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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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 8 | 8 | 16 |
| 2024 Octubre | 58 | 35 | 93 |
| 2024 Septiembre | 66 | 25 | 91 |
| 2024 Agosto | 71 | 36 | 107 |
| 2024 Julio | 73 | 32 | 105 |
| 2024 Junio | 93 | 40 | 133 |
| 2024 Mayo | 71 | 26 | 97 |
| 2024 Abril | 73 | 24 | 97 |
| 2024 Marzo | 173 | 25 | 198 |
| 2024 Febrero | 107 | 19 | 126 |
| 2024 Enero | 108 | 33 | 141 |
| 2023 Diciembre | 129 | 36 | 165 |
| 2023 Noviembre | 141 | 26 | 167 |
| 2023 Octubre | 112 | 35 | 147 |
| 2023 Septiembre | 74 | 29 | 103 |
| 2023 Agosto | 101 | 18 | 119 |
| 2023 Julio | 161 | 33 | 194 |
| 2023 Junio | 128 | 26 | 154 |
| 2023 Mayo | 98 | 26 | 124 |
| 2023 Abril | 98 | 28 | 126 |
| 2023 Marzo | 107 | 26 | 133 |
| 2023 Febrero | 90 | 19 | 109 |
| 2023 Enero | 103 | 23 | 126 |
| 2022 Diciembre | 122 | 33 | 155 |
| 2022 Noviembre | 124 | 23 | 147 |
| 2022 Octubre | 159 | 29 | 188 |
| 2022 Septiembre | 109 | 54 | 163 |
| 2022 Agosto | 89 | 42 | 131 |
| 2022 Julio | 82 | 37 | 119 |
| 2022 Junio | 50 | 26 | 76 |
| 2022 Mayo | 35 | 38 | 73 |
| 2022 Abril | 41 | 25 | 66 |
| 2022 Marzo | 37 | 43 | 80 |
| 2022 Febrero | 24 | 19 | 43 |
| 2022 Enero | 44 | 39 | 83 |
| 2021 Diciembre | 23 | 41 | 64 |
| 2021 Noviembre | 36 | 54 | 90 |
| 2021 Octubre | 34 | 59 | 93 |
| 2021 Septiembre | 27 | 31 | 58 |
| 2021 Agosto | 35 | 32 | 67 |
| 2021 Julio | 25 | 31 | 56 |
| 2021 Junio | 27 | 31 | 58 |
| 2021 Mayo | 29 | 49 | 78 |
| 2021 Abril | 75 | 95 | 170 |
| 2021 Marzo | 98 | 28 | 126 |
| 2021 Febrero | 49 | 31 | 80 |
| 2021 Enero | 39 | 24 | 63 |
| 2020 Diciembre | 24 | 11 | 35 |
| 2020 Noviembre | 28 | 24 | 52 |
| 2020 Octubre | 39 | 25 | 64 |
| 2020 Septiembre | 24 | 16 | 40 |
| 2020 Agosto | 23 | 28 | 51 |
| 2020 Julio | 35 | 18 | 53 |
| 2020 Junio | 36 | 31 | 67 |
| 2020 Mayo | 16 | 20 | 36 |
| 2020 Abril | 27 | 14 | 41 |
| 2020 Marzo | 31 | 27 | 58 |
| 2020 Febrero | 3 | 0 | 3 |
| 2020 Enero | 4 | 0 | 4 |
| 2019 Diciembre | 8 | 0 | 8 |
| 2019 Noviembre | 4 | 0 | 4 |
| 2019 Septiembre | 8 | 0 | 8 |
| 2019 Agosto | 4 | 0 | 4 |
| 2019 Julio | 4 | 0 | 4 |
| 2019 Junio | 4 | 0 | 4 |
| 2019 Mayo | 7 | 0 | 7 |
| 2019 Abril | 3 | 0 | 3 |
| 2019 Febrero | 4 | 0 | 4 |
| 2018 Diciembre | 6 | 2 | 8 |
| 2018 Noviembre | 2 | 0 | 2 |
| 2018 Octubre | 1 | 0 | 1 |
| 2018 Septiembre | 4 | 0 | 4 |
| 2018 Junio | 1 | 0 | 1 |
| 2018 Mayo | 1 | 0 | 1 |
| 2018 Abril | 2 | 1 | 3 |
| 2018 Marzo | 0 | 2 | 2 |
| 2018 Febrero | 22 | 3 | 25 |
| 2018 Enero | 30 | 12 | 42 |
| 2017 Diciembre | 24 | 14 | 38 |
| 2017 Noviembre | 42 | 8 | 50 |
| 2017 Octubre | 28 | 12 | 40 |
| 2017 Septiembre | 25 | 20 | 45 |
| 2017 Agosto | 35 | 55 | 90 |
| 2017 Julio | 52 | 239 | 291 |
| 2017 Junio | 6 | 23 | 29 |
| 2017 Mayo | 0 | 18 | 18 |
| 2017 Abril | 0 | 19 | 19 |
| 2017 Marzo | 0 | 30 | 30 |
| 2017 Febrero | 0 | 43 | 43 |
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