BACKGROUND:Bullous pemphigoid (BP) is the most common autoimmune bullous disease. It is characterized by the development of tense blisters and pruritus. BP is a chronic disease that requires long-term treatment often associated with serious side effects. Developments in understanding the disease have led to novel treatment approaches evaluated in clinical trials. However, the pooling of trial data remains challenging due to inconsistent outcome reporting. OBJECTIVES:To provide an overview of BP outcome measurement over the last two decades by mapping and listing all previously reported treatment outcomes and outcome measurement instruments (OMIs). METHODS:A large scoping review was performed using scientific databases and trial registries (January 2002-August 2025). Study selection and data extraction were performed independently by a minimum of two reviewers. Eligible study designs were clinical trials, prospective cohort studies and systematic reviews. Retrospective studies were excluded. All identified outcomes and OMIs were mapped into overarching domains for insights into outcome measurement trends over time, including the uptake of consensus definitions. RESULTS:Eighty studies were included, consisting of clinical trials (n = 27), prospective cohort studies (n = 27) and systematic reviews (n = 26). A total of 659 outcomes were extracted verbatim and classified into 46 outcome domains across 10 outcome domain areas. Clinical response, safety and immunological response comprised a major part of outcome measurement. Moreover, steroid toxicity has increasingly been considered in clinical trials. Definitions and timepoints of clinical response varied considerably. An imbalance between patient-reported (PROs) and clinician-reported outcomes was revealed, with PROs being in the minority, as well as a diverging focus between primary analyses in clinical trials and secondary analyses in systematic reviews. OMIs used to measure patient impact and quality of life were mainly generic and only sparsely used. CONCLUSIONS:Over the past two decades, there has been considerable heterogeneity in reported outcomes and OMIs in BP research. Despite standardization efforts, most studies lack well-defined, consistent outcomes. Redefinition of some endpoints and a consensus-based approach towards outcome uniformity should bridge regulatory requirements with validated sensitive measurement and PROs. This approach would enhance the clinical relevance of trial endpoints while maintaining standardization, ultimately advancing research quality and therapeutic development.

Treatment of pemphigoid gestationis (PG) mainly consists of systemic and potent topical corticosteroids. This retrospective case series describes patients with severe PG treated with dupilumab, including serological follow-up, and reviews all published cases. PG was confirmed by direct immunofluorescence (linear C3 and/or IgG deposition along the basement membrane zone) and serology (IgG epidermal staining on salt-split skin or anti-BP180 NC16A IgG ELISA). Pruritus, quality of life and anti-BP180 NC16A IgG and anti-BP180 NC16A IgE were monitored longitudinally. In 5 pregnant women, dupilumab was initiated with a 600 mg loading dose followed by 300 mg biweekly. Baseline pruritus was severe (NRS 8–10), with high DLQI scores (18–30). Blistering ceased within 1 week in 2 patients and within 4 weeks in 1. Two patients required weekly dosing for disease control. Systemic corticosteroids were discontinued in 3 patients and tapered to ≤10 mg/day in 2 before delivery. In one case, anti-BP180 IgG paralleled clinical improvement. Anti-BP180 IgE remained negative. All patients delivered healthy infants. In 10 reported cases, pruritus improved rapidly and systemic corticosteroids were tapered. These findings suggest dupilumab may be a promising corticosteroid-sparing option for PG, with rapid clinical response and a favourable safety profile, despite off-label use in pregnancy.

Cutaneous squamous cell carcinoma (cSCC) is a prevalent skin cancer in the general population that poses so far unresolved challenges in high-risk groups such as organ transplant recipients and individuals with recessive dystrophic epidermolysis bullosa. Although most cases of cSCC respond well to standard treatments, these 2 groups often face more aggressive disease, characterized by higher rates of metastasis and cancer-specific mortality. The tumor microenvironment plays a pivotal role in cSCC progression, influencing tumor growth, immune evasion, and therapy response. Therefore, this scoping review aims to systematically investigate how the tumor microenvironment in these high-risk cSCC differs from that of sporadic cSCC, highlight shared tumorigenic mechanisms, and identify knowledge gaps for future research. Specifically, we review immune cell infiltration, epithelial–mesenchymal transition, extracellular matrix remodeling, and related biomarkers, while also exploring potential therapeutic targets. It is surmised that both organ transplant recipients cSCC and recessive dystrophic epidermolysis bullosa cSCC may exhibit a permissive tumor microenvironment, potentially characterized by immune dysfunction and enhanced TGFβ signaling, contributing to tumor aggressiveness. Notably, organ transplant recipients cSCC primarily demonstrates immune exhaustion, whereas recessive dystrophic epidermolysis bullosa cSCC is driven by chronic tissue damage with concomitant extracellular matrix remodeling. A better understanding of tumor microenvironment features in these high-risk cSCC may help develop novel targeted therapies to improve patient outcomes.

