title: Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients.
abstract: OBJECTIVE
  Evaluation of long-term safety of rituximab in rheumatoid arthritis (RA).
  
  
  METHODS
  Pooled observed case analysis of data from patients with moderate-to-severe, active RA treated with rituximab in a global clinical trial programme.
  
  
  RESULTS
  As of September 2010, 3194 patients had received up to 17 rituximab courses over 9.5 years (11 962 patient-years). Of these, 627 had >5 years' follow-up (4418 patient-years). A pooled placebo population (n=818) (placebo+methotrexate (MTX)) was also analysed. Serious adverse event and infection rates generally remained stable over time and multiple courses. The overall serious infection event (SIE) rate was 3.94/100 patient-years (3.26/100 patient-years in patients observed for >5 years) and was comparable with placebo+MTX (3.79/100 patient-years). Serious opportunistic infections were rare. Overall, 22.4% (n=717) of rituximab-treated patients developed low immunoglobulin (Ig)M and 3.5% (n=112) low IgG levels for ≥4 months after ≥1 course. SIE rates were similar before and during/after development of low Ig levels; however, in patients with low IgG, rates were higher than in patients who never developed low IgG. Rates of myocardial infarction and stroke were consistent with rates in the general RA population. No increased risk of malignancy over time was observed.
  
  
  CONCLUSIONS
  This analysis demonstrates that rituximab remains generally well tolerated over time and multiple courses, with a safety profile consistent with published data and clinical trial experience. Overall, the findings indicate that there was no evidence of an increased safety risk or increased reporting rates of any types of adverse events with prolonged exposure to rituximab during the 9.5 years of observation.
authors.affiliation: Unit for Clinical Therapy Research, The Karolinska Institute, Stockholm, Sweden. ronald.van.vollenhoven@ki.se
authors.forename: Ronald F
authors.initials: RF
authors.lastname: van Vollenhoven
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: Clifton O
authors.initials: CO
authors.lastname: Bingham
authors.forename: Edward C
authors.initials: EC
authors.lastname: Keystone
authors.forename: Roy M
authors.initials: RM
authors.lastname: Fleischmann
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Furst
authors.forename: Nicola
authors.initials: N
authors.lastname: Tyson
authors.forename: Neil
authors.initials: N
authors.lastname: Collinson
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Lehane
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000009:adverse effects*; D018501:Antirheumatic Agents / Q000009:adverse effects*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007136:Immunoglobulins; D007391:International Cooperation; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D009894:Opportunistic Infections / Q000139:chemically induced / Q000453:epidemiology; D000069283:Rituximab
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D007136:Immunoglobulins; D000069283:Rituximab; D008727:Methotrexate
keywords: B cells; Rheumatoid Arthritis; Treatment