Institute of Dermatology

Abstract Introduction and aims Dominant dystrophic epidermolysis bullosa (DDEB) is a congenital blistering skin disease caused by mutant collagen VII (C7) chains interfering with the folding of wildtype (WT) C7, which weakens dermoepidermal junctions. Base editors (BEs) offer unique advantage in precisely correcting the mutant COL7A1 allele while preserving the WT allele. While our group has previously demonstrated the use of adenine base editor 8e (ABE8e) to correct recessive dystrophic epidermolysis bullosa (RDEB), this is the first report of ABE8e being applied to DDEB. Methods Primary fibroblasts from patients with DDEB carrying the COL7A1 exon 73 c.6127G>A mutation were electroporated with ABE8e mRNA and single guide (sg)RNA. Base editing efficiency was evaluated by semiquantitative analysis of Sanger sequencing chromatographs in EditR. Protein-level correction was assessed using a C7 Western blot. In preparation for future in vivo base editing, we validated a DDEB mouse model carrying the Col7a1 exon 73 c.6085C>G mutation using Sanger sequencing. Results Sanger sequencing analysis revealed that ABE8e achieved 19–41% editing efficiency in correcting the c.6127G>A mutation, with a 2 : 1 sgRNA-to-ABE8e ratio yielding higher efficiency than a 1 : 2 ratio. However, Western blot analysis did not show consistent protein-level correction. Sanger sequencing confirmed that our DDEB mouse model is heterozygous for the Col7a1 c.6085G>C mutation. Conclusions This study demonstrated partial DNA-level correction of the COL7A1 c.6127 G>A allele in ABE8e-electroporated primary DDEB fibroblasts ex vivo. However, this editing did not result in increased C7 protein levels. Notably, Western blots assess differences in C7 quantity, but not stability – a key factor in DDEB pathology. Further replication of DNA-level correction and evaluation of C7 stability using a trypsin digestion assay will be essential. These efforts will lay the foundation for transitioning from ex vivo experiments to in vivo correction of the Col7a1 c.6085C>G mutation in our DDEB mouse model.

Lupus erythematosus (LE) encompasses a spectrum of autoimmune diseases with significant heterogeneity, ranging from cutaneous lupus erythematosus (CLE), confined to the skin, to systemic lupus erythematosus (SLE), which affects multiple internal organs. The underlying pathogenesis of lupus skin lesions and the heterogeneity among various subtypes remain elusive and require further investigation. This review synthesizes recent progress in elucidating the mechanisms of lupus skin injury, providing novel perspectives on diagnosis and therapeutic strategies, while also outlining promising avenues for future investigation. Key insights include the active pathogenic role of keratinocytes, essential involvement of neutrophils, the central role of type I interferon (IFN-I) signaling, and a preactivated molecular state in nonlesional skin. Emerging distinctions between CLE and SLE lesions, as well as the role of photosensitivity, are also examined. These findings highlight modifiable environmental factors as critical parts for LE prevention and establish a new paradigm for future precision medicine in LE. These novel findings enrich the complex pathogenic network underlying lupus skin injury, accelerating the transition toward precision medicine. Rational prevention, early diagnosis, and targeted treatment represent the core principles and a promising vision for the future evolution of lupus management.

Energy-based devices (EBDs) and injectable hyaluronic acid gels, such as VYC-12L, are each effective treatment modalities for improving skin quality. To assess the rationale and potential benefits of adding VYC-12L to EBD treatments, and consider how they can be practically integrated into a single treatment plan. Eight clinicians with various specialties and extensive experience of these modalities completed a written questionnaire and were individually interviewed. Their collective clinical expertise and experience form the basis of this guidance. Using both VYC-12L and EBDs within a single treatment plan offers many potential benefits for improving skin quality-based on mechanistic synergies and complementary abilities to address different attributes and multiple anatomical layers. Careful consideration should be given to appropriate sequencing. VYC-12L and non-ablative EBDs can be used on the same day, but treatment fields must be appropriately managed and aseptic technique rigorously upheld. When administering VYC-12L, maintaining the correct injection depth is essential to positive outcomes. Practitioners should undertake appropriate training and select the injection tools that optimize control. Multimodal treatment using VYC-12L and EBDs together can provide a more comprehensive, tailored approach to skin-quality improvement, delivering high levels of patient satisfaction.

