Dystrophic epidermolysis bullosa pruriginosa: a new case series of a rare phenotype unveils skewed Th2 immunity

Abstract

Background Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) is a rare subtype of hereditary epidermolysis bullosa, with a poorly understood pathogenesis and no satisfactory treatment.Objectives To assess the clinical and biological features, genetic basis and therapeutic management, to better characterize this rare genodermatosis. MethodsWe have conducted a retrospective study, reviewing the clinical presentation, genetic diagnosis, immunohistopathological findings and biological characteristics and management of patients with dystrophic epidermolysis bullosa pruriginosa. This study was conducted in the Department of Dermatology at Saint-Louis Hospital and the Department of Genetics at Necker Hospital (Paris, France). All patients with a diagnosis of DEB-Pr seen between 2010 and 2020 were included.Results Seven patients were included, the average age of 50.1 years [range 36-76]. Pruriginous-lichenified papules, plaques or nodules appeared at 27.6 years on average [range 7-66] on pretibial areas and forearms, associated with milia and toenails dystrophy. All patients received multiple treatments, but none could sustainably reduce pruritus.Immunohistopathological analysis of lesion skin revealed subepidermal blister with fibrosis, milia and mast cell infiltration. Serum TNFa, IL1b and IL6 levels were elevated in 2/6 patients. Total serum IgE levels were increased in 7/7 patients, with no history of atopy. Immunophenotyping of circulating T-cells revealed an increased Th2 subset in 4/4 patients, with reduced Th1 and Th17 subpopulations. Genetic analysis of COL7A1 identified 7 distinct causative mutations, six of which were new. Intra-familial clinical variability was documented in 5/7 patients and was associated with the co-inheritance of a recessive COL7A1 mutation or an FLG2 mutation in 2 families. ConclusionOur study confirms the stereotyped presentation of DEB-Pr with large intra-familial variability in disease expression. Mast cell infiltration, elevated IgE and increased Th2 subset without atopy strongly support a role of Th2-mediated immunity in DEB-Pr, and further argue for new targeted therapeutic options such as dupilumab.

Dupilumab in the treatment of genodermatosis: A systematic review

“…demonstrated flattened bullous lesions on the back of both hands 15 days after the first dupilumab injection 22 . According to the study by Darbord et al., serum analysis of EBP patients showed an elevated IgE level and an increase in the Th2 subset of circulating T cells, although the serum levels of IL‐4, IL‐5, and IL‐13 were not measured in this study 9 . The atypical Th2 activity may explain the potential therapeutic effects of dupilumab in these patients.…”

New insight of itch mediators and proinflammatory cytokines in epidermolysis bullosa

“…Recently, six previous reports have documented successful treatment of DEB‐Pr with dupilumab, a monoclonal antibody targeting the IL‐4 receptor alpha (IL‐4Rα) that provides dual blockade of IL‐4 and IL‐13, which play an important role in the pathogenesis of AD 4,26,51–53 . In addition, Darbord et al 54 reported mast cell infiltration of the lesional skin, high serum total IgE levels and increased Th2 subsets in circulating T cells in patients with DEB‐Pr. These findings suggest that DEB‐Pr is driven by the Th2 immune response 4 .…”

Dupilumab: Advances in the off‐label usage ofIL4/IL13antagonist in dermatoses

“…Six DEB‐Pr patients was reported to benefit from dupilumab treatment 67–71 : total treatment duration differ from 3 months to 22 months with significant improvements were observed in all these six patients. A retrospective study revealed an activation of type 2 immune response including mast cell infiltration, elevated IgE and increased Th2 subset in DEB‐Pr patients, confirming the possible efficacy of dupilumab 66 . Despite the issue of persistent treatment duration and partial improvement, dupilumab have proved a new option for DEB‐Pr.…”

“…A retrospective study revealed an activation of type 2 immune response including mast cell infiltration, elevated IgE and increased Th2 subset in DEB-Pr patients, confirming the possible efficacy of dupilumab. 66 Despite the issue of persistent treatment duration and partial improvement, dupilumab have proved a new option for DEB-Pr.…”

“…Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) is a type of hereditary epidermolysis bullosa characterized by insufferable pruritus and hypertrophic nodule on the extensors. 66 DEB-Pr is caused by COL7A1 gene mutations, which encoding an essential dermoepidermal anchor fiber: collagen VII. Rare of its pathogenesis and immunological mechanism are known so far.…”