Case and Research Letter
Postherpetic Granulomatous Dermatitis in a Man Treated With Nivolumab
Dermatitis granulomatosa postherpética en un paciente tratado con nivolumab
P. Martín-Carrasco
, C. Pérez-Ruiz, T. de Zulueta-Dorado, J. Conejo-Mir
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Unidad de Gestión Clínica de Dermatología, Hospital Universitario Virgen del Rocío, Sevilla, Spain
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Martín-Carrasco, C. Pérez-Ruiz, T. de Zulueta-Dorado, J. Conejo-Mir" "autores" => array:4 [ 0 => array:4 [ "nombre" => "P." "apellidos" => "Martín-Carrasco" "email" => array:1 [ 0 => "Pablo_ronda@hotmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "C." "apellidos" => "Pérez-Ruiz" ] 2 => array:2 [ "nombre" => "T." "apellidos" => "de Zulueta-Dorado" ] 3 => array:2 [ "nombre" => "J." "apellidos" => "Conejo-Mir" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Unidad de Gestión Clínica de Dermatología, Hospital Universitario Virgen del Rocío, Sevilla, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Dermatitis granulomatosa postherpética en un paciente tratado con nivolumab" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1667 "Ancho" => 1250 "Tamanyo" => 326860 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Erythematous-brownish nodular lesions with central scarring. The lesions are limited to the areas affected by varicella-zoster virus reactivation 2 years earlier (left scapular region).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">A 62-year-old man with a past history of smoking and systemic hypertension was diagnosed with metastatic nonsmall cell lung cancer with squamous differentiation, with hilar lymph nodes and invasion of the left suprarenal gland. He was therefore started on treatment with docetaxel, which he continued for 2 months before it was withdrawn due to disease progression. He then commenced treatment with nivolumab, 3<span class="elsevierStyleHsp" style=""></span>mg/kg intravenously every 2 weeks. A few days after the second cycle of this drug, the patient developed asymptomatic, erythematous-brownish nodular lesions in the left pectoral region, on the left arm, and in the left scapular region. The lesions coincided topographically with the areas in which the patient had developed varicella-zoster virus reactivation 2 years prior to diagnosis of the cancer and were limited exclusively to the areas of residual scarring from that episode; they thus presented a zosteriform distribution (<a class="elsevierStyleCrossRefs" href="#fig0005">Figs. 1 and 2</a>). Histology revealed dermal granulomas with no lymphocytic corona or central necrosis, indicating sarcoid-type granulomas (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). No multinucleated cells were observed. In view of these findings, extensive blood tests were requested, including angiotensin converting enzyme activity, and a Mantoux test. All the results were normal or negative. No abnormal findings other than those relating to the patient's lung disease were observed on chest x-ray and thoraco-abdominal computed tomography.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Treatment was prescribed with corticosteroids and topical calcineurin inhibitors. Despite this, the lesions persisted unchanged until the patient's death 6 months later; he had continued treatment with nivolumab throughout this period.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Postherpetic granulomatous dermatoses are the most common of the various types of skin reaction that can develop in areas in which varicella-zoster virus reactivation has occurred.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">1</span></a> These dermatoses can arise months or even years after the initial episode of reactivation. Their appearance is related to the concept of the Wolf isotopic response,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">2</span></a> which consists of the development of a new dermatosis at the site of a previous, distinct dermatosis. Various granulomatous dermatoses have been reported: granuloma annulare, granulomatous vasculitis, sarcoid or tuberculoid granuloma, granulomatous folliculitis, and other nonspecific granulomatous dermatoses.