RMD Open (Nov 2022)
Effectiveness and safety of tocilizumab in patients with systemic sclerosis: a propensity score matched controlled observational study of the EUSTAR cohort
- ,
- Pavel I Novikov,
- Thierry Martin,
- Eric Hachulla,
- Vanessa Smith,
- Maurizio Cutolo,
- Yannick Allanore,
- Camillo Ribi,
- Oliver Distler,
- Britta Maurer,
- Paolo Airo,
- Cosimo Bruni,
- Veronica Codullo,
- Luc Mouthon,
- Marie Vanthuyne,
- Elisabetta Zanatta,
- Simona Rednic,
- Ulf Müller-Ladner,
- Nemanja Damjanov,
- Anna-Maria Hoffmann-Vold,
- Michele Iudici,
- Suzana Jordan,
- Jean Sibilia,
- Mengtao Li,
- Roger Hesselstrand,
- Elise Siegert,
- László Czirják,
- Armando Gabrielli,
- Dominique Farge Bancel,
- Yolanda Braun-Moscovici,
- Nicolas Hunzelmann,
- Raffaele Pellerito,
- Jörg Henes,
- Bojana Stamenkovic,
- Carlo Francesco Selmi,
- Mohammed Tikly,
- Merete Engelhart,
- Valeria Riccieri,
- Cord Sunderkötter,
- Francesca Ingegnoli,
- Francesco Paolo Cantatore,
- Susanne Ullman,
- Maria Rosa Pozzi,
- Piotr Wiland,
- Juan Jose Alegre-Sancho,
- Brigitte Krummel-Lorenz,
- Ellen De Langhe,
- Branimir Anic,
- Carolina de Souza Müller,
- Simon Stebbings,
- Alessandra Vacca,
- Lisa Stamp,
- Kamal Solanki,
- Douglas Veale,
- Esthela Loyo,
- Edoardo Rosato,
- Cristina-Mihaela Tanaseanu,
- Rosario Foti,
- Codrina Ancuta,
- Ira Litinsky,
- Lesley Ann Saketkoo,
- Eduardo Kerzberg,
- Tim Schmeiser,
- Piercarlo Sarzi Puttini,
- Fabio Cacciapaglia,
- Marie-Elise Truchetet,
- Muriel Elhai,
- Juan José Alegre Sancho,
- Ivan Castellví,
- Serena Vettori,
- Vivien M Hsu,
- Masataka Kuwana,
- Sule Yavuz,
- Radim Becvar,
- Patricia E Carreira,
- Eugene J Kucharz,
- Bernard Coleiro,
- Paul Hasler,
- Carlos de la Puente,
- Svetlana Agachi,
- Thierry Zenone,
- Francesco Del Galdo,
- Doron Rimar,
- Alessandro Giollo,
- Lidia P Ananieva,
- Ina Kötter,
- Mislav Radic,
- Dominik Majewski,
- Kristine Herrmann,
- Goda Seskute,
- Lorinda S Chung,
- Laura Belloli,
- Ulrike Held,
- FJ López-Longo,
- Joerg H W Distler,
- Maria João Salvador,
- Simon Kuster,
- Klaus Steigmiller,
- Ana-Maria Gheorghiu,
- Katarzyna Romanowska-Prochnicka,
- Yuichiro Shirai,
- Chris Denton,
- Ruxandra M Ionescu,
- Stefan Heitmann Vera Ortiz-Santamaria,
- Walid Ahmed Abdel Atty Mohamed,
- Paloma Garcíadela Peña Lefebvre,
- Vera Bernardino
Affiliations
- Pavel I Novikov
- 1 Department of Rheumatology, Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russian Federation
- Thierry Martin
- 16 Department of Rheumatology, Emergency County Teaching Hospital, Cluj-Napoca, Romania
- Eric Hachulla
- 30 Internal Medicine, Lille University School of Medicine, Lille, France
- Vanessa Smith
- Department of Rheumatology, Ghent University Hospital, Ghent, Belgium
- Maurizio Cutolo
- 15 Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Genova, Italy
- Yannick Allanore
- Department of Rheumatology A, Hospital Cochin, Paris, Île-de-France, France
- Camillo Ribi
- 5 Division of Immunology and Allergy, University Hospital Center of Lausanne, Lausanne, Switzerland
- Oliver Distler
- Department of Rheumatology, Zurich University Hospital, University of Zurich, Zurich, Switzerland
- Britta Maurer
- Department of Rheumatology and Immunology, Inselspital, Bern University Hospital, Bern, Switzerland
- Paolo Airo
- 1 Rheumatology and Clinical Immunology Unit, ASST Spedali Civili, Brescia, Italy
- Cosimo Bruni
- Department of Experimental and Clinical Medicine, Division of Rheumatology, Università degli Studi di Firenze, Firenze, Italy
- Veronica Codullo
