OP0238 IMMUNOSUPPRESSION WITH TARGETED DMARDS REDUCES MORBIDITY AND MORTALITY IN PRE-CAPILLARY PULMONARY HYPERTENSION ASSOCIATED WITH SYSTEMIC SCLEROSIS: A EUSTAR ANALYSIS

Background Pre-capillary pulmonary hypertension (precapPH) affects 9-15% of patients with systemic sclerosis (SSc) and may be associated with interstitial lung disease (ILD) of variable extent. Immunosuppressants (IMS) are standard of care for treating ILD, skin or musculoskeletal manifestations in SSc. However, their beneficial effect on precapPH remains unclear. Objectives To determine whether exposure to IMS in SSc-precapPH affects morbidity and mortality in the EUSTAR cohort. Methods In the approved EUSTAR project CP111, we included SSc patients with precapPH (mPAP ≥21 mmHg, PWP ≤15 mmHg, PVR ≥2 WU) with data on IMS (csDMARDs - prednisone ≥10 mg/day, cyclophosphamide, mycophenolate mofetil, azathioprine, methotrexate; targeted therapies: abatacept, rituximab, tocilizumab, TNFi, JAKi), pulmonary arterial hypertension (PAH) medications (bosentan, macitentan, ambrisentan, sildenafil, tadalafil, riociguat, selexipag, prostanoids) and at least 3 months follow-up after precapPH diagnosis by right heart catheterization. We considered exposure to a drug if it was ongoing at or prescribed after precapPH diagnosis and administered for at least 30 days. Patients were clustered into group 1 or group 3 precapPH based on ILD presence on HRCT and FVC <70%, as proposed in the INCREASE trial. The morbidity-mortality outcome was defined by the first event between death or precapPH worsening (following the SERAPHIN trial: one of ≥15% 6MWD decrease, worsening of NYHA class, onset of right heart failure, additional PAH medication, starting iv/sc prostanoids, lung transplantation, atrial septostomy). We evaluated the association between IMS and time to first event with a multiple Cox regression model for time dependent covariates, with robust Sandwich variance estimate and backward selection. The baseline confounders were chosen on experts’ opinion and included SSc-related risk factors for mortality or IMS prescription (sex, age, diffuse skin subset, renal crisis, digital ulcers, muscle weakness, joint synovitis, ILD on HRCT, LVEF%, FVC%, DLCO%) and PAH risk stratification parameters (mPAP, increased BNP/NTproBNP, NYHA class >II, reduced cardiac index, reduced 6MWD). PAH medications (none, mono, double or triple therapy) were also included as time-dependent confounder. Results 755 SSc-precapPH patients from 54 EUSTAR centers were included (18% males, age 63±11 years, disease duration 11±9 years, 29% diffuse skin subset, 60% ILD on HRCT): 377 (50%) received IMS [365 (47%) csDMARDs, 68 (9%) targeted therapies] and 642 (85%) PAH medications. Patients treated with IMS had more frequently ILD (78 vs 43%), diffuse skin (41 vs 18%), joint (16 vs 7%) and muscle (22 vs 10%) involvement. In 2.9 (1.2-5.4) years median follow-up, 546 (70%) patients developed a morbidity-mortality event. While overall IMS exposure did not associate with the outcome, targeted therapies were associated with reduced risk of morbidity-mortality [HR 0.59 (95% CI 0.36-0.96), p=0.04; Figure 1a]. When clustering into group 1 [n=561, 40% IMS, n=32 (6%) targeted therapies] or group 3 [n=194, 80% IMS, n=36 (19%) targeted therapies], less morbidity-mortality events were recorded for group 1 (69% vs 81%). Despite the rarer use, the protective effect of targeted therapies for morbidity-mortality was confirmed in