Case and Research Letter
Split doses of Methotrexate in patients with moderate to severe Psoriasis
Dosis divididas de metotrexato en pacientes con psoriasis moderada a severa
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Rodríguez-Zúñiga, F. Cortez-Franco, E. Qujiano-Gomero" "autores" => array:3 [ 0 => array:4 [ "nombre" => "M.J.M." "apellidos" => "Rodríguez-Zúñiga" "email" => array:2 [ 0 => "milton_rz@hotmail.com" 1 => "mijomax@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "F." "apellidos" => "Cortez-Franco" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "E." "apellidos" => "Qujiano-Gomero" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Dermatología del Hospital Nacional Daniel Alcides Carrión, Callao, Peru" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Universidad Nacional Mayor de San Marcos, Lima, Peru" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Dosis divididas de metotrexato en pacientes con psoriasis moderada a severa" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Psoriasis is the most common inflammatory skin condition with a worldwide prevalence of 2%. Systemic or topical treatment is decided according to the severity of the disease.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> For systemic treatment, Methotrexate (MTX) remains effective and medically accessible: it is widely used in hospitals in Latin America, where biological therapy is still limited for economic reasons.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The article: “Methotrexate in Moderate to Severe Psoriasis: Review of the Literature and Expert Recommendations”<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> outlines very important and interesting recommendations on the use of this drug in Psoriasis. However, one point that has not been taken into account is the split of MTX in two or three weekly doses, with the benefit of both efficacy and reduced side effects.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The benefits of fractional doses are listed below. As indicated in the article, MTX has significant gastrointestinal adverse effects that hinder its use, and increases with higher oral doses; but can be avoided or reduced with parenteral route, and with folates.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> In addition, a divided dose of MTX is an alternative for reducing gastrointestinal side effects in patients with Psoriasis.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> Second, with high MTX enteral doses, bioavailability decreases (for limiting absorption); therefore it is beneficial to divide MTX into smaller doses and thus increase its concentration systemically,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> increasing efficiency without worsening adverse effects.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Although MTX experience with divided doses for Psoriasis has been well known and accepted<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> for several decades,<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> it is based on a limited number of studies.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5,9</span></a> Thus, further experience with divided doses of MTX has been carried out in rheumatologic patients, but these are also limited.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Weinstein and Frost<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> first proposed the divided dose of MTX for Psoriasis in 1971. They showed that small doses of 2.5–7.5<span class="elsevierStyleHsp" style=""></span>mg of MTX given at intervals of 12<span class="elsevierStyleHsp" style=""></span>h for a total of three doses every week had an improvement from 75% to 100% in 26 patients with severe Psoriasis, with minimal adverse effects (nausea, oral ulcers and hives).</p><p id="par0030" class="elsevierStylePara elsevierViewall">Chladek et al.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> conducted a study that related the pharmacodynamics and pharmacokinetics of divided doses (2.5<span class="elsevierStyleHsp" style=""></span>mg and 5<span class="elsevierStyleHsp" style=""></span>mg three times a week) and weekly full doses (7.5<span class="elsevierStyleHsp" style=""></span>mg and 15<span class="elsevierStyleHsp" style=""></span>mg) of MTX with the Psoriasis Area Severity Index of 41 patients with severe disease. They concluded that split doses of MTX were associated with greater efficacy and lower risk of acute adverse effects during anti-psoriatic therapy.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In the rheumatology field, Dhaon et al.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> randomly divided 135 patients with rheumatoid arthritis into three groups: group 1 on split 7.5<span class="elsevierStyleHsp" style=""></span>mg doses of oral MTX two or three times weekly; group 2 on single 15–22.5<span class="elsevierStyleHsp" style=""></span>mg of oral MTX weekly; and group 3 on single intramuscular 15–22.5<span class="elsevierStyleHsp" style=""></span>mg dose of MTX weekly. Clinical efficacy of split and intramuscular doses was superior to single oral dose, but intramuscular administration lead to greater discomfort on patients. In addition, split doses group showed the lowest rates of gastrointestinal side effects, with higher levels of alopecia.