Epidemiology and Comorbidity Burden in Dermatitis Herpetiformis: Two Systematic Reviews and Meta-Analyses

BACKGROUND: Dermatitis herpetiformis (DH) is a rare, chronic, autoimmune blistering disorder and the cutaneous manifestation of celiac disease (CD). Despite a well-established pathogenic link with CD, DH remains frequently underdiagnosed, and both its epidemiology and associated comorbidity burden are incompletely characterized. While CD benefits from standardized diagnostic pathways, DH is frequently diagnosed clinically, contributing to under-recognition diagnostic delay, and fragmented evidence on associated comorbidities. To address these gaps, we conducted two systematic reviews and meta-analyses: one assessing the prevalence of DH among individuals with CD, and the second synthesizing comorbidities burden associated with DH. METHODS: Both reviews followed PRISMA 2020 guidelines and were registered in PROSPERO. PubMed, Embase, Web of Science, and Scopus were searched for observational studies and randomized trials reporting extractable numerator and denominator data on DH occurrence in CD or comorbidities in DH. Studies published from 1990 onward were included without language restrictions. Study selection and data extraction were performed independently using Covidence. Risk of bias was assessed with the Joanna Briggs Institute Checklist. Meta-analyses were conducted using generalized linear mixed models, with subgroup, sensitivity, and meta-regression analyses when feasible. RESULTS: A total of 7271 records were identified. After duplicate removal and title and abstract screening, 393 articles were assessed for eligibility. Twenty-four studies met the inclusion criteria for the first meta-analysis, and 22 for the second. DH appeared as an uncommon but clinically relevant manifestation of CD, with a pooled prevalence of 6.8% (95% CI: 5.0-9.3, I² = 98.9 lower in children (2.6%, 95% CI: 1.4-4.5) than adults (8.6%, 95% CI: 5.8-12.6). Pediatric cohorts were underrepresented, and the geographic distribution of studies was skewed toward European countries. Sex-specific analyses suggested a slightly higher prevalence in males. The comorbidity review identified 48 pre-specified conditions across seven clinical domains, including cardiovascular (5 studies), neurological (4 studies), rheumatological/immunological (13 studies), nephrological (3 studies), gastrointestinal (8 studies), endocrinological (22 studies), and oncological (15 studies). Substantial heterogeneity was observed across studies, reflecting both genuine epidemiological variation and methodological inconsistency. Notably, comorbidity assessment was rarely the primary objective of included studies. Autoimmune endocrine disorders were the most frequent comorbidities, with type 1 diabetes mellitus showing a pooled prevalence of 2.1% (95% CI 1.6-2.7) and Hashimoto’s thyroiditis 11.1% (95% CI 4.4-25.2). Among dermatologic conditions, vitiligo was reported in ten studies, with a pooled prevalence of 1.6% (95% CI 1.0-2.5). Pernicious anemia and autoimmune atrophic gastritis were rare but consistently reported, with a pooled prevalence of 2.0% (95% CI 1.1-3.6). CONCLUSIONS: DH represents a relatively infrequent but clinically significant manifestation of CD and is associated with a broad, heterogeneous comorbidity profile that differs in prevalence and distribution from that observed in patients with CD without DH, particularly with respect to autoimmune and metabolic conditions. Current evidence is limited by small study populations, geographic concentration, and non-standardized outcome assessment. These findings highlight the need for large, longitudinal, population-based studies with harmonized definitions to better delineate the epidemiology and multisystem impact of DH, and to support integrated, long-term patient management strategies.