title: The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial.
abstract: OBJECTIVE
  To examine the efficacy and safety of different rituximab doses plus methotrexate (MTX), with or without glucocorticoids, in patients with active rheumatoid arthritis (RA) resistant to disease-modifying antirheumatic drugs (DMARDs), including biologic agents.
  
  
  METHODS
  A total of 465 patients were randomized into 9 treatment groups: 3 rituximab groups (placebo [n = 149], 500 mg [n = 124], or 1,000 mg [n = 192] on days 1 and 15) each also taking either placebo glucocorticoids, intravenous methylprednisolone premedication, or intravenous methylprednisolone premedication plus oral prednisone for 2 weeks. All patients received MTX (10-25 mg/week); no other DMARDs were permitted.
  
  
  RESULTS
  Significantly more patients who received 2 500-mg or 2 1,000-mg infusions of rituximab met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 24 (55% and 54%, respectively) compared with placebo (28%; P < 0.0001). ACR50 responses were achieved by 33%, 34%, and 13% of patients, respectively (P < 0.001), and ACR70 responses were achieved by 13%, 20%, and 5% of patients (P < 0.05). Changes in the Disease Activity Score in 28 joints (-1.79, -2.05, -0.67; P < 0.0001) and moderate to good responses on the European League Against Rheumatism criteria (P < 0.0001) reflected the ACR criteria responses. Glucocorticoids did not contribute significantly to the primary efficacy end point, ACR20 response at 24 weeks. Intravenous glucocorticoid premedication reduced the frequency and intensity of first infusion-associated events; oral glucocorticoids conferred no additional safety benefit. Rituximab was well tolerated; the type and severity of infections was similar to those for placebo.
  
  
  CONCLUSIONS
  Both rituximab doses were effective and well tolerated when added to MTX therapy in patients with active RA. The primary end point (ACR20 response) was independent of glucocorticoids, although intravenous glucocorticoid premedication improved tolerability during the first rituximab infusion.
authors.affiliation: Academic Unit of Musculoskeletal Disease, Chapel Allerton Hospital, Leeds, UK. p.emery@leeds.ac.uk
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: Roy
authors.initials: R
authors.lastname: Fleischmann
authors.forename: Anna
authors.initials: A
authors.lastname: Filipowicz-Sosnowska
authors.forename: Joy
authors.initials: J
authors.lastname: Schechtman
authors.forename: Leszek
authors.initials: L
authors.lastname: Szczepanski
authors.forename: Arthur
authors.initials: A
authors.lastname: Kavanaugh
authors.forename: Artur J
authors.initials: AJ
authors.lastname: Racewicz
authors.forename: Ronald F
authors.initials: RF
authors.lastname: van Vollenhoven
authors.forename: Nicole F
authors.initials: NF
authors.lastname: Li
authors.forename: Sunil
authors.initials: S
authors.lastname: Agarwal
authors.forename: Eva W
authors.initials: EW
authors.lastname: Hessey
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Shaw
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004311:Double-Blind Method; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects; D008875:Middle Aged; D000069283:Rituximab; D012449:Safety
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D005938:Glucocorticoids; D007155:Immunologic Factors; D000069283:Rituximab; D008727:Methotrexate