Interindividual and intra-articular variation of proinflammatory cytokines in patients with rheumatoid arthritis:: potential implications for treatment

Objectives-Assessment of the numbers and spatial distribution of cells producing interleukin 1 alpha (IL1 alpha), interleukin 1 beta (IL1 beta), tumour necrosis factor alpha (TNF alpha), and interleukin 6 (IL6) in the synovial membranes of patients with rheumatoid arthritis (RA). Methods-Synovial tissue specimens from 40 patients with RA and eight patients with non-rheumatic disease were obtained by arthroscopy guided biopsy techniques or during joint surgery. A modified immunohistochemical method detecting cytokine producing rather than cytokine binding cells was applied to determine cytokine synthesis in fixed cryopreserved sections. Computerised image analysis methods provided comparative quantitative assessments. Results-A wide variation between subjects was recorded for both quantities and profiles of expressed cytokines, despite similar macroscopic and histopathological features of inflammation. IL1 alpha and IL1 beta were the most abundant monokines identified, though produced at different sites. IL1 alpha was predominantly seen in vascular endothelial cells, whereas IL1 beta staining was mainly shown in macrophages and fibroblasts. Concordant results for the detection of TNF alpha at protein and mRNA levels were obtained with an unexpectedly low number of TNF alpha producing cells compared with IL1 expressing cells in many patients with RA. Specimens acquired arthroscopically from areas with maximum signs of macroscopic inflammation showed an increased number of TNF alpha producing cells in pannus tissue compared with that occurring in synovial villi of a given joint. This clustered distribution was not found for cells expressing any of the other studied cytokines. Conclusion-The recorded heterogeneous profile of proinflammatory cytokine synthesis in the synovial membrane among patients with RA may provide a clue for an understanding of the wide variation in responsiveness to different modes of antirheumatic treatment between patients.