Case And Research Letter
Acral Erosions and Ulcers: An Early Sign of Severe Acute Methotrexate Toxicity
Erosiones y úlceras acrales: manifestación precoz de toxicidad aguda grave por metrotexato
L. Maroñas-Jiménez
, M. Castellanos-González, J. Sanz Bueno, F. Vanaclocha Sebastián
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Servicio de Dermatología y Venereología, Hospital Universitario 12 de Octubre, Madrid, Spain
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Detalle clínico de las lesiones del segundo paciente: erosiones espiculadas profundas con halo violáceo periférico y costra hemorrágica en la superficie. B. Placa erosiva de superficie exudativo-costrosa en la aleta nasal derecha.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "L. Maroñas-Jiménez, M. Castellanos-González, J. Sanz Bueno, F. Vanaclocha Sebastián" "autores" => array:4 [ 0 => array:2 [ "nombre" => "L." "apellidos" => "Maroñas-Jiménez" ] 1 => array:2 [ "nombre" => "M." "apellidos" => "Castellanos-González" ] 2 => array:2 [ "nombre" => "J." "apellidos" => "Sanz Bueno" ] 3 => array:2 [ "nombre" => "F." 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Plana Pla, J. Bassas Vila, M.A. Toro Montecinos, C. Ferrandiz Foraster" "autores" => array:4 [ 0 => array:2 [ "nombre" => "A." "apellidos" => "Plana Pla" ] 1 => array:2 [ "nombre" => "J." "apellidos" => "Bassas Vila" ] 2 => array:2 [ "nombre" => "M.A." "apellidos" => "Toro Montecinos" ] 3 => array:2 [ "nombre" => "C." 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Maroñas-Jiménez, M. Castellanos-González, J. Sanz Bueno, F. Vanaclocha Sebastián" "autores" => array:4 [ 0 => array:4 [ "nombre" => "L." "apellidos" => "Maroñas-Jiménez" "email" => array:1 [ 0 => "lydia.maroasjimenez@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "M." "apellidos" => "Castellanos-González" ] 2 => array:2 [ "nombre" => "J." "apellidos" => "Sanz Bueno" ] 3 => array:2 [ "nombre" => "F." "apellidos" => "Vanaclocha Sebastián" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Dermatología y Venereología, Hospital Universitario 12 de Octubre, Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding Author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Erosiones y úlceras acrales: manifestación precoz de toxicidad aguda grave por metrotexato" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 662 "Ancho" => 1002 "Tamanyo" => 134953 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A and B, Bilateral, symmetrical, crusted erosive lesions with a retiform distribution on the dorsum of the feet and hands.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Methotrexate (MTX) is a drug with a good safety profile that is frequently used in dermatology. Although serious complications due to acute MTX toxicity typically occur in the context of antineoplastic doses (up to 1-3<span class="elsevierStyleHsp" style=""></span>g/m<span class="elsevierStyleSup">2</span> in some tumors), they occasionally occur in patients treated with considerably lower doses, and the early identification of these effects is essential. We present 3 patients who developed acute myelosuppression secondary to treatment with MTX. The initial signs in all the patients were similar forms of skin lesions; clinical observation of these lesions can be the key to the early diagnosis of this important condition.