has received grants from Inventiva, Roche and Sanofi, Consultant of: Yannick Allanore has received fees from Actelion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Curzion, Inventiva, Roche, Sanofi, Peter Wung Shareholder of: I own Sanofi stock, Employee of: I work for Sanofi, Christina Soubrane Employee of: I work for Sanofi., Corinne Esperet Employee of: I work for Sanofi., MARRACHE Frederic Employee of: I work for Sanofi, Raphael Bejuit Employee of: I work for Sanofi., Amel Lahmar Employee of: I work for Sanofi., Dinesh Khanna Shareholder of: Eicos Sciences, Inc./Civi Biopharma, Inc., Grant/research support from: Dr Khanna was supported by NIH/NIAMS K24AR063120, Consultant of: Acceleron, Actelion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Corbus Pharmaceuticals, Horizon Therapeutic, Galapagos, Roche/Genentech, GlaxoSmithKline, Mitsubishi Tanabe, Sanofi-Aventis/Genzyme, UCB, Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer

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: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 COVID-19 pandemic requires measures to reduce patient exposure to the risk of contamination, in particular by limiting hospital admissions and promoting lockdown. In order to respond to these healthcare measures, patients were offered to replace intravenous infusions (IV) of abatacept (ABT) and tocilizumab (TCZ) to subcutaneous injections (SC).Objectives:To assess the outcome of patients who switched from IV ABT or TCZ to SC during the COVID-19 pandemic.Methods:A survey was conducted in December 2020 in partnership with the national AFP-RIC patient association to assess the outcome and satisfaction of patients who switched from ABT or TCZ IV to SC during the first wave of COVID-19 pandemic.We also analysed the outcome of patients who switched from IV ABT or TCZ to SC in the rheumatology department of Cochin Hospital during the lockdown in April/may 2020. Articular activity parameters (swollen joint count, pain joint count, visual analogic pain scale, CRP, DAS-28 activity score) were assessed at medical visits before and 6 months after switching from IV to SC.The data collected from the AFP-RIC patient association and the rheumatology department of Cochin Hospital were then aggregated and analyzed by Chi-square and Wilcoxon tests.Results:81 patients responded to the survey carried out by AFP-RIC patient association, including 29 treated with IV ABT (n=15, 52%) or TCZ (n=14, 48%). 17/29 (59%) were offered to switch from IV to SC, 14/17 patients (82%) accepted and 7 patients were still receiving ABT or TCZ SC injections in December 2020. In the rheumatology department of Cochin hospital, 71 patients were scheduled in April/May 2020 to receive IV ABT or TCZ, and 27 (38%) switched to SC. After 6 months, 19 patients (70%) had maintained SC injections, were satisfied with this injection route of administration and their articular activity parameters were unchanged (Table 1).Table 1.Course of Disease parameters evaluated in the 19 patients who maintained abatacept or tocilizumab SC injections in the Rheumatology department of Cochin HospitalParameter, mean(SD)Inclusion visitSwitch to SC(n=19)6 month visit (n=19)P-valueDAS282.3 (1.2)2.3 (0.7)0.62Tender joint count2.5 (3.5)1.3 (1.7)0.49Swollen joint count1.3 (2.5)0.9 (0.6)0.35Patient Global Health (cm)3.2 (1.9)2.6 (1.8)0.60CRP (mg/L)3.2 (4.1)5.2 (4.9)0.56CRP: C-Reactive Protein, SD: Standard DeviationThe combined analysis of these two populations included 41 patients (33 rheumatoid arthritis, RA, 7 juvenile idiopathic arthritis, JIA and 1 polymyalgia rheumatica) who switched to SC ABT or TCZ. 26/41 (63.5%) patients maintained SC injections and IV was re-established in 15/41 (36.5%). Reasons for returning to IV were poor tolerance of SC injections (n=6, 40%), worsening symptoms (n=11, 73%), patient preference to see a rheumatologist in hospital (n=10, 67%) and the high number of SC injections (n=2, 13%). The proportion of patients returning to IV was higher in RA patients compared to patients with JIA (42% vs. 14%, p = 0.08). Age and disease duration were not significantly different between patients who maintained SC injections and those who returned to IV (respectively p=0.97 and p=0.63).Conclusion:Our study suggests that switching from IV ABT or TCZ to SC is an acceptable procedure during the COVID-19 pandemic, especially for patients with JIA.Acknowledgements:Association AFP-RIC (Angélique Hochedé, Cyrielle Beller, Sandrine Rollot) and the members of the association for their help in the conduction of the surveyDisclosure of Interests:None declared.

