Responses to cytokine inhibitors associate with cellular composition in models of immune-mediated inflammatory arthritis
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Colleges, School and Institutes
Background: Immune-mediated inflammatory arthritis (IMIA) is a heterogeneous group of diseases including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (SpA). Disease-modifying antirheumatic drugs (DMARDs) target very different cellular components of the disease processes. Characterization of the pathobiological subtypes of IMIA could provide more specific treatment approaches for each disease. For example, RA has been proposed to consist of at least three synovial pathotypes (lymphoid, myeloid, and fibroid), and only a subgroup of RA patients have erosive disease. Objectives: The objective of this study was to evaluate the effects of various DMARDs on different synovial cell subsets using human ex vivo models of immune-mediated inflammatory arthritis. Methods: Synovial fluid and blood samples were obtained from a study population consisting of patients with RA, PsA, or peripheral SpA with at least one swollen joint (n=18). The DMARDs used in this study were methotrexate, adalimumab, etanercept, tocilizumab, anakinra, ustekinumab, secukinumab, tofacitinib, and baricitinib. Paired synovial fluid mononuclear cells (SFMCs), peripheral blood mononuclear cells (PBMCs), and fibroblast-like synovial cells (FLSs) were used in three different previously optimized ex vivo models. Results: In SFMCs cultured for 48 hours, all DMARDs except anakinra decreased the production of MCP-1. In SFMCs cultured for 21 days, only the two TNF inhibitors adalimumab and etanercept decreased the secretion of TRAP (P<0.01, P<0.001). In the FLS and PBMC 48-hour co-cultures, only tocilizumab (P<0.001) and the two Janus kinase inhibitors tofacitinib and baricitinib (P<0.05 and P<0.05) decreased the production of MCP-1 by around 50%. Conclusions: TNF inhibition was effective in preventing inflammatory osteoclastogenesis while tocilizumab, tofacitinib, and baricitinib had superior efficacy in cultures dominated by FLSs Taken together, this study reveals that responses to cytokine inhibitors associate with cellular composition in models of IMIA. In particular, this study provides new evidence on the differential effect of DMARDs on leucocytes compared with stromal cells.
|Journal||ACR Open Rheumatology|
|Publication status||Accepted/In press - 24 Sep 2019|