- 1 Rheumatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Lombardia, Italy
- Luc Mouthon
- Department of Internal Medicine, National Reference Center for Rare Systemic Autoimmune Diseases, AP-HP, APHP.CUP, Hôpital Cochin, Paris, France
- Marie Vanthuyne
- 23 Department of Rheumatology, Université Catholique de Louvain, Louvain-la-Neuve, Belgium
- Elisabetta Zanatta
- 12 Dipartimento di Medicina, DIMED, Universita degli Studi di Padova, Padova, Italy
- Simona Rednic
- 1University of Medicine and Pharmacy ‘Iuliu Hatieganu’, Cluj-Napoca, Romania
- Ulf Müller-Ladner
- Nemanja Damjanov
- Institute of Rheumatology, University of Belgrade Medical School, Belgrade, Serbia
- Anna-Maria Hoffmann-Vold
- Department of Rheumatology, Oslo University Hospital, Oslo, Norway
- Michele Iudici
- 3 Division of Rheumatology, Department of Internal Medicine and Department of Medicine, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland
- Suzana Jordan
- Department of Rheumatology, University of Zurich, University Hospital Zurich, Zurich, Switzerland
- Jean Sibilia
- 1 Service de Rhumatologie, Centre National de Référence des Maladies Auto-immunes Systémiques Rares Est Sud-Ouest (RESO), Hôpitaux universitaires de Strasbourg, Strasbourg, France
- Mengtao Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Roger Hesselstrand
- Department of Clinical Sciences, Lund, Section for Rheumatology, Lund University and Skåne University Hospital, Lund, Skåne, Sweden
- Elise Siegert
- 4 Department of Rheumatology and Clinical Immunology, Charité University Hospital Berlin, Berlin, Germany
- László Czirják
- Department of Rheumatology and Immunology, University of Pecs, Pecs, Hungary
- Armando Gabrielli
- 10Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche and Ospedali Riuniti, Ancona, Italy
- Dominique Farge Bancel
- Department of Internal Medicine, Hopital Saint-Louis, Paris, France
- Yolanda Braun-Moscovici
- 1 B. Shine Department of Rheumatology, Rambam Health Care Campus, Haifa, Israel
- Nicolas Hunzelmann
- Department of Dermatology, University of Cologne, Cologne, Germany
- Raffaele Pellerito
- 8Unit of Rheumatology, Ospedale Mauriziano, Torino, Italy
- Jörg Henes
- Medizinische Universitätsklinik, Abt II (Onkologie, Hämatologie, Rheumatologie, Immunologie, Pulmonologie), Tübingen, Germany
- Bojana Stamenkovic
- Institute for Prevention, Treatment and Rehabilitation of Rheumatic and Cardiovascular Diseases, Niska Banja, Serbia and Montenegro
- Carlo Francesco Selmi
- Mohammed Tikly
- Dept of Rheuamatology, University of the Witwatersrand Faculty of Health Sciences, Johannesburg, South Africa
- Merete Engelhart
- Valeria Riccieri
- 1 Dipartimento di Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari - Reumatologia, Università degli Studi di Roma La Sapienza, Roma, Italy
- Cord Sunderkötter
- Francesca Ingegnoli
- Dept. of Clinical Sciences & Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Università degli Studi di Milano, Milano, Italy
- Francesco Paolo Cantatore
- Susanne Ullman
- 36 University Hospital of Copenhagen, Department of Dermatology, Hospital Bispebjerg, Copenhagen, Denmark
- Maria Rosa Pozzi
- Piotr Wiland
- 22Department of Rheumatology and Internal Medicine, Wroclaw Medical University, Wroclaw, Poland
- Juan Jose Alegre-Sancho
- Department of Rheumatology, Hospital Universitario Dr Peset, Valencia, Spain
- Brigitte Krummel-Lorenz
- 23 Endokrinologikum Frankfurt, Frankfurt, Germany
- Ellen De Langhe
- Division of Rheumatology and Department of Development and Regeneration, University Hospital Leuven and Laboratory Tissue Homeostasis and Disease, Leuven, Belgium
