title: Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid arthritis treated with rituximab.
abstract: OBJECTIVE
  For patients with rheumatoid arthritis (RA), yearly influenza vaccination is recommended. However, its efficacy in patients treated with rituximab is unknown. The objectives of this study were to investigate the efficacy of influenza vaccination in RA patients treated with rituximab and to investigate the duration of the possible suppression of the humoral immune response following rituximab treatment. We also undertook to assess the safety of influenza vaccination and the effects of previous influenza vaccination.
  
  
  METHODS
  Trivalent influenza subunit vaccine was administered to 23 RA patients who had received rituximab (4-8 weeks after rituximab for 11 patients [the early rituximab subgroup] and 6-10 months after rituximab for 12 patients [the late rituximab subgroup]), 20 RA patients receiving methotrexate (MTX), and 29 healthy controls. Levels of antibodies against the 3 vaccine strains were measured before and 28 days after vaccination using hemagglutination inhibition assay. The Disease Activity Score in 28 joints (DAS28) was used to assess RA activity.
  
  
  RESULTS
  Following vaccination, geometric mean titers (GMTs) of antiinfluenza antibodies significantly increased for all influenza strains in the MTX-treated group and in healthy controls, but for no strains in the rituximab-treated group. However, in the late rituximab subgroup, a rise in GMT for the A/H3N2 and A/H1N1 strains was demonstrated, in the absence of a repopulation of CD19+ cells at the time of vaccination. Seroconversion and seroprotection occurred less often in the rituximab-treated group than in the MTX-treated group for the A/H3N2 and A/H1N1 strains, while seroprotection occurred less often in the rituximab-treated group than in the healthy controls for the A/H1N1 strain. Compared with unvaccinated patients in the rituximab-treated group, previously vaccinated patients in the rituximab-treated group had higher pre- and postvaccination GMTs for the A/H1N1 strain. The DAS28 did not change after vaccination.
  
  
  CONCLUSIONS
  Rituximab reduces humoral responses following influenza vaccination in RA patients, with a modestly restored response 6-10 months after rituximab administration. Previous influenza vaccination in rituximab-treated patients increases pre- and postvaccination titers. RA activity was not influenced.
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, University Medical Center Groningen, Groningen, The Netherlands. s.van.assen@int.umcg.nl
authors.forename: Sander
authors.initials: S
authors.lastname: van Assen
authors.forename: Albert
authors.initials: A
authors.lastname: Holvast
authors.forename: Cornelis A
authors.initials: CA
authors.lastname: Benne
authors.forename: Marcel D
authors.initials: MD
authors.lastname: Posthumus
authors.forename: Miek A
authors.initials: MA
authors.lastname: van Leeuwen
authors.forename: Alexandre E
authors.initials: AE
authors.lastname: Voskuyl
authors.forename: Marlies
authors.initials: M
authors.lastname: Blom
authors.forename: Anke P
authors.initials: AP
authors.lastname: Risselada
authors.forename: Aalzen
authors.initials: A
authors.lastname: de Haan
authors.forename: Johanna
authors.initials: J
authors.lastname: Westra
authors.forename: Cees G M
authors.initials: CG
authors.lastname: Kallenberg
authors.forename: Marc
authors.initials: M
authors.lastname: Bijl
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D000914:Antibodies, Viral / Q000097:blood; D018951:Antigens, CD20 / Q000276:immunology; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D004359:Drug Therapy, Combination; D005260:Female; D006385:Hemagglutination Inhibition Tests; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology; D007115:Immunization Schedule; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage*; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D000069283:Rituximab; D015164:Vaccines, Inactivated / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000914:Antibodies, Viral; D018951:Antigens, CD20; D018501:Antirheumatic Agents; D007252:Influenza Vaccines; D015164:Vaccines, Inactivated; D000069283:Rituximab; D008727:Methotrexate