title: IgG4 production against adalimumab during long term treatment of RA patients.
abstract: OBJECTIVE
  A substantial part of rheumatoid arthritis (RA) patients is chronically treated with adalimumab. Some of these patients produce antibodies against adalimumab, which correlate with lower serum drug levels and reduced clinical response. Long term exposure to antigens may result in antigen specific IgG4 production as was demonstrated in studies on prolonged exposure to antigens such as different allergens, Factor VIII and IFN-β. Here, we investigate whether long term treatment of RA patients with the therapeutic monoclonal antibody adalimumab leads to the production of specific IgG4 antibodies.
  
  
  METHODS
  We developed radio immunoassays to detect total IgG or IgG4 against adalimumab and applied these in a cohort of 271 consecutive RA patients during 3 years of adalimumab treatment.
  
  
  RESULTS
  In 32 % of the 271 patients antibodies against adalimumab were detectable. IgG4 antibodies were detected in 29 % of the patients. The proportion IgG4 of total IgG against adalimumab varies widely between patients, and IgG4 was found to contribute significantly to the anti drug antibody (ADA) response in some patients.
  
  
  CONCLUSIONS
  In the immune response against adalimumab in adalimumab-treated RA patients a considerable part of the ADA is IgG4. Although IgG4 is often considered to be harmless due to its lack of effector function, neutralization of adalimumab by IgG4 antibodies will lead to a reduced clinical response.
authors.affiliation: Department of Immunopathology, Sanquin Research and Landsteiner Laboratory Academic Medical Centre, Amsterdam, The Netherlands. p.schouwenburgvan@sanquin.nl
authors.forename: Pauline A
authors.initials: PA
authors.lastname: van Schouwenburg
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Krieckaert
authors.forename: Michael
authors.initials: M
authors.lastname: Nurmohamed
authors.forename: Margreet
authors.initials: M
authors.lastname: Hart
authors.forename: Theo
authors.initials: T
authors.lastname: Rispens
authors.forename: Lucien
authors.initials: L
authors.lastname: Aarden
authors.forename: Diana
authors.initials: D
authors.lastname: Wouters
authors.forename: Gerrit Jan
authors.initials: GJ
authors.lastname: Wolbink
mesh_terms: D000068879:Adalimumab; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology* / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000276:immunology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D000068879:Adalimumab