- Branimir Anic
- 24University Hospital Zagreb, Zagreb, Croatia
- Carolina de Souza Müller
- Rheumatology Division, Clinics Hospital, Federal University of Paraná, Curitiba, Brazil
- Simon Stebbings
- 16 Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
- Alessandra Vacca
- 17 Chair and Rheumatology Unit, University Clinic AOU Cagliari, Monserrato, Italy
- Lisa Stamp
- 6Department of Medicine, University of Otago, Christchurch, New Zealand
- Kamal Solanki
- Rheumatology Unit, Waikato University Hospital, Hamilton City, Hamilton, New Zealand
- Douglas Veale
- 33 Department of Rheumatology, Klinikum Bielefeld, Bielefeld, Germany
- Esthela Loyo
- Reumatologia e Inmunologia Clinica, Hospital Regional Universitario Jose Ma Cabral y Baez, Clinica Corominas, Santiago, Dominican Republic
- Edoardo Rosato
- 3 Dipartimento di Medicina Traslazionale e di Precisione, Sapienza University of Rome, Roma, Italy
- Cristina-Mihaela Tanaseanu
- Rosario Foti
- Rheumatology Unit, Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele Catania, Catania, Italy
- Codrina Ancuta
- Department of Rheumatology and Rehabilitation, Gr.T.Popa University of Medicine and Pharmacy, Iasi, Romania
- Ira Litinsky
- 1 Rheumatology Department, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Lesley Ann Saketkoo
- 33 University Medical Center Comprehensive Pulmonary Hypertension Center (UMC-CPHC); Tulane University Lung Center Tulane, New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center New Orleans, New Orleans, Louisiana, USA
- Eduardo Kerzberg
- Department of Rheumatology, University of Buenos Aires, Buenos Aires, Argentina
- Tim Schmeiser
- Krankenhaus St. Josef, Wuppertal, Germany
- Piercarlo Sarzi Puttini
- 7 Rheumatology Unit, L. Sacco University Hospital of Milan, Milan, Italy
- Fabio Cacciapaglia
- Rheumatology Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
- Marie-Elise Truchetet
- ImmunoConcEpt, CNRS, UMR 5164, University of Bordeaux, Talence, France
- Muriel Elhai
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
- Juan José Alegre Sancho
- 2 Department of Rheumatology, Hospital Universitario Dr. Peset, Valencia, Spain
- Ivan Castellví
- Servicio de Reumatología, Hospital de Sant Pau, Barcelona, Spain
- Serena Vettori
- Rheumatology Department, Second University of Naples, Naples, Italy
- Vivien M Hsu
- UMDNJ Scleroderma Program, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
- Masataka Kuwana
- 4 Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan
- Sule Yavuz
- Rheumatology, Istanbul Bilim Universitesi, Istanbul, Turkey
- Radim Becvar
- 2Department of Rheumatology, 1st Faculty of Medicine, Institute of Rheumatology, Charles University, Prague, Czech Republic
- Patricia E Carreira
- Servicio de Reumatología, Hospital Universitario 12 de Octubre, Madrid, Spain
- Eugene J Kucharz
- Professor emeritus, Department of Internal Medicine, Rheumatology and Clinical Immunology, Medical University of Silesia, Katowice, Poland
- Bernard Coleiro
- `Stella Maris` Balzan, Balzan, Malta
- Paul Hasler
- Carlos de la Puente
- Svetlana Agachi
- Thierry Zenone
- Department of Internal Medicine, CH, Valence, France
- Francesco Del Galdo
- Scleroderma Center, Leeds Institute of Molecular Medicine, Section of Musculoskeletal Diseases, University of Leeds, Leeds, UK
- Doron Rimar
- 1 Rheumatology, Bnai-Zion medical center, Haifa, Israel
- Alessandro Giollo
- Rheumatology Unit, University of Verona, Verona, Italy
- Lidia P Ananieva