Background:Interstitial lung disease (ILD) is the leading cause of mortality in patients with Systemic Sclerosis (SSc). Forced Vital Capacity (FVC) is a major indicator of severity in SSc ILD. The ELF serum test and its constituent biomarkers (HA, PIIINP and TIMP-1) have shown to correlate with FVC in two large, independent multicentre cohorts of 457 patients, but also showed a correlation with age.Objectives:Here we aimed to investigate the relationship of the ELF biomarkers and age in a large population of healthy controls and to identify a combined clinical and biomarkers model to stratify for risk of ILD progression in a multicentre longitudinal cohort of patients with SSc.Methods:ELF score was measured in sera from 925 healthy controls in one centre and 869 longitudinal samples from 254 SSc patients from 6 centres across 4 European countries. Clinical data were recorded according to EUSTAR Minimal Essential dataset. FVC% change over time was estimated by Mixed-effects modelling. Patients were then divided in two groups: progressors, with a %FVC drop > 3%/year (according to published MCID) and a group of patients with stable or improving FVC. Lasso penalised regression was carried out with biomarkers and the available clinical and demographic variables at patient’s first visit as potential predictors. The resulting linear predictor was used to derive two thresholds, one for optimal sensitivity (rule-out) and one for optimal specificity (rule-in). Patients within thresholds were further selected according to the ratio of TIMP-1: PIIINP (Figure 1).Results:HA was the only ELF biomarker that correlated significantly with age in the healthy control cohort. Therefore, we defined by linear regression a “residual HA” which accounted for age. TIMP1, PIIINP and residual HA were then considered as distinct biomarkers in the analysis of the SSc cohort. 189 SSc patients with 785 time-points had complete datasets and were included in the analysis. Median follow up was 33 months (IQR 18-48). One-hundred and forty patients (74%) were classified as non progressors, 94 (50%) with no change or improving FVC and 46 (24%) with FVC drop Conclusion:Building on the face and content validity of the biomarkers included in the ELF score, here we identify an easy to assess combined clinical and biomarker model to stratify patients for their risk of ILD progression. Despite its derivation from a large multicentre cohort, independent validation will determine the clinical value of Scleroscore as a stratification tool for risk of progression of SSc ILD.Disclosure of Interests:Michelle Hutchinson: None declared, Giuseppina Abignano: None declared, Jelena Blagojevic: None declared, Silvia Laura Bosello: None declared, Yannick Allanore Grant/research support from: Alpine, Boehringer Ingelheim, Genentech/Roche, Medsenic, and Sanofi, Christopher Denton Consultant of: Corbus, Actelion, GlaxoSmithKline, Bayer, Sanofi, Galapagos, Inventiva, Boehringer Ingelheim, Roche, CSL Behring, Acceleron, Horizon, Arxx Therapeutics, Grant/research support from: Corbus, Actelion, GlaxoSmithKline, Bayer, Sanofi, Galapagos, Inventiva, Boehringer Ingelheim, Roche, CSL Behring, Acceleron, Horizon, Arxx Therapeutics, 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, Paul Emery Consultant of: Lilly, Abbvie, Roche, Grant/research support from: Lilly, Marco Matucci-Cerinic Consultant of: Chemomab, Lilly, Abbvie, Actelion, Francesco Del Galdo Speakers bureau: Astra-Zeneca, Boehringer Ingelheim, Actelion, Consultant of: Astra-Zeneca, Mitsubishi-Tanabe, Capella Biosciences, Chemomab, Actelion, Boehringer-Ingelheim, Grant/research support from: Capella Biosciences, Chemomab, Kymab, Mitsubishi-Tanabe

