Authors
Carolina Flores-Muñoz, Paula Díaz, Ignacia Fuentes, Margarita Calvo
Published in
The British journal of dermatology. Sep 18, 2026. Epub Sep 18, 2026.
Abstract
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe inherited disorder characterised by type VII collagen impairment, leading to dermo-epidermal junction (DEJ) instability and chronic skin fragility. Pain is a near-universal and quality-of-life-limiting feature; however, explanations centred solely on tissue injury and inflammation do not fully account for its persistence or treatment resistance. Increasing evidence supports a broader framework in which disrupted skin-nerve homeostasis within the neurocutaneous unit (NCU) contributes to pain generation. This narrative, hypothesis-driven review integrates clinical, experimental and translational evidence to examine the role of the NCU, the functional interface between keratinocytes and intraepidermal sensory fibres, in RDEB pain. Chronic injury, persistent inflammation and DEJ disruption create a microenvironment that is unfavourable for sensory nerve maintenance and repair. Clinical and experimental findings support the presence of small-fibre pathology, reflected by reduced intraepidermal nerve fibre density, altered sensory thresholds and neuropathic pain descriptors. Mechanistically, repeated injury appears to impair reinnervation and contribute to progressive distal sensory fibre loss within a hostile cutaneous microenvironment. Keratinocyte dysfunction drives this process through impaired neurotrophic support and the sustained release of pro-inflammatory mediators that directly sensitise nociceptors. In parallel, dermal fibrosis and extracellular matrix remodelling may constrain axonal regeneration. Molecular studies further demonstrate a persistent inflammatory and pro-fibrotic signature in RDEB skin, including clinically non-lesional areas. These converging abnormalities suggest that disrupted skin-nerve homeostasis is an important contributor to disease-associated pain. Translational evidence suggests partial reversibility, with pain reduction observed following therapies targeting neuropathic mechanisms or restoring DEJ integrity. Together, these findings support a framework in which altered neurocutaneous interactions contribute substantially to pain in RDEB, underscoring the need for mechanism-based and potentially early neuroprotective strategies.
PMID:
42754976
Bibliographic data and abstract were imported from PubMed on 18 Sep 2026.
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