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Background: Pain is common in the genetic skin fragility disorder epidermolysis bullosa (EB), from skin and mucosal injury and inflammation as well as extra-mucocutaneous sites. Individuals living with EB have identified pain as a priority for better treatments., Objectives: The Prospective EB Longitudinal Evaluation Study (PEBLES) is a prospective register study exploring the natural history of RDEB across all ages from birth to death. Here, we investigated the characteristics and treatment of pain in different RDEB subtypes., Methods: Information was collected from individuals with different RDEB subtypes over an 8-year period. Data included visual analogue scale (VAS) ratings of background and procedural pain, its location, intensity and impact on sleep, as well as pain medication. Disease severity scores and quality of life measures were correlated to pain scores., Results: Sixty-one participants (13 children, 48 adults) completed a total of 361 reviews. Pain was common, experienced by 93% of participants at index review, with 80% suffering both background and procedural pain. Across all RDEB patients, the median VAS for background pain was 40 (out of 100) [interquartile range 20,60] and for those having regular dressing changes, median procedural pain was 52 [40,80]. Severe (RDEB-S) and pruriginosa (RDEB-Pru) groups had the greatest increase in procedural compared to background pain of 20 and 22 VAS points, respectively. Correlations between disease severity and quality of life impairment were observed across most groups, particularly RDEB-S. Over half of those studied experienced pain frequently or constantly, and in one third pain disturbed sleep at least 4 nights per week. Skin was the commonest source of pain in all subtypes except inversa RDEB where the mouth was the main site. Despite frequent and severe pain, one third of participants used no medication for pain and, in those that did, pain levels remained high suggesting ineffectiveness of current pain management approaches and a significant unmet need in RDEB., Conclusion: The frequency, severity, and impact of pain in all RDEB patients is significant, particularly in RDEB-S and RDEB-Pru. Our findings highlight that current RDEB pain management is poorly effective and that further research is needed to address this symptom., (© 2024. The Author(s).)

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin disease caused by mutations in the type VII collagen gene (COL7A1; 3p21.31). Mutations in this gene lead to an alteration in function or reduced amounts of collagen VII. This alteration of collagen VII leads to skin fragility and lesions at minor injuries with difficult healing. Cutaneous squamous cell carcinoma (cSCC) is more frequent in patients with RDEB than in the general population because of chronic wound formation; it constitutes a major cause of morbidity and is often cited as a cause of death for these patients. There is little experience with the treatment of cSCC in patients with RDEB. We report the case of a 19-year-old female patient with RDBE and inoperable locally advanced cSCC of the left arm. Because of the lack of therapy options, therapy with cemiplimab was started at a dose of 350 mg administered intravenously every 3 weeks. A confirmed clinical response was observed after the second cycle of treatment with no toxicity. During follow-up, the patient had a notable clinical response with no auto-immune adverse reactions. This shows that cemiplimab has a good safety profile for cSCC in patients with RDEB and is a valuable therapy option.

Background: Dominant dystrophic epidermolysis bullosa (DDEB) is characterized by trauma-induced blisters and, in some individuals, intense pruritus. Precisely what causes itch in DDEB and optimal ways to reduce it have not been fully determined., Objectives: To characterize DDEB skin transcriptomes to identify therapeutic targets to reduce pruritus in patients., Methods: Using bulk RNA sequencing, we evaluated affected and unaffected skin biopsy samples from six patients with DDEB (all with the very itchy pruriginosa subtype) and four healthy individuals. Single-cell transcriptomes of affected (n = 2) and unaffected (n = 1) DDEB skin and healthy skin (n = 2) were obtained. Dupilumab treatment was provided for three patients., Results: The skin bulk transcriptome showed significant enrichment of T helper (Th)1/2 and Th17 pathways in affected DDEB skin compared with nonlesional DDEB skin and healthy skin. Single-cell transcriptomics showed an association of glycolytically active GATA3+ Th2 cells in affected DDEB skin. Treatment with dupilumab in three people with DDEB led to significantly reduced visual analogue scale (VAS) itch scores after 12 weeks (mean VAS 3.83) compared with pretreatment (mean VAS 7.83). Bulk RNAseq and quantitative polymerase chain reaction showed that healthy skin and dupilumab-treated epidermolysis bullosa (EB) pruriginosa skin have similar transcriptomic profiles and reduced Th1/Th2 and Th17 pathway enrichment., Conclusions: Single-cell RNAseq helps define an enhanced DDEB-associated Th2 profile and rationalizes drug repurposing of anti-Th2 drugs in treating DDEB pruritus., Competing Interests: Conflicts of interest J.A.M. currently serves on the Editorial Advisory Board of BJD. The other authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Epidermolysis bullosa (EB) encompasses a range of rare genetic dermatological conditions characterized by mucocutaneous fragility and a predisposition to blister formation, often triggered by minimal trauma. Blisters in the pharynx and esophagus are well-documented, particularly in dystrophic EB (DEB). However, there have been few reports of mucocutaneous squamous cell carcinoma (SCC) in the head and neck region, for which surgery is usually avoided. This report presents the first case of free jejunal flap reconstruction after total pharyngolaryngoesophagectomy for hypopharyngeal cancer in a 57-year-old patient with DEB. The patient with a known diagnosis of DEB had a history of SCC of the left hand and esophageal dilatation for esophageal stricture. PET-CT imaging during examination of systemic metastases associated with the left-hand SCC revealed abnormal accumulation in the hypopharynx, which was confirmed as SCC by biopsy. Total pharyngolaryngoesophagectomy was performed, followed by reconstruction of the defect using a free jejunal flap. A segment of the jejunum, approximately 15 cm in length, was transplanted with multiple vascular pedicles. The patient made an uneventful recovery postoperatively and was able to continue oral intake 15 months later with no complications and no recurrence of SCC in the head and neck region. While cutaneous SCC is common in DEB, extracutaneous SCC is relatively rare. In most previous cases, non-surgical approaches with radiotherapy and chemotherapy were chosen due to skin fragility and multimorbidity. In the present case, vascular fragility and mucosal damage of the intestinal tract were not observed, and routine vascular and enteric anastomoses could be performed, with an uneventful postoperative course. Our findings suggest that highly invasive surgery, including free tissue transplantation such as with a free jejunal flap, can be performed in patients with DEB., (© 2024 Wiley Periodicals LLC.)

