Case and Research Letters
Toxic epidermal necrolysis induced by vemurafenib
Necrólisis epidérmica tóxica por vemurafenib
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Miguel-Gómez, S. Pérez-Gala, P. Jaén-Olasolo" "autores" => array:3 [ 0 => array:2 [ "nombre" => "L." "apellidos" => "Miguel-Gómez" ] 1 => array:2 [ "nombre" => "S." "apellidos" => "Pérez-Gala" ] 2 => array:2 [ "nombre" => "P." 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Lapresta, A. Dotor, C. González-Herrada" "autores" => array:3 [ 0 => array:4 [ "nombre" => "A." "apellidos" => "Lapresta" "email" => array:1 [ 0 => "amlapresta@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "A." "apellidos" => "Dotor" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "C." "apellidos" => "González-Herrada" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital Universitario de Getafe, Getafe, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Anatomía Patológica, Hospital Universitario de Getafe, Getafe, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Necrólisis epidérmica tóxica por vemurafenib" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1627 "Ancho" => 1221 "Tamanyo" => 697919 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Histology showed extensive, confluent necrosis in the epidermis and subepidermal detachment. In the upper dermis, there was a predominantly perivascular lymphoplasmacytic infiltrate (hematoxylin-eosin, original magnification ×2.5).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">We report the case of a 68-year-old man diagnosed with a nodular melanoma (Breslow depth, 11<span class="elsevierStyleHsp" style=""></span>mm) in the right submammary region. He had no relevant past history and reported taking no medication, Radiography showed enlarged bilateral axillary, mediastinal, and hilar lymph nodes and multiple bilateral micronodules in the upper and lower lobes of the lung. These nodules showed high uptake, suggestive of metastatic lesions, on the positron emission tomography–computed tomography scan. Assessment of the <span class="elsevierStyleItalic">BRAF</span> V600E mutation was positive. With a diagnosis of BRAF-positive stage IV metastatic melanoma, treatment was initiated with vemurafenib 960 mg every 12<span class="elsevierStyleHsp" style=""></span>hours. No reduction was observed in the metastases after almost a month of treatment.</p><p id="par0010" class="elsevierStylePara elsevierViewall">At week 4 of treatment, the patient presented at the emergency department of his reference hospital with itching and reddening of the face and scalp. He reported no previous symptoms or fever. The physical examination revealed an exanthematous macular-papular rash on the neck, trunk, and extremities. The patient was admitted and treated with oral corticosteroids and antibiotics. Over the next 48<span class="elsevierStyleHsp" style=""></span>hours, he developed dysphagia, a tendency towards low blood pressure, and decreased urine output. A severe drug reaction was suspected and the patient was transferred to the burn unit at our hospital. On arrival, 72<span class="elsevierStyleHsp" style=""></span>hours after the onset of symptoms, he was afebrile, hemodynamically stable, and breathing spontaneously. Physical examination showed extensive body surface involvement (85%) and epidermal detachment (60%), in addition to erosions affecting the ocular, oral, and genital mucosa (<a class="elsevierStyleCrossRefs" href="#fig0005">Figs. 1 and 2</a>). His heart rate was 95<span class="elsevierStyleHsp" style=""></span>bpm and oxygen saturation was 100%.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Radiologic evaluation on admission showed enlarged hila and hilar and parahilar lymph nodes. There were no areas of consolidation. The most relevant laboratory findings were a C-reactive protein level of 86, a prothrombin ratio of 60.5%, and an internationalized normal ratio of 1.25. Biopsy showed extensive confluent necrosis in the epidermis and subepidermal detachment. There was a predominantly perivascular lymphoplasmacytic infiltrate in the dermis (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). The patient was diagnosed with toxic epidermal necrolysis due to vemurafenib, with a score of 3 on the SCORTEN scale. Vemurafenib had been withdrawn on admission, and treatment initiated with intravenous ciclosporin 75<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>hours, in addition to selective digestive decontamination, vitamin and nutritional support, and fluid therapy. The necrotic areas of the skin were removed, cleaned with saline solution and chlorhexidine, and covered with Biobrane dressings (Smith & Nephew).