Abstract

Objective: To determine whether the heterogeneous clinical response to TNFα blocking therapy in rheumatoid arthritis (RA) can be predicted by TNFα expression in the synovium before initiation of treatment.

Methods: Prior to initiation of infliximab treatment, arthroscopic synovial tissue biopsies were obtained from 143 patients with active RA. At week 16 clinical response was evaluated using the Disease Activity Score (DAS28). Immunohistochemistry was used to analyze the cell infiltrate as well as the expression of various cytokines, adhesion molecules, and growth factors. Stained sections were evaluated by digital image analysis. T-test were used to compare responders (decrease in DAS28 ≥ 1.2) with non-responders (decrease in DAS28 <1.2) and multivariable regression was used to identify the independent predictors of clinical response.

Results: Synovial tissue analysis confirmed our hypothesis that the baseline level of TNFα expression is a significant predictor of response to TNFα blocking therapy. TNFα expression in the intimal lining layer and synovial sublining were significantly higher in responders than in non-responders (P = 0.047 and P = 0.008, respectively). The numbers of macrophages, macrophage subsets, and T cells (all able to produce TNFα) were also significantly higher in responders than in non-responders. The expression of IL-1β, IL-6, IL-18, IL-10, E-selectin, ICAM-1, VCAM-1, VEGF, and bFGF was not associated with response to anti-TNFα treatment.

Conclusion: The effects of TNFα blockade are in part dependent on synovial TNFα expression and infiltration by TNFα producing inflammatory cells. Clinical response cannot be predicted completely, indicating involvement of other as yet unknown mechanisms.