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">3</span></a> In all cases, the lesions are limited exclusively to the area affected by the previous herpes zoster, presenting as papules, nodules, or depressed scars.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">1</span></a> The pathogenesis is not fully understood. It is thought that the formation of granulomas may be related to a delayed hypersensitivity reaction to proteins and glycoproteins of the viral envelope,<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">4</span></a> rather than complete viral structures<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">5</span></a> as, on many occasions, viral DNA is not detected on polymerase chain reaction testing of the granulomatous lesions.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">6</span></a> These reactions have sometimes occurred in patients with lymphoproliferative syndromes,<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">7,8</span></a> then being related to changes in the number and function of immunoglobulins, in cellular immunity, and increased hypersensitivity reactions.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Nivolumab is a human monoclonal antibody of the G4 immunoglobulin type. It binds to and blocks the programmed death<span class="elsevierStyleHsp" style=""></span>1 (PD-1) receptor, which is a negative regulator of T-cell activity.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">9</span></a> It is approved for the treatment of metastatic melanoma and squamous cell lung cancer.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">9</span></a> The mechanism of action of nivolumab is similar to that of ipilimumab, another monoclonal antibody used in the treatment of advanced unresectable melanoma; ipilimumab inhibits cytotoxic T-lymphocyte–associated antigen 4, which is a negative regulator of T cells. For this reason, this group of drugs is known as immune check-point inhibitors. The appearance of systemic and cutaneous granulomatous reactions mediated by nivolumab and ipilimumab has been reported on several occasions and is related to their induction of T-cell activation. For example, there has been a case of disseminated granuloma annulare in a patient treated with ipilimumab,<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">10</span></a> and several cases of sarcoidosis in patients treated with nivolumab. Those cases presented as a Lofgren syndrome, including infiltrative lesions in cosmetic tattoos,<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">11</span></a> with findings including mediastinal lymph nodes and skin lesions,<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">12</span></a> or limited to cutaneous sarcoidosis lesions with no systemic involvement.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">13</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">After performing additional tests to exclude systemic sarcoidosis, and accepting that sarcoid granulomas can present in numerous diseases other than sarcoidosis, we consider that our patient presented a nivolumab-mediated granulomatous dermatitis secondary to herpes zoster, and that this is the first such case to be reported. We suggest that blockade of the PD-1 receptor by nivolumab stimulates the T cells, promoting hypersensitivity reactions and the formation of granulomas to the proteins of the varicella-zoster virus envelope, thus triggering the postherpetic granulomatous dermatitis.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of Interest</span><p id="par0030" 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: Martín-Carrasco P, Pérez-Ruiz C, de Zulueta-Dorado T, Conejo-Mir J. Dermatitis granulomatosa postherpética en un paciente tratado con nivolumab. Actas Dermosifiliogr. 