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:COVID-19 pandemic is a global emergency which may overlap on the clinical and radiological scenario of ILD in SSc. In clinical practice, the striking similarities observed at computed tomography (CT) between the diseases make it difficult to distinguish a COVID-19 superinfection from a progression of SSc-ILD.Objectives:The aim of our study was to identify the main CT features that may help distinguishing SSc-ILD from COVID-19 pneumonia.Methods:22 international readers were included and divided in the radiologist group (RAD) and non-radiologist group (nRAD). The RAD group included non-chest RAD and chest-RAD. A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study.Results:Fibrosis inside focal ground glass opacities (GGO) in the upper lobes; fibrosis in the lower lobe GGO; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT parameters most frequently associated with SSc-ILD. The CT parameters most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONS in the lower lobes (p Conclusion:The CT differential diagnosis between COVID-19 Pneumonia and SSc-ILD is possible and may be fostered in practice by the use of a radiological score. In the case where an overlap of both diseases is suspected, the presence of consolidation in the lower lobes may suggest a COVID-19 pneumonia while the presence of fibrosis inside GGO may indicate a SSc-ILD.References:[1]Orlandi M, Landini N, Bruni C, et al. Infection or autoimmunity? The clinical challenge of interstitial lung disease in systemic sclerosis during COVID 19 pandemic. J Rheumatol. 2020 Dec 1: jrheum.200832[2]Simpson S, Kay FU, Abbara S, et al. Radiological Society of North America Expert Consensus Statement on Reporting Chest CT Findings Related to COVID-19. Endorsed by the Society of Thoracic Radiology, the American College of Radiology, and RSNA [published online ahead of print, 2020 Apr 28]. J Thorac Imaging. 2020;10.1097/RTI.0000000000000524.[3]Cheng C, Li C, Zhao T, et al. COVID-19 with rheumatic diseases: a report of 5 cases. Clin Rheumatol. 2020;39(7):2025-2029.[4]Mariano RZ, Rio APTD, Reis F. Covid-19 overlapping with systemic sclerosis. Rev Soc Bras Med Trop. 2020 Sep 21;53:e20200450.Disclosure of Interests:None declared

Background:The ACR Composite Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) was developed to measure the probability of improvement in response to treatment in patients with early diffuse cutaneous SSc (dcSSc), accounting for new/worsening cardiopulmonary involvement and/or renal crisis, and changes in modified Rodnan skin score, forced vital capacity, health assessment questionnaire disability index, and patient’s and physician’s global impressions. In patients with SSc-ILD, treatment response may be reflected as slower progression, stabilisation or improvement.Objectives:Using data from patients with dcSSc and ILD in the placebo group of the SENSCIS trial, we analysed the probability of improvement using the ACR CRISS score at week 52. We also evaluated whether the CRISS numerator could provide information on the spectrum of responses in this patient population.Methods:The SENSCIS trial enrolled subjects with SSc-ILD with onset of first non-Raynaud symptom ≤7 years before screening, FVC ≥40% predicted, and fibrotic ILD ≥10% extent on an HRCT scan. Subjects on prednisone ≤10 mg/day (or equivalent) and/or stable therapy with mycophenolate or methotrexate were allowed to participate. Subjects were randomised to receive nintedanib or placebo. Subjects were not randomised by use of mycophenolate. In patients randomised to receive placebo who had dcSSc and/or mRSS >15 at baseline, we analysed the ACR CRISS and its numerator at week 52 in subgroups by use of mycophenolate at baseline. Analyses were exploratory and descriptive.Results:Of 117 analysed subjects in the placebo group who had dcSSc and/or mRSS >15 at baseline, 60 (51.3%) were taking mycophenolate at baseline. Compared with patients not taking mycophenolate at baseline, those taking mycophenolate had a lower mean age (48.4 [SD 11.8] vs 53.1 [13.4] years), lower mean FVC % predicted (68.8 [17.0] vs 73.0 [14.6]), and a greater proportion were female (76.7% vs 71.9%); median time since first onset of non-Raynaud symptom was similar (3.9 vs 4.5 years, respectively) as was mean (SD) mRSS (16.5 [7.7] vs 15.9 [8.0], respectively). One patient (taking mycophenolate at baseline) had limited cutaneous SSc. At week 52, median (Q1, Q3) ACR CRISS score was 0.036 (0.001, 0.601) in subjects taking mycophenolate and 