Functional genotype-phenotype associations in recessive dystrophic epidermolysis bullosa.

BACKGROUND: Genotype-phenotype associations in recessive dystrophic epidermolysis bullosa (RDEB) have been difficult to elucidate. OBJECTIVE: To investigate RDEB genotype-phenotype associations and explore a functional approach to genotype classification. METHODS: Clinical examination and genetic testing of RDEB subjects, including assessment of clinical disease by RDEB subtype and extent of blistering. Genotypes were evaluated according to each variant's effect on type VII collagen function per updated literature and subsequently categorized by degree of impact on VII collagen function as low-impact (splice/missense, missense/missense), medium-impact (premature termination codon [PTC]/missense, splice/splice), and high-impact (PTC/PTC, PTC/splice). Genotype-phenotype associations were investigated using Kruskal-Wallis and Fisher's exact tests, and age-adjusted regressions. RESULTS: Eighty-three participants were included. High-impact variants were associated with worse RDEB subtype and clinical disease, including increased prevalence of generalized blistering (55.6% for low-impact vs 72.7% medium-impact vs 90.4% high-impact variants, P = .002). In age-adjusted regressions, participants with high-impact variants had 40.8-fold greater odds of squamous cell carcinoma compared to low-impact variants (P = .02), and 5.7-fold greater odds of death compared to medium-impact variants (P = .05). LIMITATIONS: Cross-sectional design. CONCLUSION: Functional genotype categories may stratify RDEB severity; high-impact variants correlated with worse clinical outcomes. Further validation in larger cohorts is needed.

Inpatient management of epidermolysis bullosa: Consensus-based hands-on instructions for neonates and postneonates.

BACKGROUND: Epidermolysis bullosa (EB), characterized by skin fragility and blistering, often requires hospitalization. Training for inpatient management of EB is limited, with no unified recommendations available in North America. OBJECTIVE: To develop consensus-derived best practices for hands-on inpatient management of EB in both the neonatal and postneonatal period. METHODS: A modified Delphi method (expert-based input via 2 surveys and a final review) was implemented. Available guidelines from EB Clinical Research Consortium centers were analyzed to determine areas of focus and formulate statements to be voted on by EB Clinical Research Consortium members, experienced EB nurses, and select family members. Study participants evaluated statements using a Likert scale: statements with at least 70% agreement were accepted; statements with 30% or more disagreement were rejected. RESULTS: Ten areas of focus were identified. Delphi participants included 15 dermatologists, 8 nurses, and 6 nonhealth care caregivers. Consensus was established on 103/119 neonatal statements and 105/122 postneonatal statements; no statements were rejected. Most recommendations applied to both age groups. LIMITATIONS: Recommendations may require adjustment based on individual patient's clinical context. CONCLUSION: Using the Delphi method, a consensus-derived resource for hospital-based health care professionals who manage patients with EB has been developed to improve the quality of inpatient care.

Topical everolimus therapy for epidermal nevi associated with woolly hair nevus in a patient with a mosaic HRAS mutation.

A patient with woolly hair nevus syndrome, presented with epidermal facial nevi by the age of 12 years. Despite transient improvement with topical 1% sirolimus cream, the facial nevus grew larger. The patient was then treated with topical 1% everolimus cream resulting in a reduction in the size of the nevus. This case highlights a novel use of topical 1% everolimus cream, which previously has not been used to treat epidermal nevi.

Assessing pain catastrophizing and functional disability in pediatric epidermolysis bullosa patients.

BACKGROUND/OBJECTIVES: The primary objective was to assess pain catastrophizing and functional disability in pediatric patients with epidermolysis bullosa (EB) and their parents/guardians. Secondary objectives included examining relationships between pain catastrophizing, functional disability, and correlations with other factors (e.g., age, disease severity, and percent of body surface area (BSA) involved). METHODS: Patients with EB ages 8-16 and their parents/guardians who were English or Spanish speaking completed a one-time online survey. Parent measures included: demographics questionnaire, Pain Catastrophizing Scale-Parent (PCS), and Parent Functional Disability Inventory (FDI). Child measures included: PCS child and child FDI. Higher scores on both scales indicate higher levels of catastrophizing and functional disability. RESULTS: Of 31 children, the mean age was 11.47 years and the majority (70.97%) had dystrophic EB. Mean scores were: 35.84 = PCS parent; 34.58 = PCS child; 30.87 = parent FDI; 29.77 = child FDI. Total scores for PCS parent, parent FDI, and child FDI increased significantly with disease severity and percentage of involved BSA (p < .01 for all). Total scores for PCS child increased significantly with percent of EB skin involvement (p = .04) but not disease severity. Older children reported more functional disability than their parents and younger children (p = .02). CONCLUSIONS: Our results demonstrate significant positive correlations between negative thoughts related to pain and the experience of functional difficulties in patients with EB and their caregivers. Psychological, psychiatric, and/or behavioral interventions to help managing chronic pain may be effective for patients with EB.

