Nivolumab-related mucous membrane pemphigoid
2019; Elsevier BV; Volume: 121; Linguagem: Inglês
10.1016/j.ejca.2019.08.030
ISSN1879-0852
AutoresV. Sibaud, Émmanuelle Vigarios, Aurore Siegfried, Chloé Bost, Nicolás Meyer, C. Pagès-Laurent,
Tópico(s)Drug-Induced Adverse Reactions
ResumoDermatologic immune-related adverse events (IRaes) are among the most frequent toxicities reported with anti–programmed cell death (PD)-1 or anti–programmed cell death ligand (PD-L1) therapies, affecting up to 40% of treated patients [ 1 Weber J.S. Hodi F.S. Wolchok J.D. Topalian S.L. Schadendorf D. Larkin J. et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017; 35: 785-792 Crossref PubMed Scopus (575) Google Scholar , 2 Wang Y. Zhou S. Yang F. Qi X. Wang X. Guan X. et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis. JAMA Oncol. 2019 Apr 25; ([Epub ahead of print])https://doi.org/10.1001/jamaoncol.2019.0393 Crossref Scopus (220) Google Scholar ]. They have been associated with a variety of dermatologic manifestations including eczema-like rash, pruritus, lichenoid reactions, induction or reactivation of preexisting psoriasis, vitiligo and granulomatous reactions [ [3] Sibaud V. Dermatologic reactions to immune checkpoint inhibitors : skin toxicities and immunotherapy. Am J Clin Dermatol. 2018; 19: 345-361 Crossref PubMed Scopus (203) Google Scholar ]. They may also induce or reactivate autoimmune skin diseases [ [4] Menzies A.M. Johnson D.B. Ramanujam S. Atkinson V.G. Wong A.N.M. Park J.J. et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol. 2017; 28: 368-376 Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar ]. The risk of developing autoimmune blistering disorders with immune checkpoint inhibitors is well established, with approximately 1% of treated patients being affected [ [5] Siegel J. Totonchy M. Damsky W. Berk-Krauss J. Castiglione Jr., F. Sznol M. et al. Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: a retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy. J Am Acad Dermatol. 2018; 79: 1081-1088 Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar ]. Most reported cases are bullous pemphigoid [ 5 Siegel J. Totonchy M. Damsky W. Berk-Krauss J. Castiglione Jr., F. Sznol M. et al. Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: a retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy. J Am Acad Dermatol. 2018; 79: 1081-1088 Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar , 6 Naidoo J. Schindler K. Querfeld C. Busam K. Cunningham J. Page D.B. et al. Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1. Cancer Immunol Res. 2016; 4: 383-389 Crossref PubMed Scopus (166) Google Scholar , 7 Lopez A.T. Khanna T. Antonov N. Audrey-Bayan C. Geskin L. A review of bullous pemphigoid associated with PD-1 and PD-L1 inhibitors. Int J Dermatol. 2018; 57: 664-669 Crossref PubMed Scopus (74) Google Scholar ], but reports of mucous membrane pemphigoid (MMP) in association with pembrolizumab are now emerging [ 8 Bezinelli L.M. Eduardo F.P. Migliorati C.A. Ferreira M.H. Taranto P. Sales D.B. et al. A severe, refractory case of mucous membrane pemphigoid after treatment with pembrolizumab: brief communication. J Immunother. 2019 Jun 25; ([Epub ahead of print])https://doi.org/10.1097/CJI.0000000000000280 Crossref PubMed Scopus (11) Google Scholar , 9 Zumelzu C. Alexandre M. Le Roux C. Weber P. Guyot A. Levy A. et al. Mucous membrane pemphigoid, bullous pemphigoid, and anti-programmed death-1/programmed death-ligand 1: a case report of an elderly woman with mucous membrane pemphigoid developing after pembrolizumab therapy for metastatic melanoma and review of the literature. Front Med. 2018; 5: 268https://doi.org/10.3389/fmed.2018.00268. eCollection 2018 Crossref Google Scholar , 10 Haug V. Behle V. Benoit S. Kneitz H. Schilling B. Goebeler M. et al. Pembrolizumab-associated mucous membrane pemphigoid in a patient with Merkel cell carcinoma. Br J Dermatol. 2018; 179: 993-994 Crossref PubMed Scopus (18) Google Scholar ] (Table 1). Table 1Characteristics of reported patients developing mucous membrane pemphigoid with anti–PD-1 therapies. Case No./sex/age (years) Underlying malignancies Anti–PD-1 Time to onset Oral mucosal lesions Extra-oral lesions Perilesional DIF Standard IIF Salt-split skin IIF ELISA Management MMP outcome 1/M/62 (10) Merkel cell carcinoma Pembrolizumab 13 weeks Oral erosions, blisters and aphthous ulcers on the tongue and buccal mucosa None Linear deposits of C3 along the DEJ Not done Circulating IgG and IgA binding the roof of the blister Positive anti–BP180 NC16A Pembrolizumab discontinuationTopical steroids and doxycycline Healing after 6 weeks 2/F/83 (9) Malignant melanoma Pembrolizumab 6 months after pembrolizumab discontinuation Painful gingivitis with blisters, pseudomembrane-covered erosion None Linear deposits of IgG and C3 along the DEJ Negative Negative Negative Pembrolizumab already discontinuedTopical steroids and doxycycline Healing after 6 weeks 3/F/47 (8) Ovarian clear cell adenocarcinoma Pembrolizumab 6 weeks Multiple ulcerative lesions covering oral mucosa (including gingiva) Fibrosis of the upper respiratory tractLaryngeal stenosis Linear deposits of IgG along the DEJ Not done Circulating IgG binding the roof of the cleavage Negative Pembrolizumab discontinuationRituximab intravenous immunoglobulin therapyPrednisone Initial improvement with scarring processDeath (due to sepsis) Present case/F/70 Malignant melanoma Nivolumab 12 weeks Painful desquamative gingivitis None Linear deposits of IgG, IgA and C3 along the DEJ Negative Negative Positive anti–BP180 NC16A a No detection at treatment initiation. NivolumabContinuationTopical steroids Stable disease DIF: direct immunofluorescence; DEJ: dermoepidermal junction; IIF: indirect immunofluorescence; ELISA: enzyme-linked immunosorbent microscopy; MMP: mucous membrane pemphigoid. a No detection at treatment initiation. Open table in a new tab DIF: direct immunofluorescence; DEJ: dermoepidermal junction; IIF: indirect immunofluorescence; ELISA: enzyme-linked immunosorbent microscopy; MMP: mucous membrane pemphigoid.
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