Deconstructing progressive inflammatory fibrosis in recessive dystrophic epidermolysis bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited blistering skin disease, resulting from biallelic mutations in COL7A1, the gene encoding type VII collagen (C7). At mucocutaneous barriers, tissue integrity relies upon linked extracellular matrix (ECM) proteins forming a physiologic suture, connecting basal epidermal keratinocytes to the underlying dermis. C7 secreted from epidermal keratinocytes and dermal fibroblasts homotrimerizes in the upper dermis to form anchoring fibrils, a critical component of this suture. Clinical manifestations of RDEB are apparent at birth and include exquisite skin fragility, pain and itch, high metabolic demand, and complications downstream of systemic inflammation. Dermal fibrosis is a critical complication of RDEB. Repeated cycles of mechanical injury and healing trigger characteristic fibrotic changes. In addition to functional limitations from joint strictures and pseudosyndactyly formation, dermal fibrosis in RDEB is a nidus for and potential driver of aggressive squamous cell carcinoma (SCC), the leading cause of death in RDEB. A greater understanding of fibrosis in RDEB promises to inform impactful, life-prolonging clinical trials in this patient population with no proven systemic therapy or cure.