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 ± 21 pg/ml at baseline, 48 ± 18 pg/ml after third cycle, P = 0·03) along with IL-17 (1197 ± 203 pg/ml at baseline, 623 ± 213 pg/ml after third cycle, P = 0·03) and tended to increase the frequency of circulating regulatory T cells (3·1 ± 1 cells/μl at baseline, 7·7 ± 2 cells/μl after third cycle). Rituximab also significantly decreased IL-15 trans-presentation on surface monocytes of patients negative for IL-15 serum (mean fluorescence intensity: 4·82 ± 1·30 at baseline, 1·42 ± 0·69 after third cycle P = 0·05). Reduction of serum IL-15 was associated with decrease in CD8(+)  CD45RO(+) /RA(+) ratio (1·17 ± 0·21 at baseline, 0·36 ± 0·06 at third cycle, P = 0·02). DAS28, erythrocyte sedimentation rate and C-reactive protein correlated significantly with CD8(+)  CD45RO(+) /RA(+) ratio (R = 0·323, R = 0·357, R = 0·369 respectively, P < 0·001). Our results suggest that sustained clinical improvement after rituximab treatment is associated with IL-15/memory T-cell-related mechanisms beyond circulating B cells.
Rheumatology Unit, Internal Medicine Department Hospital Sant Pau, Barcelona, Spain.
César
C
Díaz-Torné
M Angels
MA
Ortiz de Juana
Carme
C
Geli
Elisabet
E
Cantó
Ana
A
Laiz
Héctor
H
Corominas
Jordi
J
Casademont
Josep M
JM
de Llobet
Cándido
C
Juárez
César
C
Díaz-López
Sílvia
S
Vidal
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology* / Q000627:therapeutic use; D018941:Antigens, CD19 / Q000276:immunology; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D019409:Interleukin-15 / Q000037:antagonists & inhibitors* / Q000097:blood / Q000276:immunology; D008297:Male; D008875:Middle Aged; D000069283:Rituximab
D058846:Antibodies, Monoclonal, Murine-Derived; D018941:Antigens, CD19; D018501:Antirheumatic Agents; D019409:Interleukin-15; D000069283:Rituximab
T cells; rheumatoid arthritis; rituximab