Efficacy of methotrexate in comparison to biologics in rheumatoid arthritis.

This paper reviews trials comparing the efficacy of MTX and biologic agents. So far, the clinical evaluations of 9 biologics have been published. Three TNF inhibitors - etanercept, adalimumab, golimumab - and the IL 6 receptor inhibitor tocilizumab have been investigated in MTX naïve patients using a parallel design. The trials had 3 treatment arms: monotherapies of MTX and of the biologic compound, and the combination of both. The other biologics - infliximab, certolizumab pegol, anakinra, rituximab, and abatacept - were investigated in patients who experienced inadequate response to MTX, and were treated with MTX + biologic agent versus MTX + placebo. That design does not provide a real comparison between MTX and the biologics but may indirectly give an indication of the relative efficacy of the different biologic agents. In all trials providing a head to head comparison, MTX and biologics were similarly effective as measured by ACR and EULAR response criteria including clinical remission. In general, improvement started earlier with biologic treatment than with MTX therapy. Inhibition of radiological progression was stronger with biologics probably since TNF inhibitors, in addition to their anti-inflammatory effect, directly reduce osteoclast activity. The efficacy of biologics was significantly potentiated when they were combined with MTX. Based on the trial results the efficacy of MTX may be underestimated: the initial dose of MTX was too low and was increased only gradually. The trial design with ITT analysis and LOCF may have been disadvantageous for MTX since more patients treated with MTX withdrew and thereby had less time under treatment. Folic acid supplementation may have reduced the efficacy of MTX by interfering with its mechanism of action. Nonetheless, all trials confirmed a surprisingly good performance of MTX in comparison with biologics.