Rituximab-induced interleukin-15 reduction associated with clinical improvement in rheumatoid arthritis

Rituximab therapy alters all aspects of B-cell participation in the disturbed immune response of rheumatoid arthritis patients. To determine the impact of B-cell depletion on other immune compartments, we analysed levels of soluble and surface interleukin-15 (IL-15) along with the frequency of IL-15-related subsets after rituximab treatment. We then studied the correlation of observed changes with clinical activity. Heparinized blood samples from 33 rheumatoid arthritis patients were collected on days 0, 30, 90 and 180 after each of three rituximab cycles. Serum cytokine levels were determined by ELISA. Interleukin-15 trans-presentation was analysed by cytometry. Flow cytometry with monoclonal antibodies was performed to analyse circulating cell subsets. Interleukin-15 was detected in the serum of 25 patients before initiating the treatment. Rituximab then progressively reduced serum IL-15 (138 +/- 21pg/ml at baseline, 48 +/- 18pg/ml after third cycle, P=0 center dot 03) along with IL-17 (1197 +/- 203pg/ml at baseline, 623 +/- 213pg/ml after third cycle, P=0 center dot 03) and tended to increase the frequency of circulating regulatory T cells (3 center dot 1 +/- 1cells/l at baseline, 7 center dot 7 +/- 2cells/l after third cycle). Rituximab also significantly decreased IL-15 trans-presentation on surface monocytes of patients negative for IL-15 serum (mean fluorescence intensity: 4 center dot 82 +/- 1 center dot 30 at baseline, 1 center dot 42 +/- 0 center dot 69 after third cycle P=0 center dot 05). Reduction of serum IL-15 was associated with decrease in CD8+CD45RO+/RA+ ratio (1 center dot 17 +/- 0 center dot 21 at baseline, 0 center dot 36 +/- 0 center dot 06 at third cycle, P=0 center dot 02). DAS28, erythrocyte sedimentation rate and C-reactive protein correlated significantly with CD8+CD45RO+/RA+ ratio (R=0 center dot 323, R=0 center dot 357, R=0 center dot 369 respectively, P<0 center dot 001). Our results suggest that sustained clinical improvement after rituximab treatment is associated with IL-15/memory T-cell-related mechanisms beyond circulating B cells.