FcγRIIIa Expression on Monocytes in Rheumatoid Arthritis: Role in Immune-Complex Stimulated TNF Production and Non-Response to Methotrexate Therapy

Objective: The expression of Fc gamma RIIIa/CD16 may render monocytes targets for activation by IgG-containing immune complexes (IC). We investigated whether Fc gamma RIIIa/CD16 was upregulated in rheumatoid arthritis (RA), associated with TNF production in response to IC-stimulation, and if this predicted response to methotrexate therapy. Methods: Fc gamma RIIIa/CD16 expression on CD14(low) and CD14(++) monocytes was measured by flow cytometry in healthy controls and RA patients (early and long-standing disease). Intracellular TNF-staining was carried out after in vitro LPS or heat-aggregated immunoglobulin (HAG) activation. Fc gamma RIIIa/CD16 expression pre- and post-steroid/methotrexate treatment was examined. Results: Increased Fc gamma RIIIa/CD16 expression on CD14(++) monocytes in long-standing RA patients compared to controls was demonstrated (p = 0.002) with intermediate levels in early-RA patients. HAG-induced TNF-production in RA patients was correlated with the percentage of CD14(++) monocytes expressing Fc gamma RIIIa/CD16 (p<0.001). The percentage of CD14(++) monocytes expressing Fc gamma RIIIa/CD16 at baseline in early DMARD-naive RA patients was negatively correlated with DAS28-ESR improvement 14-weeks post-methotrexate therapy (p = 0.003) and was significantly increased in EULAR non-responders compared to moderate (p = 0.01) or good responders (p = 0.003). Fc gamma RIIIa/CD16 expression was not correlated with age, presence of systemic inflammation or autoantibody titers. Conclusion: Increased Fc gamma RIIIa/CD16 expression on CD14(++) monocytes in RA may result in a cell that has increased responsiveness to IC-stimulation. This monocyte subset may contribute to non-response to methotrexate therapy.