Long-term safety and efficacy of gene-corrected autologous keratinocyte grafts for recessive dystrophic epidermolysis bullosa.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating blistering genodermatosis caused by mutations in the COL7A1 gene, which encodes for type VII collagen and is necessary for dermal-epidermal adhesion and integrity. Disease manifestations include severe and debilitating wounds, aggressive squamous cell carcinomas, and premature death; however, there are currently no approved therapies. This Phase 1/2a, open-label study evaluated the long-term efficacy and safety of gene-corrected autologous keratinocyte grafts (EB-101) for chronic RDEB wounds. METHODS: Autologous keratinocytes were harvested from participants with severe RDEB, transduced with a retrovirus containing the full-length COL7A1 gene, and grown into 5 × 7 cm (35 cm2) sheets. Gene-corrected keratinocyte sheets were then transplanted onto chronic RDEB wounds present for ≥ 12 weeks. RESULTS: Seven adult participants with severe RDEB were grafted with six sheets each (42 total sheets) onto wounds and followed for a mean of 5.9 years (range 4-8 years). Long-term improvements in wound healing and symptoms were observed. At year five, 70% (21/30) of treated sites demonstrated ≥ 50% wound healing compared to baseline by investigator global assessment. No sites with ≥ 50% wound healing were painful or pruritic, compared to 67% (6/9) of sites with < 50% wound healing (p < 0.001) at year five. Grafts were well-tolerated throughout long-term follow-up. No serious adverse events related to treatment were reported over a mean of 5.9 years of follow-up. No persistent systemic autoimmunity against type VII collagen or replication-competent retrovirus infections were identified, and no participants developed squamous cell carcinomas related to treatment during long-term follow-up. CONCLUSIONS: Treatment with EB-101 appears safe and efficacious, and produces long-term improvements in wound healing, pain, and itch for RDEB patients. Results from the Phase 3 randomized controlled trial are forthcoming. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01263379. Registered December 15, 2010. https://clinicaltrials.gov/ct2/show/NCT01263379.

A global, cross-sectional survey of patient-reported outcomes, disease burden, and quality of life in epidermolysis bullosa simplex.

BACKGROUND: Epidermolysis bullosa simplex (EBS) comprises a group of rare, blistering genodermatoses. Prior work has been limited by small sample sizes, and much remains unexplored about the disease burden and health-related quality of life (QOL) of patients with EBS. The aim of this study was to characterize the most common patient-reported clinical manifestations and the health-related impact of QOL in EBS, and to examine differences in disease burden by age. METHODS: Patients with a diagnosis of epidermolysis bullosa (EB) or their caregivers completed a one-time online survey administered by EBCare, an international online EB registry. Survey data from respondents self-reporting a diagnosis of EBS were analyzed for clinical and wound manifestations, medication use, and QOL (using Quality of Life in Epidermolysis Bullosa [QOLEB] scores). Differences across age groups were assessed using Kruskal-Wallis and Fisher's exact tests. RESULTS: There were 214 survey respondents with EBS. The mean age was 32.8 years (standard deviation = 19.2). Many respondents reported blisters (93%), recurrent wounds (89%), pain (74%), chronic wounds (59%), itch (55%), and difficulty walking (44%). Mean QOLEB score was 14.7 (standard deviation = 7.5) indicating a "moderate" impact on QOL, and 12% of respondents required regular use of opiates. Findings were consistent in subgroup analyses restricted to respondents with diagnostic confirmation via genetic testing or skin biopsy (n = 63 of 214). Age-stratified analyses revealed differences in disease burden: younger respondents were more likely to self-report severe disease (24% vs. 19% vs. 5% for respondents aged 0-9 vs. 10-17 vs. 18 + , p = 0.001), failure to thrive (9% vs. 15% vs. 3%, p = 0.02), and use of gastrostomy tubes (15% vs. 12% vs. 1%, p < 0.001) and topical antibiotics (67% vs. 69% vs. 34%, p < 0.001), while older respondents were more likely to be overweight or obese (6% vs. 0% vs. 51%, p < 0.001) and have difficulty walking (24% vs. 46% vs. 48%, p = 0.04). CONCLUSIONS: In the largest international cross-sectional survey of EBS patients conducted, respondents reported extensive disease burden including significant wounding, pain, itch, difficulty walking, and impact on QOL. Age stratified disease manifestations. These findings suggest significant unmet need, and treatment and counseling for EBS patients should consider age-specific differences.