2017;108:783–784.</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" => 1667 "Ancho" => 1250 "Tamanyo" => 326860 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Erythematous-brownish nodular lesions with central scarring. The lesions are limited to the areas affected by varicella-zoster virus reactivation 2 years earlier (left scapular region).</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" => 1667 "Ancho" => 1250 "Tamanyo" => 335079 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Erythematous-brownish nodular lesions with central scarring. The lesions were limited to the areas affected by varicella-zoster virus reactivation 2 years earlier (left arm).</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" => 1219 "Ancho" => 1625 "Tamanyo" => 482395 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Sarcoid-type granuloma in the dermis. Hematoxylin and eosin, original magnification<span class="elsevierStyleHsp" style=""></span>×20.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:13 [ 0 => array:3 [ "identificador" => "bib0070" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Reacciones granulomatosas secundarias a herpes zóster" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S. Álvarez-Ruiz" 1 => "A. Alonso" 2 => "S. Pérez-Gala" 3 => "E. Daudén" 4 => "F. Fraga" 5 => "A. 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 9 | 12 | 21 |
| 2024 Octubre | 96 | 51 | 147 |
| 2024 Septiembre | 99 | 56 | 155 |
| 2024 Agosto | 133 | 88 | 221 |
| 2024 Julio | 110 | 68 | 178 |
| 2024 Junio | 121 | 55 | 176 |
| 2024 Mayo | 91 | 46 | 137 |
| 2024 Abril | 99 | 35 | 134 |
| 2024 Marzo | 107 | 31 | 138 |
| 2024 Febrero | 94 | 37 | 131 |
| 2024 Enero | 101 | 39 | 140 |
| 2023 Diciembre | 92 | 14 | 106 |
| 2023 Noviembre | 112 | 28 | 140 |
| 2023 Octubre | 95 | 30 | 125 |
| 2023 Septiembre | 113 | 37 | 150 |
| 2023 Agosto | 112 | 19 | 131 |
| 2023 Julio | 112 | 30 | 142 |
| 2023 Junio | 89 | 23 | 112 |
| 2023 Mayo | 126 | 23 | 149 |
| 2023 Abril | 99 | 25 | 124 |
| 2023 Marzo | 76 | 22 | 98 |
| 2023 Febrero | 91 | 33 | 124 |
| 2023 Enero | 69 | 26 | 95 |
| 2022 Diciembre | 84 | 32 | 116 |
| 2022 Noviembre | 52 | 29 | 81 |
| 2022 Octubre | 65 | 23 | 88 |
| 2022 Septiembre | 61 | 46 | 107 |
| 2022 Agosto | 58 | 45 | 103 |
| 2022 Julio | 52 | 38 | 90 |
| 2022 Junio | 39 | 20 | 59 |
| 2022 Mayo | 109 | 37 | 146 |
| 2022 Abril | 144 | 36 | 180 |
| 2022 Marzo | 132 | 53 | 185 |
| 2022 Febrero | 122 | 26 | 148 |
| 2022 Enero | 116 | 40 | 156 |
| 2021 Diciembre | 76 | 33 | 109 |
| 2021 Noviembre | 98 | 42 | 140 |
| 2021 Octubre | 94 | 54 | 148 |
| 2021 Septiembre | 73 | 41 | 114 |
| 2021 Agosto | 76 | 26 | 102 |
| 2021 Julio | 48 | 34 | 82 |
| 2021 Junio | 62 | 27 | 89 |
| 2021 Mayo | 78 | 42 | 120 |
| 2021 Abril | 127 | 51 | 178 |
| 2021 Marzo | 99 | 30 | 129 |
| 2021 Febrero | 76 | 21 | 97 |
| 2021 Enero | 56 | 22 | 78 |
| 2020 Diciembre | 59 | 19 | 78 |
| 2020 Noviembre | 67 | 24 | 91 |
| 2020 Octubre | 43 | 15 | 58 |
| 2020 Septiembre | 53 | 17 | 70 |
| 2020 Agosto | 29 | 29 | 58 |
| 2020 Julio | 36 | 17 | 53 |
| 2020 Junio | 56 | 33 | 89 |
| 2020 Mayo | 22 | 20 | 42 |
| 2020 Abril | 30 | 18 | 48 |
| 2020 Marzo | 31 | 16 | 47 |
| 2020 Febrero | 2 | 0 | 2 |
| 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 | 6 | 0 | 6 |
| 2019 Mayo | 4 | 0 | 4 |
| 2019 Abril | 4 | 0 | 4 |
| 2019 Marzo | 4 | 0 | 4 |
| 2019 Febrero | 1 | 0 | 1 |
| 2019 Enero | 3 | 0 | 3 |
| 2018 Diciembre | 3 | 0 | 3 |
| 2018 Noviembre | 2 | 0 | 2 |
| 2018 Octubre | 3 | 0 | 3 |
| 2018 Septiembre | 3 | 0 | 3 |
| 2018 Febrero | 53 | 9 | 62 |
| 2018 Enero | 47 | 8 | 55 |
| 2017 Diciembre | 100 | 14 | 114 |
| 2017 Noviembre | 47 | 7 | 54 |
| 2017 Octubre | 138 | 36 | 174 |
| 2017 Septiembre | 8 | 10 | 18 |
| 2017 Agosto | 4 | 11 | 15 |
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