0.002 (0.000, 0.112) in subjects not taking mycophenolate at baseline, and mean (SD) ACR CRISS score was 0.28 (0.37) in subjects taking mycophenolate and 0.16 (0.31) in subjects not taking mycophenolate at baseline (Figure 1). In these groups, respectively, 25.0% and 14.0% of subjects had CRISS score >0.6 (considered improved) at week 52. The CRISS numerator provided a broader distribution of response values, but was not informative in this patient population.Conclusion:In exploratory analyses, among subjects with dcSSc and ILD who received placebo in the SENSCIS trial, the proportion considered improved at week 52 based on ACR CRISS score was numerically greater in patients taking than not taking mycophenolate at baseline. There remains a need for composite scores that provide better interpretation of the magnitude of response in patients with SSc.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:Francesco Del Galdo Speakers bureau: Actelion and AstraZeneca, Consultant of: Actelion, AstraZeneca, Boehringer Ingelheim, Capella BioScience, ChemomAb and Mitsubishi Tanabe Pharma, Grant/research support from: Capella BioScience, Kymab and Mitsubishi Tanabe Pharma, Oliver Distler Consultant of: AbbVie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Bayer, Blade Therapeutics, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos NV, GlaxoSmithKline, Glenmark Pharmaceuticals, Horizon (Curzion) Pharmaceuticals, Inventiva, IQVIA, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Target Bioscience, Topadur Pharma and UCB, Grant/research support from: Kymera Therapeutics and Mitsubishi Tanabe Pharma, 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, Yannick Allanore Consultant of: Boehringer Ingelheim, Medsenic, Menarini and Sanofi, Grant/research support from: Alpine Pharmaceuticals, Daniel Wachtlin Employee of: Currently an employee of Boehringer Ingelheim, Margarida Alves Employee of: Currently an employee of Boehringer Ingelheim, 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, 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.

Background:Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Its use has been associated with hypersensitivity pneumonitis and diffuse lung disease. Whether MTX exposure increases the risk of interstitial lung disease (ILD) in patients with RA is disputed.Objectives:We aimed to evaluate the association of antecedent MTX use with development of RA-ILD.Methods:Through a case-control study design with derivation and international validation samples, we examined the association of MTX exposure with ILD in 482 patients with RA-ILD and 741 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques.Results:Analysis of the derivation sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted odds ratio [OR], 0.48; 95% confidence interval [CI], 0.25 to 0.92; P=0.028), which was confirmed in the validation samples (pooled adjusted OR, 0.39; 95% CI, 0.23 to 0.68; PConclusion:Our results suggest that MTX is not a risk factor for RA-ILD and support a possible disease modifying effect of MTX on development of RA-ILD.Disclosure of Interests:Pierre-Antoine Juge: None declared, Joyce S. Lee Consultant of: Celgene, Genentech, Boehringer Ingelheim, Jessica Lau: None declared, Leticia Kawano: None declared, Jorge Rojas-Serrano: None declared, Marco Sebastiani: None declared, Gouri Koduri: None declared, Eric Matteson Grant/research support from: Pfizer, Consultant of: Boehringer Ingelheim, Gilead, TympoBio, Arena Pharmaceuticals, Speakers bureau: Simply Speaking, Karina Bonfiglioli Consultant of: Roche, Abbvie, Pfizer, Janssen and BMS, Marcio Sawamura: None declared, Ronaldo Kairalla: None declared, Lorenzo Cavagna: None declared, Emanuele Bozzalla Cassione: None declared, Andreina Manfredi: None declared, Mayra Mejia: None declared, Pedro Rodríguez Henríquez: None declared, Montserrat I. Gonzalez-Perez: None declared, Ramcés Falfan-Valencia: None declared, Ivette Buendia-Roldan: None declared, Glora Perez-Rubio: None declared, Esther Ebstein Consultant of: BMS, Employee of: BMS, Steven Gazal: None declared, Raphael Borie Consultant of: Roche, Boehringer