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

Charlie Bridegwood, Kassem Sharif, Jane Freeston, Benazir Saleem, Tobias Russell, Abdulla Watad, Almas Khan, Peter Loughenbury, Abhay Rao, Miriam Wittmann, Dennis McGonagle
Rheumatology 2020 November 30

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.

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