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Summary: Background: Several new genes and clinical subtypes have been identified since the publication in 2014 of the report of the last International Consensus Meeting on Epidermolysis Bullosa (EB). Objectives: We sought to reclassify disorders with skin fragility, with a focus on EB, based on new clinical and molecular data. Methods: This was a consensus expert review. Results: In this latest consensus report, we introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Other disorders with skin fragility, where blisters are a minor part of the clinical picture or are not seen because skin cleavage is very superficial, are classified as separate categories. These include peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility. Because of the common manifestation of skin fragility, these 'EB‐related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Conclusions: The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and genetic features of EB. What is already known about this topic? Epidermolysis bullosa (EB) is a group of genetic disorders with skin blistering.The last updated recommendations on diagnosis and classification were published in 2014. What does this study add? We introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype.Clinical and genetic aspects, genotype–phenotype correlations, disease‐modifying factors and natural history of EB are reviewed.Other disorders with skin fragility, e.g. peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility are classified as separate categories; these 'EB‐related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Linked Comment:Pope. Br J Dermatol 2020; 183:603. Linked Comment:Pope. Br J Dermatol 2020; 183:603. Plain language summary available online [ABSTRACT FROM AUTHOR]

Summary: Background: Generalized severe epidermolysis bullosa simplex (EBS‐gen sev) is a genetic blistering skin disease in which autosomal dominant mutations in either the keratin KRT5 or KRT14 genes lead to impaired function of the intermediate filament cytoskeleton in the basal epidermis. Here we present an ex vivo RNA trans‐splicing‐based therapeutic approach to correct the phenotype. Objectives: To correct a mutation within exon 1 of the KRT14 gene, using a 5′‐trans‐splicing approach, where any mutation within the first seven exons could be replaced by a single therapeutic molecule. Methods: A therapeutic RNA trans‐splicing molecule containing wild‐type exons 1–7 was stably transduced into an EBS patient‐derived keratinocyte line. Trans‐splicing was confirmed via reverse‐transcriptase polymerase chain reaction, Western blotting and immunofluorescence microscopy. Skin equivalents generated from corrected keratinocytes were grafted onto nude mice and analysed about 8 weeks post‐transplantation for regular epidermal stratification, trans‐splicing‐induced green fluorescent protein expression and blistering. Results: Transplanted skin equivalents generated from trans‐splicing‐corrected patient keratinocytes showed a stable and blister‐free epidermis. KRT14 correction disrupted EBS‐gen sev‐associated proinflammatory signalling, as shown at the mRNA and protein levels. Disruption of the pathogenic feedback loop in addition to overall downregulation of KRT14 expression highlighted the effect of KRT14 correction on the EBS pathomechanism. Conclusions: Our data demonstrate that trans‐splicing‐mediated mRNA therapy is an effective method for the correction of dominantly inherited KRT14 mutations at the transcriptional level. This results in the rescue of the EBS‐gen sev phenotype and stabilization of the epidermis in a xenograft mouse model. What's already known about this topic? RTM163, described in this study, was previously used in a transient in vitro transfection system, where the ability to correct KRT14 at the mRNA level was demonstrated. What does this study add? In this study, we stably transduced RTM163 in a second patient‐derived keratinocyte line.Successful trans‐splicing was confirmed in this cell line.The expression of disease‐related marker genes, which are characteristically deregulated in epidermolysis bullosa simplex, were analysed.For the first time this study showed that RNA trans‐splicing molecule‐transduced patient keratinocytes can differentiate into a phenotypically normal and blister‐free epidermis in a xenograft mouse model. What is the translational message? This study shows the feasibility of using spliceosome‐mediated RNA trans‐splicing to generate a stable and blister‐free epidermis in vivo.Combined with pre‐existing ex vivo gene therapeutic methods, this might be a valid option for future treatments of dominantly inherited genodermatoses. Linked Comment: Bremer and van den Akker. Br J Dermatol 2019; 180:17–19. [ABSTRACT FROM AUTHOR]

Linked Article: Ebens et al. Br J Dermatol 2021; 184:1161–1169. [ABSTRACT FROM AUTHOR]

