Successful treatment of rheumatoid arthritis is associated with a reduction in synovial membrane cytokines and cell adhesion molecule expression

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Abstract
Objective. To investigate the change in synovial membrane cytokine content and cell adhesion molecule expression in sequential biopsies from the same knee joint of patients with rheumatoid arthritis, before and following anti‐rheumatic drug treatment and to assess the relationship of these changes with clinical responses to the drug treatment. Methods. A selected group of patients with rheumatoid arthritis, some of whom had achieved a disease remission based on American College of Rheumatology (ACR) criteria, were included in this study. Sequential synovial biopsies obtained before and throughout the treatment period were studied by immunohistochemical labelling techniques for the cellular content, production of a range of pro‐ and anti‐inflammatory cytokines and the expression of cell adhesion molecules. The staining was quantitated using computer‐assisted digital image analysis. Results. There was a decrease in tumour necrosis factor‐α (TNFα) and interleukin‐1β (IL‐1β) production in the synovial membrane lining and sublining of all patients who responded to treatment. The changes in IL‐1 receptor antagonist production were variable. Paradoxically, there was a trend to decreased synovial membrane production of the anti‐inflammatory cytokines, IL‐10 and transforming growth factor‐β (TGFβ), while IL‐4 was not detectable in any of the synovial membrane biopsies. A significant reduction in the density and total amount of E‐selectin expression in the synovial membrane was seen. Similarly, intercellular adhesion molecule‐1 (ICAM‐1) expression in the lining and sublining was decreased in those patients who had a significant clinical response to drug treatment or attained disease remission. There were no consistent or significant changes seen in the expression of other cell adhesion molecules in the synovial membranes of these patients. Conclusions. Successful drug treatment of rheumatoid arthritis patients is characterized at the synovial membrane level by a decrease in TNFα, IL‐10 and TGFβ production. Some (E‐selectin and ICAM‐1) but not all (P‐selectin, VCAM‐1, PECAM‐1) cell adhesion molecules are modulated in patients who respond clinically to drug treatment. E‐selectin and ICAM‐1 may be important targets for the development of future drug treatments for rheumatoid arthritis.