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Pharmacokinetic studies demonstrate enhanced bioavailability of the drug with multiple dosing, supporting the clinical superiority of divided doses compared to single oral dose. Hoekstra et al.,<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> compared blood samples of 10 rheumatoid arthritis patients with fluorescence polarization immunoassay technique who received a single oral dose of 25–35<span class="elsevierStyleHsp" style=""></span>mg MTX, and after one week, divided two or three doses every 8<span class="elsevierStyleHsp" style=""></span>h. Bioavailability of split doses was 28% significantly higher than single doses and similar to that of subcutaneous doses, obtained from a previous study. The authors concluded that when high-dose of MTX is needed, the divided dose is an effective and comparable alternative to subcutaneous administration.</p><p id="par0045" class="elsevierStylePara elsevierViewall">After demonstrating and bringing up the efficacy and safety of MTX split oral doses in patients with Psoriasis, it is important to remember that there are limitations and drawbacks in their use, mainly with delivery errors. Because patients must take three weekly doses of 2.5<span class="elsevierStyleHsp" style=""></span>mg or 5<span class="elsevierStyleHsp" style=""></span>mg, and MTX tablets are mainly available at 2.5<span class="elsevierStyleHsp" style=""></span>mg and 10<span class="elsevierStyleHsp" style=""></span>mg in this region, patients may accidentally fail in both: reduncing or increasing the dose. However, in our experience this accident is very uncommon.</p><p id="par0050" class="elsevierStylePara elsevierViewall">In conclusion, MTX remains as a first-line treatment for severe Psoriasis, and accessible in many Latin American countries. Enteral and parenteral weekly divided doses of MTX show similar efficacy and safety in several studies both in psoriatic and rheumatologic patients. Therefore, we should continue proposing low split oral doses in future guidelines and consensus, in comparison to the single oral dose, with the benefit of achieving greater adherence by reducing adverse effects, taking into account their limitations.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interest</span><p id="par0055" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Global epidemiology of psoriasis: a systematic review of incidence and prevalence" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "R. 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Knuif" 5 => "M. van de Laar" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Rheumatol" "fecha" => "2006" "volumen" => "33" "paginaInicial" => "481" "paginaFinal" => "485" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16463431" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/15782190/0000010800000006/v1_201706300050/S157821901730210X/v1_201706300050/en/main.assets" "Apartado" => array:4 [ "identificador" => "6157" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Case and Research Letters" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/15782190/0000010800000006/v1_201706300050/S157821901730210X/v1_201706300050/en/main.pdf?idApp=UINPBA000044&text.app=https://actasdermo.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S157821901730210X?idApp=UINPBA000044" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 16 | 10 | 26 |
| 2024 October | 176 | 44 | 220 |
| 2024 September | 198 | 46 | 244 |
| 2024 August | 220 | 72 | 292 |
| 2024 July | 210 | 37 | 247 |
| 2024 June | 185 | 35 | 220 |
| 2024 May | 173 | 32 | 205 |
| 2024 April | 124 | 22 | 146 |
| 2024 March | 118 | 26 | 144 |
| 2024 February | 83 | 30 | 113 |
| 2024 January | 115 | 37 | 152 |
| 2023 December | 88 | 22 | 110 |
| 2023 November | 93 | 34 | 127 |
| 2023 October | 112 | 25 | 137 |
| 2023 September | 127 | 33 | 160 |
| 2023 August | 122 | 16 | 138 |
| 2023 July | 168 | 31 | 199 |
| 2023 June | 108 | 20 | 128 |
| 2023 May | 199 | 28 | 227 |
| 2023 April | 118 | 18 | 136 |
| 2023 March | 144 | 24 | 168 |
| 2023 February | 46 | 26 | 72 |
| 2023 January | 40 | 34 | 74 |
| 2022 December | 57 | 50 | 107 |
| 2022 November | 26 | 30 | 56 |
| 2022 October | 36 | 19 | 55 |
| 2022 September | 20 | 36 | 56 |
| 2022 August | 22 | 27 | 49 |
| 2022 July | 19 | 40 | 59 |
| 2022 June | 27 | 28 | 55 |
| 2022 May | 140 | 31 | 171 |
| 2022 April | 129 | 36 | 165 |
| 2022 March | 148 | 52 | 200 |
| 2022 February | 108 | 26 | 134 |
| 2022 January | 151 | 50 | 201 |
| 2021 December | 116 | 47 | 163 |
| 2021 November | 137 | 47 | 184 |
| 2021 October | 129 | 56 | 185 |
| 2021 September | 122 | 40 | 162 |
| 2021 August | 134 | 28 | 162 |
| 2021 July | 107 | 41 | 148 |
| 2021 June | 138 | 28 | 166 |
| 2021 May | 127 | 46 | 173 |
| 2021 April | 254 | 62 | 316 |
| 2021 March | 149 | 31 | 180 |
| 2021 February | 97 | 22 | 119 |
| 2021 January | 106 | 22 | 128 |
| 2020 December | 93 | 10 | 103 |
| 2020 November | 83 | 19 | 102 |
| 2020 October | 76 | 13 | 89 |
| 2020 September | 60 | 15 | 75 |
| 2020 August | 48 | 19 | 67 |
| 2020 July | 34 | 17 | 51 |
| 2020 June | 36 | 30 | 66 |
| 2020 May | 19 | 6 | 25 |
| 2020 April | 23 | 14 | 37 |
| 2020 March | 14 | 12 | 26 |
| 2020 February | 5 | 0 | 5 |
| 2020 January | 4 | 0 | 4 |
| 2019 December | 4 | 0 | 4 |
| 2019 November | 4 | 0 | 4 |
| 2019 September | 4 | 0 | 4 |
| 2019 August | 4 | 0 | 4 |
| 2019 July | 4 | 0 | 4 |
| 2019 June | 4 | 0 | 4 |
| 2019 May | 4 | 0 | 4 |
| 2019 April | 3 | 0 | 3 |
| 2019 March | 1 | 0 | 1 |
| 2019 February | 2 | 0 | 2 |
| 2018 December | 3 | 0 | 3 |
| 2018 October | 3 | 0 | 3 |
| 2018 September | 4 | 0 | 4 |
| 2018 March | 0 | 1 | 1 |
| 2018 February | 12 | 4 | 16 |
| 2018 January | 22 | 6 | 28 |
| 2017 December | 31 | 10 | 41 |
| 2017 November | 15 | 4 | 19 |
| 2017 October | 21 | 10 | 31 |
| 2017 September | 18 | 7 | 25 |
| 2017 August | 34 | 19 | 53 |
| 2017 July | 44 | 29 | 73 |
| 2017 June | 4 | 1 | 5 |
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