Responses to cytokine inhibitors associate with cellular composition in models of immune-mediated inflammatory arthritis

Morten A. Nielsen, Søren Lomholt, Anders Mellemkjær, Morten N Andersen, Christopher Buckley, Tue W Kragstrup

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Abstract

Objective: 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 (DMARD s) 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. The objective of this study was to evaluate the effects of various DMARD s on different synovial cell subsets using human ex vivo models of IMIA .
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 DMARD s used in this study were methotrexate, adalimumab, etanercept, tocilizumab, anakinra, ustekinumab, secukinumab, tofacitinib, and baricitinib. Paired synovial fluid mononuclear cells (SFMC s), peripheral blood mononuclear cells (PBMC s), and fibroblast‐like synovial cells (FLS s) were used in three different previously optimized ex vivo models.
Results: In SFMC s cultured for 48 hours, all DMARD s except anakinra decreased the production of monocyte chemoattractant protein (MCP )‐1. In SFMC s cultured for 21 days, only the two tumor necrosis factor alpha (TNF α) inhibitors adalimumab and etanercept decreased the secretion of tartrate‐resistant acid phosphatase (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 (both P < 0.05) decreased the production of MCP ‐1 by around 50%.
Conclusion: TNF α inhibition was effective in preventing inflammatory osteoclastogenesis, whereas tocilizumab, tofacitinib, and baricitinib had superior efficacy in cultures dominated by FLS s. 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 DMARD s on leukocytes compared with stromal cells.
Original languageEnglish
Pages (from-to)3-10
Number of pages8
JournalACR Open Rheumatology
Volume2
Issue number1
Early online date11 Nov 2019
DOIs
Publication statusPublished - Jan 2020

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