Letter to the Editor
Consensus on the Use of Methotrexate Beyond the Clinical Recommendation: Adjusted Dose and Pharmacogenetics
Consenso sobre el uso de metotrexato más allá de la recomendación clínica: dosis ajustada y farmacogenética
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"etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Hèctor" "apellidos" => "Corominas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Juliana" "apellidos" => "Salazar" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "Montserrat" "apellidos" => "Baiget" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Unitat de Reumatologia, Servei de Medicina Interna, Hospital de Sant Pau, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servei de Reumatologia, Hospital Moisès Broggi, Sant Joan Despí, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servei de Genètica, Hospital de Sant Pau, Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Consenso sobre el uso de metotrexato más allá de la recomendación clínica: dosis ajustada y farmacogenética" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">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 <span class="elsevierStyleItalic">Reumatología Clínica</span>.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a> 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).</p><p id="par0010" class="elsevierStylePara elsevierViewall">EULAR recommends to start treatment with DMARDs as soon as the diagnosis of RA is established.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">2</span></a> 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<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>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 2.5–5<span class="elsevierStyleHsp" style=""></span>mg every 2–6 weeks depending on clinical severity, reaching a maximum dose of 25<span class="elsevierStyleHsp" style=""></span>mg.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Notwithstanding the usefulness of the document, we would like to provide 2 comments that we consider could be of special interest.</p><p id="par0020" class="elsevierStylePara elsevierViewall">First, the average normal dose of MTX used in most studies is of 15<span class="elsevierStyleHsp" style=""></span>mg/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 60<span class="elsevierStyleHsp" style=""></span>kg (132 pounds) patients as in 90<span class="elsevierStyleHsp" style=""></span>kg (198 pounds) patients. Possibly, a good approximation could be to adjust it to a dose of 0.2–0.3<span class="elsevierStyleHsp" style=""></span>mg/kg.</p><p id="par0025" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">3</span></a> 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.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">4</span></a> 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.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">5,6</span></a> 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.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">7</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">8</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">9</span></a></p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Moya P, Corominas H, Salazar J, Baiget M. Consenso sobre el uso de metotrexato más allá de la recomendación clínica: dosis ajustada y farmacogenética. Reumatol Clin. 2015;11:261–262.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:9 [ 0 => array:3 [ "identificador" => "bib0050" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recomendaciones para el uso del metotrexato en artritis reumatoide: incremento y reducción de dosis y vías de administración" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Tornero Molina" 1 => "F.J. Ballina García" 2 => "J. Calvo Alén" 3 => "M.A. Caracuel Ruiz" 4 => "J. Carbonell Abelló" 5 => "A. 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Cerdà-Gabaroi" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Parmacogenomics" "fecha" => "2014" "volumen" => "15" "paginaInicial" => "1079" "paginaFinal" => "1090" "itemHostRev" => array:3 [ "pii" => "S0302283808011743" "estado" => "S300" "issn" => "03022838" ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0085" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Ranganathan" 1 => "R. Culverhouse" 2 => "S. Marsh" 3 => "A. Mody" 4 => "T.J. Scott-Horton" 5 => "R. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 13 | 10 | 23 |
| 2024 October | 34 | 32 | 66 |
| 2024 September | 28 | 19 | 47 |
| 2024 August | 52 | 30 | 82 |
| 2024 July | 48 | 30 | 78 |
| 2024 June | 40 | 40 | 80 |
| 2024 May | 40 | 19 | 59 |
| 2024 April | 35 | 25 | 60 |
| 2024 March | 49 | 20 | 69 |
| 2024 February | 23 | 23 | 46 |
| 2024 January | 32 | 23 | 55 |
| 2023 December | 25 | 30 | 55 |
| 2023 November | 32 | 24 | 56 |
| 2023 October | 27 | 27 | 54 |
| 2023 September | 45 | 41 | 86 |
| 2023 August | 24 | 16 | 40 |
| 2023 July | 34 | 28 | 62 |
| 2023 June | 29 | 27 | 56 |
| 2023 May | 38 | 24 | 62 |
| 2023 April | 27 | 14 | 41 |
| 2023 March | 38 | 29 | 67 |
| 2023 February | 36 | 26 | 62 |
| 2023 January | 46 | 19 | 65 |
| 2022 December | 45 | 41 | 86 |
| 2022 November | 44 | 31 | 75 |
| 2022 October | 37 | 34 | 71 |
| 2022 September | 27 | 36 | 63 |
| 2022 August | 44 | 49 | 93 |
| 2022 July | 22 | 37 | 59 |
| 2022 June | 30 | 39 | 69 |
| 2022 May | 31 | 29 | 60 |
| 2022 April | 37 | 44 | 81 |
| 2022 March | 51 | 50 | 101 |
| 2022 February | 21 | 48 | 69 |
| 2022 January | 27 | 46 | 73 |
| 2021 December | 34 | 41 | 75 |
| 2021 November | 27 | 41 | 68 |
| 2021 October | 34 | 52 | 86 |
| 2021 September | 24 | 42 | 66 |
| 2021 August | 28 | 43 | 71 |
| 2021 July | 26 | 37 | 63 |
| 2021 June | 29 | 56 | 85 |
| 2021 May | 35 | 33 | 68 |
| 2021 April | 57 | 112 | 169 |
| 2021 March | 42 | 19 | 61 |
| 2021 February | 39 | 27 | 66 |
| 2021 January | 37 | 22 | 59 |
| 2020 December | 25 | 14 | 39 |
| 2020 November | 28 | 19 | 47 |
| 2020 October | 16 | 17 | 33 |
| 2020 September | 36 | 18 | 54 |
| 2020 August | 26 | 15 | 41 |
| 2020 July | 15 | 25 | 40 |
| 2020 June | 35 | 23 | 58 |
| 2020 May | 26 | 9 | 35 |
| 2020 April | 24 | 20 | 44 |
| 2020 March | 21 | 10 | 31 |
| 2020 February | 1 | 0 | 1 |
| 2018 May | 3 | 0 | 3 |
| 2018 April | 43 | 7 | 50 |
| 2018 March | 60 | 3 | 63 |
| 2018 February | 20 | 3 | 23 |
| 2018 January | 16 | 3 | 19 |
| 2017 December | 21 | 3 | 24 |
| 2017 November | 14 | 2 | 16 |
| 2017 October | 32 | 5 | 37 |
| 2017 September | 14 | 3 | 17 |
| 2017 August | 13 | 15 | 28 |
| 2017 July | 20 | 9 | 29 |
| 2017 June | 45 | 8 | 53 |
| 2017 May | 35 | 11 | 46 |
| 2017 April | 33 | 43 | 76 |
| 2017 March | 23 | 7 | 30 |
| 2017 February | 12 | 6 | 18 |
| 2017 January | 21 | 4 | 25 |
| 2016 December | 32 | 11 | 43 |
| 2016 November | 35 | 4 | 39 |
| 2016 October | 47 | 11 | 58 |
| 2016 September | 56 | 16 | 72 |
| 2016 August | 42 | 16 | 58 |
| 2016 July | 32 | 22 | 54 |
| 2015 December | 2 | 0 | 2 |
| 2015 November | 1 | 26 | 27 |
| 2015 October | 3 | 34 | 37 |
| 2015 September | 3 | 0 | 3 |
| 2015 August | 5 | 50 | 55 |
| 2015 July | 30 | 29 | 59 |
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