Patient-reported outcomes and quality of life in dominant dystrophic epidermolysis bullosa: A global cross-sectional survey.

INTRODUCTION: Dystrophic epidermolysis bullosa is a debilitating skin condition, without curative treatment. Previous research has focused on the recessive variant, which is known to cause severe disease. Limited work focusing on the clinical manifestations and outcomes of dominant dystrophic epidermolysis bullosa is found (DDEB). METHODS: Analysis of an online survey of 42 DDEB patients. RESULTS: Self-reported severity of disease did not correlate with size of the wound or number of dressing changes, but did correlate with severity of pain reported in the last 12 months (3.4 mild vs 6.8 severe disease, P = 0.0002). Patients with severe DDEB also reported more severe internal disease symptoms, such as difficulty swallowing (62.5%, P = 0.01) and greater analgesic use during dressing changes (4.4% mild vs 81.3% severe, P = <0.001). DISCUSSION: Patient perception of disease severity in DDEB appears to be most impacted by pain, presence of chronic open wounds, difficulty swallowing, difficulty walking, and anal strictures. As research on DDEB increases, future studies focused on these symptoms might be the most impactful for DDEB patients. However, distinguishing DDEB from other subtypes remains a challenge.

Cannabinoid use and effects in patients with epidermolysis bullosa: an international cross-sectional survey study.

BACKGROUND: Epidermolysis bullosa (EB) patient anecdotes and case reports indicate that cannabinoid-based medicines (CBMs) may alleviate pain and pruritus and improve wound healing. CBM use has not been characterized in the EB patient population. OBJECTIVES: To evaluate CBM use among EB patients, including CBM types, effects on symptoms (e.g., pain and pruritus), disease process (e.g., blistering, wounds, and inflammation), well-being (e.g., sleep, appetite) and concomitant medications. METHODS: English-speaking EB patients or caregivers completed an online international, anonymous, cross-sectional survey regarding CBM use. Respondents reported the types of CBMs, subsequent effects including perceived EB symptom alteration, changes in medication use, and side effects. RESULTS: Seventy-one EB patients from five continents reported using or having used CBMs to treat their EB. Missing question responses ranged between 0 (0%) and 33 (46%). Most used more than one CBM preparation (mean: 2.4 ± 1.5) and route of administration (mean: 2.1 ± 1.1). Topical and ingested were the most common routes. Pain and pruritus were reported retrospectively to decrease by 3 points (scale: 0-10; p < 0.001 for both) after CBM use. Most reported that CBM use improved their overall EB symptoms (95%), pain (94%), pruritus (91%) and wound healing (81%). Most participants (79%) reported decreased use of pain medications. The most common side-effect was dry mouth (44%). CONCLUSIONS: CBMs improve the perception of pain, pruritus, wound healing, and well-being in EB patients and reduced concomitant medication use. Nevertheless, a direct relation between the use of CBMs and reduction of the above-mentioned symptoms cannot be proven by these data. Therefore, future controlled studies using pharmaceutically standardised CBM preparations in EB are warranted to delineate the risks and benefits of CBMs.

Diagnosis and Care of the Newborn with Epidermolysis Bullosa.

