Objectives To evaluate if optimal dose of either oral or injectable regimens of methotrexate (MTX) of 25 mg/week was used in the comparator arms of studies comparing biologic drugs with MTX in rheumatoid arthritis (RA).
Methods A systematic literature search was carried out in MEDLINE, EMBASE and the Cochrane Library databases for randomised controlled trials comparing biologics with MTX in RA. A systematic review was performed among studies that met predefined criteria focusing on assessment of dose of MTX used in the comparator arm. Study authors were contacted when necessary. Study quality was assessed.
Results A total of 3276 references were identified and 13 trials were included. We obtained maximal dose and regimen for all. The maximal dose of MTX used in the comparator arm of the trials was no more than 20 mg/week in any trial and for all but one trial, MTX was given orally and not by injection. The trial that used an injectable form reached a maximum of 15 mg/week.
Conclusions A suboptimal dose of MTX was used in biological clinical trials performed in RA, particularly regarding route of administration. This may have biased findings in favour of biological agents.
- DMARDs (biologic)
- Rheumatoid Arthritis
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Numerous studies have demonstrated that studies sponsored by the manufacturing company are often more favourable to the sponsor's product compared with 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.1
Methotrexate (MTX) is the anchor drug in rheumatoid arthritis (RA). In trials conducted among Disease-Modifying Antirheumatic Drugs (DMARD) naïve patients with RA, trials have often compared MTX to biological agents and have reported superiority of biological treatment. No study, to our knowledge, has examined whether the dose of MTX used in such trials was optimal.
Evidence supports that the absorption of oral MTX is variable, when used at doses greater than 15 mg/week and that injectable MTX at the higher doses reaches higher therapeutic levels2 and efficacy3 than oral MTX. The European League against Rheumatism (EULAR) and expert opinion recommends up-titration of MTX up to 25 mg/week for achieving disease control.4 ,5
Trials comparing biological agents with MTX serve as the basis for practice and for recommendations as to which treatments are efficacious. We carried out 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.
We aimed to determine if MTX was used at its recommended dose in clinical trials evaluating the efficacy of biological drugs in RA. We reformulated the research question using the Population,Intervention, Comparison, Outcome, Study design (PICOS) method. Patients were subjects with RA; the intervention was a biological drug; the comparison was MTX; the outcome was clinical measurement of disease activity and the study design was randomised controlled trial (RCT).
Systematic literature search
A systematic literature search for articles published up to November 2014 was carried out in MEDLINE, EMBASE and the Cochrane Library, using the following search terms: rheumatoid arthritis, antitnf, anti tnf alpha, tumor necrosis factor alpha inhibitor, infliximab, cA2, remicade, adalimumab, D2E7, humira, etanercept, TNFR-Fc fusion protein, p75TNFR-FC, enbrel, golimumab, CNTO-148, simponi, certolizumab, certolizumab pegol, cdp870, cimzia, rituximab, anti-CD20, rituxan, mabthera, abatacept, ctla4 Ig, orencia, tocilizumab, atlizumab, actemra, roactemra, tofacitinib, xeljanz. No language restriction was used. Review articles were retrieved to identify additional references by hand search. For the purposes of simplicity of labelling, we shall designate all the primary drugs compared with MTX as biologics even though we realise that tofacitinib, developed to have biologic effects, is in fact a small molecule.
The following inclusion criteria were applied: RCT, RA, 18 years old or greater, biologic therapy in one group, MTX in one group, clinical outcome measures and study duration of at least 6 months and ≤24 months. Articles that did not fulfil all the inclusion criteria, included MTX partial responders, used combined biologic drugs or presented only radiological outcomes, were excluded.
Studies were assessed by two independent investigators (JD and DD or MB). Disagreements regarding study eligibility were resolved by discussion. Relevant articles were selected in a three-step procedure. First, titles were screened. When a title seemed relevant, the abstract was reviewed. Articles that addressed the topic of interest in the abstract were selected and reviewed in full paper.
Data extraction was performed by two independent investigators (JD and DD or MB) using a piloted form. Disagreements were resolved by discussion. From each study we collected the source (main author, journal, publication year), disease duration, former treatment, biologic used (route, combination with MTX), MTX dose and regimen, use of injectable placebo, time point of outcome, number of subjects, outcome measure, superiority of biologic reported (y/n) according to the conclusion presented in the paper, industry sponsorship and intention-to-treat analysis. If necessary, authors were contacted to provide additional information regarding MTX maximum dose. To evaluate the methodological quality of studies, the Cochrane risk of bias tool was used.6
A total of 3276 references were identified with the systematic search strategy after eliminating duplicates. Title screening left 414 abstracts for revision. After selecting abstracts, 75 articles/conference abstracts were retrieved for full paper review. For our current study, 13 fulfilled the inclusion criteria (figure 1). Of these, three studied adalimumab, two infliximab, two etanercept, one golimumab, one abatacept, one rituximab, two tocilizumab and one tofacitinib (table 1).7–19 All but one study11 was sponsored by industry and in all industry-sponsored studies, the product of industrial sponsor was the biological agent.
