title: Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis.
abstract: Tumour necrosis factor alpha (TNF alpha) is a critical inflammatory mediator in rheumatoid arthritis, and may therefore be a useful target for specific immunotherapy. In support of this hypothesis, we previously observed beneficial responses in patients with active rheumatoid arthritis after open-label administration of a chimeric monoclonal antibody to TNF alpha (cA2). We now report the results of a four-centre, randomised double-blind trial of a single infusion of 1 or 10 mg/kg cA2 compared with placebo in 73 patients with active rheumatoid arthritis. The primary endpoint of the study was the achievement at week 4 of a Paulus 20% response, an amalgam of six clinical, observational, and laboratory variables. Intention-to-treat analysis of data from individual patients showed only 2 of 24 placebo recipients responding at this time, compared with 11 of 25 patients treated with low-dose cA2 (p = 0.0083) and 19 of 24 patients treated with high-dose cA2 (p < 0.0001). Over half of the high-dose cA2 patients responded by the more stringent 50% Paulus criteria at this time (p = 0.0005). The magnitude of these responses was impressive, with maximum mean improvements in individual disease-activity assessments, such as tender or swollen-joint counts and in serum C-reactive protein, exceeding 60% for patients on high-dose treatment. There were two severe adverse events. 1 patient on 1 mg/kg cA2 developed pneumonia ("possibly" treatment-related) and 1 on 10 mg/kg had a fracture ("probably not" treatment-related). The results provide the first good evidence that specific cytokine blockade can be effective in human inflammatory disease and define a new direction for the treatment of rheumatoid arthritis.
authors.affiliation: Kennedy Institute of Rheumatology, Hammersmith, London, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Elliott
authors.forename: R N
authors.initials: RN
authors.lastname: Maini
authors.forename: M
authors.initials: M
authors.lastname: Feldmann
authors.forename: J R
authors.initials: JR
authors.lastname: Kalden
authors.forename: C
authors.initials: C
authors.lastname: Antoni
authors.forename: J S
authors.initials: JS
authors.lastname: Smolen
authors.forename: B
authors.initials: B
authors.lastname: Leeb
authors.forename: F C
authors.initials: FC
authors.lastname: Breedveld
authors.forename: J D
authors.initials: JD
authors.lastname: Macfarlane
authors.forename: H
authors.initials: H
authors.lastname: Bijl
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000473:pathology / Q000628:therapy*; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000069285:Infliximab; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement; D010919:Placebos; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D010919:Placebos; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab