Case and Research Letter
Relapse of morphea during Nivolumab therapy for lung adenocarcinoma
Recaída de morfea durante tratamiento con Nivolumab en adenocarcinoma de pulmón
A. Alegre-Sánchez
, P. Fonda-Pascual, D. Saceda-Corralo, E. de las Heras-Alonso
Corresponding author
Dermatology Service, Ramon y Cajal Hospital, Madrid, Spain
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Alegre-Sánchez, P. Fonda-Pascual, D. Saceda-Corralo, E. de las Heras-Alonso" "autores" => array:4 [ 0 => array:4 [ "nombre" => "A." "apellidos" => "Alegre-Sánchez" "email" => array:1 [ 0 => "adrian.alegresanchez@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "P." "apellidos" => "Fonda-Pascual" ] 2 => array:2 [ "nombre" => "D." "apellidos" => "Saceda-Corralo" ] 3 => array:2 [ "nombre" => "E." "apellidos" => "de las Heras-Alonso" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Dermatology Service, Ramon y Cajal Hospital, Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Recaída de morfea durante tratamiento con Nivolumab en adenocarcinoma de pulmón" ] ] "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" => 1036 "Ancho" => 1583 "Tamanyo" => 152134 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Patches in both breasts and left inframammary fold, showing a shinny white color, liliaceous ring and atrophic surface.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Nivolumab is a Programmed Death-1 (PD1) receptor (PD-1) inhibitor, first approved as cancer immune-checkpoint inhibitor therapy for stage IV malignant melanoma, with recent indications in different tumors such as non-small cell lung cancer, prostate cancer, renal-cell cancer or ovarian cancer. A wide variety of skin reactions have been described associated to cancer immunotherapy.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1–7</span></a> We present a case of morphea relapsing during Nivolumab treatment.</p><p id="par0010" class="elsevierStylePara elsevierViewall">A 65 year-old woman came to our clinic referred by the Oncology department of our hospital. She was being followed due to a stage IV lung adenocarcinoma for which she had received different therapies. Just 2 months after initiating treatment with Nivolumab (3<span class="elsevierStyleHsp" style=""></span>mg/kg every 2 weeks), she developed cutaneous lesions on the trunk. On the physical examination she presented three patches: one on each breast, and one on the left inframammary fold (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). These lesions had a shiny white color with a discrete lilaceous ring. To the touch, they presented as clearly atrophic. She reported occasional itching but no other symptoms. The patient had a past medical history of morphea 8 years before (histologically diagnosed), having been treated with topical corticosteroids and oral methotrexate, with remission of the disease for more than 6 years. Postinflammatory hyperpigmentation was not detected.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">A skin biopsy of one of the patches was performed. Histological examination demonstrated findings of lichen sclerosus with underlying morphea (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Nivolumab was stopped after 6 months of treatment because of the lack of efficacy in oncological terms. In subsequent visits to our clinics, the patient showed improvement of her cutaneous lesions, without any topical or systemic treatment.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Relapse of morphea has been described in 50% of patients in the first 2 years after diagnosis.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> In the presented case, more than 6 years had passed since the last exacerbation of morphea, and this episode of relapsing happened only 2 weeks after initiating Nivolumab. Although natural evolution of the disease may have played a role, we considered Nivolumab as a possible trigger.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Many other medications have been associated with the development of morphea. The formation of autoantibodies and subsequent microvasculature injury has been proposed in the pathogenesis of these cases of drug-induced morphea.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In different clinical trials, anti-PD1 therapies such as Pembrolizumab or Nivolumab showed a relatively safe profile, with a low incidence of major adverse effects (drug-related grade 3 or 4 toxic effects only in 14% of the patients), being those related with pneumonitis the most severe of them.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> These adverse reactions related with immune-checkpoints inhibitors have been named as immune-related adverse events (irAEs). When focusing on the skin irAEs, non-specficic macular papular rash and pruritus have been described as the most common ones. Interestingly, vitiligo has also been reported, but only in patients with melanoma. Urticaria, alopecia and mucosal involvement are other frequently described skin irAEs.