Epidermolysis bullosa (EB) is a group of rare genetic disorders that are characterized by fragile skin. Because of its rarity, many neonatologists may not be familiar with the current diagnosis and treatment recommendations for EB. The classification of EB was updated in 2020. The diagnosis of EB is now more heavily based on genetic rather than clinical or histologic features. In this review, we summarize the basic classification of EB, the preferred methods of diagnosis including a panel of next-generation sequencing for all types of EB, as well as specific immunofluorescence and electron microscopy of skin biopsies in special circumstances. We also review the principles of skin care for the newborn with EB and discuss the possible associated comorbidities including infectious, gastrointestinal, respiratory, and genitourinary complications. Lastly, we discuss the approach to educating the family about the diagnosis, prognosis, and care of an infant with EB and describe resources for the successful transition of the infant from the hospital to the home.

A systematic literature review of the disease burden in patients with recessive dystrophic epidermolysis bullosa.

BACKGROUND/OBJECTIVE: Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic collagen disorder characterized by skin fragility leading to blistering, wounds, and scarring. There are currently no approved curative therapies. The objective of this manuscript is to provide a comprehensive literature review of the disease burden caused by RDEB. METHODS: A systematic literature review was conducted in MEDLINE and Embase in accordance with PRISMA guidelines. Observational and interventional studies on the economic, clinical, or humanistic burden of RDEB were included. RESULTS: Sixty-five studies were included in the review. Patients had considerable wound burden, with 60% reporting wounds covering more than 30% of their body. Increases in pain and itch were seen with larger wound size. Chronic wounds were larger and more painful than recurrent wounds. Commonly reported symptoms and complications included lesions and blistering, anemia, nail dystrophy and loss, milia, infections, musculoskeletal contractures, strictures or stenoses, constipation, malnutrition/nutritional problems, pseudosyndactyly, ocular manifestations, and dental caries. Many patients underwent esophageal dilation (29-74%; median dilations, 2-6) and gastrostomy tube placement (8-58%). In the severely affected population, risk of squamous cell carcinoma (SCC) was 76% and mortality from SCC reached 84% by age 40. Patients with RDEB experienced worsened quality of life (QOL), decreased functioning and social activities, and increased pain and itch when compared to other EB subtypes, other skin diseases, and the general population. Families of patients reported experiencing high rates of burden including financial burden (50-54%) and negative impact on private life (79%). Direct medical costs were high, though reported in few studies; annual payer-borne total medical costs in Ireland were $84,534 and annual patient-borne medical costs in Korea were $7392. Estimated annual US costs for wound dressings ranged from $4000 to $245,000. Patients spent considerable time changing dressings: often daily (13-54% of patients) with up to three hours per change (15-40%). CONCLUSION: Patients with RDEB and their families/caregivers experience significant economic, humanistic, and clinical burden. Further research is needed to better understand the costs of disease, how the burden of disease changes over the patient lifetime and to better characterize QOL impact, and how RDEB compares with other chronic, debilitating disorders.

Clinical characteristics associated with increased wound size in patients with recessive dystrophic epidermolysis bullosa.

As more therapeutic clinical trials focus on treatment of individual wounds in patients with recessive dystrophic epidermolysis bullosa, it has become crucial to understand the baseline clinical characteristics of these wounds. To investigate these features, we administered an RDEB-specific wound survey. Forty participants reported on location, size, pain, infection frequency, wound type, and duration of 189 wounds; a subset of 22 participants reported on pruritus in 63 wounds. Increased wound size was significantly associated with increased pain, increased pruritus, longer wound duration, increased infection frequency, and patients with mutations resulting in truncated type VII collagen.

Patient-reported outcomes and quality of life in recessive dystrophic epidermolysis bullosa: A global cross-sectional survey.

BACKGROUND: A spectrum of skin disease severity exists in patients with recessive dystrophic epidermolysis bullosa (RDEB). OBJECTIVE: To characterize the patient-reported outcomes and quality of life (QOL) in patients with RDEB. METHODS: A cross-sectional study of patients with RDEB surveyed through the global EBCare Registry. Patient-reported outcomes included skin disease severity, wound characteristics, pain, itch, extracutaneous symptoms, and medications. QOL was measured by using the validated Quality of Life in Epidermolysis Bullosa instrument. RESULTS: A total of 85 patients with RDEB reported 1226 wounds (937 recurrent wounds and 289 chronic open wounds). Overall skin disease severity was self-reported as mild (26%; 22/83), moderate (48%; 40/83), or severe (25%; 21/83). Worsening skin disease severity was significantly associated with larger wounds, increased opiate use, anemia, gastrostomy tube use, infections, osteoporosis, and squamous cell carcinoma. Larger wound size was associated with worse quality of life scores. LIMITATIONS: All data were self-reported from an online epidermolysis bullosa patient registry. CONCLUSIONS: This study shows a significant correlation between larger wound size with worsening skin disease severity and quality of life in participants with RDEB. Worsening skin disease severity significantly correlated with key clinical manifestations. These results show that patients with RDEB are able to self-report their skin disease severity and wounds.