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The first patient was a woman of 65 years of age with rheumatoid arthritis. She had been on treatment for 1 month with MTX, 20<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h, ibuprofen, 600<span class="elsevierStyleHsp" style=""></span>mg/8<span class="elsevierStyleHsp" style=""></span>h, and prednisone, 10<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h. She came to the emergency department with a 3-day history of fever and mucositis associated with painful edema of the hands of sudden onset and ulcers on both feet (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). After 48<span class="elsevierStyleHsp" style=""></span>hours of in-hospital observation, she developed severe pancytopenia with a neutrophil count of 400/μL (normal range, 1800-7600/μL), hemoglobin (Hb) of 9<span class="elsevierStyleHsp" style=""></span>g/dL (normal range, 11.4-15.1<span class="elsevierStyleHsp" style=""></span>g/dL), mean cell volume of 100<span class="elsevierStyleHsp" style=""></span>fL, and platelet count of 66 000/μL (normal range, 140 000-450 000/μL). Blood and urine cultures, microbiology study of the mucosas, and serology for human immunodeficiency virus, syphilis, hepatitis B and C viruses, parvovirus B19, cytomegalovirus, Epstein-Barr virus, and toxoplasma were negative.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The second case was a 60-year-old man and the third case a 55-year-old woman; both patients had a history of mycosis fungoides for which they had been treated with MTX, the man for 4 months at a dose of 20 mg/wk and the woman for 6 months at a dose of 25<span class="elsevierStyleHsp" style=""></span>mg/wk. For the previous month they had also been treated with sulfamethoxazole/trimethoprim (SMX/TMP) 800/160<span class="elsevierStyleHsp" style=""></span>mg 3 times a week as prophylaxis for sepsis of cutaneous origin. They were seen for very painful acral erosions that had been present for a week (<a class="elsevierStyleCrossRefs" href="#fig0010">Figs. 2 and 3</a>). Blood tests in the man revealed a marked fall in the Hb to 7.9<span class="elsevierStyleHsp" style=""></span>g/dL from a value of 11.7<span class="elsevierStyleHsp" style=""></span>g/dL 2 weeks earlier, and in the woman revealed moderate bicytopenia that had not previously been detected (Hb of 10<span class="elsevierStyleHsp" style=""></span>g/dl and a white cell count of 2000/μL with 600 neutrophils/μL). Cultures of the skin lesions were negative for viruses and bacteria in both patients.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">In all 3 patients, biopsy revealed reactive epidermal hyperplasia with areas of ulceration with a fibrin-covered base and dermal eosinophilia. The administration of MTX was interrupted and symptomatic treatment was started, leading to resolution of the skin lesions in less than 1 month in all cases. In the first patient it was necessary to add specific treatment (folinic acid and granulocyte colony stimulating factor) because of the severe pancytopenia, which showed a favorable response.</p><p id="par0025" class="elsevierStylePara elsevierViewall">MTX is an antimetabolite. It is a folic acid analog that competitively and reversibly inhibits the enzyme dihydrofolate reductase (DHFR), a key enzyme for cell DNA synthesis. This mechanism explains its antiproliferative activity and the profile of adverse effects at high doses; acute myelosuppression is the manifestation that carries the greatest threat to life.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> When used as at anti-inflammatory doses, the number of drug molecules bound to the enzyme is insufficient to achieve inhibition, and it is postulated that the effect a low doses may be related to the formation of intracellular polyglutamates.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However, the marked inter- and intraindividual variability in its metabolism<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> and the possible coexistence of factors that increase its cellular availability means that, in practice, we must considered all patients on treatment with MTX to be susceptible to develop serious complications. Our 3 cases presented factors that could favor cytotoxicity: in the first patient, incorrect dosage (daily instead of weekly) leading to overdose, and treatment with ibuprofen, which interferes with the renal excretion of MTX and increases its free fraction in the plasma by displacing MTX from its protein binding sites; in the other patients, prophylaxis with SMX/TMP impeded the transformation of para-aminobenzoic acid into folic acid (SMX effect) and directly inhibited DHFR (TMP effect).