Tissue and systemic inflammation in dystrophic epidermolysis bullosa: a systematic review and meta-analysis

Abstract

Background: Dystrophic epidermolysis bullosa (DEB) is a rare inherited skin disorder caused by mutations in the type VII collagen gene, leading to mucocutaneous blistering. Subsequent inflammation contributes to chronic wounds, scarring, and systemic complications. There is controversy over whether and how inflammation should be therapeutically targeted.

Objective: This systematic review and meta-analysis aim to question tissue and systemic inflammation in DEB and identify inflammatory patterns and research gaps to improve patient management.

Methods: A comprehensive search of MEDLINE via PubMed was conducted to identify studies examining "DEB and tissue or systemic inflammation". Out of 663 studies identified, 37 met the inclusion criteria. Data for synthesis were extracted from studies assessing systemic inflammatory parameter levels in DEB patients. For outcomes with multiple available studies, we performed an exploratory network meta-analysis to compare the standardized mean difference in systemic inflammatory parameters across three patient groups: DEB patients, healthy controls, and patients with other types of epidermolysis bullosa (EB).

Results: The point estimate results for IL-4, IL-6, tumor necrosis factor-alpha, C-reactive protein, immunoglobulin (Ig) A, IgG, and IgM, as well as anti-collagen VII, anti-BP230, anti-BP180 autoantibodies suggested elevated values in DEB patients compared to healthy patients or other EB patients. The estimated standardized mean differences showed lower values of interleukin (IL)-10, hemoglobin and serum albumin in DEB patients compared to controls or other EB patients.

Conclusion: Current evidence is limited by small and heterogeneous patient cohorts, variability in study designs and reporting methods, and a predominant reliance on observational and retrospective descriptive studies. Well-designed clinical trials and prospective studies are necessary to further investigate inflammatory pathways and assess the efficacy of (targeted) anti-inflammatory therapies but are difficult to perform and cost-intensive. AI tools for small-data may support research in this field. PROSPERO Registration Number CRD42024535352.

Keywords: Autoantibodies; Cytokines; Dystrophic epidermolysis bullosa; Epidermolysis bullosa; Network meta-analysis; Systemic inflammation; Tissue inflammation.

Fig. 1

Prisma 2020 flow diagram for systematic reviews

Fig. 2

Summary estimates for comparisons with multiple sources of evidence. Values less than 0 indicate lower levels of the marker in the comparator group when compared to DEB. Values greater than 0 indicate higher levels of the marker in comparator group when compared to DEB. HB: hemoglobin, CRP: C-reactive protein, C7: collagen type VII autoantibodies, BP180: anti-BP180 autoantibodies, BP230: anti-BP230 autoantibodies, IgG: immunoglobulin G, IgM: immunoglobulin M, IgA: immunoglobulin A, TNF-a: tumor necrosis factor alpha, IL-4: interleukin 4, IL-6: interleukin 6, IL-10: interleukin 10, P: patients with dystrophic epidermolysis bullosa, PH: patients with other forms of epidermolysis bullosa, H: healthy controls, CI: 95% confidence intervals for the standardized mean difference estimates, PI: 95% prediction intervals for the standardized mean differences using the z-distribution, which were generated for comparisons involving more than two studies using the t-distribution

Fig. 3

Proposed model of cutaneous inflammation in DEB [38], illustrating its progression across disease stages. In the acute phase, inflammation is driven by acute-phase reactants (CRP, IL-6, SAA) and type I cytokines (IFN-γ, TNF-α), triggered by acute blisters, wounds, and bacterial colonization. As the disease advances and wounds become recurrent or chronic, type II inflammation emerges, characterized by blisters, eczematous lesions, and elevated IL-4, IL-13, IL-31, and autoantibodies. Concurrently, type III inflammation arises, involving impaired barrier homeostasis, delayed wound healing, and IL-17 activity. In advanced chronic stages, tissue destruction exacerbates type IV inflammation, marked by fibrosis and scarring mediated by TGF-β, compounding previous inflammatory pathways. These overlapping processes contribute to systemic inflammation and drive the pathogenesis of aggressive cutaneous squamous cell carcinomas in DEB. Representative images depict the progression of skin changes on the back of a male RDEB patient at ages 8, 12, and 23 years. CRP: C-reactive protein, TNF-a: tumor necrosis factor alpha, IL: interleukin, TGF-β: Transforming growth factor β, SAA: serum amyloid A