Immunosuppression with Targeted Therapies Reduces Morbidity and Mortality in Pre-Capillary Pulmonary Hypertension Associated with Systemic Sclerosis: A EUSTAR Analysis

Cosimo Bruni¹, Havard Fretheim², Lorenzo Tofani³, Yannick Weber¹, Eric Hachulla⁴, Patricia Carreira⁵, Dilia Giuggioli⁶, Paolo Airò⁷, Elise Siegert⁸, Ulf Müller-Ladner⁹, marco Matucci Cerinic¹⁰, Gabriela Riemekasten¹¹, Carmen Pilar Simeon-Aznar¹², Jeska de Vries-Bouwstra¹³, Lesley Ann Saketkoo¹⁴, Joerg Distler¹⁵, Alexandra Balbir-Gurman¹⁶, Ivan Castellvi¹⁷, Elisabetta Zanatta¹⁸, Vanessa Smith¹⁹, Christopher Denton²⁰, Britta Maurer²¹, Alessandro Giollo¹⁸, Florenzo Iannone²², Lorenzo Dagna²³, Marie-Elise Truchetet²⁴, Masataka Kuwana²⁵, Yannick ALLANORE²⁶, Yoshiya Tanaka²⁷, Mickael Martin²⁸, Edoardo Rosato²⁹, Ana Maria Gheorghiu³⁰, Francesco Del Galdo³¹, Kamal Solanki³², Alessandra Vacca³³, CATARINA RESENDE³⁴, SUSANA VIEIRA³⁵, Laszlo Czirjak³⁶, Marko Barisic³⁷, Francesco Paolo Cantatore³⁸, valeria Riccieri³⁹, Kristofer Andréasson⁴⁰, Lorinda Chung⁴¹, Carolina Muller⁴², Daniela OPRIS-BELINSKI⁴³, Simona Rednic⁴⁴, Petros Sfikakis⁴⁵, Yair Levy⁴⁶, Anna Maria Hoffmann-Vold⁴⁷, Oliver Distler¹, Vivien Hsu⁴⁸, Stefan Heitmann⁴⁹, Gianluca Moroncini⁵⁰, Michele Iudici⁵¹, Joerg Henes⁵², Ellen De Langhe⁵³, Ariane Herrick⁵⁴ and Carlomaurizio Montecucco⁵⁵, ¹Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland, ²Oslo University Hospital, Oslo, Norway, ³Department of Statistics, Computer Science, Applications, University of Florence, Florence, Italy, ⁴University of Lille, Lille, France, ⁵Hospital Universitario 12 de Octubre, Madrid, Spain, ⁶Scleroderma Unit, Rheumatology Unit, University Hospital of Modena and Reggio Emilia, Modena, Italy, ⁷Spedali Civili di Brescia, Scleroderma UNIT, UOC Reumatologia ed Immunologia Clinica, Piazzale Spedali Civili 1, 25123, Brescia, Italy, ⁸Department of Rheumatology, Charité University Hospital, Charité Platz 1, D-10117, Berlin, Germany, ⁹Justus Liebig University Gießen, Campus Kerckhoff, Bad Nauheim, Germany, ¹⁰Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Hospital, Milan, Milan, Italy, ¹¹University Clinic Schleswit-Holstein (UKSH), Lübeck, Germany, ¹²Department of Internal Medicine, Systemic Autoimmune Diseases Unit, Hospital Universitario Vall d'Hebronh, Barcelona, Spain, ¹³Leiden University Medical Center, Leiden, Netherlands, ¹⁴University Medical Center - Comprehensive Pulmonary Hypertension Center and ILD Clinic Programs // New Orleans Scleroderma and Sarcoidosis Patient Care & Research Centeris, New Orleans, LA, ¹⁵Clinic for Rheumatology University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University, Düsseldorf, Germany; Hiller Research Center, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University, Düsseldorf, Germany, ¹⁶Rheumatology Institute, Rambam Health Care Campus and Rappaport Faculty of |Medicine, Technion, Haifa, Israel, ¹⁷Rheumatology, Hospital