Maximum dose of MTX was reported in 8 of the 13 trials. We were able to obtain additional information regarding MTX doses for the remaining five studies. Overall, none of the studies used doses of more than 20 mg. Further, only one study allowed the use of injectable MTX and in this study the maximum dose was 15 mg/week (table 2).
In all but two studies subjects received injected placebo.8 ,12 Regarding clinical outcomes reported, with the exception of tocilizumab and tofacitinib studies, all trials reported no difference in efficacy. However, Bathon et al7 emphasised etanercept monotherapy had a quicker onset of action and was superior in radiological outcomes. All studies concluded that a combination of MTX with biologic drugs was superior to MTX monotherapy.
Methodological quality of studies
Details regarding internal validity of trials are presented in online supplementary table S1. None of them was considered at high risk of bias, but not all items were clearly reported in eight studies.
To our knowledge, this is the first systematic review that evaluates the dosage of the comparator MTX in biologic drug trials in RA. We found that in all trials in which there was a direct comparison with biologic drugs, MTX was not used at the maximum recommended dose. Moreover, injectable forms of MTX were only used in one of these trials, and in this trial it was not used at full dose.
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. Studies have shown that oral MTX has variable bioavailability between individuals and a decreasing relative bioavailability with increasing doses. Response to therapy is achieved only with maximum dose (25–30 mg/week) in a proportion of subjects, and there are no identified predictors that identify these patients.3 On the other hand, subcutaneous MTX has been shown to have a better bioavailability at high doses, and clinical studies support that it is more effective at an equal dose than oral MTX. As Schiff et al2 concluded recently in a cross-over study evaluating routes of administration in the same subject, drug-exposure limitations of oral MTX at doses ≥15 mg may be overcome with subcutaneous administration.
Industry sponsorship bias has been documented by studies in different fields of medicine.1 A common theme in these studies has been the underdosing of the standard treatment comparator when a new drug is being tested. We suggest a similar phenomenon has occurred with the development of biologics in RA. Further, this suggests that the presumed superiority of some biologics either combined with MTX or as monotherapy over MTX may be overstated, given the suboptimal MTX regimens used. However, even though the superiority of parenteral higher dosing of MTX was known in the 1990s,20 before 2009 evidence regarding this benefit was scarce and most biologic trials were designed before this date. In addition, only recently has fast escalation of MTX up to 25 mg been adopted widely and this may have influenced the early trials presented. 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.
It may be argued that using injectable MTX in case of oral MTX failure would compromise blinding, but internal validity would probably not be harmed to an extent to justify not using the maximum effective dose. An alternative would have been the use of a study design like High Induction Therapy with Anti-Rheumatic Drugs (HIT HARD) in which only subcutaneous MTX was used to make sure everybody reached maximum levels of the drug without affecting blinding.11
Regarding the quality of studies, there was lack of reporting of important aspects in several trials, such as allocation concealment and blinding. Patient-reported and physician-reported outcomes used in activity scores may be affected by knowledge of the intervention.
Strengths of this study are that a comprehensive literature search was performed and no study was excluded due to language restrictions. In addition, authors were contacted when MTX dose/route was not clear and they all provided information about the MTX regimen used. A potential limitation is we did not perform a ‘grey literature’ search but 30 meta-analyses were hand searched and it is unlikely that studies were missed.
A suboptimal dose of MTX was used in biological drugs clinical trials performed in RA, particularly in relation to route of administration. This may have biased findings in favour of biologic agents in RA trials.
We thank the researchers who kindly provided additional data from their studies: Josef S Smolen, Gerd R Burmester, Rene Westhovens, Eun Bong Lee and Patrick Durez.
Handling editor Tore K Kvien
Contributors All authors participated in drafting the manuscript or revising it critically for important intellectual content, and all authors approved the final version to be published. Study conception and design: JD, DF and ML. Acquisition, analysis and interpretation of data: JD, DF, DD and MB.
Funding This research study was supported by NIH AR47785.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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