Introduction: Epidermolysis bullosa (EB) is a rare genetic disorder characterized by skin fragility and blister formation. The phenotypic presentation is broad with four major types, being Recessive Dystrophic EB (RDEB) the most severe, including oral anomalies such as severe microstomia, ankyloglossia, vestibule obliteration and occlusal anomalies, turning orthodontic treatment into a challenge., Aim: This case report aims to present the comprehensive treatment of a patient with severe RDEB, including periodontal surgery, orthodontic fixed braces with mini-screws and oral rehabilitation with anterior veneers., Case Report: A 27-year-old female patient with severe RDEB received orthodontic treatment in the upper jaw to improve malalignment and anterior crossbite. After 13 months of treatment with fixed appliances, miniscrews were placed in the anterior segment to intrude and procline the upper incisors. Oral surgery was performed to increase the vestibule depth of the upper lip. Once edge-to-edge occlusion was obtained, anterior veneers were placed to improve aesthetic and stabilize occlusion, especially with the lack of posterior support., Discussion: The multidisciplinary treatment approach, involving orthodontic treatment, periodontal surgery and oral rehabilitation, played a crucial role in achieving favorable results. This case highlights the successful use of miniscrews as a viable orthodontic approach for patients with severe RDEB., (© 2023 Special Care Dentistry Association and Wiley Periodicals LLC.)

Background: Pruritus is a highly burdensome symptom in patients with epidermolysis bullosa, especially recessive dystrophic epidermolysis bullosa (RDEB); however, only a few studies have assessed the molecular pathogenesis of RDEB-associated pruritus. Interleukin (IL)-31 is a key cytokine implicated in pruritus associated with dermatologic diseases such as atopic dermatitis and prurigo nodularis., Objective: To investigate the role and cellular source of IL-31 in RDEB-associated pruritus., Methods: Serum and skin samples were obtained from 11 RDEB patients and 11 healthy controls. Pruritus visual analogue scale scores were determined. Serum levels of IL-31 and thymic stromal lymphopoietin (TSLP) were examined by enzyme-linked immunosorbent assay (ELISA). The expression of IL-31 and other pruritus mediators in the skin were examined through immunofluorescence staining, and their correlation with pruritus severity was analysed., Results: Serum IL-31 and TSLP were elevated in RDEB patients. IL-31 expression was increased in RDEB skin and positively correlated with pruritus severity. Most of the IL-31-expressing cells were mast cells, and some were CD206(+) M2-like macrophages. The number of substance P(+) cells was also increased in the patients' skin, and most of them were mast cells. The number of substance P(+) mast cells was correlated with the number of IL-31(+) dermal infiltrates. The number of IL-4Rα- and IL-13-expressing cells and expression of TSLP and periostin increased in RDEB skin, but without a correlation to pruritus score., Conclusion: The increased production of skin IL-31 from mast cells and M2-like macrophages may be the mechanism underlying pruritus in RDEB., (© 2023 European Academy of Dermatology and Venereology.)

Refractory pruritus is the most distressing, disease-related symptom in patients with dystrophic epidermolysis bullosa (DEB), inducing an itch-scratch-blister cycle. Chronic inflammation is a hallmark of DEB, thus upregulation of inflammatory cytokines and Janus kinase (JAK) signaling may play a role in DEB-related pruritus. We retrospectively reviewed the medical records of DEB patients with refractory pruritus who were treated with either baricitinib, a JAK1/2 inhibitor, or upadacitinib, a selective JAK1 inhibitor. Patients received baricitinib (4 mg) or upadacitinib (15 mg) once a day for 2-32 weeks. A total of 12 DEB patients (six recessive DEB and six dominant DEB) were included in this study. The mean±SD baseline pruritus visual analog scale (VAS) score was 7.5 ± 1.7. Upadacitinib or baricitinib treatment resulted in a rapid and sustained decrease in itch. Four out of 12 patients (33.3%) and seven out of 10 patients (70%) showed a decrease of at least 3 points in the pruritus VAS score from baseline at weeks 2 and 4, respectively. The mean percentage changes from baseline in pruritus VAS scores at weeks 2 and 4 were -42.9% and -52.7%, respectively. Subgroup analysis showed greater reductions in the pruritus VAS score in the baricitinib group (n = 5) compared to the upadacitinib group (n = 7), and in patients with epidermolysis bullosa pruriginosa (n = 3) compared to other subtypes of DEB (n = 9); however, these differences did not reach statistical significance. Three out of 10 (33.3%) patients showed at least a 2-point reduction in pain intensity from baseline at week 4. Eight out of 12 patients (66.7%) also showed a reduction in the number of new blisters, which correlated with a reduction in the pruritus score. No patient discontinued treatment because of serious adverse events. Our results suggest that JAK1 or JAK1/2 inhibitors could be a promising treatment option for DEB-related pruritus. Long-term safety should be assessed in future studies., (© 2023 Japanese Dermatological Association.)