Universitari de la Santa Creu i Sant Pau, Sant Just Desvern, Spain, ¹⁸Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Padova, Padua, Italy, ¹⁹Ghent University Hospital, Gent, Belgium, ²⁰University College London, London, United Kingdom, ²¹University Hospital Bern, University Bern, Bern, Switzerland, ²²Rheumatology Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari "Aldo Moro", Bari, Italy, ²³Ospedale San Raffaele, Milano, Italy, ²⁴Bordeaux University Hospital, Bordeaux, France, ²⁵Nippon Medical School Graduate School of Medicine, Tokyo, Japan, ²⁶Université Paris Cité, Paris, France, ²⁷University of Occupational and Environmental Health, Kitakyushu, Japan, ²⁸Department of Internal Medicine, INSERM U1313, Poitiers University, Poitiers University Hospital, Poitiers, France, ²⁹Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy, ³⁰Department of Internal Medicine and Rheumatology, Ion Cantacuzino Clinical Hospital, Bucharest, Romania, ³¹University of Leeds - Leeds Institute of Rheumatic and Muskuloskeletal Medicine, Leeds, United Kingdom, ³²Department of Rheumatology, Te Whatu Ora Health New Zealand Waikato, Hamilton, New Zealand, ³³II Chair of Rheumatology, University of Cagliari-Policlinico Universitario, Monserrato, Italy, ³⁴Serviço de Reumatologia e Doenças Ósseas Metabólicas, Hospital de Santa Maria, CHLN, Lisboa, Portugal, ³⁵Hospital Fernando Fonseca, Lisbon, Portugal, ³⁶Dept. Rheumatol Immunol, Medical School, university of Pecs, Pecs, Hungary, ³⁷Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, University of Zagreb, School of Medicine, University Hospital Center Zagreb, Zagreb, Croatia, ³⁸Rheumatology Clinic – Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy, ³⁹Department of Clinical, Internal and Cardiovascular Specialities, Sapienza University of Rome, Roma, Italy, ⁴⁰Lund University, Lund, Sweden, ⁴¹Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Woodside, CA, ⁴²Federal University of Parana, CURITIBA / PR, Brazil, ⁴³Saint Mary Hospital, Bucharest, Romania, ⁴⁴Prof Dr Simona Rednic, Cluj, Romania, ⁴⁵National Kapodistrian University of Athens Medical School, Athens, Greece, ⁴⁶Meir Medical Center, Autoimmune Research Laboratory, Kfar-Saba, Israel, ⁴⁷Oslo University Hospital, Department of Rheumatology, Oslo, Norway, ⁴⁸Rutgers-RWJ Medical School, South Plainfield, NJ, ⁴⁹Department of Rheumatology, Marienhospital Stuttgart, Böheimstrasse 37, D-70199, Stuttgart, Germany, ⁵⁰Marche Polytechnic University, Ancona, Italy, ⁵¹Division of Rheumatology, Department of Internal Medicine Specialties, Geneva University Hospitals, Geneva, Switzerland, ⁵²University Hospital Tuebingen, Tuebingen, Germany, ⁵³Division of Rheumatology, University Hospitals Leuven, Leuven, Belgium, ⁵⁴University of Manchester, Salford, United Kingdom, ⁵⁵Unità Operativa e Cattedra di Reumatologia, IRCCS Policlinico S Matteo, Pavia, Italy

