Letter to the Editor
Panniculitis in patients treated with BRAF/MEK inhibitors: Presentation of 4 new cases
Paniculitis en pacientes tratados con iBRAF/iMEK: presentación de 4 nuevos casos
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A and B) Clinical characteristics of 2 of the cases: erythematous-violaceous nodular lesions (→) on the legs (A) and arms (B). C) Septal panniculitis: predominantly septal lymphohistiocytic infiltrate (*). D) Lobular panniculitis: lymphohistiocytic fat lobule infiltrate (→).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) have meant a paradigm shift in the management of multiple malignancies. BRAF V600E mutations (valine to glutamic acid substitution at position 600) are a high-frequency event in melanoma (≈50%) and of low frequency in lung cancer (≈2%).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The presence of BRAF V600E mutations in tumour cells predicts the response to BRAFi, alone or in combination with MEKi.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Numerous adverse reactions of BRAFi/MEKi have been described, some of them due to paradoxical activation of the MAPK pathway in wild-type BRAF cells. The most common cutaneous adverse reactions (CAR) are photosensitivity, xerosis, palmoplantar hyperkeratosis, verrucous lesions, and squamous cell carcinomas.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Serious CARs have also been described.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Panniculitis is less common, with only fifty cases described.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2–4</span></a> Its etiopathogenesis is not well defined, and its management requires multidisciplinary action.</p><p id="par0020" class="elsevierStylePara elsevierViewall">We conducted a retrospective study of cases of panniculitis secondary to BRAFi/MEKi diagnosed at the Complexo Hospitalario Universitario de A Coruña from January 2016 to January 2019.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Of 29 patients treated with BRAFi/MEKi, 4 developed panniculitis, representing an incidence of 13.8%. Three were patients with melanoma and one had lung adenocarcinoma. The 4 cases were women in treatment with dabrafenib + trametinib, aged between 58 and 64.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The time from the start of treatment to the development of panniculitis ranged from 3 to 26 weeks.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The general presentation (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) consisted of hot, painful, erythematous nodules predominantly in BLL, especially in the pretibial area. However, 3 patients also developed lesions in the trunk, one of them in BUL. Extracutaneous symptoms such as fever or arthralgia accompanied the condition in 3 of the patients.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">The histopathological study showed lobular panniculitis in 2 patients (one accompanied by vasculitis) and septal panniculitis without vasculitis in the other 2, with lymphohistiocytic infiltrate in all of them, and with the presence of giant cells in one of the samples (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><p id="par0045" class="elsevierStylePara elsevierViewall">The treatment of panniculitis is symptomatic and must be adapted to the severity of the symptoms. Oral anti-inflammatories and topical corticosteroids were administered in all 4 cases. In addition, in those with greater systemic involvement, oral corticosteroids (prednisone 30 mg per day in tapering regimen), with improvement of symptoms in less than 2 weeks. Permanent discontinuation of the drug was not necessary.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Subsequently, 2 of the patients developed tumour progression and, therefore, the targeted therapy was discontinued, with resolution of the panniculitis.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Since the introduction of BRAFi/MEKi, there have been multiple publications about their CAR.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2–4</span></a> Panniculitis has been described in around 50 patients, with melanoma being the most commonly associated tumour. In our series, we report the first case of panniculitis in a patient with lung adenocarcinoma treated with BRAFi/MEKi.</p><p id="par0060" class="elsevierStylePara elsevierViewall">In the retrospective study by Carlos et al.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> panniculitis occurs more frequently in patients treated with vemurafenib (11.1%), followed by those receiving combined treatment with dabrafenib + trametinib (10%) and, less frequently, dabrafenib monotherapy (2.5%).</p><p id="par0065" class="elsevierStylePara elsevierViewall">According to Piroth et al.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> panniculitis affects the fat lobules in 62% of cases, the septa in 14%, and both in 24%. Vasculitis is described in 26%, with a neutrophilic infiltrate in more than half of the cases. In our series, all 4 cases had lymphohistiocytic infiltrates, 2 in the septa and 2 in the lobules, and vasculitis was detected in one of the 4 patients.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Treatment is symptomatic. The optimal dose of prednisone is not well defined, with significant variability between authors (from 15 mg to 1 mg/kg).<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In our series, we prescribed prednisone 30 mg a day as the initial dose, with an early tapering regimen, all of them showing a good response. Proper diagnosis and management of skin lesions would prevent discontinuation of targeted therapy in these patients.</p><p id="par0075" class="elsevierStylePara elsevierViewall">In conclusion, septal or lobular panniculitis is a CAR of BRAFi/MEKi. The clinical presentation consists of painful, erythematous subcutaneous nodules that may be accompanied by systemic manifestations. Knowledge of this CAR will enable appropriate symptomatic treatment to be established, avoiding discontinuation of targeted therapy in most cases.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Ethical considerations</span><p id="par0080" class="elsevierStylePara elsevierViewall">The centres’ protocols on the publication of patient data were complied with, and the privacy of the subjects was respected.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Funding</span><p id="par0085" class="elsevierStylePara elsevierViewall">There are no public or private sources of funding for the conduct of this study.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Ethical considerations" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Funding" ] 2 => 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: Cordeiro González P, Taibo Martínez A, Peña Penabad C. Paniculitis en pacientes tratados con iBRAF/iMEK: presentación de 4 nuevos casos. Med Clin (Barc). 2022;158:e8–e9.</p>" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1763 "Ancho" => 2007 "Tamanyo" => 478153 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Clinical and histopathological characteristics of panniculitis lesions. A and B) Clinical characteristics of 2 of the cases: erythematous-violaceous nodular lesions (→) on the legs (A) and arms (B). C) Septal panniculitis: predominantly septal lymphohistiocytic infiltrate (*). D) Lobular panniculitis: lymphohistiocytic fat lobule infiltrate (→).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adverse event management in patients with <span class="elsevierStyleItalic">BRAF</span>V600E-mutant non-small cell lung cancer treated with dabrafenib plus trametinib" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A. Chalmers" 1 => "L. Cannon" 2 => "W. 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