Ingelheim, Sebastien Ottaviani: None declared, Caroline Kannengiesser: None declared, Benoît Wallaert Consultant of: Roche, Boehringer Ingelheim, Yurdagul Uzunhan Consultant of: Roche, Boehringer Ingelheim,, Hilario Nunes: None declared, Dominique Valeyre Consultant of: Astra Zeneca, Roche, Boehringer Ingelheim, Nathalie Saidenberg Kermanac’h: None declared, marie-Christophe Boissier: None declared, Lidwine Wemeau Stervinou Consultant of: Roche, Janssen, BMS, Boehringer Ingelheim, Rene-Marc Flipo Speakers bureau: Novartis, Janssen, Lilly, Sylvain Marchand-Adam Consultant of: Roche, Novartis, Boehringer Ingelheim, Pascal Richette: None declared, Yannick Allanore Shareholder of: Sanofi, Roche, Consultant of: Actelion, Bayer, BMS, Boehringer Ingelheim, Inventiva, Sanofi, Claire Dromer: None declared, Marie-Elise Truchetet: None declared, Christophe Richez Consultant of: Abbvie, Amgen, Mylan, Pfizer, Sandoz and UCB., Thierry Schaeverbeke: None declared, Huguette Lioté: None declared, Gabriel Thabut Employee of: Astra Zeneca, Kevin Deane Grant/research support from: Janssen, Consultant of: Inova, ThermoFisher, Janseen, BMS and Microdrop, Joshua Solomon: None declared, Tracy Doyle: None declared, Jay H. Ryu: None declared, Ivan O. Rosas Consultant of: Boehringer Ingelheim, Gerentech, Three Lakes Partners, V. Michael Holers Grant/research support from: Janssen, Celgene, and BMS, Catherine Boileau: None declared, Marie-Pierre Debray: None declared, Raphaël Porcher: None declared, David A. Schwartz Consultant of: NuMedii, Robert Vassallo Shareholder of: Pfizer, BMS, SunPharma, Bruno Crestani Shareholder of: Apellis, Boehringer Inghelheim, Medillune, Roche, Consultant of: Boehringer Ingelhiem, Astra Zeneca, Roche, Sanofi, Philippe Dieudé: None declared

Background:Type-2 diabetes and rheumatoid arthritis (RA) are two chronic diseases characterized by tissue inflammation and insulin resistance. To date, no data have evaluated the influence of RA-induced joint and systemic inflammation on the course of type-2 diabetes.Objectives:To study the impact of RA on type-2 diabetesMethods:Observational, multicenter, cross-sectional usual-care study, including 7 rheumatology centers. This study included over a 24-month period consecutive patients with type-2 diabetes and RA, fulfilling the 2010 ACR / EULAR criteria, and diabetic controls with osteoarthritis (OA). The following data were collected: demographics, disease activity and severity indices, current treatment for RA and diabetes, history and complications of diabetes. A systematic blood test was performed, assessing inflammatory (CRP levels) and metabolic (fasting glycemia and insulin levels, HbA1c) parameters. The HOMA2%B (insulin secretion) and HOMA2%S (tissue insulin sensitivity) indices (HOMA calculator, © Diabetes Trials Unit, University of Oxford) were used to assess insulin resistance. Ra and OA patients were compared using parametric tests after adjusting for age and BMI. A multivariate logistic regression was performed ti identify factors independently associated with insulin resistance.Results:We included 122 RA patients (74% women, mean age 64+/-11 years, mean disease duration 15+/-11 11 years, 75% with positive ACPA antibodies and 64% with erosive disease) and 54 controls with OA. 64% of RA patients were treated with oral corticosteroids The characteristics of type-2 diabetes in the 54 OA patients corresponded to severe insulin-resistant diabetes: age> 65 years, high BMI> 30 kg/m2, mean HbA1c 7.3%+/-11 1.3%, 30% of insulin requirement, high frequency of other cardiovascular risk factors, macroangiopathy found in almost half of patients and biological criteria of insulin resistance (elevation of HOMA2%B and decrease of HOMA2%S).RA patients with type-2 diabetes had a younger age (64+/-11 years vs. 68+/-12 years, p=0.031) and lower BMI (27.7+/-11 5.5 vs. 31.5+/-11 6.3, pConclusion:RA patients with type-2 diabetes displayed severe, poorly controlled diabetes, highlighting the burden of comorbidities associated with RA. The clinical-biological profile of diabetic RA patients was severe insulin-resistant diabetes, with