Meeting: ACR Convergence 2023

Keywords: Biologicals, Mortality, prognostic factors, pulmonary, Systemic sclerosis

Session Information

Date: Monday, November 13, 2023

Title: Abstracts: Systemic Sclerosis & Related Disorders II: Clinical Research

Session Type: Abstract Session

Session Time: 4:00PM-5:30PM

Background/Purpose: Systemic sclerosis (SSc) associated pre-capillary pulmonary hypertension (precapPH) is a severe condition that requires prompt treatment. Although immunosuppressants (IMS) are standard of care for treating interstitial lung disease (ILD) and diffuse skin fibrosis (dcSSc), their effect on SSc-precapPH remains unclear. We aimed to test whether IMS affect morbidity and mortality in SSc-precapPH in the EUSTAR cohort.

Methods: SSc-precapPH patients (mPAP≥ 21 mmHg, PWP≤15 mmHg, PVR≥2 WU) with at least 3 months follow-up were eligible. IMS included csDMARDS (prednisone ≥10 mg/day, cyclophosphamide, mycophenolate mofetil, azathioprine, methotrexate) and targeted therapies (abatacept, rituximab, tocilizumab, TNFi, JAKi), administered after the diagnostic right heart catheterization. The WHO precapPH class was categorized into WHO group 1 (no ILD), mild WHO group 3 (ILD and forced vital capacity – FVC ≥70%) and severe WHO group 3 (ILD and FVC< 70%).

The morbidity-mortality outcome was defined by the occurrence of either death or precapPH worsening (one of 6MWD decrease≥15%, worsening of NYHA class, onset of right heart failure, additional PAH medication, starting iv/sc prostanoids, lung transplantation, atrial septostomy). Death and precapPH worsening were also separate secondary outcomes.

We evaluated the association between IMS and time to first event with a multiple Cox regression model. Baseline covariates were chosen by expert opinion, including the WHO precapPH class, SSc-related risk factors for mortality (e.g., sex, age, dcSSc, renal crisis, digital ulcers), reasons for IMS use (e.g., muscle weakness, joint synovitis), and PAH parameters for risk stratification (mPAP, BNP/NTproBNP, NYHA class, cardiac index, 6MWD). IMS and pulmonary arterial hypertension (PAH) drugs were treated as time-dependent variables.

Results: 755 SSc-precapPH patients were included (18% males, age 63±11 years, disease duration 11±9 years, 29% dcSSc, 60% ILD on HRCT). 377 (50%) received IMS [365 (47%) csDMARDs, 68 (9%) targeted therapies]. Patients receiving IMS had more frequently ILD, dcSSc, joint and muscle involvement (Table 1).

In median follow-up of 2.9 years, 70% of patients developed a morbidity-mortality event. While overall IMS exposure did not associate with outcomes, targeted therapies were associated with reduced risk of morbidity-mortality [HR 0.58, 95% CI 0.35-0.95, p=0.03] and both secondary outcomes [death, HR 0.43, 95% CI 0.21-0.89, p=0.02; precapPH worsening, HR 0.41, 95% CI 0.22-0.78, p< 0.01] – Figure 1.

When looking at specific targeted therapies, tocilizumab showed a risk reduction for morbidity-mortality and precapPH worsening (HR 0.37, 95% CI 0.17-0.81, p=0.02 and HR 0.19, 95% CI 0.05-0.78, p=0.02, respectively), while rituximab for death (HR 0.28, 95% CI 0.08-0.93, p=0.04) with a trend for precapPH worsening (HR 0.51, 95% CI 0.25-1.04, p=0.06) – Figure 2.

Conclusion: In this large EUSTAR SSc-precapPH cohort, targeted therapies are associated with reduced risk of mortality and precapPH worsening, which is independent from WHO group and other confounders. The impact of targeted therapies on long-term outcomes should be further explored in RCTs.

Table 1. Characteristics of the study population and divided according to exposure to immunosuppressants (IMS)

Figure 1. Effect of targeted therapies and csDMARDS on risk of morbidity-mortaliy (left panel), only death (central panel) and only worsening of precapPH (right panel).

Figure 1. Effect of specific immunosuppressive compounds on risk of morbidity-mortaliy (left panel), only death (central panel) and only worsening of precapPH (right panel).

