System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Review Ahead of print

PubMed: 42736088 DOI: 10.1016/j.ard.2026.08.006

Conceptual framework for the definition of disease modification in systemic sclerosis and potential implications for drug development and clinical study design.

Ann Rheum Dis

Authors: Jörg H W Distler, Shervin Assassi, Armando Gabrielli, Yannick Allanore, Lorinda Chung, Maurizio Cutolo, Francesco Del Galdo, Jeska K De Vries-Bouwstra, Robyn T Domsic, Muriel Elhai, Tracy Frech, Monique Hinchcliff, Bernhard Homey, Dinesh Khanna, Thomas Krieg, Masataka Kuwana, Alain Lescoat, Andrea H L Low, Marco Matucci-Cerinic, Zsuzsanna H McMahan, Jerry A Molitor, Luc Mouthon, Mandana Nikpour, Gabriela Riemekasten, Julia Spierings, Marie-Elise Truchetet, Vanessa Smith, John Varga, Elizabeth Volkmann, Madelon C Vonk, Jiucun Wang, Dong Xu, Honglin Zhu, Anna-Maria Hoffmann-Vold, Christopher P Denton, Oliver Distler

Affiliations

  • Department of Rheumatology, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany; Hiller Research Center, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany.
  • Department of Internal Medicine, Division of Rheumatology, UTHealth Houston, Houston, TX, USA.
  • Department of Rheumatology, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany; Hiller Research Center, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany; Foundation of Molecular Medicine and Cellular Therapy, Polytechnic University of Marche, Ancona, Italy.
  • Department of Rheumatology, Assistance Publique-Hôpitaux de Paris, Cochin Hospital, Université Paris Cité, Paris, France.
  • Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA; Palo Alto Veterans Affairs Health Care System, Palo Alto, CA, USA.
  • Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Policlinico San Martino, Genoa, Liguria, Italy; Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine and Medical Specialities (Di.M.I.), University of Genoa, Genoa, Liguria, Italy.
  • Department of Rheumatology, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.
  • Department of Rheumatology, Leiden University Medical Centre, Leiden, Netherlands.
  • Department of Medicine/Rheumatology, University of Pittsburgh School of Medicine. Pittsburgh, PA, USA.
  • Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
  • Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Tennessee Valley Health Care System, Veterans Affair Medical Center, Nashville, TN, USA.
  • Section of Rheumatology, Allergy, and Immunology, Yale School of Medicine, New Haven, CT, USA.
  • Department of Dermatology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
  • Division of Rheumatology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Translational Matrix Biology, Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Center for Molecular Medicine (CMMC) University of Cologne, Cologne, Germany.
  • Department of Allergy and Rheumatology, Nippon Medical School, Graduate School of Medicine, Tokyo, Japan.
  • Department of Internal Medicine, Centre Hospitalier Universitaire de Rennes, Univ Rennes, Rennes, France; Univ Rennes, Centre Hospitalier Universitaire de Rennes, Inserm, École des Hautes Études en Santé Publique, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France.
  • Department of Rheumatology and Immunology, Singapore General Hospital, Singapore; Duke-National University of Singapore Medical School, Singapore.
  • Unit of Immunology, Rheumatology, Allergy and Rare Diseases and Inflammation, fibrosis and aging Initiative, Istituto di Ricovero e Cura a Carattere Scientifico Ospedle San Raffaele and Vita Salute University San Raffaele, Milan, Italy.
  • Division of Rheumatic and Autoimmune Diseases, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
  • Department of Internal Medicine, Reference Center for Rare Systemic Autoimmune and Auto-Inflammatory diseases in Île-de-France, East and West, Cochin Hospital, Public Assistance-Hospitals of Paris, Paris-Centre, Paris Cité University, Paris, France.
  • The University of Sydney School of Public Health and Musculoskeletal Research Centre, Sydney, NSW, Australia; Department of Rheumatology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
  • Department of Rheumatology and Clinical Immunology, University of Lübeck, Lübeck, Germany.
  • Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands.
  • Université Bordeaux, French National Centre for Scientific Research, ImmunoConcEpT, UMR 5164, Bordeaux, France; Centre Hospitalier Universitaire de Bordeaux, FHU ACRONIM, Centre national de référence des maladies auto-immunes et systémiques rares Est/Sud-Ouest (RESO), Bordeaux, France.
  • Department of Internal Medicine, Ghent University, Ghent, Belgium; Department of Rheumatology, Ghent University Hospital, Ghent, Belgium; Unit for Molecular Immunology and Inflammation, Flanders Institute for Biotechnology Inflammation Research Centre, Ghent, Belgium.
  • Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
  • State Key Laboratory of Genetic and Development of Complex Phenotypes, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai, China.
  • Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, China; State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China.
  • Department of Rheumatology and Immunology, Provincial Clinical Research Center for Rheumatic and Immunologic Diseases, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
  • Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Department of Rheumatology, Oslo University Hospital, Oslo, Norway.
  • Centre for Rheumatology, Division of Medicine, Royal Free Campus, University College London, London, UK.
  • Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Abstract

Systemic sclerosis (SSc) is a multifaceted systemic autoimmune disease, characterised by the interplay of vascular alterations, immune dysregulation, and fibrosis. The molecular changes and the clinical presentation of SSc are highly heterogeneous and vary considerably between individual patients. This heterogeneity has hampered efforts to reach a unified and pragmatic definition of disease modification in SSc. Using a consensus approach among SSc experts, the authors seek to identify current challenges in defining SSc disease modification. The definition of disease modification in SSc requires a nuanced approach that considers molecular, mechanistic, and clinical aspects. Disease-modifying treatments in SSc should target core pathways or cells rather than regulatory mechanisms. Disease-modifying treatments should show sustained effects on disease activity and prevent progression of damage across organs, manifestations, disease stages, and disease endotypes. The complex and variable nature of SSc needs to be reflected in preclinical drug development efforts and clinical trial designs to demonstrate disease-modifying effects of drug candidates for SSc. We herein provide a first framework for the definition of disease modification of vascular, inflammatory, and fibrotic domains in SSc. Advances in our understanding of the cellular and molecular mechanisms driving the progression of SSc will enable further refinement of the definition of disease modification and guide optimal preclinical modelling and innovative clinical trial design in future efforts.

MeSH

Sclerosis, Drug Development, Pharmaceutical Preparations, Rheumatic Diseases, Therapeutics, Physical Exertion, Scleroderma, Systemic