Introduction: Autoimmune bullous diseases (AIBDs), comprising pemphigoid and pemphigus diseases, have seen limited therapeutic advances beyond rituximab for pemphigus vulgaris. As novel therapies are evaluated in clinical trials, well-defined, uniform, and relevant outcomes with patient involvement are essential. To date, however, patient-reported outcomes remain underrepresented, leaving uncertainty about whether trial results genuinely reflect patients’ expectations. This study examines perspectives of patients with AIBD on treatment outcomes and priorities to ensure that future research focuses on what matters most to them. Methods: A cross-sectional study was conducted among Dutch patients with AIBD between October 2023 and January 2024, using a self-developed questionnaire with both closed- and open-ended questions to assess patient perspectives on treatment outcomes and priorities, key factors in choosing a treatment, and indicators of treatment success. Results: Regarding skin and/or mucous membrane complaints, “the formation of new blisters and wounds” emerged as the most important complaint a treatment should address for both pemphigoid (43%) and pemphigus (86%) patients. In open-ended questions, patients with pemphigoid most frequently prioritized “pruritus” (44%), while patients with pemphigus emphasized “pain” (39%). Most important concerns regarding physical and daily functioning were “vision problems” (20%), “sleep disturbances” (20%), and “self-care difficulties” (23%) for patients with pemphigoid, whereas patients with pemphigus most commonly cited “eating and/or swallowing difficulties” (57%) and “daily activity limitations” (41%). Regarding emotional/psychological functioning, both subgroups prioritized “anxiety and/or worry” as most important concern (pemphigoid: 28%, pemphigus: 43%). Side effects were identified as the most important factor in choosing a treatment (pemphigoid: 41%, pemphigus: 39%). The absence of one or more symptoms and clinical signs (i.e., “no blisters”) was mentioned as the most important indicator of treatment success (pemphigoid: 88%, pemphigus: 91%), although minimal clinical signs (i.e., “minimal blisters”) were also considered acceptable (pemphigoid: 25%, pemphigus: 13%). Conclusion: Patients with pemphigoid and pemphigus exhibit some distinct treatment priorities, reflecting their distinct pathomechanisms. Nonetheless, both subgroups consistently prioritize not only the resolution of disease-specific clinical signs but also preservation of physical and psychological well-being, underscoring the need for more holistic and patient-centered outcome measurement to ensure the establishment of meaningful, AIBD subgroup specific treatment outcomes.

This study analysed 32 failed drug development trials and surveyed 56 experts in the field of autoimmune bullous diseases to identify key challenges in bullous pemphigoid and pemphigus research. Clinical trials primarily failed due to unmet efficacy endpoints and recruitment difficulties, with experts highlighting the need to improve endpoint selection and patient enrolment strategies through international collaboration to develop more effective trial designs and advance new therapeutic options.

Mucous membrane pemphigoid (MMP) is a rare autoimmune bullous disease that predominantly affects mucosae. Treatments for MMP often lack robust evidence and may be poorly tolerated, especially in elderly patients. This scoping review aims to provide an overview of MMP outcome measurement of the last two decades by mapping and listing all previously reported outcomes and outcome measurement instruments (OMIs). A large scoping review was performed in scientific databases and trial registries (MEDLINE, Embase, CINAHL, PsycINFO, Cochrane CENTRAL, Web of Science, the International Clinical Trials Registry Platform and Clinicaltrials.gov) covering January 2002 to December 2023. Clinical trials, prospective cohort studies, and systematic reviews were included, while retrospective studies were excluded. Thirty-nine studies met the inclusion criteria, including 20 prospective cohort studies, 13 systematic reviews, and 6 clinical trials. A total of 285 outcomes were extracted verbatim and categorized into 29 domains and 9 overarching areas. The most commonly reported outcome areas were related to clinical response, safety, and resource use. The majority were investigator-reported outcomes (85

We present a neonatal case of skin blisters and erythema. While epidermolysis bullosa was initially suspected, immunofluorescence antigen mapping and genetic testing confirmed epidermolytic ichthyosis, with a heterozygous pathogenic variant in the KRT10 gene (c.467G>A, p.Arg156His). A multidisciplinary approach is essential for accurate diagnosis and treatment of neonatal blistering conditions.

