Paraneoplastic pemphigus: a clinical, laboratorial, and therapeutic overview

Abstract

Paraneoplastic pemphigus is a rare and severe autoimmune blistering disease characterized by mucocutaneous lesions associated with benign and malignant neoplasms. Diagnostic criteria include the presence of chronic mucositis and polymorphic cutaneous lesions with occult or confirmed neoplasia; histopathological analysis exhibiting intraepidermal acantholysis, necrotic keratinocytes, and vacuolar interface dermatitis; direct immunofluorescence with intercellular deposits (IgG and C3) and at the basement membrane zone (IgG); indirect immunofluorescence with intercellular deposition of IgG (substrates: monkey esophagus and simple, columnar, and transitional epithelium); and, autoreactivity to desmogleins 1 and 3, desmocollins 1, 2, and 3, desmoplakins I and II, envoplakin, periplakin, epiplakin, plectin, BP230, and α-2-macroglobulin-like protein 1. Neoplasias frequently related to paraneoplastic pemphigus include chronic lymphocytic leukemia, non-Hodgkin lymphoma, carcinomas, Castleman disease, thymoma, and others. Currently, there is no standardized treatment for paraneoplastic pemphigus. Systemic corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, rituximab, cyclophosphamide, plasmapheresis, and intravenous immunoglobulin have been used, with variable outcomes. Reported survival rates in 1, 2, and 5 years are 49%, 41%, and 38%, respectively.

Deep pemphigus (pemphigus vulgaris, pemphigus vegetans and paraneoplastic pemphigus) in dogs, cats and horses: a comprehensive review

“…The pathogenic IgG AA in PNP are polyclonal and target a wide array of keratinocyte-derived proteins such as DSG3, DSG1, DSC1, DSC2 and DSC3, plakin family proteins (envoplakin, periplakin, desmoplakin 1 and 2, plectin and BP230) and the alpha-2-macroglobulin-like-1 protease inhibitor [ 117 – 119 ]. The plakin family proteins envoplakin and periplakin, are most consistently targeted by PNP AA [ 113 ].…”

“…In fact, indirect IF using bladder epithelium (which is rich in plakins) is a highly specific (98%) method to differentiate PNP from other forms of pemphigus (cited in [ 113 ]). The possible mechanisms leading to autoimmunity in PNP include the tumor-induced production of AA, the cross-reactivity of tumor and epithelial antigens, as well as epitope spreading [ 117 ]. The human leukocyte antigen (HLA)-CW*14 and HLA-DRB1*03 seem to be associated with the development of PNP [ 113 ].…”

“…In humans, PNP usually occurs between 45 and 70 years of age, with no sex predisposition to develop the disease [ 117 ]; it has also been reported in children and adolescents [ 121 ]. In another study of 104 patients with PNP, the affected age ranged from 11 to 83 years (average: 56.7), with a female-to-male ratio of 1.7 [ 122 ].…”

“…Human patients with PNP usually present with severe systemic signs (e.g., malaise, weakness and weight loss) in addition to skin and/or mucosal lesions [ 117 ]. The main characteristic feature of human PNP, and often the first presenting sign, is a stomatitis that presents as erosions and ulcers affecting the oropharynx and extending to the vermilion border of the lips [ 113 , 117 ]. Indeed, mucosal and mucocutaneous regions (i.e., oral, conjunctiva, anogenital) are most commonly affected in patients with PNP [ 113 , 117 ].…”

“…The main characteristic feature of human PNP, and often the first presenting sign, is a stomatitis that presents as erosions and ulcers affecting the oropharynx and extending to the vermilion border of the lips [ 113 , 117 ]. Indeed, mucosal and mucocutaneous regions (i.e., oral, conjunctiva, anogenital) are most commonly affected in patients with PNP [ 113 , 117 ]. The skin lesions of PNP are polymorphic, and they can develop days, weeks of months after the onset of mucosal lesions [ 117 ]; these lesions may resemble those of EM (i.e., targetoid erythematous papules with central blisters), PV (i.e., flaccid blisters that rupture and form erosions and/or ulcers), or even graft-versus-host disease (i.e., erythematous-to-violaceous papules and plaques with silvery scale) [ 113 , 117 ].…”