Suboptimal doses of methotrexate used in key RA trials may have biased results in favour of new biologic agents, experts claim.

Writing in a concise report in the Annals of the Rheumatic Diseases rheumatologist David Felson from Arthritis Research UK and colleagues said numerous studies had demonstrated that pharmaceutical company sponsored trials were often more favourable to the sponsor’s product compared to studies with other sources of sponsorship.

“One of the limitations in pharmaceutical- sponsored clinical trials is the use of a suboptimal dose of the comparator drug to provide an artefactual superiority for the investigational drug,” they wrote.

They therefore conducted a systematic review of RA clinical trials to assess if optimal doses of MTX were used in the comparator arms of foundational trials comparing biological agents with MTX.

In the 13 trials that met inclusion criteria the maximum methotrexate dose was 20 mg/week.

Recent EULAR guidelines and expert opinion recommend titration up to 25 mg/week to achieve disease control, they noted.

In all but one trial methotrexate was given orally rather than subcutaneously. However, injection leads to higher therapeutic levels and efficacy compared to the same oral dose when doses exceed 15 mg/week.

“A dose-effect relationship exists for MTX in RA treatment…Therefore, for it to be an appropriate comparator, the maximum dose should be used in subjects who require and tolerate it,” they wrote.

They conceded that, although the superiority of parenteral higher dosing of MTX was known in the 1990s, evidence of the benefit was scarce before 2009 and most of the biologic trials were designed before this date.

“Only recently has fast escalation of MTX up to 25 mg been adopted widely and this may have influenced the early trials presented,” they said.

“Still, bias generated due to the use of suboptimal dose of MTX as a comparator that would favour biologics may lead to exposing patients to unnecessary risk or expense.”

The 13 trials analysed in the study, which had to meet strict inclusion criteria, examined adalimumab, infliximab, etanercept, golimumab, abatacept, rituximab, tocilizumab and tofacitinib.

They were compared as monotherapy to methotrexate, or in combination with methotrexate to methotrexate alone.