AB0069 THE DOWNSTREAM EFFECT OF ADALIMUMAB INVOLVES INHIBITION OF SYNOVIAL CXCL SUBFAMILY CHEMOKINE EXPRESSION
Authors: Anne Faurschou Boisen, Elisabeth Busk Rasmussen, Tue Wenzel Kragstrup
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The many different disease modifying anti-rheumatic drugs used for the treatment of immune mediated inflammatory arthritis have very distinctive modes of action. However, the downstream effects of the different drugs are not completely understood. As more treatment options become available detailed knowledge about the different drugs will be important in the future when planning treatment strategies. Adalimumab is a fully humanized monoclonal antibody against tumor necrosis factor-alpha (TNFα). Earlier studies have found that TNFα inhibitors can decrease the production of interleukin 1 (IL-1), IL-6, IL-8 (aka CXC motif chemokine 8 (CXCL8)), monocyte chemotactic protein 1 (MCP-1) and granulocyte-macrophage colony-stimulating factor (GM-CSF).[1] However, these studies have been limited to the measurement of a subset of predefined downstream signaling molecules. <h3>Objectives</h3> The aim of this study was to make an unbiased investigation of downstream effects of adalimumab on production of a wide range of cytokines, chemokines and growth factors by synovial fluid mononuclear cells (SFMCs). <h3>Methods</h3> SFMCs were obtained from a study population consisting of patients with active RA or peripheral SpA with at least one swollen joint (for obtaining synovial fluid) (n=14). SFMCs were cultured for 48 hours with and without addition of adalimumab 5 μg/ml measuring the secretion of 96 cytokines, chemokines and growth factors by an Olink proseek multiplex panel. <h3>Results</h3> In SFMCs cultured for 48 hours, adalimumab decreased the production of IL-8 (CXCL8) (P=0.0001), CXC motif chemokine 5 (CXCL5) (P=0.0003), CXCL9 (P=0.03) and CXCL10 (P=0.03), and monocyte chemotactic protein 2 (MCP-2) (P=0.04) and increased the production of hepatocyte growth factor (HGF) (P=0.008) and tumor necrosis factor-like weak inducer of apoptosis (TWEAK) (P=0.03) after Bonferroni correction (all corrected P values). In this unbiased analysis, adalimumab did not change the production of several other cytokines and chemokines including IL-12B (P=0.07), IL-6 (P=0.07), IL-10 (P=0.12), IL-18 (P=0.19), and IL-4 (P=0.63). <h3>Conclusion</h3> This study illuminates the downstream effects of neutralizing TNFα not previously investigated. Adalimumab had a pronounced effect on downregulation of the inflammatory CXCL subfamily chemokines IL-8, CXCL5, CXCL9, and CXCL10. This helps explain findings of diminished inflammatory cell migration into joints seen in the first trials with TNFα inhibitors and could be an important mechanism of action of TNFα inhibitors.[2] Further characterization of downstream effects of the multiple DMARDs used for the treatment of immune mediated inflammatory arthritis will help guide treatment strategies for these patients. <h3>References</h3> [1] Brennan FM, Chantry D, Jackson A, Maini R, Feldmann M. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet1989;2:244–7. [2] Taylor PC, Peters AM, Paleolog E, Chapman PT, Elliott MJ, McCloskey R, et al. Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor alpha blockade in patients with rheumatoid arthritis. Arthritis Rheum. 2000;43:38–47. <h3>Disclosure of Interests</h3> Anne Faurschou Boisen: None declared, Elisabeth Busk Rasmussen: None declared, Tue Wenzel Kragstrup Consultant for: Bristol-Myers Squibb, Speakers bureau: Pfizer, Bristol-Myers Squibb, Eli-Lilly, Novartis, UCB