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1–4</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The exacerbation of preexisting autoimune disorders related to immunotherapies has also been reported. These disorders include psoriasis, sarcoidosis, bullous pemphigoid and subacute lupus erythematosus.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5–7</span></a> To the best of our knowledge, this would be the first case of morphea relapsing due to any cancer immunotherapy treatment.</p><p id="par0040" class="elsevierStylePara elsevierViewall">In conclusion, attending to the nature of this kind of immunotherapies, totally different from traditional chemotherapy, dermatologists should be aware not only of their typical irAEs, but also of the possibility of exacerbation or relapse of previously controlled skin diseases, especially immune-related ones. This will probably represent a new challenge for dermatologists in the future, as these treatments are being used more and more often. More experience is needed in order to conclude the exact relation of cancer immunotherapy and the relapse of these diseases.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interests</span><p id="par0045" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of interests" ] 1 => array:2 [ "identificador" => "xack262392" "titulo" => "Acknowledgement" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1036 "Ancho" => 1583 "Tamanyo" => 152134 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Patches in both breasts and left inframammary fold, showing a shinny white color, liliaceous ring and atrophic surface.</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" => 1452 "Ancho" => 1583 "Tamanyo" => 386054 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Histopathology (HE ×10): thickened collagen bundles in dermis, closely packed. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 7 | 3 | 10 |
| 2024 October | 69 | 40 | 109 |
| 2024 September | 67 | 20 | 87 |
| 2024 August | 73 | 49 | 122 |
| 2024 July | 67 | 27 | 94 |
| 2024 June | 69 | 29 | 98 |
| 2024 May | 58 | 30 | 88 |
| 2024 April | 68 | 25 | 93 |
| 2024 March | 69 | 26 | 95 |
| 2024 February | 56 | 28 | 84 |
| 2024 January | 51 | 33 | 84 |
| 2023 December | 54 | 16 | 70 |
| 2023 November | 72 | 17 | 89 |
| 2023 October | 65 | 22 | 87 |
| 2023 September | 44 | 33 | 77 |
| 2023 August | 34 | 14 | 48 |
| 2023 July | 30 | 31 | 61 |
| 2023 June | 34 | 22 | 56 |
| 2023 May | 40 | 30 | 70 |
| 2023 April | 35 | 15 | 50 |
| 2023 March | 40 | 22 | 62 |
| 2023 February | 39 | 22 | 61 |
| 2023 January | 42 | 38 | 80 |
| 2022 December | 52 | 40 | 92 |
| 2022 November | 22 | 29 | 51 |
| 2022 October | 22 | 18 | 40 |
| 2022 September | 22 | 32 | 54 |
| 2022 August | 51 | 23 | 74 |
| 2022 July | 38 | 34 | 72 |
| 2022 June | 32 | 29 | 61 |
| 2022 May | 26 | 24 | 50 |
| 2022 April | 26 | 36 | 62 |
| 2022 March | 43 | 42 | 85 |
| 2022 February | 30 | 20 | 50 |
| 2022 January | 49 | 35 | 84 |
| 2021 December | 31 | 30 | 61 |
| 2021 November | 25 | 46 | 71 |
| 2021 October | 45 | 48 | 93 |
| 2021 September | 27 | 49 | 76 |
| 2021 August | 31 | 30 | 61 |
| 2021 July | 30 | 29 | 59 |
| 2021 June | 27 | 30 | 57 |
| 2021 May | 40 | 51 | 91 |
| 2021 April | 56 | 79 | 135 |
| 2021 March | 69 | 41 | 110 |
| 2021 February | 40 | 37 | 77 |
| 2021 January | 32 | 32 | 64 |
| 2020 December | 40 | 34 | 74 |
| 2020 November | 25 | 23 | 48 |
| 2020 October | 28 | 24 | 52 |
| 2020 September | 32 | 18 | 50 |
| 2020 August | 28 | 36 | 64 |
| 2020 July | 29 | 24 | 53 |
| 2020 June | 30 | 32 | 62 |
| 2020 May | 19 | 12 | 31 |
| 2020 April | 26 | 18 | 44 |
| 2020 March | 25 | 16 | 41 |
| 2020 February | 8 | 0 | 8 |
| 2020 January | 4 | 0 | 4 |
| 2019 December | 8 | 0 | 8 |
| 2019 November | 2 | 0 | 2 |
| 2019 September | 11 | 0 | 11 |
| 2019 August | 7 | 0 | 7 |
| 2019 July | 4 | 0 | 4 |
| 2019 June | 4 | 0 | 4 |
| 2019 May | 4 | 1 | 5 |
| 2019 April | 2 | 3 | 5 |
| 2019 March | 1 | 2 | 3 |
| 2019 February | 6 | 0 | 6 |
| 2018 December | 5 | 2 | 7 |
| 2018 November | 4 | 0 | 4 |
| 2018 October | 5 | 0 | 5 |
| 2018 September | 2 | 0 | 2 |
| 2018 February | 14 | 6 | 20 |
| 2018 January | 20 | 8 | 28 |
| 2017 December | 28 | 13 | 41 |
| 2017 November | 14 | 8 | 22 |
| 2017 October | 10 | 7 | 17 |
| 2017 September | 18 | 7 | 25 |
| 2017 August | 19 | 11 | 30 |
| 2017 July | 14 | 6 | 20 |
| 2017 June | 22 | 15 | 37 |
| 2017 May | 17 | 11 | 28 |
| 2017 April | 25 | 13 | 38 |
| 2017 March | 22 | 14 | 36 |
| 2017 February | 33 | 23 | 56 |
| 2017 January | 47 | 35 | 82 |
| 2016 December | 5 | 3 | 8 |
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