Disclosures: C. Bruni: AbbVie/Abbott, 5, Boehringer-Ingelheim, 2, 12, Travel Support, Eli Lilly, 6; H. Fretheim: actelion, 5, bayer, 2, Boehringer-Ingelheim, 6, GlaxoSmithKlein(GSK), 5; L. Tofani: None; Y. Weber: None; E. Hachulla: Bayer, 2, CSL Behring, 5, GlaxoSmithKlein(GSK), 2, 5, 6, johnson&Johnson, 2, 5, 6, Novartis, 2, 5, Otsuka, 6, Roche-Chugai, 2, 5, 6, sanofi-genzyme, 2, 5, Sobi, 5; P. Carreira: None; D. Giuggioli: None; P. Airò: Boehringer-Ingelheim, 2, 5, 6, Bristol-Myers Squibb(BMS), 2, 5, 6, CSL Behring, 2, 5, 6, Janssen-Cilag, 2, 5, 6, Novartis, 2, 5, 6, Roche, 2, 5, 6; E. Siegert: None; U. Müller-Ladner: None; m. Matucci Cerinic: accelerong, 2, 6, actelion, 2, 6, bayer, 2, 6, biogen, 2, 6, Boehringer-Ingelheim, 2, 6, Chemomab, 2, 6, corbus, 2, 6, CSL Behring, 2, 6, Eli Lilly, 2, 6, galapagos, 2, 6, Inventiva, 2, 6, Janssen, 2, 6, Merck/MSD, 2, 6, Mitsubishi, 2, 6, Pfizer, 2, 6, regeneron, 2, 6, Roche, 2, 6, samsung, 2, 6; G. Riemekasten: None; C. Simeon-Aznar: None; J. de Vries-Bouwstra: AbbVie/Abbott, 2, 6, Boehringer-Ingelheim, 2, 6, galapagos, 5, Janssen, 2, 6, Janssen-Cilag, 5, Roche, 5; L. Saketkoo: None; J. Distler: 4D Science and FibroCure, 8, 11, AbbVie, Active Biotech, Anamar, ARXX, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, Genentech, GSK, Inventiva, Janssen, Novarti, 2, Anamar, Argenx, ARXX, BMS, Bayer Pharma, Boehringer Ingelheim, Cantargia, Celgene, CSL Behring, Galapagos, GSK, 5, Inventiva, Kiniksa, Lassen, Sanofi-Aventis, RedX, UCB, 5; A. Balbir-Gurman: None; I. Castellvi: None; E. Zanatta: None; V. Smith: Boehringer Ingelheim, 2, 5, 6, 12, Support for travel, Galapagos, 6, Janssen-Cilag, 1, 2, 5, 6; C. Denton: AbbVie, 2, Acceleron, 2, Arxx Therapeutics, 5, Bayer, 2, Boehringer-Ingelheim, 2, 6, Corbus, 2, 6, CSL Behring, 2, 5, GlaxoSmithKline, 2, 5, Horizon Therapeutics, 2, Inventiva, 2, 5, Janssen, 6, Roche, 2, Sanofi, 2, Servier, 5; B. Maurer: AbbVie/Abbott, 5, Actelion, 12, congress support, Boehringer-Ingelheim, 2, 6, GlaxoSmithKline (GSK), 6, Janssen-Cilag, 2, Medtalk, 12, congress support, Mepha, 12, congress support, Merck/MSD, 12, congress support, Novartis, 2, 6, Novartis (Biomedical Research), 5, Otsuka, 2, 6, Pfizer, 12, congress support, Protagen, 5, Roche, 12, congress support; A. Giollo: Eli Lilly, 6, galapagos, 2, 6, Novartis, 2, Sandoz, 2; F. Iannone: Abbvie, 2, 5, BMS, 2, 5, Janssen, 2, 5, Lilly, 2, 5, MSD, 2, 5, Novartis, 2, 5, Pfizer, 2, 5, Roche, 2, 5, UCB, 2, 5; L. Dagna: AbbVie/Abbott, 2, AstraZeneca, 2, biogen, 2, Boehringer-Ingelheim, 2, Bristol-Myers Squibb(BMS), 2, 5, Eli Lilly, 2, galapagos, 2, GlaxoSmithKlein(GSK), 2, Janssen, 2, Kiniksa Pharmaceuticals, 2, Novartis, 2, 6, Pfizer, 2, 5, SOBI, 2, 5, 6; M. Truchetet: AbbVie/Abbott, 2, 6, Boehringer-Ingelheim, 2, 6, Gilead, 5, 6, Merck/MSD, 6, UCB, 6, 12, support for conferences; M. Kuwana: AbbVie/Abbott, 6, Asahi-Kasei, 5, 6, Astellas, 6, AstraZeneca, 2, Boehringer-Ingelheim, 2, 5, 6, Chugai, 2, 5, 6, Corbus, 2, Eisai, 