Conceptual framework for the definition of disease modification in systemic sclerosis and potential implications for drug development and clinical study design
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.
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BibTeX
@article{distler2026conceptual,
title = {{Conceptual framework for the definition of disease modification in systemic sclerosis and potential implications for drug development and clinical study design}},
author = {Jörg Distler and Shervin Assassi and Armando Gabrielli and Yannick Allanore and Lorinda Chung and Maurizio Cutolo and Francesco Del Galdo and Jeska K de Vries-Bouwstra and Robyn T Domsic and Muriel Elhai and Tracy Frech and Monique Hinchcliff and Bernhard Homey and Dinesh Khanna and Thomas Krieg and Masataka Kuwana and Alain Lescoat and Andrea Low and Marco Matucci-Cerinic and Zsuzsanna H Mcmahan and Jerry A Molitor and Luc Mouthon and Mandana Nikpour and Gabriela Riemekasten and Julia Spierings and Marie-Elise Truchetet and Vanessa Smith and John Varga and Elizabeth Volkmann and Madelon C Vonk and Jiucun Wang and Dong Xu and Honglin Zhu and Anna-Maria Hoffmann-Vold and Christopher P Denton and Oliver Distler},
journal = {Annals of the Rheumatic Diseases},
year = {2026},
month = sep,
doi = {10.1016/j.ard.2026.08.006},
url = {https://u-bordeaux.hal.science/hal-05771416v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Conceptual framework for the definition of disease modification in systemic sclerosis and potential implications for drug development and clinical study design
AU - Jörg Distler
AU - Shervin Assassi
AU - Armando Gabrielli
AU - Yannick Allanore
AU - Lorinda Chung
AU - Maurizio Cutolo
AU - Francesco Del Galdo
AU - Jeska K de Vries-Bouwstra
AU - Robyn T Domsic
AU - Muriel Elhai
AU - Tracy Frech
AU - Monique Hinchcliff
AU - Bernhard Homey
AU - Dinesh Khanna
AU - Thomas Krieg
AU - Masataka Kuwana
AU - Alain Lescoat
AU - Andrea Low
AU - Marco Matucci-Cerinic
AU - Zsuzsanna H Mcmahan
AU - Jerry A Molitor
AU - Luc Mouthon
AU - Mandana Nikpour
AU - Gabriela Riemekasten
AU - Julia Spierings
AU - Marie-Elise Truchetet
AU - Vanessa Smith
AU - John Varga
AU - Elizabeth Volkmann
AU - Madelon C Vonk
AU - Jiucun Wang
AU - Dong Xu
AU - Honglin Zhu
AU - Anna-Maria Hoffmann-Vold
AU - Christopher P Denton
AU - Oliver Distler
PY - 2026
DA - 2026/09/30
JO - Annals of the Rheumatic Diseases
DO - 10.1016/j.ard.2026.08.006
UR - https://u-bordeaux.hal.science/hal-05771416v1
AB - 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.
SN - 0003-4967
SN - 1468-2060
ER -