Skin Fragility: Perspectives on Evidence-based Therapies

Abstract

The term skin fragility describes skin that blisters and breaks easily upon mild friction or trauma. Skin fragility can have many causes, ranging from genetic variants to a compromised immune system, infections or adverse drug reactions. Studies of genetic skin fragility disorders, such as epidermolysis bullosa, have provided better understanding of their causes and mechanisms. At least 20 genes may be involved in epidermolysis bullosa, and secondary phenomena, such as inflammation or fibrosis, can worsen the disease. No cure is yet available, but international research is developing novel approaches to cure the disease and alleviate its symptoms. This article reviews these new developments and appraises their clinical implementation.The term skin fragility disorders describes a group of conditions in which the structural integrity of the skin is compromised and its resistance to external shear forces diminished. Skin fragility can have different causes, ranging from genetic variations to inflammatory or physical phenomena. The genetic skin fragility disorders, collectively called epidermolysis bullosa, serve as a paradigm for the study of causes and mechanisms of skin fragility. Recent biomedical research has revealed substantial genetic heterogeneity of the epidermolysis bullosa group, delivered ample new knowledge on its pathophysiology, and facilitated the design of evidence-based therapeutic strategies. The therapy development process extends from in vitro testing to preclinical validation in animal models, and clinical trials. This article reviews different approaches to curative and symptom-relief therapies, and appraises their status and perspectives for clinical implementation. ActaDV ActaDV Advances in dermatology and venereologyActa Dermato-Venereologica 95 Evidence-based therapies for skin fragility Theme issue: Blistering skin disorders ActaDV ActaDV Advances in dermatology and venereology Acta Dermato-Venereologica L. Bruckner-Tuderman 96 Theme issue: Blistering skin disorders ActaDV ActaDV Advances in dermatology and venereology Acta Dermato-Venereologica L. Bruckner-Tuderman 98 Theme issue: Blistering skin disorders Advances in dermatology and venereology Acta Dermato-Venereologica 99 Evidence-based therapies for skin fragility Theme issue: Blistering skin disorders ActaDV ActaDV Advances in dermatology and venereology Acta Dermato-Venereologica L. Bruckner-Tuderman 100

The Human Epidermal Basement Membrane: A Shaped and Cell Instructive Platform That Aging Slowly Alters

“…The importance of the anchoring complexes in dermal-epidermal cohesion is illustrated in both inherited and acquired blistering diseases. Congenital inherited EB comprises a group of disorders characterized by mutations in any of the genes encoding the structural components of the anchoring complexes [226][227][228][229][230]. The breakage can occur within the epidermis, along the DEJ, or in the upper dermis.…”

Translational perspectives to treat Epidermolysis bullosa—Where do we stand?

“…This means involving affected individuals and their caregivers in decisions on study length and portfolio, target population, in-/exclusion criteria, definition of clinically meaningful endpoints, appropriate timing of outcome assessments, as well as information policies, including timely disclosure of trial results. Patient-centricity aims at reducing TA B L E 1 Emerging and ongoing clinical trials and therapeutic approaches for Epidermolysis bullosa [9,22] the patients' trial burden, for example in terms of time, travel, number of scheduled visits, literacy, personal financial expenditures, and compatibility with occupational obligations, and importantly, extent of invasive investigations on highly fragile, chronically wounded skin.…”

“…The implementation of these strategies still poses several challenges, including technical and financial issues, as well as concerns about feasibility, safety and sustainability of effects. [ 22 ] Against this background, a considerable number of therapeutic strategies, focusing on aberrant molecular and immune‐regulatory traits involved in pain, itch, protracted tissue damage and chronic wounding as well as secondary disease sequelae like inflammation, scarring and squamous cell carcinoma, have reached a clinical trial stage (Table 1).…”

“…Clinical validation of such palliative, so-called symptom-relief and disease-modifying therapies in the complex setting of EB, however, is essential. The implementation of these strategies still poses several challenges, including technical and financial issues, as well as concerns about feasibility, safety and sustainability of effects [22]. Against this background, a considerable…”

Increased abundance of Cbl E3 ligases alters PDGFR signaling in recessive dystrophic epidermolysis bullosa

“…In turn, the inflammatory and fibrotic skin environment favors the development of further disease complications, including squamous cell carcinomas at young ages [7,8]. Despite diverse therapeutic procedures that have been tested, such as partly restoring collagen VII (C7) levels, a cure for the disease does not exist and a high unmet medical need persists [9][10][11][12]. Promoting proper healing of skin wounds could be fundamental for improved quality of life and prolonged life expectancy of individuals with RDEB.…”