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Why methotrexate suboptimal dosing is a potential source of bias in biologic drugs clinical trials
  1. Josefina Durán1,
  2. David T Felson2,3
  1. 1Department of Rheumatology, Pontificia Universidad Catolica de Chile, Santiago, Region Metropolitana, Chile
  2. 2Clinical Epidemiology Unit, School of Medicine, Boston University, Boston, Massachusetts, USA
  3. 3Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester, UK
  1. Correspondence to Dr Josefina Durán, Department of Rheumatology, Pontificia Universidad Catolica de Chile, Santiago, Region Metropolitana, Chile; jgduran{at}

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We appreciate the editorial Dr Kremer1 wrote regarding our article2 and we want to clarify some of the issues he raises.

Dr Kremer states that there is no evidence of benefit from increasing the methotrexate dose from 20 to 25 mg ‘given the appropriate parenteral route of administration’. What he states is accurate; it is a bit misleading, as evidence does exist of the benefit of switching from oral to subcutaneous methotrexate, which was a focus of our paper. In a crossover trial by Schiff et al3 that we cite in our article, subjects achieved a higher effective therapeutic level with no increase in adverse events when switching from oral to subcutaneous methotrexate. It is precisely the lack of use of parenteral methotrexate, which we believe is the most important potential source of bias, and this is stated in our discussion. He questions the adverse event profile of methotrexate in a dose >20 mg, but in a comparative effectiveness trial in early rheumatoid arthritis published in 2015 by Hazlewood et al,4 only 3 out of 112 subjects who received parenteral methotrexate in a dose >20 mg failed treatment due to toxicity. In his editorial, Dr Kremer cites a study associating genetic polymorphisms with toxicity, which actually found that ‘In the overall population, the prevalence of adverse events among patients taking 25 mg/week MTX was not significantly different from that among patients taking 15 mg/week study’.5 In addition, he argues that the methotrexate consensus paper that recommends a higher methotrexate dose cited in our discussion was based on expert opinion, but the recommendations made in this paper considered a literature review that included a randomised controlled trial comparing oral versus subcutaneous methotrexate that showed the superiority of the latter and also studies comparing different dosing regimens of methotrexate, one of which compared 15 vs 25 mg of methotrexate as a starting dose and found no difference in withdrawals and dose reductions between groups.6 In addition to the two randomised controlled trials which showed a greater efficacy with subcutaneous methotrexate,7 ,8 multiple observational studies have reinforced this evidence.9 ,10 We acknowledge that the use of methotrexate in its recommended dose is not widespread, at least in the USA, but this does not justify the suboptimal dosing of methotrexate when used as a comparator in trials.

Finally, our study is not meant to be applicable to Asians, as they use methotrexate in much lower doses (<15 mg/week).


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  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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