Dystrophic epidermolysis bullosa is a rare genetic disease caused by damaging variants in COL7A1 , which encodes type VII collagen. Blistering and scarring of the ocular surface develop, potentially leading to blindness. Beremagene geperpavec (B-VEC) is a replication-deficient herpes simplex virus type 1-based gene therapy engineered to deliver functional human type VII collagen. Here, we report the case of a patient with cicatrizing conjunctivitis in both eyes caused by dystrophic epidermolysis bullosa who received ophthalmic administration of B-VEC, which was associated with improved visual acuity after surgery., (Copyright © 2024 Massachusetts Medical Society.)

Epidermolysis bullosa (EB) is a group of rare, difficult-to-treat, inherited multisystem diseases affecting epithelial integrity. Impaired wound healing is central and can lead to serious clinical complications, deformities, and symptoms with a devastating impact on quality of life (QoL). Dressing changes and wound care are central to the management of EB. Recently Oleogel-S10 (also known as birch bark extract or birch triterpenes) was approved in Europe and the UK for treating EB wounds. This approval was based on data from the EASE phase 3 study, which demonstrated Oleogel-S10 accelerated wound healing, reduced total wound burden, and decreased the frequency of dressing changes in patients with EB. A retrospective analysis of medical records was conducted for up to 24 months in 13 patients with EB treated with Oleogel-S10 through an early access programme in Colombia. Effectiveness was assessed by measuring body surface area percentage (BSAP) and total body wound burden (EBDASI). Tolerability and safety were monitored throughout. This is the first report to evaluate the effectiveness of Oleogel-S10 in clinical practice. The results showed a reduction in percentage of BSA affected, from a mean of 27.3% at baseline to 10.4% at 24-month follow-up, despite treatment interruptions. A reduction in EBDASI skin activity score of - 16.2 (24 months) together with a reduced skin damage index score of - 15.4 (18 months) was also observed. Physicians, patients, and caregivers perceived faster wound closure. Adherence with therapy by patients was good, and patients expressed satisfaction with treatment and reported improvements in self-esteem, productivity, and social interaction. Oleogel-S10 was well tolerated; however, two patients reported worsening wounds related to gauze adherence. Two deaths during treatment interruption were reported and was not considered related to Oleogel-S10. This study supports the effectiveness of Oleogel-S10 in a real-world scenario in a country with scarce resources for the treatment of EB., (© 2023. The Author(s).)

Abstract: Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) is a rare subtype of dystrophic epidermolysis bullosa, and traditional treatments have limited efficacy. Dupilumab has demonstrated remarkable efficacy in relieving pruritus. In this case study, after traditional treatment failed, providers recommended the patient begin dupilumab to treat his pruritus. The patient was administrated a loading dose of 600 mg of dupilumab and a dose of 300 mg every 2 weeks. The Dermatology Life Quality Index and Pruritic Numeric Rating Scale were used to assess the patient's situation. After several months, the patient's DEB-Pr was considered in remission. Dupilumab may be a better choice than immunosuppressants for the treatment of pruritus in patients with DEB-Pr., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Epidermolysis bullosa (EB) is a group of rare, congenital skin disorders, characterized by skin fragility and formation of blisters. The gross motor outcomes of children with EB are not known., Objectives: The primary objective of the study was to measure the proportion of gross motor delay in children with EB. The secondary objectives were to measure the difference in gross motor outcomes between EB sub-types and change in gross motor outcomes over time., Methods: Children with EB, aged between one month and five and a half years of age, attending the Sydney Children's Hospital, Epidermolysis Bullosa Clinic, were eligible. Carers completed Ages and Stages Questionnaires, Third Edition, on behalf of their children. Questionnaires were scored, and outcomes were compared to age-expected norms., Results: There were 24 participants to complete a questionnaire. Eleven participants completed additional questionnaires over the 24 month study duration. The proportion of children with EB with gross motor delay was greater than age-expected norms (29.17% vs. 2.5%). The delay occurred in children with recessive dystrophic (80%) and epidermolysis bullosa simplex (33.33%) sub-types, but not dominant dystrophic (0%). No children with Junctional EB or Kindler EB joined this study., Conclusions: This study demonstrates a difference in gross motor outcomes in children with EB. Children with recessive dystrophic and epidermolysis bullosa simplex should be prioritized for monitoring of, and intervention for, gross motor outcomes through multidisciplinary care. Further research investigating long-term outcomes for children with EB and the effectiveness of interventions would be beneficial., (© 2023 The Authors. Child: Care, Health and Development published by John Wiley & Sons Ltd.)

