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
Corresponding author
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 He was therefore started on treatment with docetaxel, which he continued for 2 months before it was withdrawn due to disease progression.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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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 7 | 12 | 19 |
| 2024 October | 96 | 51 | 147 |
| 2024 September | 99 | 56 | 155 |
| 2024 August | 133 | 88 | 221 |
| 2024 July | 110 | 68 | 178 |
| 2024 June | 121 | 55 | 176 |
| 2024 May | 91 | 46 | 137 |
| 2024 April | 99 | 35 | 134 |
| 2024 March | 107 | 31 | 138 |
| 2024 February | 94 | 37 | 131 |
| 2024 January | 101 | 39 | 140 |
| 2023 December | 92 | 14 | 106 |
| 2023 November | 112 | 28 | 140 |
| 2023 October | 95 | 30 | 125 |
| 2023 September | 113 | 37 | 150 |
| 2023 August | 112 | 19 | 131 |
| 2023 July | 112 | 30 | 142 |
| 2023 June | 89 | 23 | 112 |
| 2023 May | 126 | 23 | 149 |
| 2023 April | 99 | 25 | 124 |
| 2023 March | 76 | 22 | 98 |
| 2023 February | 91 | 33 | 124 |
| 2023 January | 69 | 26 | 95 |
| 2022 December | 84 | 32 | 116 |
| 2022 November | 52 | 29 | 81 |
| 2022 October | 65 | 23 | 88 |
| 2022 September | 61 | 46 | 107 |
| 2022 August | 58 | 45 | 103 |
| 2022 July | 52 | 38 | 90 |
| 2022 June | 39 | 20 | 59 |
| 2022 May | 109 | 37 | 146 |
| 2022 April | 144 | 36 | 180 |
| 2022 March | 132 | 53 | 185 |
| 2022 February | 122 | 26 | 148 |
| 2022 January | 116 | 40 | 156 |
| 2021 December | 76 | 33 | 109 |
| 2021 November | 98 | 42 | 140 |
| 2021 October | 94 | 54 | 148 |
| 2021 September | 73 | 41 | 114 |
| 2021 August | 76 | 26 | 102 |
| 2021 July | 48 | 34 | 82 |
| 2021 June | 62 | 27 | 89 |
| 2021 May | 78 | 42 | 120 |
| 2021 April | 127 | 51 | 178 |
| 2021 March | 99 | 30 | 129 |
| 2021 February | 76 | 21 | 97 |
| 2021 January | 56 | 22 | 78 |
| 2020 December | 59 | 19 | 78 |
| 2020 November | 67 | 24 | 91 |
| 2020 October | 43 | 15 | 58 |
| 2020 September | 53 | 17 | 70 |
| 2020 August | 29 | 29 | 58 |
| 2020 July | 36 | 17 | 53 |
| 2020 June | 56 | 33 | 89 |
| 2020 May | 22 | 20 | 42 |
| 2020 April | 30 | 18 | 48 |
| 2020 March | 31 | 16 | 47 |
| 2020 February | 2 | 0 | 2 |
| 2020 January | 4 | 0 | 4 |
| 2019 December | 8 | 0 | 8 |
| 2019 November | 4 | 0 | 4 |
| 2019 September | 8 | 0 | 8 |
| 2019 August | 4 | 0 | 4 |
| 2019 July | 4 | 0 | 4 |
| 2019 June | 6 | 0 | 6 |
| 2019 May | 4 | 0 | 4 |
| 2019 April | 4 | 0 | 4 |
| 2019 March | 4 | 0 | 4 |
| 2019 February | 1 | 0 | 1 |
| 2019 January | 3 | 0 | 3 |
| 2018 December | 3 | 0 | 3 |
| 2018 November | 2 | 0 | 2 |
| 2018 October | 3 | 0 | 3 |
| 2018 September | 3 | 0 | 3 |
| 2018 February | 53 | 9 | 62 |
| 2018 January | 47 | 8 | 55 |
| 2017 December | 100 | 14 | 114 |
| 2017 November | 47 | 7 | 54 |
| 2017 October | 138 | 36 | 174 |
| 2017 September | 8 | 10 | 18 |
| 2017 August | 4 | 11 | 15 |
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