6, GlaxoSmithKlein(GSK), 2, Horizon, 2, Janssen, 6, Kissei, 2, MBL, 2, 5, Mitsubishi Tanabe, 2, 5, 6, Mochida, 2, 6, Nippon Shinyaku, 6, Ono, 5, 6; Y. ALLANORE: AbbVie/Abbott, 2, Alpine Immunoscience, 5, AstraZeneca, 2, Bayer, 2, Boehringer-Ingelheim, 2, Janssen, 2, Medsenic, 2, 5, Mylan, 2, OSE Immunotherapeutics, 5, Prometeus, 2, Roche, 2, Sanofi, 2; Y. Tanaka: AbbVie, 6, AstraZeneca, 6, BMS, 6, Boehringer-Ingelheim, 6, Chugai, 5, 6, Eisai, 5, 6, Eli Lilly, 6, Gilead, 6, GSK, 6, Mitsubishi-Tanabe, 5, Pfizer, 6, Taiho, 6, Taisho, 5, 6; M. Martin: Boehringer-Ingelheim, 6, GlaxoSmithKlein(GSK), 6; E. Rosato: None; A. Gheorghiu: AbbVie/Abbott, 2, 6, Boehringer-Ingelheim, 2, 6, Ewopharma, 2, 6, Sandoz, 2, 6; F. Del Galdo: AbbVie/Abbott, 5, arxx, 2, AstraZeneca, 2, 5, Boehringer-Ingelheim, 2, 5, capella, 2, Chemomab, 2, GlaxoSmithKlein(GSK), 2, Janssen, 2, Mitsubishi-Tanabe, 2, 5; K. Solanki: None; A. Vacca: None; C. RESENDE: None; S. VIEIRA: None; L. Czirjak: Abbvie, AstraZeneca, Boehringer Ingelheim, MSD, 6, Roche, 6; M. Barisic: None; F. Cantatore: None; v. Riccieri: None; K. Andréasson: Janssen-Cilag, 6; L. Chung: Eicos Science, 1, 2, Eli Lilly, 1, 2, Genentech, 1, 2, IgM biosciences, 1, 2, Janssen, 1, 2, Kyverna, 1, 2, Mitsubishi Tanabe, 1, 2; C. Muller: Boehringer-Ingelheim, 1, 6, Celltrion, 1, Janssen, 1, 6; D. OPRIS-BELINSKI: AbbVie/Abbott, 2, 6, Amgen, 2, 6, AstraZeneca, 2, 6, Boehringer-Ingelheim, 2, 6, Janssen, 2, 6, Novartis, 2, 6; S. Rednic: None; P. Sfikakis: AbbVie/Abbott, 2, 5, Amgen, 2, 5, Boehringer-Ingelheim, 2, 5, Celgene, 2, 5, Eli Lilly, 2, 5, Janssen, 2, 5, Novartis, 2, 5, Pfizer, 2, 5; Y. Levy: Chemomab Ltd, 5; A. Hoffmann-Vold: Arxx Therapeutics, 2, Boehringer-Ingelheim, 2, 5, 6, 12, Support for travel, Genentech, 2, Janssen, 2, 5, 6, Medscape, 2, 6, 12, Support for travel, Roche, 2, 6, 12, Support for travel; O. Distler: 4P-Pharma, 2, 5, 6, AbbVie, 2, 5, 6, Acceleron, 2, 5, 6, Alcimed, 2, 5, 6, Altavant Sciences, 2, 5, 6, Amgen, 2, 5, 6, AnaMar, 2, 5, 6, Arxx, 2, 5, 6, AstraZeneca, 2, 5, 6, Bayer, 2, 5, 6, Blade Therapeutics, 2, 5, 6, Boehringer Ingelheim, 2, 5, 6, Citus AG, 12, Co-Founder, Corbus Pharmaceuticals, 2, 5, 6, CSL Behring, 2, 5, 6, Galapagos, 2, 5, 6, Galderma, 2, 5, 6, Glenmark, 2, 5, 6, Gossamer, 2, 5, 6, Horizon Therapeutics, 2, 5, 6, Janssen, 2, 5, 6, Kymera, 2, 5, 6, Lupin, 2, 5, 6, Medscape, 2, 5, 6, Miltenyi Biotec, 2, 5, 6, Mitsubishi Tanabe, 2, 5, 6, MSD, 2, 5, 6, Novartis, 2, 5, 6, Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143), 10, Prometheus Biosciences, 2, 5, 6, Redx Pharma, 2, 5, 6, Roivant, 2, 5, 6, Topadur, 2, 5, 6;V. Hsu: None; S. Heitmann: None; G. Moroncini: None; M. Iudici: Boehringer-Ingelheim, 1; J. Henes: AbbVie/Abbott, 2, 6, Boehringer-Ingelheim, 2, 6, Bristol-Myers Squibb(BMS), 2, 6, GlaxoSmithKlein(GSK), 2, 6, Janssen, 2, 6, Novartis, 2, 6, Pfizer, 2, 6, UCB, 2, 6; E. De Langhe: None; A. Herrick: Arena, 2, Camurus, 2, Galderma, 2, Gesynta Pharma, 2, 5, Janssen, 6; C. Montecucco: None.

