EULAR Abstract Archive

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OP0238 (2023)

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

C. Bruni^1,2, L. Tofani³, H. Fretheim⁴, Y. Weber¹, E. Hachulla⁵, P. Carreira⁶, D. Giuggioli⁷, P. Airò⁸, E. Siegert⁹, U. Müller-Ladner¹⁰, M. Matucci-Cerinic^2,11, G. Riemekasten¹², C. P. Simeon Aznar¹³, J. De Vries-Bouwstra¹⁴, L. A. Saketkoo¹⁵, J. Distler¹⁶, A. Balbir-Gurman¹⁷, I. Castellví¹⁸, E. Zanatta¹⁹, V. Smith^20,21,22, C. P. Denton²³, B. Maurer²⁴, A. Giollo^19,25, F. Iannone²⁶, L. Dagna¹¹, M. E. Truchetet²⁷, M. Kuwana²⁸, Y. Allanore²⁹, Y. Tanaka³⁰, M. Martin³¹, E. Rosato³², A. M. Gheorghiu³³, F. Del Galdo³⁴, K. Solanki³⁵, A. Vacca³⁶, C. Resende³⁷, S. Vieira³⁸, L. Czirják³⁹, M. Baresic⁴⁰, F. P. Cantatore⁴¹, V. Riccieri⁴², K. Andréasson⁴³, L. Chung⁴⁴, C. Souza Muller⁴⁵, D. Opris-Belinski⁴⁶, S. Rednic⁴⁷, P. Sfikakis⁴⁸, Y. Levy⁴⁹, V. Hsu⁵⁰, S. Heitmann⁵¹, J. Henes⁵², G. Moroncini⁵³, M. Iudici⁵⁴, E. De Langhe⁵⁵, A. Herrick⁵⁶, C. Montecucco⁵⁷, A. M. Hoffmann-Vold^1,4, O. Distler¹