</p><p id="par0030" class="elsevierStylePara elsevierViewall">Skin erosions and/or ulcers as the manifestation of acute cytotoxicity due to MTX is very rare. In the medical literature reviewed, we found only 5 cases in patients with no previous dermatosis.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4–8</span></a> All were men on low-dose treatment for rheumatoid arthritis and only one of them presented general manifestations with fever, mucositis, and acute severe pancytopenia, similar to our first patient.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Cell turnover is increased in patients with psoriasis and/or mycosis fungoides, and this increases the cutaneous tropism of MTX.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,10</span></a> Lawrence et al.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> describe 2 distinct clinical patterns with different prognoses in patients with psoriasis: type I, with erosions and/or ulcers that develop on plaques and heal within a few days after the withdrawal of MTX; and type II, with lesions on healthy skin that take weeks to resolve despite the withdrawal of treatment. The clinical recognition of this condition is important, as it must be differentiated from treatment inefficacy or a flare-up of the dermatosis; this typically occurs at the beginning or end of treatment, which could lead either to an increase in the dose or to the reintroduction of MTX. The common factor in all the cases described, both in individuals with lesions on underlying skin disease and in those with lesions on healthy skin, was the disproportionate pain of the lesions and their characteristic distribution on acral areas, as was observed in our patients.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Based on all we have described, we believe that the appearance of painful acral erosions and/or ulcers in patients receiving treatment with MTX must lead us to consider severe underlying cytotoxicity. Two fundamental factors in the prevention of potentially lethal adverse effects are detailed evaluation of all the concomitant medication and ensuring that patients understand the indicated MTX regimen.</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: Maroñas-Jiménez L, Castellanos-González M, Sanz Bueno J, Vanaclocha Sebastián F. Erosiones y úlceras acrales: manifestación precoz de toxicidad aguda grave por metrotexato. 2014 105:319–321.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 361 "Ancho" => 1001 "Tamanyo" => 82172 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A, Swelling of both hands with poorly defined areas of violaceous erythema on the bony prominences of the fingers. B, Round superficial ulcers with a clean base and hyperpigmented borders on the sole of the right foot and on the left heel.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 662 "Ancho" => 1002 "Tamanyo" => 134953 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A and B, Bilateral, symmetrical, crusted erosive lesions with a retiform distribution on the dorsum of the feet and hands.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 703 "Ancho" => 1001 "Tamanyo" => 127433 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A, Clinical image of the lesions in the second patient: deep spiculated erosions covered by a hemorrhagic scab and with a peripheral violaceous halo. B, Erosive plaque with a crusted exudative surface on the right ala nasi.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The remarkable spectrum of methotrexate toxicities" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R.J. 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 14 | 6 | 20 |
| 2024 Octubre | 114 | 55 | 169 |
