“Stepping-up” from methotrexate: a systematic review of randomised placebo controlled trials in patients with rheumatoid arthritis with an incomplete response to methotrexate

Methotrexate is presently the standard disease modifying antirheumatic drug (DMARD) for patients with active rheumatoid arthritis (RA).1 Despite its short term efficacy in clinical trials and long term effectiveness in clinical practice,2-5 many patients continue to have signs and symptoms of active disease while taking a maximally tolerated dose. Over the past decade there has been increasing interest in the use of combination therapy in patients with RA. Boers and Ramsden published the first systematic review of combination therapy in 1991 and identified two trials that provided moderate or strong evidence; neither of these studies used methotrexate.6 Tugwell and Boers updated this review in 1994 and identified four new trials that provided moderate or strong evidence; two of these trials used methotrexate in a parallel combination strategy.7Verhoeven and colleagues updated this review a second time in 1998 and identified 14 new trials published between August 1992 and July 1997.8 In their analysis, they combined these 14 new trials with the six previous trials and categorised the trials by the strategy of combination therapy: parallel, “step-up”, and “step-down”. Of these 20 trials, six used methotrexate in a parallel combination strategy, one of these trials used methotrexate in a step-down strategy, and two of these trials used methotrexate in a step-up strategy.8 Of the two trials which employed the step-up strategy in patients with an incomplete response to methotrexate, one compared the monoclonal anti-CD4 antibody cM-T412 with placebo and failed to show clinical efficacy,9whereas the other compared cyclosporin with placebo and did demonstrate additional efficacy with the combination compared with placebo.10 With the advent of newer biological treatments directed at cytokines which play a part in the pathophysiology of RA, particularly tumour necrosis factor (TNF),11 additional trials of combination therapy based …