a biological profile of insulin resistance linked to the inflammatory activity of the disease. These findings may have therapeutic implications, with the potential targeting of insulin resistance through the treatment of joint and systemic inflammation.Acknowledgments:Société Française de Rhumatologie (research grant)Bristol Myers Squibb (research grant)Disclosure of Interests:Jérôme Avouac Grant/research support from: Pfizer, Bristol Myers Squibb, Consultant of: Sanofi, Bristol Myers Squibb, Abbvie, Boerhinger, Nordic Pharma, Speakers bureau: Sanofi, Bristol Myers Squibb Abbvie, MSD, Pfizer, Nordic Pharma, Muriel ELHAI: None declared, Marine Forien: None declared, Jérémie SELLAM: None declared, Florent Eymard Consultant of: Regenlab, Anna Moltó Grant/research support from: Pfizer, UCB, Consultant of: Abbvie, BMS, MSD, Novartis, Pfizer, UCB, Laure Gossec Grant/research support from: Lilly, Mylan, Pfizer, Sandoz, Consultant of: AbbVie, Amgen, Biogen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sandoz, Sanofi-Aventis, UCB, Frédéric Banal: None declared, Joel Daminano: None declared, Philippe Dieudé: None declared, Yannick Allanore Shareholder of: Sanofi, Roche, Consultant of: Actelion, Bayer, BMS, Boehringer Ingelheim, Inventiva, Sanofi

Background:Interstitial lung disease (ILD) is the most common pulmonary manifestation of rheumatoid arthritis (RA). It has emerged in recent series as a key prognostic factor including survival. The big challenge for rheumatologists is now the risk-stratification of RA patients for ILD. Chest high-resolution computed tomography (HRCT) is the gold standard for RA-ILD diagnosis, but costs and ionizing radiation may limit its use in clinical practice. Thus, circulating biomarkers could aid in this risk-stratification.Objectives:to evaluate the merit of 3 circulating markers for the diagnosis and the progression of RA-ILD.Methods:We included consecutive patients with RA, >18 years of age, from 3 tertiary rheumatology centers (Paris, France, Tokyo, Japan and Zurich, Switzerland) over a 36-month period. All patients had at least one chest HRCT during the inclusion period. In the subset of French patients with ILD, HRCT lung images were obtained both at baseline (time of blood sample collection) and at a follow-up visit. The ILD status of patients with RA was established by chest HRCT. The chest HRCT pattern was classified as usual interstitial pneumonia, UIP or non-specific interstitial pneumonia, NSIP, by the local radiologist. Serum levels oflung epithelial-derived surfactant protein D, SDP, CCL-18 etKrebs von den Lungen-6 glycoprotein, KL-6 were measured by ELISA.Results:147 patients were included (age: 66+/-12 ans, 69% of women, disease duration 11+/-10 years). Among these patients, 40 (27%) had fibrosing ILD on HRCT: 21 had a UIP pattern, 17 a NSIP pattern, and 2 had NSIP associated with chronic obstructive pulmonary disease.SPD (21.91+/-2.17vs.15.76+/-1.34 ng/mL, p=0.017) CCL18 (102+/-13vs.78+/-5 ng/mL, p=0.026) and KL6 (961+/-128vs.376+/-26 U/mL, pA-C) were significantly higher in patients with RA-ILDvs.unaffected RA patients. KL6 values ​​were also higher in patients with UIP compared to the other HRCT patterns and in patients with lesion extension> 15% as compared to patients with milder disease. ROC curve analysis to assess the diagnostic abilities of the three markers for the diagnosis of RA-ILD showed a superiority of KL-6 (Area under the curve, AUC: 0.79 95% CI 0.72-0.86) compared to SPD (AUC: 0.66 95% CI 0.58-0.74) and CCL18 (AUC: 0.62, 95% CI 0.53-0.70) (Figure 1D). The sensitivity of KL-6 for the diagnosis of RA-ILD was 68% with a specificity of 83%. In the French subset with longitudinal data (n=15), extension of ILD was detected on 7 patients. Baseline KL6 serum levels were significantly increased in patients who experienced ILD progression (1987+/-1294 vs. 799+/-375 U/mL, p=0.027) (Figure 1E). The degree of ILD progression on HRCT was also proportional to baseline KL-6 concentrations (Figure 1F).Conclusion:KL-6 is relevant for the diagnosis and the prognosis of RA-ILD. It may be used as a circulating non-invasive