title: Multiple courses of rituximab produce sustained clinical and radiographic efficacy and safety in patients with rheumatoid arthritis and an inadequate response to 1 or more tumor necrosis factor inhibitors: 5-year data from the REFLEX study.
abstract: OBJECTIVE
  This 5-year observational posthoc analysis of the REFLEX study and its open-label extension assessed clinical efficacy, radiographic response, and safety of rituximab (RTX) in patients with rheumatoid arthritis (RA) who had an inadequate response to tumor necrosis factor (TNF) inhibitors.
  
  
  METHODS
  Patients in REFLEX were originally randomized to placebo (PBO) + methotrexate (MTX; PBO-randomized) or RTX + MTX (RTX-randomized). PBO-randomized patients were rescued with RTX as appropriate. Patients responding to initial RTX treatment could receive further RTX courses. For clinical efficacy and safety analyses, PBO-randomized patients were re-baselined prior to first RTX treatment and the data were pooled with RTX-randomized patient data. Efficacy outcomes 24 weeks after each course were calculated relative to first RTX pretreatment baseline. Radiographic outcomes were assessed relative to randomization baseline for both PBO-randomized and RTX-randomized groups.
  
  
  RESULTS
  A total of 480 patients received ≥ 1 RTX course. At 24 weeks, American College of Rheumatology 20/50/70 responses were 62.0%, 30.8%, and 13.0%, respectively at course 1 (n = 400) and 70.3%, 41.8%, and 22.0% at course 5 (n = 91). European League Against Rheumatism good/moderate responses were 77.2% and 84.4% at courses 1 (n = 390) and 5 (n = 90). Rates of adverse events (AE), serious AE, and infections generally remained stable. Rate of progressive joint damage (PJD; change in mean Total Sharp Score) decreased over time in both PBO-randomized (n = 79) and RTX-randomized (n = 105) groups. Mean change from baseline in PJD over 5 years was greater in PBO-randomized versus RTX-randomized patients (5.51 vs 3.21).
  
  
  CONCLUSIONS
  RTX re-treatment over 5 years is associated with maintained or improved efficacy, continued inhibition of PJD, and a safety profile consistent with that previously reported. A delay in initiating RTX treatment may result in increased PJD.
authors.affiliation: Mount Sinai Hospital and the University of Toronto, Toronto, Ontario, Canada. edkeystone@mtsinai.on.ca
authors.forename: Edward C
authors.initials: EC
authors.lastname: Keystone
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Cohen
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: Joel M
authors.initials: JM
authors.lastname: Kremer
authors.forename: Maxime
authors.initials: M
authors.lastname: Dougados
authors.forename: James E
authors.initials: JE
authors.lastname: Loveless
authors.forename: Carol
authors.initials: C
authors.lastname: Chung
authors.forename: Pamela
authors.initials: P
authors.lastname: Wong
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Lehane
authors.forename: Helen
authors.initials: H
authors.lastname: Tyrrell
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D004185:Disability Evaluation; D004311:Double-Blind Method; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D005260:Female; D006304:Health Status; D006801:Humans; D007596:Joints / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D000069283:Rituximab; D011795:Surveys and Questionnaires; D017211:Treatment Failure; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D000069283:Rituximab; D008727:Methotrexate