Background: Cutaneous squamous cell carcinoma (SCC) is the leading cause of death in patients with recessive dystrophic epidermolysis bullosa (RDEB). However, the survival time from first diagnosis differs between patients; some tumours spread particularly fast, while others may remain localized for years. As treatment options are limited, there is an urgent need for further insights into the pathomechanisms of RDEB tumours, to foster therapy development and support clinical decision-making., Objectives: To investigate differences in RDEB tumours of diverging aggressiveness at the molecular and phenotypic level, with a particular focus on epithelial-to-mesenchymal (EMT) transition states and thus microRNA-200b (miR-200b) as a regulator., Methods: Primary RDEB-SCC keratinocyte lines were characterized with respect to their EMT state. For this purpose, cell morphology was classified and the expression of EMT markers analysed using immunofluorescence, flow cytometry, semi-quantitative reverse transcriptase polymerase chain reaction and Western blotting. The motility of RDEB-SCC cells was determined and conditioned medium of RDEB-SCC cells was used to treat endothelial cells in an angiogenesis assay. In addition, we mined previously generated microRNA (miRNA) profiling data to identify a candidate with potential therapeutic relevance and performed transient miRNA transfection studies to investigate the candidate's ability to reverse EMT characteristics., Results: We observed high variability in EMT state in the RDEB-SCC cell lines, which correlated with in situ analysis of two available patient biopsies and respective clinical disease course. Furthermore, we identified miR-200b-3p to be downregulated in RDEB-SCCs, and the extent of deregulation significantly correlated with the EMT features of the various tumour lines. miR-200b-3p was reintroduced into RDEB-SCC cell lines with pronounced EMT features, which resulted in a significant increase in epithelial characteristics, including cell morphology, EMT marker expression, migration and angiogenic potential., Conclusions: RDEB-SCCs exist in different EMT states and the level of miR-200b is indicative of how far an RDEB-SCC has gone down the EMT path. Moreover, the reintroduction of miR-200b significantly reduced mesenchymal features., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Competing Interests: Conflicts of interest the authors declare no conflicts of interest.

Despite an increase in life expectancy and quality of life for patients suffering from severe forms of hereditary epidermolysis bullosa, the occurrence of one or more cutaneous squamous cell carcinomas remains a sometimes serious complication, sometimes life-threatening as early as adolescence. These carcinomas occur preferably on chronic wounds or dystrophic scars in areas not exposed to the sun, and are generally multifocal and recurrent. Their clinical and histological diagnosis is difficult. Regular medical and paramedical monitoring of the skin during dressing repairs enables early detection and rapid, curative surgical management. The pathophysiology of these cutaneous carcinomas is the subject of research aimed at proposing non-surgical alternatives to the patients concerned., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

The occurrence of cutaneous squamous cell carcinoma is a frequent and potentially serious complication in people with recessive dystrophic epidermolysis bullosa and junctional epidermolysis bullosa with chronic leg sores. Early diagnosis of early-stage carcinomas enables limited surgical excision and rapid healing without sequelae. Screening during skin care of patients at risk is therefore of major interest, and any atypical lesion should be shown to a doctor specializing in the disease and biopsied at the slightest doubt, preferably in an expert center for the disease., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Dystrophic epidermolysis bullosa (DEB) is a subtype of an inherited skin disorder characterized by skin and mucosal fragility due to collagen VII (COL7A1) gene mutations. Esophageal strictures leading to chronic dysphagia and acute episodes are well recognized complications within this subtype. Sloughing of esophageal mucosa and the treatment of this emergency have heretofore received limited attention in the EB literature., Methods: We retrospectively reviewed the electronic medical records of the patients who had an acute episode of sloughing of the esophageal lining between 2008 and 2021 and extracted the information regarding their clinical presentation and management., Results: Six patients out of 210 with recessive DEB severe (RDEB-S) (n = 4), RDEB intermediate (RDEB-I) (n = 1) and dominant DEB (DDEB) (n = 1) were identified. The mean age at the time of the episode was 2.7 years. All patients had early-onset severe gastroesophageal reflux. Clinically, they presented with a coughing episode (n = 6), hematemesis (n = 6), vomiting (n = 6), and choking (n = 3), followed by coughing up a string like tissue of variable length, part of the esophageal mucosal lining. Four patients recovered with medical management only, two patients required gastrostomy insertions for feeding due to severe persistent dysphagia and one also required a Nissen's fundoplication to manage severe reflux. One patient had aspiration pneumonia., Conclusions: Sloughing of varying lengths of segments of the esophagus is an emergency. The lining coughed up needs to be cut at the mouth not pulled and the emergency services called immediately for urgent assessment and management. Expert multidisciplinary care is needed to manage this rare but serious condition., (© 2023 Wiley Periodicals LLC.)