Epidermolysis bullosa (EB) comprises a heterogeneous group of rare, genetic blistering diseases. The wide variety in EB trial outcomes limits the comparability of outcomes and, consequently, the implementation of the best available treatment options. A core outcome set (COS) is a minimum set of outcomes that should be measured in all clinical trials, comprising what should be measured (i.e., outcome domains) and how it should be measured (i.e., outcome measurement instruments). This enables standardization of outcome measurement aiming at improving the comparability and quality of research. The Core Outcome Set for Epidermolysis Bullosa (COSEB) initiative aims to develop COSs for use in clinical trials for the four major EB types: EB simplex, junctional EB, dystrophic EB, and Kindler EB. This protocol focuses on the development of core outcome domain sets — outlining what should be measured in EB clinical trials. Involved stakeholders are patients and patient representatives, clinicians, researchers, methodologists, industry representatives, regulators, health technology assessors, and payers. In the initial part, working groups are formed to define long lists of candidate outcome domains for the four major EB types. Potentially relevant outcome domains will be identified based on scoping literature reviews and qualitative studies. Following consultations with a stakeholder advisory panel, a short list of candidate outcome domains will be subject to voting in Delphi consensus procedures. Finally, the definitive core outcome domain sets for the four major EB types and, if indicated, any overarching core outcome domain sets, will be confirmed in consensus meetings. The project Has been prospectively registered in the COMET registry for COSs on 23 October 2017 (registration number 1033). This protocol provides guidance to ensure a systematic, transparent, and comprehensible approach of COSEB. The final core outcome domain sets are supposed to serve as the minimum sets of what to measure in future EB trials. This will provide the basis for the subsequent outcome measurement instrument selection. Particularly in this rare disease with inherently small-sized study cohorts, this will facilitate the incorporation of meaningful outcomes and pooling of data, ultimately enhancing optimal treatment for EB. This study Has been prospectively registered in the COMET database on 23 October 2017 and updated on 24 January 2022 (registration number 1033 https://www.comet-initiative.org/studies/details/1033 ).

Introduction: Inherited ichthyosis comprises a group of rare keratinization disorders caused by abnormal epidermal barrier function. Ichthyosis is yet incurable and current treatments mainly focus on alleviating symptoms such as scaling, erythema and pruritus. Recent developments show promising results for interventions based on the immune-phenotype like biologicals or pathogenesis-based therapies such as gene therapy. However, the lack of uniform reporting and variety of treatment outcomes may complicate performing and comparing efficacy studies. The core outcome set for inherited ichthyosis (COSII) aims to develop a core outcome set (COS), i.e., the minimum of outcomes that should be measured and reported in observational and interventional studies, including a minimum set of baseline characteristics. Methods: The COSII project will follow the guidelines from the Core Outcome Measures in Effectiveness Trials (COMET) initiative, including the Core Outcome Set-Standards for Development (COS-STAD) recommendations and the Core Outcome Set Standardised Protocol (COS-STAP) checklist. The COS development methodology, including this protocol, follows the guidance of the CHORD COUSIN Collaboration 'C3'. The first stage of this project involves identifying a possible list of outcomes through performing a scoping literature review and conducting interviews with patient(s) (representatives). This list will be presented to five different stakeholder groups: healthcare professionals, researchers, patient(s) (representatives), industry representatives, and regulators. All stakeholders will rate the importance of each outcome in a three-round eDelphi survey. Ultimately, a virtual consensus meeting will be convened to finalize the COS. Ethical approval was obtained prior to the start of this project from the Medical Ethics Committee Board at Maastricht University Medical Centre (METC 2022-3192). Informed consent will be asked prior to enrolment in the eDelphi. This study is registered with the COMET. The results will be distributed via a peer-reviewed journal, communicated to all relevant parties and showcased at national and international conferences. Conclusion: This will be the first COS for inherited ichthyosis research in accordance with the Core Outcome Measures in Effectiveness Trials initiative. The development of a COS aims to improve the consistency of reporting and the heterogeneity of outcomes in ichthyosis research. .