- 6 VA Nasonova Institute of Rheumatology, Moscow, Russian Federation
- Ina Kötter
- Internal Medicine/Rheumatology/Haematology/Oncology, Universitätsklinikum Tübingen, Tübingen, Germany
- Mislav Radic
- Dominik Majewski
- Kristine Herrmann
- Goda Seskute
- Lorinda S Chung
- Division of Immunology and Rheumatology, Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA
- Laura Belloli
- Rheumatology Unit, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
- Ulrike Held
- 2 Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland
- FJ López-Longo
- Rheumatology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Joerg H W Distler
- 4Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
- Maria João Salvador
- 1Rheumatology Department – University Hospital Center of Coimbra, Coimbra, Portugal
- Simon Kuster
- Department of Rheumatology; University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Klaus Steigmiller
- Department of Biostatistics at Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland
- Ana-Maria Gheorghiu
- Department of Internal Medicine and Rheumatology, Cantacuzino Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Katarzyna Romanowska-Prochnicka
- Department of Biophysics, Physiology and Pathophysiology, Medical University of Warsaw, Warsaw, Poland
- Yuichiro Shirai
- Department of Allergy and Rheumatology, Nippon Medical School, Tokyo, Japan
- Chris Denton
- Centre for Rheumatology, University College London Medical School—Royal Free Campus, London, UK
- Ruxandra M Ionescu
- Internal Medicine and Rheumatology Department—St. Maria Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Stefan Heitmann Vera Ortiz-Santamaria
- Walid Ahmed Abdel Atty Mohamed
- Paloma Garcíadela Peña Lefebvre
- Vera Bernardino
- DOI
- https://doi.org/10.1136/rmdopen-2022-002477
- Journal volume & issue
-
Vol. 8,
no. 2
Abstract
Objectives Tocilizumab showed trends for improving skin fibrosis and prevented progression of lung fibrosis in systemic sclerosis (SSc) in randomised controlled clinical trials. We aimed to assess safety and effectiveness of tocilizumab in a real-life setting using the European Scleroderma Trial and Research (EUSTAR) database.Methods Patients with SSc fulfilling the American College of Rheumatology (ACR)/EULAR 2013 classification criteria, with baseline and follow-up visits at 12±3 months, receiving tocilizumab or standard of care as the control group, were selected. Propensity score matching was applied. Primary endpoints were the modified Rodnan skin score (mRSS) and FVC at 12±3 months compared between the groups. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months.Results Ninety-three patients with SSc treated with tocilizumab and 3180 patients with SSc with standard of care fulfilled the inclusion criteria. Comparison between groups did not show significant differences, but favoured tocilizumab across all predefined primary and secondary endpoints: mRSS was lower in the tocilizumab group (difference −1.0, 95% CI −3.7 to 1.8, p=0.48). Similarly, FVC % predicted was higher in the tocilizumab group (difference 1.5 (−6.1 to 9.1), p=0.70). The percentage of progressive/regressive patients favoured tocilizumab over controls. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles.Conclusion Although this large, observational, controlled, real-life EUSTAR study did not show significant effectiveness of tocilizumab on skin and lung fibrosis, the consistency of direction of all predefined endpoints generates hypothesis for potential effectiveness in a broader SSc population.