To cite this abstract in AMA style:

Bruni C, Fretheim H, Tofani L, Weber Y, Hachulla E, Carreira P, Giuggioli D, Airò P, Siegert E, Müller-Ladner U, Matucci Cerinic m, Riemekasten G, Simeon-Aznar C, de Vries-Bouwstra J, Saketkoo L, Distler J, Balbir-Gurman A, Castellvi I, Zanatta E, Smith V, Denton C, Maurer B, Giollo A, Iannone F, Dagna L, Truchetet M, Kuwana M, ALLANORE Y, Tanaka Y, Martin M, Rosato E, Gheorghiu A, Del Galdo F, Solanki K, Vacca A, RESENDE C, VIEIRA S, Czirjak L, Barisic M, Cantatore F, Riccieri v, Andréasson K, Chung L, Muller C, OPRIS-BELINSKI D, Rednic S, Sfikakis P, Levy Y, Hoffmann-Vold A, Distler O, Hsu V, Heitmann S, Moroncini G, Iudici M, Henes J, De Langhe E, Herrick A, Montecucco C. Immunosuppression with Targeted Therapies Reduces Morbidity and Mortality in Pre-Capillary Pulmonary Hypertension Associated with Systemic Sclerosis: A EUSTAR Analysis [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/immunosuppression-with-targeted-therapies-reduces-morbidity-and-mortality-in-pre-capillary-pulmonary-hypertension-associated-with-systemic-sclerosis-a-eustar-analysis/. Accessed .

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