first-line marker to stratify for indication of HRCT. Indeed, given the emerging lung issues in RA patients, this simple and highly reproducible marker, which is already available in routine care in some countries, could be a good prerequisite to chest HRCT in rheumatology clinics.Figure 1A-F.Concentrations of serum markers, diagnostic value and performance of KL-6 for the progression of rheumatoid arthritis-associated interstitial lung disease A-C,Concentrations of SPD (ng/mL) (A), CCL18 (ng/mL) (B) and KL-6 (U/mL) (C) in patients with with or without RA-associated ILD.D,ROC curve illustrating the diagnostic value of SPD, CCL18 and KL-6 for diagnosis of RA-ILD.E,Concentrations of KL-6 (U/mL) according to the progression on chest HRCT of RA-ILD.F,Degree of mean ILD progression on chest HRCT according to baseline KL-6 concentrations. *pDisclosure of Interests:Jérôme Avouac Grant/research support from: Pfizer, Bristol Myers Squibb, Consultant of: Sanofi, Bristol Myers Squibb, Abbvie, Boerhinger, Nordic Pharma, Speakers bureau: Sanofi, Bristol Myers Squibb Abbvie, MSD, Pfizer, Nordic Pharma, Alexia Steelandt: None declared, Anne Cauvet: None declared, Yuichiro Shirai: None declared, Masataka Kuwana Grant/research support from: Acetelion, Consultant of: Acetelion, Bayer, Chugai, Corbus Pharmaceuticals, CSL Behring and Reata Pharmaceuticals. He was a member of the SENSCIS trial Steering Committee (Boehringer Ingelheim), 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, Yannick Allanore Shareholder of: Sanofi, Roche, Consultant of: Actelion, Bayer, BMS, Boehringer Ingelheim, Inventiva, Sanofi

Hypothesizing a pathophysiological role of anti-topoisomerase I antibodies (anti-topo I) through autoantibody-dependent cell-mediated cytotoxicity (ADCC) and cytotoxic effectors expressing receptors for the Fc portion of IgG in systemic sclerosis (SSc), 267 SSc patients (56 with anti-topo I and 102 with anti-centromere antibodies (ACA)) were genotyped for the functional FCGR3A-V158F polymorphism. A descriptive analysis of patients according to their clinical and immunological status and FCGR3A-158 V/F genotypes was performed using multiple correspondence analysis. This descriptive analysis revealed an association between the FCGR3A-158 VV genotype and the presence of anti-topo I. By contrast, no relationship was found between FCGR3A polymorphism and the presence of ACA. SSc patients with anti-topo I appear to be more frequently homozygous for the high-affinity FcγRIIIA-coding allele, suggesting that some autoantibodies may be pathogenic through ADCC.

Cardiovascular diseases, vasospasm, and dysimmunity have been implicated in normal tension glaucoma (NTG).To investigate the prevalence of ocular abnormalities suggestive of glaucoma damage in systemic sclerosis (SSc).61 patients with SSc (mean (SD) age 56.2 (12) years, mean (SD) disease duration 9.9 (9) years; 41 with limited cutaneous disease) and 37 control subjects with osteoarthritis (mean (SD) age 55.9 (12) years) were studied. They were systematically referred to an ophthalmologist. The evaluation was based on aplanation tonometry, ophthalmoscopy with retinal photography (evaluation of cup/disc ratio (c/d)), and automated static perimetry (determination of mean defects (MD)). Statistical analyses were performed with the chi(2), Mann-Whitney, and Spearman tests.The mean visual acuity and intraocular pressure were similar in both groups. An excavation with a c/d0.3 was found in 27 eyes from patients with SSc and 5 eyes from controls (p = 0.009); a c/d0.7 was found in 4 eyes from patients with SSc and none in the controls (NS). Visual field defects (MD-2 dB) were found in 55 eyes from patients with SSc and in 18 eyes from controls (p0.0001). A concomitant c/d0.3 and MD-2 dB was found in 21 eyes from 12 patients with SSc but in none of the control eyes (p0.0001).Ocular abnormalities suggesting glaucomatous neuropathy without ocular hypertension were dramatically more prevalent in patients with SSc. These abnormalities seem to be mild but justify long term follow up. They are consistent with the vascular pathogenic hypothesis for NTG.