Background: Epidermolysis bullosa (EB) features skin and mucosal fragility due to pathogenic variants in genes encoding components of the cutaneous basement membrane. Based on the level of separation within the dermal-epidermal junction, EB is sub-classified into four major types including EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler EB (KEB) with 16 EB-associated genes reported to date., Methods: We ascertained a cohort of 151 EB patients of various Middle Eastern ethnic backgrounds., Results: The cohort was comprised of EBS (64%, 97/151), DEB (21%, 31/151), JEB (12%, 18/151), and KEB (3%, 5/151). KRT14 and KRT5 variants were most common among EBS patients with 43% (42/97) and 46% (45/97) of EBS patients carrying mutations in either of these two genes, respectively. Truncal involvement was more common in KRT14-associated EBS as compared to EBS due to KRT5 mutations (p < .05). Mutations in COL17A1 and laminin 332-encoding genes were identified in 55% (10/18) and 45% (8/18) of JEB patients. Scarring alopecia, caries, and EB nevi were most common among JEB patients carrying COL17A1 mutations as compared to laminin 332-associated JEB (p < .05). Abnormal nails were evident in most DEB and JEB patients while poikiloderma was exclusively observed in KEB (p < .001)., Conclusions: EB patients of Middle Eastern origin were found to feature specific phenotype-genotype correlations of relevance to the diagnosis and genetic counseling of patients in this region., (© 2023 The Authors. Pediatric Dermatology published by Wiley Periodicals LLC.)

Background: Itch is common and distressing in epidermolysis bullosa (EB) but has not previously been studied in depth in different recessive dystrophic EB (RDEB) subtypes., Objectives: As part of a prospective register study of the natural history of RDEB we explored features of itch, medications used, and correlation with disease severity and quality of life., Methods: Fifty individuals with RDEB aged 8 years and above completed the Leuven Itch Scale (LIS) (total 243 reviews over a 7-year period). Data included itch frequency, severity, duration, distress, circumstances, consequences, itch surface area and medications for itch. The iscorEB disease severity score and the validated EB quality of life tool, QOLEB, were compared to LIS domains and analysed by RDEB subtype., Results: Itch was frequent, present in the preceding month in 93% of reviews. Itch severity and distress were significantly greater in severe (RDEB-S) and pruriginosa (RDEB-Pru) subtypes compared to intermediate RDEB (RDEB-I). Itch medications were reported in just over half of reviews including emollients, topical corticosteroids and antihistamines; the proportion of participants not using medication despite frequent pruritus suggests limited efficacy. In inversa RDEB (RDEB-Inv) and RDEB-I, LIS domains correlated with iscorEB and QOLEB. In contrast to previous studies, correlations were lacking in RDEB-S suggesting that global disease burden relatively reduces the contribution of itch., Conclusions: This comprehensive study of RDEB-associated itch highlights differences between RDEB subtypes, suggests an unmet need for effective treatments and could serve as control data for future clinical trials incorporating itch as an endpoint., (© 2023. Institut National de la Santé et de la Recherche Médicale (INSERM).)

Cutaneous squamous cell carcinoma (cSCC) is a major complication of recessive dystrophic epidermolysis bullosa (RDEB) that has high morbidity and mortality rates and unmet therapeutic needs. The aim of this study was to evaluate the molecular pattern of cSCC and the clinical course of immunotherapy in 2 RDEB patients with multiple advanced cSCC. Clinical course and disease staging were evaluated retrospectively. The tumour tissues were subjected to immunohistochemical staining. DNA from the blood and cSCC samples was subjected to massive parallel sequencing, and somatic mutations were determined. Patient 1 survived for over 2 years as disease control was achieved with cemiplimab and intralesional interleukin-2. The target advanced cSCC demonstrated a high rate of somatic mutations and strong expression of the immune markers, indoleamine 2,3-dioxygenase, programmed cell death protein ligand 1, and lymphocyte-activation gene 3. The patient ultimately succumbed to complications of oesophageal carcinoma. Patient 2 had an undifferentiated cSCC on the foot, which displayed a low mutational burden and did not express immune markers. The tumour progressed quickly even with cemiplimab therapy. These 2 cases underscore the challenges of cSCC treatment for RDEB. Multiple tumours with different molecular and immune profiles occur concomitantly or sequentially, and surgical excision is not always possible because of the anatomical and tissue constraints imposed by the disease itself. In conclusion, programmed cell death protein 1 inhibitors are approved and effective in treating metastatic and locally advanced cSCC. Our experience and the literature suggest that cemiplimab is an option in patients with RDEB if surgery is not. Somatic mutations and the immune microenvironment should be characterized to predict therapeutic response, particularly in aggressive undifferentiated tumours.