group 1 (HR 0.24, 95% CI 0.02-0.64, p=0.01, Figure 1b) but not in group 3 (Figure 1c). When looking at specific target therapies, a risk reduction for the morbidity-mortality outcome was noted for tocilizumab [in the whole cohort (n treated=21; HR 0.37, 95%CI 0.18-0.77, p=0.03) and in group 1 (n treated=10; HR 0.09, 95% CI 0.01-0.69, p=0.02)] and rituximab (in group 1, n treated= 24, HR 0.29, 95% CI 0.10-0.84, p=0.01). Conclusion In this large EUSTAR SSc-precapPH cohort, targeted therapies are associated with a significantly reduced risk of mortality and precapPH worsening over time. This is the first large study adjusted for confounders supporting a potential effect of targeted therapies on SSc-precapPH. Acknowledgements On behalf of the EUSTAR collaborators. Disclosure of Interests Cosimo Bruni Speakers bureau: Eli-Lilly, Consultant of: Boehringer Ingelheim, Grant/research support from: Gruppo Italiano Lotta alla Sclerodermia (GILS), European Scleroderma Trials and Research Group (EUSTAR), Foundation for research in Rheumatology (FOREUM), Scleroderma Clinical Trials Consortium (SCTC). Educational grants from AbbVie., Lorenzo Tofani: None declared, Håvard Fretheim Speakers bureau: Boehringer Ingelheim, Consultant of: Bayer, Grant/research support from: GSK, Actelion, Yannick Weber: None declared, Eric Hachulla Speakers bureau: Johnson & Johnson, GlaxoSmithKline, Roche-Chugai, Otsuka, Consultant of: Bayer, Boehringer Ingelheim, GlaxoSmithKline, Johnson & Johnson, Roche-Chugai, Sanofi-Genzyme, Novartis, Grant/research support from: CSL Behring, GlaxoSmithKline, Johnson & Johnson, Roche-Chugai, Sanofi-Genzyme, Sobi, Novartis, Patricia Carreira Speakers bureau: (last 5 years): Janssen, Lilly, VivaCell, Emerald Health Pharmaceuticals, Gesynta Pharma, Boehringer Ingelheim, Abbie, Sanofi Genzyme, Mitsubishi Tanabe, Consultant of: (last 5 years): Janssen, Lilly, VivaCell, Emerald Health Pharmaceuticals, Gesynta Pharma, Boehringer Ingelheim, Abbie, Sanofi Genzyme, Mitsubishi Tanabe, Dilia Giuggioli: None declared, Paolo Airò Speakers bureau: Bristol Myers Squibb, Bohringer Ingelheim, Roche, Novartis, CSL Behring Janssen- Cilag, Consultant of: Bristol Myers Squibb, Bohringer Ingelheim, Roche, Novartis, CSL Behring Janssen- Cilag, Grant/research support from: Bristol Myers Squibb, Bohringer Ingelheim, Roche, Novartis, CSL Behring Janssen- Cilag, Elise Siegert: None declared, Ulf Müller-Ladner: None declared, Marco Matucci-Cerinic Speakers bureau: Actelion, Janssen, Inventiva, Bayer, Biogen, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, Roche, Consultant of: Actelion, Janssen, Inventiva, Bayer, Biogen, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, Roche, Gabriela Riemekasten: None declared, Carmen Pilar Simeon Aznar: None declared, Jeska de Vries-Bouwstra Speakers bureau: ABBvie, Janssen, Boehringer-Ingerlheim, Consultant of: ABBvie, Janssen, Boehringer-Ingerlheim, Grant/research support from: Janssen-Cilag, Galapagos, Roche, Lesley Ann Saketkoo: None declared, Joerg Distler: None declared, Alexandra Balbir-Gurman: None declared, Ivan Castellví: None declared, Elisabetta Zanatta: None declared, Vanessa Smith: None declared, Christopher P Denton: None declared, Britta Maurer Speakers bureau: Boehringer-Ingelheim, GSK, Novartis, Consultant of: Novartis, Boehringer Ingelheim, Janssen-Cilag, Grant/research support from: AbbVie, Protagen, Novartis Biomedical. congress support from Medtalk, Pfizer, Roche, Actelion, Mepha, and