Background Epidermolysis bullosa (EB) is a rare, genetically and clinically heterogeneous group of skin fragility disorders. No cure is currently available, but many novel and repurposed treatments are upcoming. For adequate evaluation and comparison of clinical studies in EB, well-defined and consistent consensus-endorsed outcomes and outcome measurement instruments are necessary. Objectives To identify previously reported outcomes in EB clinical research, group these outcomes by outcome domains and areas and summarize respective outcome measurement instruments. Methods A systematic literature search was performed in the databases MEDLINE, Embase, Scopus, Cochrane CENTRAL, CINAHL, PsycINFO and trial registries covering the period between January 1991 and September 2021. Studies were included if they evaluated a treatment in a minimum of three patients with EB. Two reviewers independently performed the study selection and data extraction. All identified outcomes and their respective instruments were mapped onto overarching outcome domains. The outcome domains were stratified according to subgroups of EB type, age group, intervention, decade and phase of clinical trial. Results The included studies (n = 207) covered a range of study designs and geographical settings. A total of 1280 outcomes were extracted verbatim and inductively mapped onto 80 outcome domains and 14 outcome areas. We found a steady increase in the number of published clinical trials and outcomes reported over the past 30 years. The included studies mainly focused on recessive dystrophic EB (43%). Wound healing was reported most frequently across all studies and referred to as a primary outcome in 31% of trials. Great heterogeneity of reported outcomes was observed within all stratified subgroups. Moreover, a diverse range of outcome measurement instruments (n = 200) was identified. Conclusions We show substantial heterogeneity in reported outcomes and outcome measurement instruments in EB clinical research over the past 30 years. This review is the first step towards harmonization of outcomes in EB, which is necessary to expedite the clinical translation of novel treatments for patients with EB. This scoping review reveals heterogeneously reported outcomes and outcome measurement instruments throughout the research landscape of epidermolysis bullosa (EB), a group of rare, genetic skin fragility disorders. The authors also describe the benefits of a harmonized and consensus-based EB outcome assessment.

BackgroundInherited epidermolysis bullosa (EB) comprises a group of genetic disorders characterized by skin fragility and unique oral features. It requires interdisciplinary care from several health professionals, including oral health teams. Modern dentistry encompasses a wide range of therapeutic options performed by specialists from different fields.ObjectiveTo guide clinicians caring for patients with different types of EB to seek care from different dental services.MethodsDental treatment needs for patients with EB were identified based on a systematic literature review. A panel of experts was consulted and invited to provide additional information through an open-ended question over 7 months. A Delphi study was applied over two rounds to the resulting pathways design. The threshold of consensus was set a priori at 75%. Patients' representatives revised the final document.ResultsThe panel (n = 17) agreed on a total of 55 recommendations divided into six groups according to the severity of oral compromise in EB (52 recommendations were agreed on in round 1, and three were agreed on in round 2).ConclusionsDental care pathways are presented for each type of EB. Specific considerations are discussed according to clinical features, including age of first referral, frequency of follow-up appointments, and list of dental specialties involved in the care of patients with EB.

Desmoplakin (DSP) is a desmosomal component expressed in skin and heart, essential for desmosome stability and intermediate filament connection. Pathogenic variants in the DSP gene encoding DSP, lead to heterogeneous skin, adnexa and heart-related phenotypes, including skin fragility, woolly hair (WH), palmoplantar keratoderma (PPK) and arrhythmogenic/dilated cardiomyopathy (ACM/DCM). The ambiguity of computer-based prediction analysis of pathogenicity and effect of DSP variants, indicates a necessity for functional analysis. Here, we report a heterozygous DSP variant that was not previously described, NM_004415.4:c.3337C>T (NM_004415.4(NP_004406.2):p.(Arg1113*)) in a patient with PPK, WH and ACM. RNA and protein analysis revealed similar to 50% reduction of DSP mRNA and protein expression. Patient's keratinocytes showed fragile cell-cell connections and perinuclear retracted intermediate filaments. Epidermal growth factor receptor (EGFR) is a transmembrane protein expressed in the basal epidermal layer involved in proliferation and differentiation, processes that are disrupted in the development of PPK, and in the regulation of the desmosome. In skin of the abovementioned patient, evident EGFR upregulation was observed. EGFR inhibition in patient's keratinocytes strongly increased DSP expression at the plasma membrane, improved intermediate filament connection with the membrane edges and reduced the cell-cell fragility. This cell phenotypic recovery was due to a translocation of DSP to the plasma membrane together with an increased number of desmosomes. These results indicate a therapeutic potential of EGFR inhibitors for disorders caused by DSP haploinsufficiency.