Introduction: Dystrophic epidermolysis bullosa (DEB) is one of the most severe forms of congenital epidermolysis bullosa and characterized by the formation of many surgical complications. Esophageal stenosis is a common complication of DEB and occurs in almost 76% of cases. Balloon dilatation (BD) under X-ray control is the main therapeutic technique, however conservative treatment is necessary to prevent restenosis. The use of the drug losartan is promising due to its antifibrotic effect through the suppression of transforming growth factor-β1 (TGF-β1)., Purpose: To evaluate the efficacy of losartan in the prevention of restenosis after BD of esophageal stenosis in children with DEB., Materials and Methods: The study included 19 children from 2 to 16 years old (mean age 9.2 ± 3.58 years) with DEB and X-ray confirmed esophageal stenosis. All children underwent BD. In the main group 9 children after BD have received losartan, in the control group of 10 children - only standard therapy. The observation period was 12 months., Results: In the main group, 1 child (11.1%) required repeated dilatation, in the control group - 4 children (40%). Indicators of nutritional deficiency (THINC scale) and the disease severity index (EBDASI) were significantly lower in the group of children treated with losartan. No undesirable actions of the drug were recorded., Conclusions: In this study losartan showed its safety, contributed to a decrease in the restenosis frequency and an improvement in the nutritional status of children with DEB after BD. However, further studies are required to confirm its effectiveness., Level of Evidence: IV., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Epidermolysis bullosa (EB) is an inherited disorder characterised by skin fragility and the appearance of blisters and wounds. Patient wounds are often colonised or infected with bacteria, leading to impaired healing, pain and high risk of death by sepsis. Little is known about the impact of bacterial composition and susceptibility in wound resolution, and there is a need for longitudinal studies to understand healing outcomes with different types of bacterial colonisation. A prospective longitudinal study of 70 wounds from 15 severe EB patients (Junctional and Recessive Dystrophic EB) from Chile. Wounds were selected independently of their infected status. Wound cultures, including bacterial species identification, composition and Staphylococcus aureus (SA) antibiotic susceptibility were registered. Wounds were separated into categories according to their healing capacity, recognising chronic, and healing wounds. Hundred-one of the 102 wound cultures were positive for bacterial growth. From these, 100 were SA-positive; 31 were resistant to Ciprofloxacin (31%) and only seven were methicillin-resistant SA (7%). Ciprofloxacin-resistant SA was found significantly predominant in chronic wounds (**P < .01). Interestingly, atoxigenic Corynebacterium diphtheriae (CD) was identified and found to be the second most abundant recovered bacteria (31/101), present almost always in combination with SA (30/31). CD was only found in Recessive Dystrophic EB patients and not related to wound chronicity. Other less frequent bacterial species found included Pseudomonas aeruginosa, Streptococus spp. and Proteus spp. Infection was negatively associated with the healing status of wounds., (© 2022 The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Background and Objectives: To describe the prevalence, severity, and management of anemia in a cohort of children with recessive dystrophic epidermolysis bullosa (RDEB) and to highlight the use of soluble transferrin receptor (sTfR) to diagnose iron deficiency in this chronic inflammatory state., Methods: We studied a cohort of 114 patients with RDEB followed at a pediatric hospital-based Epidermolysis Bullosa Center from 2010 to 2020; data were prospectively tracked in a comprehensive clinical database that captured all visits, laboratory tests, iron infusions, and transfusions. The primary outcome was occurrence of anemia, which was assessed by age and sex, with and without transfusion support. Secondary outcomes included iron status using a combination of ferritin and sTfR levels, the cumulative incidence of parenteral iron therapy and transfusions, and survival., Results: In RDEB, anemia begins in the first year of life and becomes more frequent and severe with age. The prevalence of iron deficiency anemia (IDA) estimated by ferritin was 33.6% (37/110), but the sTfR/log 10 -ferritin ratio indicated a 1.5-fold higher true prevalence of IDA of 50.6% (41/81). 53.5% (61/114) received parenteral iron infusions, transfusions, or both. Higher ferritin was associated with earlier mortality., Conclusions: Individuals with RDEB have a high burden of anemia (IDA and anemia of inflammation) that requires frequent medical interventions. The sTfR/log 10 -ferritin ratio improves the detection of iron deficiency in the context of inflammation and guides therapy., (© 2023 The Authors. Pediatric Dermatology published by Wiley Periodicals LLC.)

Purpose: Dystrophic epidermolysis bullosa (DEB) is a devastating condition that causes painful corneal abrasions and vision loss. Epidermolysis Bullosa Eye Disease Index (EB-EDI) for the first time captures and quantifies EB-specific assessment of ocular symptoms and activities of daily living scales. This survey will become critical in developing new interventions on patients' quality of life., Methods: Three-part set of the EB-EDI baseline, EB-EDI interval, and Ocular Surface Disease Index (OSDI) survey was distributed to 92 patients with DEB who previously reported eye symptoms on previous surveys. It was then posted online through several EB patient organizations. We compared the EB-EDI with the gold standard OSDI and examined the repeatability of the EB-EDI over a 7- to 15-day interval., Results: Of the 45 individuals who initially responded, 30 of 45 (67%) completed the surveys sent 7 to 15 days later. The age of participants ranged from 6 to 51 years (mean 21 ± 15 years), and 60% (18 of 30) of participants were younger than 18 years. The overall Cronbach alpha values for the subscales of EB-EDI baseline and interval tools presented a good internal consistency (≥0.7). From 2 visits, the domain scores of EB-EDI baseline (0.94) and interval tools (0.83) were shown to have excellent test-retest reliability (intraclass correlation coefficient >0.8). By comparison, OSDI had the intraclass correlation coefficient score of 0.72 ± 0.11. The convergent validation analysis showed that correlations between the domain scores of EB-EDI baseline and interval tools and the subscales of the OSDI reached the hypothesized strength., Conclusions: Based on a 30-person repeated-measures study, we found that the EB-EDI has excellent reliability and validity specifically in patients with DEB., Competing Interests: V. M. Chen is a consultant for Phoenix Tissue Repair, Inc. The remaining authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Epidermolysis bullosa or butterfly wing disease is a rare genetic disorder of connective tissue associated with the formation of blisters. The clinical manifestations are very diverse and affect not only the skin cover, but also mucosal surfaces of the gastrointestinal, urogenital and respiratory systems. A large proportion of patients suffer from severe constipation with the development of megacolon. The case report describes intestinal obstruction in a patient with a dystrophic form of epidermolysis bullosa which required surgical treatment.

