Background/Purpose: Immune mediated inflammatory arthritis are very heterogeneous diseases including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (SpA). The available biological and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) target very different components of the disease processes. However, how to choose the right treatment for the individual patient is not clear. Characterization of the pathobiological subtypes of immune mediated inflammatory arthritis could provide more specific treatment approaches for each disease. E.g., RA has been proposed to consist of the three synovial phenotypes 1) ”lymphocyte”, 2) ”macrophage”, and 3) ”fibroblast” and only a subgroup of patients has erosive disease. The objective of this study was to study the effects of different DMARDs on different synovial cell subsets using several human ex vivo models of immune mediated inflammatory arthritis.

Methods: Synovial fluid was obtained from a study population consisting of patients with active rheumatoid arthritis (RA) or peripheral spondyloarthritis (SpA) with at least one swollen joint. The DMARDs used in this study are shown in Table 1. Synovial fluid mononuclear cells (SFMCs) containing primarily synovial monocytes and lymphocytes were cultured for 48 hours (here termed the “macrophage-lymphocyte model”) and assessed for secretion of monocyte chemoattractant protein-1 (MCP-1) (n=14). Fibroblast-like synovial cells (FLSs) were co-cultured with autologous peripheral blood mononuclear cells (PBMCs) (here termed the “fibroblast model”) and assessed for secretion of MCP-1 (n=6). SFMCs were cultured for 21 days (here termed the “osteoclast model”) and assessed for secretion of tartrate-resistant acid phosphatase (TRAP) (n=10). MCP-1 and TRAP were measured by commercially available ELISA kits.

Results: The macrophage-lymphocyte model; In SFMCs cultured for 48 hours, all DMARDs except anakinra decreased the production of MCP-1 (all P<0.05). The osteoclast model;In SFMCs cultured for 21 days, only the two inhibitors of TNFaadalimumaband etanercept decreased the secretion of TRAP by roughly 25% (P<0.01, P<0.001). The fibroblast model; InFLS-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%.

Conclusion: This study reveals differential effects of different DMARDs on different synovial cell subsets using human ex vivo models of immune mediated inflammatory arthritis. Most DMARDs were effective in the “macrophage-lymphocyte model”, only the two TNFainhibitors were effective in the “osteoclast model”, whereas tocilizumab, tofacitinib and baricitinib were superior in the “fibroblast model”. Studies like this could help guide future studies of personalizing DMARDs to treat immune mediated inflammatory arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/in-vitro-proof-of-concept-of-pathobiology-guided-therapy-in-immune-mediated-inflammatory-arthritis/