Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a controlled clinical trial.
OBJECTIVE
To examine immunization responses in patients with rheumatoid arthritis (RA) treated with rituximab and to investigate the effects of rituximab-induced CD20+ B cell depletion on immune responses to tetanus toxoid (T cell-dependent antigen), pneumococcal polysaccharide (T cell-independent antigen), and keyhole limpet hemocyanin (KLH) (neoantigen) and on delayed-type hypersensitivity (DTH).


METHODS
In a controlled trial, we enrolled 103 patients with active RA receiving a stable dose of methotrexate (MTX). Tetanus toxoid, pneumococcal polysaccharide, and KLH vaccines as well as a Candida albicans skin test were administered to 1 group of patients receiving rituximab plus MTX (called rituximab-treated patients) for 36 weeks and to 1 group of patients receiving MTX alone for 12 weeks. The primary end point was the proportion of patients with a >or=4-fold rise in antitetanus IgG levels. Antitetanus, antipneumococcal, and anti-KLH serum IgG levels were measured prior to and 4 weeks following vaccine administration. The DTH response to C albicans was measured 2-3 days following placement.


RESULTS
Responses to tetanus toxoid vaccine (>or=4-fold rise) were similar in both groups (39.1% of rituximab-treated patients and 42.3% of patients treated with MTX alone). The ability to maintain a positive DTH response to the C albicans skin test was comparable in both groups (77.4% of rituximab-treated patients and 70% of patients treated with MTX alone), showing no effect of rituximab treatment. Rituximab-treated patients had decreased responses to pneumococcal polysaccharide vaccine (57% of patients had a 2-fold rise in titer in response to >or=1 serotype, compared with 82% of patients treated with MTX alone) and to KLH vaccine (47% of patients had detectable anti-KLH IgG, compared with 93% of patients treated with MTX alone).


CONCLUSIONS
Recall responses to the T cell-dependent protein antigen tetanus toxoid as well as DTH responses were preserved in rituximab-treated RA patients 24 weeks after treatment. Responses to neoantigen (KLH) and T cell-independent responses to pneumococcal vaccine were decreased, but many patients were able to mount responses. These data suggest that polysaccharide and primary immunizations should be administered prior to rituximab infusions to maximize responses.
Bingham
Clifton O
CO
Division of Rheumatology, Johns Hopkins University, Baltimore, Maryland 21224, USA. Clifton.bingham@jhmi.edu
Looney
R John
RJ
Deodhar
Atul
A
Halsey
Neal
N
Greenwald
Maria
M
Codding
Christine
C
Trzaskoma
Benjamin
B
Martin
Flavius
F
Agarwal
Sunil
S
Kelman
Ariella
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology*; D018951:Antigens, CD20 / Q000378:metabolism; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000276:immunology; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D007252:Influenza Vaccines / Q000008:administration & dosage; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D022242:Pneumococcal Vaccines / Q000008:administration & dosage; D000069283:Rituximab; D012882:Skin Tests; D013745:Tetanus Toxoid / Q000008:administration & dosage; D014612:Vaccines / Q000008:administration & dosage*; D055815:Young Adult
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D018501:Antirheumatic Agents; D007252:Influenza Vaccines; D022242:Pneumococcal Vaccines; D013745:Tetanus Toxoid; D014612:Vaccines; D000069283:Rituximab; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin; D008727:Methotrexate