title: Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial.
abstract: OBJECTIVE
  B cells are likely to contribute to the pathogenesis of systemic lupus erythematosus (SLE), and rituximab induces depletion of B cells. The Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial tested the efficacy and safety of rituximab versus placebo in patients with moderately-to-severely active extrarenal SLE.
  
  
  METHODS
  Patients entered with >or=1 British Isles Lupus Assessment Group (BILAG) A score or >or=2 BILAG B scores despite background immunosuppressant therapy, which was continued during the trial. Prednisone was added and subsequently tapered. Patients were randomized at a ratio of 2:1 to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182.
  
  
  RESULTS
  In the intent-to-treat analysis of 257 patients, background treatment was evenly distributed among azathioprine, mycophenolate mofetil, and methotrexate. Fifty-three percent of the patients had >or=1 BILAG A score at entry, and 57% of the patients were categorized as being steroid dependent. No differences were observed between placebo and rituximab in the primary and secondary efficacy end points, including the BILAG-defined response, in terms of both area under the curve and landmark analyses. A beneficial effect of rituximab on the primary end point was observed in the African American and Hispanic subgroups. Safety and tolerability were similar in patients receiving placebo and those receiving rituximab.
  
  
  CONCLUSIONS
  The EXPLORER trial enrolled patients with moderately-to-severely active SLE and used aggressive background treatment and sensitive cutoffs for nonresponse. No differences were noted between placebo and rituximab in the primary and secondary end points. Further evaluation of patient subsets, biomarkers, and exploratory outcome models may improve the design of future SLE clinical trials.
authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. JTMmail@aol.com
authors.forename: Joan T
authors.initials: JT
authors.lastname: Merrill
authors.forename: C Michael
authors.initials: CM
authors.lastname: Neuwelt
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wallace
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Shanahan
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Latinis
authors.forename: James C
authors.initials: JC
authors.lastname: Oates
authors.forename: Tammy O
authors.initials: TO
authors.lastname: Utset
authors.forename: Caroline
authors.initials: C
authors.lastname: Gordon
authors.forename: David A
authors.initials: DA
authors.lastname: Isenberg
authors.forename: Hsin-Ju
authors.initials: HJ
authors.lastname: Hsieh
authors.forename: David
authors.initials: D
authors.lastname: Zhang
authors.forename: Paul G
authors.initials: PG
authors.lastname: Brunetta
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000009:adverse effects / Q000627:therapeutic use*; D008180:Lupus Erythematosus, Systemic / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D011788:Quality of Life; D000069283:Rituximab; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D007155:Immunologic Factors; D000069283:Rituximab