Background. Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and potentially life-threatening mucocutaneous blistering diseases that clinically can resemble autoimmune bullous diseases. Moreover, it has been shown that autoantibodies against epidermal proteins are present in SJS/TEN. Objectives. To establish the presence of antibodies against desmosomal and hemidesmosomal proteins in confirmed SJS/TEN patients. Methods. Serum of SJS/TEN patients diagnosed based on clinical criteria, e.g., epidermal detachment with erosions and severe mucosal lesions, (suspicion of) a culprit drug, and matching histologic results was evaluated by various techniques, e.g., indirect immunofluorescence on monkey esophagus, salt split skin and rat bladder, immunoblotting (IB) and immunoprecipitation (IP), ELISAs against desmogleins and BP180, keratinocyte footprint assay, and keratinocyte binding assay. Results. A total of 28 patients were included in this study, 15 men and 13 women with a mean age of 56 years. In most patients, none of the serological tests were positive. In two patients, an elevated DSG3 titer was found suspicious for pemphigus vulgaris. Three patients had elevated NC16a titers, suggesting bullous pemphigoid. However, in all these patients, no other tests were positive and in these patients, the biopsy for direct immunofluorescence showed no evidence for an autoimmune bullous disease. Three patients showed reactivity against rat bladder rat bladder; these were, however, completely negative for A2ML1, envoplakin, and periplakin in the IB as well as the IP. Conclusions. Serological analysis for desmosomal and hemidesmosomal antibodies is reliable to rule an autoimmune bullous disease in patients with suspected SJS/TEN. However, one should not rely on one single test method since false positive results can occur. Moreover, this study also makes it less plausible that antibodies against desmosomal and/or hemidesmosomal components are involved in the pathogenesis of SJS/TEN.

Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss-of-function variants in desmosomal genes leads to a variety of skin- and heart-related phenotypes. In this study, we report TUFT1 as a desmosome-associated protein, implicated in epidermal integrity. In two siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma but without a cardiac phenotype, we identified a homozygous splice-site variant in the TUFT1 gene, leading to aberrant mRNA splicing and loss of TUFT1 protein. Patients' skin and keratinocytes showed acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance. Immunolabeling and transfection studies showed that TUFT1 is positioned within the desmosome and that its location is dependent on the presence of the desmoplakin carboxy-terminal tail. A Tuft1-knockout mouse model mimicked the patients' phenotypes. Altogether, this study reveals TUFT1 as a desmosome-associated protein, whose absence causes skin fragility, woolly hair, and palmoplantar keratoderma.

Background: Genome diagnostics is considered gold standard diagnostics for epidermolysis bullosa (EB), a phenotypically and genetically heterogeneous group of rare disorders characterized by blistering and wounding of mucocutaneous tissues. EB is caused by pathogenic variants in genes encoding proteins of the dermo-epidermal junction. Accurate genetic diagnosis of EB is crucial for prognostication, counselling and precision-medicine. Genome diagnostics for EB started in 1991 with the introduction of Sanger sequencing (SS), analysing one gene at a time. In 2013, SS was superseded by next-generation sequencing (NGS), that allow for high-throughput sequencing of multiple genes in parallel. Several studies have shown a beneficial role for NGS in EB diagnostics, but its true benefit has not been quantified. Objectives: To determine the benefit of NGS in EB by systematically evaluating the performance of different genome diagnostics used over time based on robust data from the Dutch EB Registry. Methods: The diagnostic performances of SS and NGS were systematically evaluated in a retrospective observational study including all index cases with a clinical diagnosis of EB in whom genome diagnostics was performed between 01 January 1994 and 01 January 2022 (n = 308), registered at the Dutch EB Expertise Centre. Results: Over time, a genetic diagnosis was made in 289/308 (94%) EB cases. The diagnostic yield increased from 89% (SS) to 95% (NGS). Most importantly, NGS significantly reduced diagnostic turnaround time (39 days vs. 211 days, p < 0.001). The likelihood of detecting variants of uncertain significance and additional findings increased from 5% and 1% (SS) to 22% and 13% (NGS) respectively. Conclusions: Our study quantifies the benefit of NGS-based methods and demonstrate they have had a major impact on EB diagnostics through an increased diagnostic yield and a dramatically decreased turnaround time (39 days). Although our diagnostic yield is high (95%), further improvement of genome diagnostics is urgently needed to provide a genetic diagnosis in all EB patients.