| 2024 Septiembre | 115 | 26 | 141 |
| 2024 Agosto | 167 | 80 | 247 |
| 2024 Julio | 116 | 61 | 177 |
| 2024 Junio | 154 | 53 | 207 |
| 2024 Mayo | 110 | 43 | 153 |
| 2024 Abril | 108 | 32 | 140 |
| 2024 Marzo | 110 | 44 | 154 |
| 2024 Febrero | 81 | 31 | 112 |
| 2024 Enero | 108 | 36 | 144 |
| 2023 Diciembre | 76 | 17 | 93 |
| 2023 Noviembre | 87 | 24 | 111 |
| 2023 Octubre | 113 | 36 | 149 |
| 2023 Septiembre | 80 | 37 | 117 |
| 2023 Agosto | 80 | 18 | 98 |
| 2023 Julio | 114 | 28 | 142 |
| 2023 Junio | 89 | 21 | 110 |
| 2023 Mayo | 107 | 17 | 124 |
| 2023 Abril | 98 | 26 | 124 |
| 2023 Marzo | 78 | 17 | 95 |
| 2023 Febrero | 85 | 25 | 110 |
| 2023 Enero | 58 | 35 | 93 |
| 2022 Diciembre | 60 | 35 | 95 |
| 2022 Noviembre | 36 | 22 | 58 |
| 2022 Octubre | 38 | 19 | 57 |
| 2022 Septiembre | 38 | 33 | 71 |
| 2022 Agosto | 33 | 30 | 63 |
| 2022 Julio | 35 | 33 | 68 |
| 2022 Junio | 38 | 22 | 60 |
| 2022 Mayo | 60 | 34 | 94 |
| 2022 Abril | 74 | 32 | 106 |
| 2022 Marzo | 70 | 48 | 118 |
| 2022 Febrero | 71 | 28 | 99 |
| 2022 Enero | 62 | 26 | 88 |
| 2021 Diciembre | 52 | 36 | 88 |
| 2021 Noviembre | 64 | 37 | 101 |
| 2021 Octubre | 71 | 48 | 119 |
| 2021 Septiembre | 59 | 37 | 96 |
| 2021 Agosto | 55 | 31 | 86 |
| 2021 Julio | 88 | 33 | 121 |
| 2021 Junio | 62 | 28 | 90 |
| 2021 Mayo | 64 | 26 | 90 |
| 2021 Abril | 112 | 69 | 181 |
| 2021 Marzo | 84 | 28 | 112 |
| 2021 Febrero | 40 | 36 | 76 |
| 2021 Enero | 41 | 17 | 58 |
| 2020 Diciembre | 42 | 14 | 56 |
| 2020 Noviembre | 18 | 14 | 32 |
| 2020 Octubre | 31 | 16 | 47 |
| 2020 Septiembre | 29 | 16 | 45 |
| 2020 Agosto | 33 | 17 | 50 |
| 2020 Julio | 33 | 13 | 46 |
| 2020 Junio | 24 | 25 | 49 |
| 2020 Mayo | 28 | 15 | 43 |
| 2020 Abril | 34 | 11 | 45 |
| 2020 Marzo | 34 | 11 | 45 |
| 2020 Febrero | 5 | 1 | 6 |
| 2020 Enero | 4 | 0 | 4 |
| 2019 Diciembre | 8 | 2 | 10 |
| 2019 Noviembre | 4 | 1 | 5 |
| 2019 Octubre | 0 | 3 | 3 |
| 2019 Septiembre | 4 | 0 | 4 |
| 2019 Agosto | 4 | 2 | 6 |
| 2019 Julio | 4 | 3 | 7 |
| 2019 Junio | 6 | 12 | 18 |
| 2019 Mayo | 4 | 17 | 21 |
| 2019 Abril | 2 | 13 | 15 |
| 2019 Marzo | 4 | 10 | 14 |
| 2019 Febrero | 2 | 1 | 3 |
| 2019 Enero | 2 | 6 | 8 |
| 2018 Diciembre | 4 | 0 | 4 |
| 2018 Octubre | 6 | 0 | 6 |
| 2018 Septiembre | 4 | 2 | 6 |
| 2018 Agosto | 0 | 2 | 2 |
| 2018 Julio | 0 | 1 | 1 |
| 2018 Junio | 0 | 5 | 5 |
| 2018 Mayo | 0 | 8 | 8 |
| 2018 Abril | 0 | 2 | 2 |
| 2018 Marzo | 0 | 1 | 1 |
| 2018 Febrero | 49 | 7 | 56 |
| 2018 Enero | 53 | 5 | 58 |
| 2017 Diciembre | 61 | 9 | 70 |
| 2017 Noviembre | 52 | 5 | 57 |
| 2017 Octubre | 44 | 17 | 61 |
| 2017 Septiembre | 53 | 19 | 72 |
| 2017 Agosto | 73 | 23 | 96 |
| 2017 Julio | 62 | 41 | 103 |
| 2017 Junio | 61 | 35 | 96 |
| 2017 Mayo | 72 | 36 | 108 |
| 2017 Abril | 53 | 49 | 102 |
| 2017 Marzo | 64 | 26 | 90 |
| 2017 Febrero | 40 | 16 | 56 |
| 2017 Enero | 36 | 23 | 59 |
| 2016 Diciembre | 56 | 13 | 69 |
| 2016 Noviembre | 72 | 11 | 83 |
| 2016 Octubre | 91 | 17 | 108 |
| 2016 Septiembre | 152 | 15 | 167 |
| 2016 Agosto | 67 | 16 | 83 |
| 2016 Julio | 41 | 10 | 51 |
| 2016 Junio | 11 | 12 | 23 |
| 2016 Mayo | 6 | 9 | 15 |
| 2016 Abril | 14 | 1 | 15 |
| 2016 Marzo | 7 | 1 | 8 |
| 2016 Febrero | 4 | 3 | 7 |
| 2016 Enero | 9 | 3 | 12 |
| 2015 Diciembre | 6 | 1 | 7 |
| 2015 Noviembre | 11 | 2 | 13 |
| 2015 Octubre | 9 | 4 | 13 |
| 2015 Septiembre | 8 | 0 | 8 |
| 2015 Agosto | 10 | 2 | 12 |
| 2015 Julio | 70 | 11 | 81 |
| 2015 Junio | 74 | 9 | 83 |
| 2015 Mayo | 54 | 2 | 56 |
| 2015 Abril | 43 | 5 | 48 |
| 2015 Marzo | 25 | 2 | 27 |
| 2015 Febrero | 45 | 3 | 48 |
| 2015 Enero | 44 | 1 | 45 |
| 2014 Diciembre | 53 | 5 | 58 |
| 2014 Noviembre | 28 | 3 | 31 |
| 2014 Octubre | 37 | 5 | 42 |
| 2014 Septiembre | 28 | 3 | 31 |
| 2014 Agosto | 16 | 2 | 18 |
| 2014 Julio | 25 | 7 | 32 |
| 2014 Junio | 26 | 9 | 35 |
| 2014 Mayo | 35 | 22 | 57 |
| 2014 Abril | 26 | 9 | 35 |
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