title: Drug survival, efficacy and toxicity of monotherapy with a fully human anti-tumour necrosis factor-alpha antibody compared with methotrexate in long-standing rheumatoid arthritis.
abstract: OBJECTIVE
  To compare the 48-week drug survival, efficacy and toxicity of monotherapy with a fully human anti-tumour necrosis factor-alpha (TNF-alpha) monoclonal antibody (moAb) and methotrexate (MTX) in patients with active long-standing rheumatoid arthritis (RA). Secondary aims were to identify potential predictors for clinical response.
  
  
  METHODS
  Patients with RA, enrolled in phase I trials with a human anti-TNF-alpha moAb and followed for at least 48 weeks at our centre, were compared with patients receiving MTX monotherapy without folate supplementation. The first 6 weeks of anti-TNF therapy were placebo-controlled and followed by an open-label study. Patients treated with MTX participated in a 48-week, double-blind, phase III study of MTX alone vs MTX with folate supplementation, which was co-ordinated by our department. The studies with anti-TNF-alpha and MTX were performed in the same period and had very similar inclusion, exclusion, response and stop criteria.
  
  
  RESULTS
  Sixty-one patients treated with anti-TNF-alpha moAb were compared with 137 receiving MTX monotherapy. At baseline, patients in the anti-TNF-alpha group had a longer disease duration (median 108 vs 50 months, P=0.0001) and a more protracted history of second-line anti-rheumatic drugs than those treated with MTX (median 4 vs 1, P=0.0001). The 48-week dropout rate was lower among patients treated with anti-TNF (23 vs 45% in the MTX group, P<0.005). Proportional hazard analysis showed a significantly lower dropout risk among anti-TNF-treated patients [relative risk (95% confidence interval): 0.28 (0.12-0.6) uncorrected and 0.17 (0.06-0.45) corrected for confounders). The 48-week area under the curve for the disease activity score (DAS) was smaller in the anti-TNF-alpha group than in the MTX group (P=0.005). The percentage of responders was higher in the anti-TNF-alpha group over the whole study period. The median percentage of visits in which a patient fulfilled the European League Against Rheumatism (EULAR) response criteria was 83% in the anti-TNF-alpha group vs 40% in the MTX group (P=0.0001). Clinical and demographic characteristics were, in general, poor predictors for response to therapy at week 48. The clinical response after the first anti-TNF-alpha dose tended to increase the chance of prolonged efficacy of this approach [relative risk (95% confidence interval): 2 (0.75-6.0)]. The previous number of second-line drugs was the only predictive variable for response to MTX to which it was inversely related [relative risk (95% confidence interval): -0.71 (-0.57 to -0.88)].
  
  
  CONCLUSIONS
  In patients with active, long-standing RA, blocking TNF-alpha is more effective and better tolerated than MTX monotherapy. An early response increases the chance of a sustained effect of anti-TNF-alpha. In contrast to MTX, the response to anti-TNF-alpha is not affected by previous disease-modifying anti-rheumatic drug history.
authors.affiliation: Department of Rheumatology and. Department of Epidemiology, University Medical Centre, Nijmegen, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Barrera
authors.forename: A
authors.initials: A
authors.lastname: van der Maas
authors.forename: A E
authors.initials: AE
authors.lastname: van Ede
authors.forename: B A L M
authors.initials: BA
authors.lastname: Kiemeney
authors.forename: R F J M
authors.initials: RF
authors.lastname: Laan
authors.forename: L B A
authors.initials: LB
authors.lastname: van de Putte
authors.forename: P L C M
authors.initials: PL
authors.lastname: van Riel
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D010352:Patient Dropouts; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D008727:Methotrexate