</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">During the first 48<span class="elsevierStyleHsp" style=""></span>hours of admission at our hospital, the lesions progressed to affect 90% of the total body surface. On day 4, the necrolysis stopped and the first signs of reepithelialization were seen. Reepithelialization was complete 2 weeks later.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Immediate complications were femoral deep vein thrombosis, followed by pulmonary embolism. Delayed complications included nail loss and adhesions in both external ear canals and in the balanopreputial sulcus. Finally, the patient required amniotic membrane transplantation due to necrosis of the conjunctival membranes.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The patient was discharged a month later. Ciclosporin was progressively tapered to zero, with administration of 150<span class="elsevierStyleHsp" style=""></span>mg and 100<span class="elsevierStyleHsp" style=""></span>mg for 5 days each. The patient returned to his reference hospital, where treatment with ipilimumab and radiation therapy reduced the metastases. He is currently stable and in good general health.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Vemurafenib is a selective inhibitor of the <span class="elsevierStyleItalic">BRAF</span> V600 mutation that was approved by the US Food and Drug Agency for the treatment of metastatic or unresectable melanoma in 2011.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a> About 40% to 60% of melanomas are BRAF-positive, and the mutation causes constitutive activation of the mitogen-activated protein kinase pathway, which in turn leads to uncontrolled cell growth and increased cell proliferation and invasive capacity.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">2,3</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Most mutations are V600E (valine to glutamic acid substitution), but there are also other less common mutations, such as V600K.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">4</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In the BRIM3 phase 3 clinical trial, 675 patients were randomly allocated to treatment with either vemurafenib or dacarbazine. In the vemurafenib group, there was a 63% reduction in the risk of death and a 74% reduction in the risk of death or disease progression.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a> In addition, the phase 1 and 2 trials showed response rates of up to 50% and an overall mean survival of between 14 and 16 months.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">5,6</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Treatment with vemurafenib, however, is not free of adverse effects, among which cutaneous toxicity is the most common. The most common cutaneous effects are rash, photosensitivity, pruritus, alopecia, palmar erythrodysesthesia, verrucal keratosis, keratoacanthomas, and squamous cell carcinomas. Almost 40% of patients develop a rash, which generally does not require treatment to be discontinued as most cases are mild (grade 1) or moderate (grade 2). Dose reductions or treatment discontinuation are only necessary in patients with severe rash (grade 3) or intolerable grade 2 rash.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">7</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Severe cutaneous reactions to vemurafenib are very uncommon, and just 1 case of Steven-Johnson syndrome and another of toxic epidermal necrolysis were reported in the BRIM3 study.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">However, new cases of severe cutaneous toxicity have appeared since the launch of the drug. Wantz et al.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">8</span></a> reported one of the first cases of toxic epidermal necrolysis due to vemurafenib in Europe. Treatment was discontinued and the necrolysis resolved, but the patient died from melanoma some months later.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">8</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The suspected drug should be withdrawn in all cases of toxic epidermal necrolysis and patients should be managed by specialized units. Although is no scientific evidence supporting the use of systemic therapy, at our hospital we use ciclosporin, as it rapidly stops progression of the rash, is well tolerated, and does not increase the risk of infection or death.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">9</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">We have presented the first case of toxic epidermal necrolysis due to vemurafenib in Spain. We believe that patients on this drug should be closely monitored by a dermatologist, with careful attention paid to the development of skin rash with signs of severity, such as epidermal detachment or mucosal involvement.