Regulation of entheseal IL-23 expression by IL-4 and IL-13 as an explanation for arthropathy development under dupilumab therapy

• Published in: Rheumatology (Oxford, England) Vol. 60; no. 5; pp. 2461 - 2466
• Main Authors: Bridgewood, Charlie, Sharif, Kassem, Freeston, Jane, Saleem, Benazir, Russell, Tobias, Watad, Abdulla, Khan, Almas, Loughenbury, Peter, Rao, Abhay, Wittmann, Miriam, McGonagle, Dennis
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 14.05.2021
• Subjects: IL-4; enthesitis; atopic dermatitis; IL-13; dupilumab
• DOI: 10.1093/rheumatology/keaa568
• ISSN: 1462-0324

Abstract Objectives Dupilumab blocks the IL-4 receptor (IL-4R) and thus signalling of the ‘Th2’ cytokines IL-4 and IL-13. It has a license to treat atopic eczema and was recently linked to emergent enthesitis and psoriasis. We investigated the cellular and functional basis for how IL-4/IL-13 regulates the IL-23–IL-17 axis in entheseal stromal, myeloid and lymphocyte cells. Methods Immunohistochemistry was performed on healthy enthesis samples from patients undergoing elective spinal surgery to investigate entheseal tissue IL-4R expression and cytokine expression by intracellular flow cytometry for IL-4 and IL-13. Digested human enthesis samples were stimulated with lipopolysaccharide (LPS) for IL-23 induction, either alone or with IL-4 or IL-13. Enthesis fibroblasts were stimulated with TNF and IL-17 with and without IL-4 or IL-13 to assess the effect on CCL20 secretion. Synovial fluid samples from PsA patients were also analysed by ELISA for levels of IL-4 and IL-13. Results The IL-4/IL-13 receptor was present in both the peri-entheseal bone and enthesis soft tissue, and entheseal-derived T cells produced basal levels of IL-4, but not IL-13. Both IL-4 and IL-13 attenuated LPS-induced entheseal IL-23 production. IL-4 also downregulated secretion of TNF/IL-17A-induced CCL20 from entheseal fibroblasts. Both IL-13 and IL-4 were also detectable in the synovial fluid of PsA patients. We also noted a seronegative inflammatory oligoarthritis whilst under dupilumab therapy. Conclusion Our findings suggest a previously unknown protective role for IL-4/IL-13 in entheseal induction of the IL-23–IL-17 axis. These findings point towards a novel explanation for IL-13 pathway single nucleotide polymorphisms in PsA and also a molecular explanation for why anti-IL-4/IL-13 therapy may induce musculoskeletal entheseal pathology as recently reported.