MSD., Alessandro Giollo Speakers bureau: Galapagos, Eli Lilly, Consultant of: Galapagos, Sandoz, Novartis, Florenzo Iannone: None declared, Lorenzo Dagna Speakers bureau: Novartis and SOBI, Consultant of: Abbvie, AstraZeneca, Biogen, Boehringer-Ingelheim, BMS, Eli Lilly, Galapagos, GSK, Janssen, Kiniksa Pharmaceuticals, Novartis, Pfizer, SOBI, Grant/research support from: BMS, Celltrion, Kiniksa pharmaceuticals, Pfizer and SOBI, Marie-Elise Truchetet: None declared, Masataka Kuwana: None declared, Yannick Allanore Consultant of: AbbVie, AstraZeneca, Bayer, Boehringer-Ingelheim, Mylan, Janssen, Medsenic, Prometheus, Sanofi, Roche, Grant/research support from: Alpine Immunosciences, Medsenic, OSE Immunotherapeutics, Yoshiya Tanaka: None declared, Mickael Martin Speakers bureau: Boehringer Ingelheim, Edoardo Rosato: None declared, Ana Maria Gheorghiu Speakers bureau: Sandoz, Boehringer Ingelheim, Ewopharma, Abbvie, Consultant of: Sandoz, Boehringer Ingelheim, Ewopharma, Abbvie, Francesco Del Galdo: None declared, Kamal Solanki: None declared, ALESSANDRA VACCA: None declared, Catarina Resende: None declared, Susana Vieira: None declared, László Czirják: None declared, Marko Baresic: None declared, Francesco Paolo Cantatore: None declared, Valeria Riccieri: None declared, Kristofer Andréasson: None declared, Lorinda Chung: None declared, CAROLINA SOUZA MULLER: None declared, Daniela Opris-Belinski Speakers bureau: Abbvie, Amgen, AstraZeneca, Boehringer Ingelheim, Janssen, Novartis, Consultant of: Abbvie, Amgen, AstraZeneca, Boehringer Ingelheim, Janssen, Novartis, Simona Rednic: None declared, Petros Sfikakis: None declared, Yair Levy: None declared, Vivian Hsu: None declared, Stefan Heitmann: None declared, Jörg Henes Speakers bureau: Abbvie, Boehringer Ingelheim, GSK, BMS, Janssen, Novartis, Pfizer, UCB, Consultant of: Abbvie, Boehringer Ingelheim, GSK, BMS, Janssen, Novartis, Pfizer, UCB, Gianluca Moroncini: None declared, Michele Iudici: None declared, Ellen De Langhe: None declared, Ariane Herrick: None declared, Carlomaurizio Montecucco: None declared, Anna-Maria Hoffmann-Vold Speakers bureau: ehringer Ingelheim, Jannsen, Medscape, Merck Sharp & Dohme and Roche, Consultant of: ARXX, Boehringer Ingelheim, Genentech, Jannsen, Medscape, Merck Sharp & Dohme and Roche, Grant/research support from: Boehringer Ingelheim, Jannsen, Oliver Distler Speakers bureau: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Arxx, AstraZeneca, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, iQvia, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe; Novartis, Prometheus, Redxpharna, Roivant and Topadur in the area of potential treatments of scleroderma and its complications., Consultant of: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Arxx, AstraZeneca, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, iQvia, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe; Novartis, Prometheus, Redxpharna, Roivant and Topadur in the area of potential treatments of scleroderma and its complications., Grant/research support from: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Arxx, AstraZeneca, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, iQvia, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe; Novartis, Prometheus, Redxpharna, Roivant and Topadur in the area of potential treatments of scleroderma and its complications. Research grants: Kymera, Mitsubishi Tanabe.

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