Dominant dystrophic epidermolysis bullosa (DDEB), an inherited disorder due to type VII collagen mutations, is characterized by blisters and erosions that heal with scarring, atrophy, and milia. There is no established role for laser in the management of patients with DDEB. Pulsed dye laser (PDL) is most often used to target vascular skin lesions. We describe a patient with DDEB with marked improvement in erythema as well as fewer and less symptomatic episodes of blistering following treatment with PDL., (© 2022 Wiley Periodicals LLC.)

Background: Epidermolysis bullosa (EB) is a complex and heterogeneous dermatological disease. Four main types of EB have been described, each of them with distinct characteristics: EB simplex (EBS), dystrophic EB (DEB), junctional EB (JEB) and Kindler EB (KEB). Each main type varies in its manifestations, severity, and genetic abnormality., Methods: We sought mutations in 19 genes known to cause EB and 10 genes associated with other dermatologic diseases in 35 Peruvian pediatric patients of a rich Amerindian genetic background. Whole exome sequencing and bioinformatics analysis was performed., Results: Thirty-four of 35 families revealed an EB mutation. Dystrophic EB was the most frequently diagnosed type, with 19 (56%) patients, followed by EBS (35%), JEB (6%), and KEB (3%). We found 37 mutations in seven genes; 27 (73%) were missense mutations; 22 (59%) were novel mutations. Five cases changed their initial diagnosis of EBS. Four were reclassified as DEB and one as JEB. Inspection into other non-EB genes revealed a variant, c.7130C&gt;A, in the gene FLGR2, which was present in 31 of the 34 patients (91%)., Conclusion: We were able to confirm and identify pathological mutations in 34 of 35 patients.

Abstract: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic condition in which mutations in the type VII collagen gene ( COL7A1 ) lead to decreased expression of this anchoring protein of the skin, causing the loss of stability at the dermo-epidermal junction. Most patients with RDEB experience neuropathic pain and itch due to the development of a small fibre neuropathy, characterised by decreased intraepidermal innervation and thermal hypoaesthesia. To understand the physiopathology of this neuropathy, we used a mouse model of RDEB (Col7a1 flNeo/flNeo ) and performed a detailed characterisation of the somatosensory system. Col7a1 flNeo/flNeo mice showed a decrease in heat sensitivity, an increase in spontaneous scratching, and a significant decrease in intraepidermal nerve fibre density in the hindpaw; these changes were distal because there was no significant loss of unmyelinated or myelinated fibres in the nerve trunk. Of interest, we observed a decrease in axon diameter in both myelinated and unmyelinated fibres. This axonal damage was not associated with inflammation of the dorsal root ganglion or central projection targets at the time of assessment. These results suggest that in RDEB, there is a distal degeneration of axons produced by exclusive damage of small fibres in the epidermis, and in contrast with traumatic and acute neuropathies, it does not induce sustained neuroinflammation. Thus, this animal model emphasizes the importance of a healthy cutaneous environment for maintenance of epidermal innervation and faithfully replicates the pathology in humans, offering the opportunity to use this model in the development of treatments for pain for patients with RDEB., (Copyright © 2022 International Association for the Study of Pain.)

Inherited epidermolysis bullosa (EB) is a group of genetic rare diseases associated with skin fragility, which leads to the formation of blisters, erosions, and scars on the skin and mucous membranes. Epidermolysis bullosa includes four main types and some several clinical subtypes including EB simplex, junctional EB, dystrophic EB, and Kindler's EB. Ocular involvement ranged from 51 to 68% in EB and can cause irreversible damages if not properly managed. Corneal erosions are the most common finding among series, including our cohort. We review here clinical and pathological features of ocular involvement in EB and the main keys for management, with a focus on recent innovative therapies., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Recessive dystrophic epidermolysis bullosa (RDEB) is a hereditary blistering disorder characterized by skin fragility, chronic inflammation, malnutrition, and fibrosis. Metabolomics is an emerging investigative field that helps elucidate disease pathophysiology and identify biomarkers. However, previous metabolomic studies in RDEB are limited., Objective: To investigate the plasma metabolomic profiles in RDEB patients., Methods: We recruited 10 RDEB patients and 10 age-/gender-matched healthy controls. Peripheral blood samples were collected and plasma metabolomic profiling was performed by LC-MS/MS analysis. MS data processing and compound identification were executed by MS-DIAL. Enrichment analysis was performed by MetaboAnalyst 5.0., Results: Metabolomic analyses demonstrated that most amino acid levels were downregulated in RDEB patients, and the extent of insufficiency correlated with clinical severity. Several metabolites were dysregulated in RDEB, including glutamine and glutamate metabolism, tryptophan-to-kynurenine ratio, phenylalanine-to-tyrosine ratio, and succinate accumulation., Limitations: The study was limited by small case numbers and the unrepresentativeness of a single time-point blood sample., Conclusion: Our study demonstrated the altered metabolomic profiles in RDEB, reflecting the disease severity, the chronic inflammatory and malnourished status, while the fibrotic signatures were not evident., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2022 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: Paediatric patients with recessive dystrophic epidermolysis bullosa (RDEB) are at risk of vitamin D deficiency, owing to lack of sunlight from reduced mobility and having large areas of skin being covered with dressings, and to impaired nutritional intake and status., Aim: To establish an appropriate level of vitamin D supplementation in paediatric patients with RDEB., Methods: Patients with RDEB attending the EB tertiary multidisciplinary team clinic were enrolled. Serum levels of total 25(OH)D were retrospectively recorded for the study period 2012-2018. Data from clinical records on supplements, bone mineral density (BMD) Z scores, compliance, and use of enteral feeds and/or formula were also recorded., Results: In total, 24 patients met the inclusion criteria: 20 with severe RDEB, 3 with RDEB inversa and 1 with intermediate RDEB. Of the 24 patients, 21 (88%) were advised to take a vitamin D3 supplement in line with Department of Health Guidelines (UK), with the remaining 3 patients receiving sufficient intake from formula or enteral feeds. Thirteen of the 24 (54%) had vitamin D deficiency or insufficiency despite advice to supplement; 9 of these 13 (69%) subsequently started or increased the dosage of vitamin D supplements and levels became sufficient (> 50 nmol/L), while the remaining 4 patients (31%) continued to have persistent insufficient levels due to noncompliance with supplements. Reasons for noncompliance were palatability, cost and forgetting to take the tablets. The dose required to maintain sufficient serum levels increased with age, up to 300% of the reference nutrient intake (RNI)., Conclusion: All patients with RDEB require a supplement or a formula or enteral/sip feed containing vitamin D to maintain sufficient serum vitamin D. The dose required increases with age and can be up to three times higher than the RNI for the normal population. Compliance may improve using a once-weekly loading dose of vitamin D3. Vitamin D deficiency was not solely causative of a low BMD Z score., (© 2022 British Association of Dermatologists.)