International audience; Objective. Tuberculosis (TB) is associated with anti-tumor necrosis factor (anti-TNF) monoclonal anti-body (mAb) therapy, but whether this association is drug-specific remains a concern. Our objective was to describe cases of TB associated with anti-TNF mAb therapy, identify risk factors, and estimate the incidence. Methods. We conducted an incidence study and a case-control analysis to investigate the risk of newly diagnosed TB associated with the use of anti-TNF agents. As part of the French Research Axed on Tolerance of Biotherapies (RATIO) registry, for 3 years we collected cases of TB among French patients receiving anti-TNF mAb therapy for any indication; for each case, 2 patients treated with anti-TNF agents served as control subjects. Results. We collected 69 cases of TB in patients treated for rheumatoid arthritis (n = 40), spondylarthritides (n = 18), inflammatory colitis (n = 9), psoriasis (n = 1) and Behcet's disease (n = 1) with infliximab (n = 36), adalimumab (n = 28), and etanercept (n = 5). None of the patients had received correct chemoprophylactic treatment. The sex- and age-adjusted incidence rate of TB was 116.7 per 100,000 patient-years. The standardized incidence ratio (SIR) was 12.2 (95% confidence interval [95% CI] 9.7-15.5) and was higher for therapy with infliximab and adalimumab than for therapy with etanercept (SIR 18.6 [95% CI 13.4-25.8] and SIR 29.3 [95% CI 20.3-42.4] versus SIR 1.8 [95% CI 0.7-4.3], respectively). In the case-control analysis, exposure to infliximab or adalimumab versus etanercept was an independent risk factor for TB (odds ratio [OR] 13.3 [95% CI 2.6-69.0] and OR 17.1 [95% CI 3.6-80.6], respectively). Other risk factors were age, the first year of anti-TNF mAb treatment, and being born in an endemic area. Conclusion. The risk of TB is higher for patients receiving anti-TNF mAb therapy than for those receiving soluble TNF receptor therapy. The increased risk with early anti-TNF treatment and the absence of correct chemoprophylactic treatment favor the reactivation of latent TB.

The co-occurrence of other autoimmune diseases within patients with systemic sclerosis (SSc) is a frequent condition affecting about one quarter of SSc-patients according to a recent meta-analysis performed by our group. Polyautoimmunity as well as the familial aggregation of autoimmune diseases strengthen the concept of “shared autoimmunity”, suggested by recent genetic studies. Epidemiologic studies have reported wide ranges of prevalence of co-occurrence of other autoimmune diseases in SSc. In our meta-analysis, based on 6102 SSc patients, the most prevalent associated autoimmune diseases were autoimmune thyroiditis (10.4%) followed by Sjogren Syndrome (7.7%) and dermatomyositis/polymyositis (5.6%), whereas co-occurrence of primary biliary cirrhosis, rheumatoid arthritis and systemic lupus erythematosus was observed in less than 5% of the patients. Some reports have suggested that patients with SSc and polyautoimmunity might have a milder disease, could occur more frequently in women and would be associated with the limited cutaneous subtype of SSc and anticentromere positive autoantibodies. However, we will present in the session cases illustrating that some SSc-patients with polyautoimmunity may develop a more severe SSc with severe organ damages. Further studies are warranted to increase the knowledge about the mechanisms of autoimmunity and polyautoimmunity and the specificities of this SSc-phenotype, in order to raise potential new approaches for the management and the treatment of SSc-patients with polyautoimmunity. Disclosure of Interest Y. Allanore Grant/research support from: Actelion, Bristol-Meyers Squibb, Inventiva, Pfizer, Roche/Genentech, Servier., Consultant for: Actelion, Bayer, Biogen, Bristol-Meyers Squibb, Inventiva, Medac, Pfizer, Roche/Genentech, Sanofi-Aventis and Servier.

Antisynthetase syndrome was first described by Marguerie et al as a combination of polymyositis (or at least creatine kinase elevation), diffuse interstitial lung disease and autoantibodies to t-RNA synthetase.1 Joint signs and symptoms occur in up to 90% of patients with polymyositis or dermatomyositis2 and/or antisynthetase syndrome, occasionally as the initial manifestations. They include arthralgia, polyarthritis and deforming arthropathy with subluxation. To establish a multicentre registry of patients with joint manifestations of antisynthetase syndrome, a standardised form was posted on the CRI (Club Rhumatismes et Inflammation) website (http://www.cri-net.com), which is part of the French Society for Rheumatology, with the partnership of the French Society of Internal Medicine. During a …