Induced Remission of Metastatic Squamous Cell Carcinoma with an Immune Checkpoint Inhibitor in a Patient with Recessive Dystrophic Epidermolysis Bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a genodermatosis that leads to skin fragility and chronic wound formation. Patients with RDEB are at risk for cutaneous squamous cell carcinoma (SCC) which is a major cause of morbidity and mortality in these patients. No standard of care exists for the treatment of SCC in this patient population and therapy is based on anecdotal reports and expert opinion. We report a 32-year-old man with RDEB with previously localized SCC who later developed metastatic SCC. He was started on cemiplimab (an immune checkpoint inhibitor) 350 mg IV every 3 weeks. An objective radiological response was noted within 3 cycles. On 14 months follow-up, there was a durable response to treatment clinically and on imaging, without immune-related adverse events. To our knowledge, this is the first case report describing safe administration of immune checkpoint inhibitors in a patient with RDEB with objective and durable response of metastatic SCC. Larger case series and controlled clinical trials are needed to further investigate these medications in the RDEB population, given their high burden of aggressive and often lethal SCC.

Financial burden of epidermolysis bullosa on patients in the United States.

Individuals with epidermolysis bullosa (EB), a group of genodermatoses with skin fragility, often require specialized and expensive bandaging. We analyzed the results from an online survey of 249 EB patients and caregivers living in the United States to investigate the financial impact of EB. Of respondents with severe EB subtypes (recessive dystrophic and junctional), 73% reported a major or moderate financial impact and 26% spent greater than $1000 per month on wound care supplies. These results demonstrate the high financial burden associated with epidermolysis bullosa in the United States and support the need for a federally funded EB bandage program.

Phase 1/2a clinical trial of gene-corrected autologous cell therapy for recessive dystrophic epidermolysis bullosa.

BACKGROUNDRecessive dystrophic epidermolysis bullosa (RDEB) patients have mutations in the COL7A1 gene and thus lack functional type VII collagen (C7) protein; they have marked skin fragility and blistering. This single-center phase 1/2a open-label study evaluated the long-term efficacy, safety, and patient-reported outcomes in RDEB patients treated with gene-corrected autologous cell therapy.METHODSAutologous keratinocytes were isolated from participant skin biopsies. Epidermal sheets were prepared from cells transduced with a retrovirus carrying the full-length human COL7A1 gene. These gene-corrected autologous epidermal sheets measured 5 × 7 cm (35 cm2) and were transplanted onto 6 wound sites in each of 7 adult participants (n = 42 sites total) from 2013 to 2017. Participants were followed for 2 to 5 years.RESULTSNo participants experienced any serious related adverse events. Wound healing of 50% or greater by Investigator Global Assessment was present in 95% (36 of 38) of treated wounds versus 0% (0 of 6) of untreated control wounds at 6 months (P < 0.0001). At year 1, 68% (26 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.025). At year 2, 71% (27 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.019).CONCLUSIONC7 expression persisted up to 2 years after treatment in 2 participants. Treated wounds with 50% or greater healing demonstrated improvement in patient-reported pain, itch, and wound durability. This study provides additional data to support the clinically meaningful benefit of treating chronic RDEB wounds with ex vivo, C7 gene-corrected autologous cell therapy. This approach was safe and promoted wound healing that was associated with improved patient-reported outcomes.TRIAL REGISTRATIONClinicaltrials.gov identifier: NCT01263379.FUNDINGEpidermolysis Bullosa Research Partnership, Epidermolysis Bullosa Medical Research Foundation, NIH R01 AR055914, Office of Research and Development at the Palo Alto Veteran's Affairs Medical Center, and the Dermatology Foundation.