Epidermolysis bullosa (EB) is a group of rare congenital diseases caused by mutations in structural proteins of the dermal/epidermal junction that are characterized by extreme epithelial fragility, which determines the formation of bullae and erosions either spontaneously or after local mechanical traumas. In EB patients, skin fragility leads to many possible complications and comorbidities. One of the most feared complications is the development of cutaneous squamous cell carcinomas (SCCs) that particularly in the dystrophic recessive EB subtype can be extremely aggressive and often metastatic. SCCs in EB patients generally arise more often in the extremities, where chronic blisters and scars are generally located. SCCs represent a big therapeutic challenge in the EB population. No standard of care exists for the treatment of SCC in these patients, and therapy is based on small case studies. Moreover, the pathogenesis of cSCC in EB patients is still unclear. Many theories have been indeed postulated in order to explain why cSCC behaves so much more aggressively in EB patients compared to the general population. cSCC in EB seems to be the result of many complex interactions among cancer cells, skin microenvironment, susceptibility to DNA mutations and host immune response. In this review, we analyze the different pathogenetic mechanisms of cSCC in EB patients, as well as new therapies for this condition.

Introduction: Recessive dystrophic epidermolysis bullosa is a rare genetic condition characterized by fragile skin and mucous membrane, caused by mutations in the COL7A1 gene. AA amyloidosis is a rare complication of these genodermatosis., Observations: Two patients with recessive dystrophic epidermolysis bullosa, generalized severe in the first case and generalized intermediate in the second case, developed at the age of 38 and 28, respectively, nephrotic syndrome. The diagnosis of secondary renal amyloidosis was confirmed by renal biopsy in the first case and by minor salivary gland biopsy in the second case. Death occurred 2 months after diagnosis in both cases., Conclusion: Renal involvement is quite common in AA amyloidosis in patients with recessive dystrophic epidermolysis bullosa. Nephrotic syndrome and rapid decline in renal function renal are characteristic features. The prognosis is poor due to underlying conditions and the lack of an etiological treatment., (Copyright © 2021 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.)

Background: The rare inversa subtype of recessive dystrophic epidermolysis bullosa (RDEB-I) is characterized by predominant intertriginous skin blistering and marked mucosal involvement. Specific recessive missense mutations in the collagen VII triple helix are implicated in the disease. To date, otological complications have been reported infrequently in this patient group., Methods: We conducted an observational, retrospective, double institution case record review of patients with RDEB-I who presented with otological complications between January 2000 and June 2020. Diagnosis was established on the basis of clinical features, family history and mutation analysis of the COL7A1 gene., Results: In total, 11 (44%) of 25 patients with RDEB-I in our database (2 paediatric, 9 adult; mean age 40.9 years, range 8-72 years) experienced otological complications. Of these 11 patients, 10 (90.9%) had recurrent otitis externa, 7 (63.6%) had meatal stenosis and 7 (63.6%) had recurrent blistering of the external auditory canals. All 11 patients reported hearing difficulties, with conductive hearing loss confirmed by audiology testing in 6 (54.5%) of these. Of the 11 patients, 3 (27.3%) went on to have implantable hearing aids [2 bone-anchored hearing aids (BAHA) and 1 middle ear implant (MEI)] fitted with favourable outcome, while a fourth paediatric patient presented with a cholesteatoma that was surgically managed., Discussion: We observed a higher prevalence of otological morbidity in RDEB-I than previously reported, and present the first case of cholesteatoma in epidermolysis bullosa (EB). Our data indicate that BAHA and MEI are safe and effective treatment options for hearing loss in EB. Clinicians should be vigilant in screening for ear symptoms in RDEB-I and consider early referral to an Ear, Nose and Throat specialist., (© 2021 British Association of Dermatologists.)