Abstract Biosampling with subsequent multiomic profiling of blood and skin is a fundamental component of clinical research studies, and vital to understanding disease and drug development. Risks to study participants are poorly described, particularly in the context of atopic dermatitis, where skin colonization with Staphylococcus aureus is common. It is therefore important to understand the acceptability of biopsies in this patient cohort. We undertook a single-site longitudinal cohort study of patients with atopic dermatitis commencing systemic immunomodulator therapy as part of the ‘mySkinomics’ study (REC: 24/LO/0361). Participants were invited to donate blood samples and 6-mm punch biopsies from affected areas of skin at baseline and day 3, day 14 and month 3 of treatment. Acceptability of serial skin biopsies was assessed based on the proportion of those approached who consented to providing serial biopsies, the retention of participants throughout the sampling schedule, and the biopsy adverse event rate. Data were extracted from the adverse event reporting log, based on participant self-reporting and/or clinical observation during the 6-month study follow-up period postbiopsy. In total, 227 people with atopic dermatitis were approached to take part in mySkinomics, of whom 55.1% (125) enrolled. Among these 125 participants the mean age was 36.7 years and 46.6% were female. In terms of ethnicity, 59.2% were White, 25.6% Asian, 8.0% Black or Black British, and 7.2% other. Of those approached, 33.0% (n = 75) consented to provide both blood and skin samples. A further 18.5% (n = 42) provided blood samples but not skin samples, and 48.5% (n = 110) declined to take part. Of those who provided a skin sample at baseline, 55% (41 of 75 participants) subsequently provided a complete set of skin biopsies, while 45% (34 of 75 participants) provided a partial set of skin biopsies. In total, 238 biopsies were obtained (mean 3.2 biopsies per participant, median 4, range 1–4). Of the 75 participants who provided at least 1 skin biopsy, 29% (n = 22) experienced an adverse event. Of the total biopsies (n = 238), adverse events were documented in 14.3% (n = 34 biopsies). Suspected infections were documented in 13.0% (31 biopsies), with 2.5% requiring systemic antibiotics (6 biopsies). Wound dehiscence occurred in 5.0% (n = 12) and hypertrophic scarring occurred in 2.1% (five biopsies). Overall, almost one-third of participants consented to providing four serial biopsies, with over half of these completing the full sampling schedule. Adverse events were reported following 14.3% of biopsies, and these findings have informed the study-related biopsy sampling protocol. Further work is required to fully elucidate the acceptability of skin biopsies in this cohort, and to determine the contribution of disease-specific factors to the observed complication rate.

Abstract Janus kinase (JAK) inhibitors have emerged as a promising therapeutic option in palmoplantar pustulosis (PPP). However, they have an evolving side-effect profile, particularly relating to cardiovascular disease and malignancy. PPP is closely associated with smoking, but the wider comorbidity burden is poorly described. A potential overlap in risk profiles may therefore impact on the feasibility of JAK inhibitors as a therapy in PPP. We conducted a systematic review to quantify the prevalence of comorbidities, including cardiovascular risk factors and malignancy, in individuals with PPP (PROSPERO: CRD42024508151). A systematic search of six databases was conducted on 29 July 2024. Studies reporting the prevalence of the relevant comorbidities in adults (≥ 18 years) with PPP were included. The quality of included studies was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data. To determine the prevalence of comorbidities in our at-risk population with PPP, following quality assessment, we meta-analysed studies conducted in a specialist setting. Population-based studies based on coding and claims databases were excluded. Prevalence estimates for comorbidities were pooled using a random effects model and are presented with 95% confidence intervals (CIs). Of 23 727 references identified, 86 studies met the inclusion criteria for the systematic review, comprising 72 studies conducted in a specialist setting and 14 population-based database studies. Quality assessment identified that only 33 of 86 (38%) studies specified the diagnostic criteria for comorbidities. Following quality assessment, 57 studies were included in the meta-analysis. The most prevalent cardiovascular risk factors were smoking (78.2%, 95% CI 73.6–82.6), hypertension (28.6%, 95% CI 24.4–32.8), hyperlipidaemia (28.3%, 95% CI 22.3–34.3) and obesity (25.2%, 95% CI 17.7–32.7). The prevalences of major adverse cardiovascular events (myocardial infarction, stroke or transient ischaemic attack) and malignancy were 6.9% (95% CI 3.8–9.9) and 6.9% (95% CI 2.6–11.2), respectively. These data highlight a high prevalence of smoking and cardiovascular risk factors in people with PPP, meaning that JAK inhibitors may be relatively contraindicated in an important proportion of this patient cohort. These findings have been incorporated into the design of the JAKPPPOT study, a mixed-methods, single-arm feasibility trial exploring the use of the JAK inhibitor upadacitinib in PPP (REC: 24/NE/0147; opened November 2024). Trial information materials were adapted to better reflect the potential overlap in risk factors identified by this meta-analysis, and a reduced dosing strategy was introduced for participants with relevant cardiovascular disease risk factors. The findings of this trial will better inform future treatment decision making for people with PPP.