Interleukin 4-receptor-α blockade in localised scleroderma: a phase 2 proof-of-concept study
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Sabine A Eming1, Alexander Kreuter2, Matthias Hahn3
1Department of Dermatology, Cluster of Excellence Cellular Stress Responses in Ageing-associated Diseases, Center for Molecular Medicine Cologne, Institute of Zoology, Developmental Biology, University of Cologne, Cologne, Germany.
Objectives:
Fibrotic diseases are a major therapeutic challenge. In humans, fibrosing diseases are often associated with an interleukin (IL-) 4/TH2 signature. In preclinical mouse models, development of fibrosis critically depends on IL-4/signal transducer and activator of transcription 6 (STAT6). Yet, the role of IL-4/IL-13 in human fibrosing diseases remains unknown, and treatment development requires a deeper understanding of the role of IL-4/IL-13 in the pathogenesis. The local inflammation and the development of fibrosis in localised scleroderma (LS) are similar to those in systemic sclerosis and other fibrosing diseases.
Methods:
In this article, we investigated the role of IL-4/IL-13 signalling in LS in a randomised, placebo-controlled clinical trial (ClinicalTrials.gov registration: NCT04200755). We studied the effect of 6 months of blocking IL-4-receptor α with dupilumab on disease progression, sclerosis-associated inflammation, and sclerosis-specific gene expression.
Results:
Already this short-term intervention resulted in a significant clinical improvement over placebo, a significant attenuation of the local inflammation, a specific and significant reduction of the IL-4/IL-13-dependent gene signature, and a partial suppression of genes coding for fibrosis-inducing proteins.
Conclusions:
Thus, selective inhibition of IL-4/IL-13 prevents the progression of LS and is promising for therapeutic prevention of other fibrosing diseases.