We have read with great interest the original document entitled “Recommendations on the use of methotrexate in rheumatoid arthritis: dose increase and reduction and routes of administration” published by Tornero Molina et al. in Reumatología Clínica.1 First of all, we want to congratulate the authors of this eminently practical consensus, since it allows us to know in depth the experts’ clinical practice in the handling of disease-modifying antirheumatic drugs (DMARD) in the treatment of rheumatoid arthritis (RA).

EULAR recommends to start treatment with DMARDs as soon as the diagnosis of RA is established.2 Methotrexate (MTX) is the cornerstone of the treatment, which has 2 differentiated routes of administration. Consensus recommends the subcutaneous route of administration as a start in polymedicated patients, with overweight or obesity, under the suspicion of low adherence, depending on patient's preferences, with the purpose of reducing the dose to prevent gastrointestinal adverse effects and in active disease (DAS28>4). Moreover, the switch from the oral route to the subcutaneous route is posed as an option in cases of inefficiency, better cost-effectiveness profile and non-compliance with oral treatment. Consensus advises increases of 2.5–5mg every 2–6 weeks depending on clinical severity, reaching a maximum dose of 25mg.

Notwithstanding the usefulness of the document, we would like to provide 2 comments that we consider could be of special interest.

First, the average normal dose of MTX used in most studies is of 15mg/week. Nevertheless, we consider calculating the MTX dose in accordance with the weight of the patient to be treated. The patient's weight, among other variables, indirectly intervenes in drug's plasma concentration, so it cannot be the same in 60kg (132 pounds) patients as in 90kg (198 pounds) patients. Possibly, a good approximation could be to adjust it to a dose of 0.2–0.3mg/kg.

Another issue we find worth mentioning is the introduction of MTX pharmacogenetics in the clinical practice of RA. Several polymorphisms that can predict favourable response and toxicity to the drug have been defined, getting us closer to the concept of personalised medicine in the treatment with MTX.3 In the last decade, there have been descriptions of allelic variations in genes that participate in the folates metabolic pathway, either at transmembrane transportation level or at intracellular level, which are associated to the lack of response to MTX or MTX toxicity.4 Our collaboration group's previous experiences with other drugs, such as azathioprine, have allowed us to adjust the drug dose depending on the existing enzyme level.5,6 More recently, after analysing 27 genetic variations in the dihydrofolate reductase (DHFR), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC) and cyclin D1 (CCND1) genes, we reached the conclusion that variants in the MTHFR and DHFR genes might be considered as pharmacogenetic markers of response in patients with RA, and ATIC gene variants might be considered as toxicity markers.7

Nevertheless, we cannot fail to mention that pharmacogenetics has addressed the search for MTX toxicity and response predictors to MTX in a dissimilar manner. The different studies that have been published do not show coherent results, either due to the clinical heterogeneity of the sample, due to the differences in the way they define efficiency and toxicity, or due to the small size of the sample.8

Thus, we considered that, once the most frequent variables allowing us to predict beforehand favourable drug response or possible drug toxicity have been confirmed, the pharmacogenetic study should be routine to optimise the most efficient route of administration and dose. This consideration opens the door, in a not too distant future, to a personalised medicine for each patient that could be extended with the study of different therapeutic targets.9