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of Interest</span><p id="par0075" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of Interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Lapresta A, Dotor A, González-Herrada C. Necrólisis epidérmica tóxica por vemurafenib. Actas Dermosifiliogr. 2015;106:682–683.</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" => 1221 "Ancho" => 1628 "Tamanyo" => 354872 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Generalized eruption consisting of erythematous macules, with a tendency to coalesce, flaccid blisters, and areas with erosions covered with Biobrane dressings.</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" => 1221 "Ancho" => 1628 "Tamanyo" => 295783 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Higher-magnification image showing large superficial blisters and areas of necrosis.</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" => 1627 "Ancho" => 1221 "Tamanyo" => 697919 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Histology showed extensive, confluent necrosis in the epidermis and subepidermal detachment. In the upper dermis, there was a predominantly perivascular lymphoplasmacytic infiltrate (hematoxylin-eosin, original magnification ×2.5).</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" => "Improved survival with vemurafenib in melanoma with BRAF V600E mutation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.B. Chapman" 1 => "A. Hauschild" 2 => "C. Robert" 3 => "J.B. Haanen" 4 => "P. Ascierto" 5 => "J. Larkin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1103782" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med." 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 11 | 4 | 15 |
| 2024 Octubre | 89 | 40 | 129 |
| 2024 Septiembre | 84 | 21 | 105 |
| 2024 Agosto | 107 | 57 | 164 |
| 2024 Julio | 80 | 31 | 111 |
| 2024 Junio | 102 | 29 | 131 |
| 2024 Mayo | 60 | 29 | 89 |
| 2024 Abril | 78 | 24 | 102 |
| 2024 Marzo | 73 | 30 | 103 |
| 2024 Febrero | 53 | 40 | 93 |
| 2024 Enero | 58 | 28 | 86 |
| 2023 Diciembre | 70 | 19 | 89 |
| 2023 Noviembre | 75 | 26 | 101 |
| 2023 Octubre | 84 | 28 | 112 |
| 2023 Septiembre | 79 | 39 | 118 |
| 2023 Agosto | 52 | 22 | 74 |
| 2023 Julio | 54 | 29 | 83 |
| 2023 Junio | 53 | 21 | 74 |
| 2023 Mayo | 72 | 24 | 96 |
| 2023 Abril | 64 | 20 | 84 |
| 2023 Marzo | 55 | 27 | 82 |
| 2023 Febrero | 39 | 21 | 60 |
| 2023 Enero | 39 | 29 | 68 |
| 2022 Diciembre | 45 | 44 | 89 |
| 2022 Noviembre | 37 | 24 | 61 |
| 2022 Octubre | 24 | 24 | 48 |
| 2022 Septiembre | 25 | 39 | 64 |
| 2022 Agosto | 26 | 36 | 62 |
| 2022 Julio | 26 | 37 | 63 |
| 2022 Junio | 35 | 25 | 60 |
| 2022 Mayo | 34 | 39 | 73 |
| 2022 Abril | 47 | 36 | 83 |
| 2022 Marzo | 36 | 50 | 86 |
| 2022 Febrero | 23 | 29 | 52 |
| 2022 Enero | 25 | 38 | 63 |
| 2021 Diciembre | 37 | 39 | 76 |
| 2021 Noviembre | 45 | 40 | 85 |
| 2021 Octubre | 32 | 49 | 81 |
| 2021 Septiembre | 24 | 31 | 55 |
| 2021 Agosto | 25 | 16 | 41 |
| 2021 Julio | 22 | 25 | 47 |
| 2021 Junio | 15 | 20 | 35 |
| 2021 Mayo | 31 | 19 | 50 |
| 2021 Abril | 63 | 56 | 119 |
| 2021 Marzo | 54 | 23 | 77 |
| 2021 Febrero | 65 | 25 | 90 |
| 2021 Enero | 30 | 15 | 45 |
| 2020 Diciembre | 24 | 12 | 36 |
| 2020 Noviembre | 27 | 21 | 48 |
| 2020 Octubre | 29 | 5 | 34 |
| 2020 Septiembre | 43 | 17 | 60 |
| 2020 Agosto | 21 | 21 | 42 |
| 2020 Julio | 31 | 16 | 47 |
| 2020 Junio | 34 | 30 | 64 |
| 2020 Mayo | 28 | 8 | 36 |
| 2020 Abril | 33 | 11 | 44 |
| 2020 Marzo | 29 | 11 | 40 |
| 2020 Febrero | 3 | 0 | 3 |
| 2020 Enero | 4 | 4 | 8 |
| 2019 Diciembre | 8 | 0 | 8 |
| 2019 Noviembre | 4 | 1 | 5 |
| 2019 Septiembre | 8 | 1 | 9 |
| 2019 Agosto | 4 | 0 | 4 |
| 2019 Julio | 2 | 0 | 2 |
| 2019 Junio | 6 | 1 | 7 |
| 2019 Mayo | 2 | 8 | 10 |
| 2019 Abril | 0 | 1 | 1 |
| 2019 Marzo | 2 | 3 | 5 |
| 2019 Enero | 6 | 0 | 6 |
| 2018 Diciembre | 11 | 0 | 11 |
| 2018 Noviembre | 3 | 0 | 3 |
| 2018 Octubre | 4 | 0 | 4 |
| 2018 Septiembre | 8 | 0 | 8 |
| 2018 Marzo | 1 | 0 | 1 |
| 2018 Febrero | 81 | 4 | 85 |
| 2018 Enero | 29 | 5 | 34 |
| 2017 Diciembre | 67 | 10 | 77 |
| 2017 Noviembre | 18 | 2 | 20 |
| 2017 Octubre | 20 | 8 | 28 |
| 2017 Septiembre | 13 | 7 | 20 |
| 2017 Agosto | 23 | 6 | 29 |
| 2017 Julio | 17 | 9 | 26 |
| 2017 Junio | 18 | 10 | 28 |
| 2017 Mayo | 18 | 6 | 24 |
| 2017 Abril | 22 | 7 | 29 |
| 2017 Marzo | 21 | 10 | 31 |
| 2017 Febrero | 14 | 9 | 23 |
| 2017 Enero | 14 | 6 | 20 |
| 2016 Diciembre | 15 | 21 | 36 |
| 2016 Noviembre | 28 | 25 | 53 |
| 2016 Octubre | 20 | 28 | 48 |
| 2016 Agosto | 1 | 1 | 2 |
| 2016 Julio | 1 | 2 | 3 |
| 2016 Junio | 4 | 0 | 4 |
| 2016 Mayo | 1 | 0 | 1 |
| 2016 Abril | 3 | 0 | 3 |
| 2016 Febrero | 0 | 4 | 4 |
| 2015 Noviembre | 0 | 2 | 2 |
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