Assessment of rituximab's immunomodulatory synovial effects (ARISE trial). 1: clinical and synovial biomarker results.
OBJECTIVE
Treatment with the anti-CD20 monoclonal antibody (mAb) rituximab is effective in rheumatoid arthritis (RA). Marked depletion of circulating B cells, seen in almost all patients, does not correlate with efficacy. The potential synovial immunomodulatory effects of rituximab have not been fully defined.


METHODS
The ARISE trial is an open label, serial synovial biopsy (pre-treatment and 8 weeks) study of rituximab, given 1 g intravenously on days 0 and 14 without peri-infusional steroids, in active RA patients on concomitant methotrexate (MTX). Synovial tissue was analysed by immunohistochemistry with digital image analysis and gene expression by real-time PCR.


RESULTS
The mean (SD) baseline DAS28 score was 6.5 (0.4), and mean MTX dose 17.3 mg/week. Of 13 patients, 11 had failed prior tumour necrosis factor (TNF) inhibitor therapy. With treatment, all patients experienced near complete depletion of circulating B cell numbers. During the 6 months after treatment, 7/13 patients achieved an American College of Rheumatology (ACR) 20% improvement (ACR20) response, 3/13 an ACR50 response and 2/13 an ACR70 response. There was a significant decrease in synovial B cells after treatment, but only a small trend towards greater reduction among clinical responders. Among the three patients with ACR50 responses there was a significant decrease in synovial immunoglobulin synthesis.


CONCLUSIONS
These data suggest that unlike those in circulation, synovial B cells are decreased but are not eliminated by rituximab therapy. Patients with higher levels of response may have more consistent depletion of synovial B cells, and may also have an alteration in synovial B cell function, as indicated by decreases in synovial immunoglobulin synthesis. Thus, effects on synovial B cells may be necessary but not sufficient for inducing clinical efficacy. Other effects, such as on primary lymph organ B cell antigen presentation or cytokine production, may be operative.
Kavanaugh
A
A
University of California, San Diego, Division of Rheumatology, Allergy, and Immunology, 9500 Gilman Drive, Mail Code 0943, La Jolla, CA 92093-0943, USA. akavanaugh@ucsd.edu
Rosengren
S
S
Lee
S J
SJ
Hammaker
D
D
Firestein
G S
GS
Kalunian
K
K
Wei
N
N
Boyle
D L
DL
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012217:Rheumatoid Factor / Q000097:blood; D000069283:Rituximab; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000187:drug effects* / Q000276:immunology; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D018501:Antirheumatic Agents; D015415:Biomarkers; D016207:Cytokines; D007136:Immunoglobulins; D018836:Inflammation Mediators; D000069283:Rituximab; D012217:Rheumatoid Factor