Background Patients with recessive dystrophic epidermolysis bullosa (RDEB) have an increased risk of developing rapidly progressive and metastatic cutaneous squamous cell carcinomas (SCC). It is unclear why these SCC behave more aggressively than sporadic SCC. Matrix metalloproteinases (MMP) are a family of endopeptidases that contribute to growth, invasion and metastasis of SCC. The role of MMP in RDEB-associated SCC is not known. Objectives To investigate the expression of MMP-7, MMP-13 and MMP-9 in RDEB-associated SCC in comparison with sporadic SCC and Bowen’s disease. Methods Immunohistochemical analysis of 25 RDEB-associated SCC, 61 sporadic SCC and 28 sporadic lesions of Bowen’s disease was carried out using monoclonal antibodies for MMP-7, MMP-9, MMP-13 and E-cadherin and syndecan-1. Results MMP-7 was detected in all RDEB-associated SCC, in tumour cells within the invasive edge, where E-cadherin and syndecan-1 were markedly diminished or absent. MMP-7 expression was also observed in 98% of sporadic SCC and in 68% of Bowen’s diseases. MMP-7 staining was significantly stronger in RDEB-associated SCC than in sporadic SCC, and was most abundant in poorly differentiated tumours. MMP-13 was detected in tumour cells in 96% of RDEB-associated SCC and in all sporadic cutaneous SCC. MMP-9 was detected in the inflammatory cells in all SCC examined. Conclusions These results identify MMP-7 and MMP-13 as tumour cell-specific markers for SCC progression and as potential therapeutic targets in RDEB-associated SCC. The pattern of immunolabelling suggests that MMP-7 may shed E-cadherin and syndecan-1 from the SCC cell surface. [ABSTRACT FROM AUTHOR]

We report a 72-year-old male patient with a nodular malignant melanoma that was associated with focal suprabasal acantholysis (FSA). This phenomenon, which is regarded as an incidental finding by dermatopathologists, may be associated with inflammatory and also neoplastic skin diseases. Haematoxylin and eosin stained sections from an erythematous plaque surrounding the patient’s tumour showed FSA, direct immunofluorescence (DIF) and indirect immunofluorescence (IIF) on normal human skin, monkey oesophagus and rat urinary bladder were negative. On electron microscopy few desmosomes could be detected in the basal cell layer of the acantholytic areas and there was a nearly complete loss of these structures in the spinous cell layer. Only remnants of cytoplasmic plaques and keratin filaments could be observed in those areas. In contrast, adherens junctions appeared to be well preserved. An enzyme-linked immunosorbent assay (ELISA) using recombinant fusion proteins as antigens did not show circulating autoantibodies against desmoglein 1 (Dsg1) or desmoglein 3 (Dsg3). In contrast, immunoblotting revealed autoantibodies directed against keratinocyte antigens with a molecular weight of 85 kDa and 250 kDa, the first band corresponding to the molecular weight of comigrating plakoglobin. Immunoprecipitation with patient serum also revealed a 85-kDa band. We conclude that these autoantibodies, probably in conjunction with cofactors produced by the tumour, could play a part in the pathogenesis of this variant of FSA, for which we propose the term ‘localized paraneoplastic pemphigus.’. [ABSTRACT FROM AUTHOR]

Epidermolysis bullosa acquisita (EBA) is an autoimmune bullous disease with frequent ocular involvement, but visual loss is rare. In contrast, EBA patients with predominant IgA autoantibodies more frequently develop severe ocular involvement, which tends to be refractory to therapy. We report two patients with ‘IgA–EBA’ with ocular involvement. Both initially presented with a generalized bullous disease, and direct immunofluorescence microscopy demonstrated IgA in the basement membrane zone of the skin, and in the conjunctiva and cornea of patient 1. On salt-split patient skin, IgA was found predominantly on the dermal side of the artificial split in both patients. Direct immunoelectron microscopy demonstrated IgA below the lamina densa in close association with the anchoring fibrils in both patients. In patient 1, who had a prolonged course of the disease, the skin disorder responded well to treatment with cyclosporin, but the ocular involvement ended in bilateral blindness despite repeated surgical treatment. In patient 2, the blister formation and scarring conjunctivitis was stopped by a combination of prednisolone and colchicine. These patients show that in subepithelial blistering diseases, early delineation of disease nosology is critical to detect subtypes with severe ocular involvement such as ‘IgA–EBA’. In addition, colchicine may be a valuable alternative in the treatment of EBA with ocular involvement. [ABSTRACT FROM AUTHOR]

Linked Article: Condorelli et al. Br J Dermatol 2019; 181:1017–1027. [ABSTRACT FROM AUTHOR]