¹University of Zurich, Rheumatology, Zürich, Switzerland
²University of Florence, Experimental and Clinical Medicine, Division of Rheumatology, Firenze, Italy
³University of Florence, Statistics, Computer Science, Applications, Firenze, Italy
⁴Oslo University Hospital, Rheumatology, Oslo, Norway
⁵University of Lille - Huriez Hospital, Department of Internal Medicine and Clinical immunology, Lille, France
⁶University Hospital October 12, Rheumatology, Madrid, Spain
⁷University of Modena and Reggio Emilia, Rheumatology, Modena, Italy
⁸Spedali Civili di Brescia, Scleroderma UNIT, UOC Reumatologia ed Immunologia Clinica, Brescia, Italy
⁹Charité – Universitätsmedizin Berlin, Rheumatology, Berlin, Germany
¹⁰Kerckhoff-Klinik, Abteilung für Rheumatologie und Klinische Immunologie, Bad Nauheim, Germany
¹¹San Raffaele Hospital, Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UniRAR), Milano, Italy
¹²University of Lübeck, Department of Rheumatology and Clinical Immunology, University Clinic Schleswig-Holstein, Lübeck, Germany
¹³Hospital Universitari Vall d’Hebron, Rheumatology, Barcelona, Spain
¹⁴Leiden University Medical Center (LUMC), Rheumatology, Leiden, Netherlands
¹⁵Tulane University and Louisiana State University Schools of Medicine, University Medical Center Scleroderma and Sarcoidosis Patient Care and Research Center, New Orleans, United States of America
¹⁶Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Department of Internal Medicine 3-Rheumatology and Immunology, Erlangen, Germany
¹⁷Rambam Health Care Campus, B. Shine Rheumatology Institute, Haifa, Israel
¹⁸Sant Pau Art Nouveau Site, Rheumatology, Barcelona, Spain
¹⁹University of Padova, Rheumatology Unit, Department of Clinical and Experimental Medicine, Padova, Italy
²⁰Ghent University Hospital, Department of Rheumatology, Gent, Belgium
²¹Ghent University Hospital, Department of Internal Medicine, Gent, Belgium
²²Vlaams Instituut voor Biotechnologie, Inflammation Research Center (IRC), Unit for Molecular Immunology and Inflammation, Gent, Belgium
²³University College London Medical School-Royal Free Campus, Centre for Rheumatology, London, United Kingdom
²⁴Inselspital, Bern University Hospital, Department of Rheumatology and Immunology, Bern, Switzerland
²⁵University of Verona, Rheumatology Unit, Department of Medicine, Verona, Italy
²⁶University of Bari Aldo Moro, Rheumatology Unit - DiMePReJ, Bari, Italy
²⁷Bordeaux University - Bordeaux University Hospital, Department of Rheumatology, UMR5164 ImmunoConcept, Bordeaux, France
²⁸Nippon Medical School Hospital, rheumatology, Tokyo, Japan
²⁹Paris 5 University, Cochin Hospital, Rheumatology A, Paris, France
³⁰Hospital of University of Occupational and Environmental Health, Rheumatology, Kitakyushu, Japan
³¹Poitiers University Hospital, Department of Internal Medicine, INSERM U1313, Poitiers, France
³²Sapienza University of Rome, Department of Translational and Precision Medicine, Roma, Italy
³³Clinical Hospital Dr. Ion Cantacuzino, Department of Internal Medicine and Rheumatology, București, Romania
³⁴University of Leeds, Raynaud’s and Scleroderma Programme, Institute of Rheumatic and Musculoskeletal Medicine, and Biomedical Research Centre, Leeds, United Kingdom
³⁵Waikato Hospital, Rheumatology Unit, Hamilton, New Zealand
³⁶Policlinico Universitario Monserrato “Duilio Casula”, Rheumatology, Monserrato, Italy
³⁷Hospital de Santa Maria, Serviço de Reumatologia e Doenças Ósseas Metabólicas, Lisboa, Portugal
³⁸Hospital Fernando Fonseca, Systemic Immunomediated Diseases Unit, Department of Medicine IV, Amadora, Portugal
³⁹University of Pécs Medical School, Department of Immunology and Rheumatology, Pécs, Hungary
⁴⁰School of Medicine, University of Zagreb, Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, Zagreb, Croatia
⁴¹University of Foggia - Department of Economics, Rheumatology Clinic – Department of Medical and Surgical Sciences, Foggia, Italy
⁴²Sapienza University of Rome, Department of Clinical, Internal and Cardiovascular Specialities, Roma, Italy
⁴³Lund University, Section of Rheumatology, Department of Clinical Sciences, Lund, Sweden
⁴⁴Stanford University School Medicine, Division of Immunology and Rheumatology, Palo Alto, United States of America
⁴⁵Hospital de Clinicas da Universidade Federal do Parana, Rheumatology, Curitiba, Brazil
⁴⁶Carol Davila University of Medicine and Pharmacy, Department of Internal Medicine and Rheumatology -Sf. Maria Hospital, București, Romania
⁴⁷Iuliu Hațieganu University of Medicine and Pharmacy, Clinica Reumatologie, Cluj-Napoca, Romania
⁴⁸Athens University Medical School, Rheumatology Unit, First Propaedeutic and Internal Medicine, Athens, Greece
⁴⁹Meir Medical Center, Rheumatology, Kefar Sava, Israel
⁵⁰Rutgers Robert Wood Johnson Medical School, Department of Medicine, Division of Rheumatology, New Brunswick, United States of America
⁵¹Marienhospital Stuttgart, Department of Rheumatology, Stuttgart, Germany
⁵²Tübingen University Hospital, Center for Interdisciplinary Rheumatology, Immunology and Autoinmmune Diseases (INDIRA), Tübingen, Germany
⁵³Marche Polytechnic University, Clinica Medica, Azienda Ospedaliero-Universitaria delle Marche, Ancona, Italy
⁵⁴Geneva University Hospitals and University of Geneva, Division of Rheumatology, Internal Medicine Specialties, Genève, Switzerland
⁵⁵University Hospitals Leuven, Division of Rheumatology, Leuven, Belgium
⁵⁶The University of Manchester, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
⁵⁷Fondazione I.R.C.C.S. Policlinico San Matteo, Unita’ Operativa e Cattedra di Reumatologia, Pavia, Italy

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].

Image/graph:

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.

Keywords: bDMARD, Systemic sclerosis, Lungs

DOI: 10.1136/annrheumdis-2023-eular.2018

Citation: , volume 82, supplement 1, year 2023, page 157

Session: Update on the treatment of scleroderma lung disease (Oral Presentations)

version:	1.02