A case of junctional epidermolysis bullosa intermediate with collagen XVII deficiency treated with dupilumab.

Inherited epidermolysis bullosa is a heterogeneous group of hereditary skin diseases characterized by skin (mucosa) fragility, which leads to blistering. Junctional epidermolysis bullosa is associated with mutations in genes expressing proteins of the dermo-epidermal junction. Dupilumab, an antibody that directly targets interleukin (IL)-4 receptor alpha, may be an effective treatment for dystrophic epidermolysis bullosa. We describe a case of junctional epidermolysis bullosa that improved with dupilumab.

Molecular and Clinical Outcomes After Intravenous Gentamicin Treatment for Patients With Junctional Epidermolysis Bullosa Caused by Nonsense Variants.

IMPORTANCE: Junctional epidermolysis bullosa (JEB) is an incurable blistering skin disorder with high infant mortality often caused by nonsense variants in the genes that encode laminin 332. OBJECTIVE: To evaluate the safety and outcomes following intravenous gentamicin readthrough therapy and subsequent laminin 332 expression in patients with JEB. DESIGN, SETTING, AND PARTICIPANTS: This open-label, pilot nonrandomized clinical trial assessed 1 course of low- or high-dose intravenous gentamicin, including follow-up at 30 and 90 days after treatment. Five pediatric patients with JEB (2 with intermediate JEB and 3 with severe JEB) and confirmed nonsense variants in LAMA3 or LAMB3 in 1 or 2 alleles and decreased expression of laminin 332 at the dermal-epidermal junction of their skin participated in the study, which was performed at a single institution in collaboration with physicians and home infusion services near the patients from April 1, 2019, to February 28, 2021, with follow-up until May 31, 2021. INTERVENTIONS: Three patients received gentamicin at 7.5 mg/kg daily for 14 days, and 2 patients received gentamicin at 10 mg/kg daily for 24 days. MAIN OUTCOMES AND MEASURES: Primary outcomes were change in expression of laminin 332 in patients' skin and assessments for safety (ototoxic effects, nephrotoxic effects, and autoimmune response). Secondary outcomes included wound healing in monitored wounds and Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) score. RESULTS: After gentamicin treatment, all 5 patients (age range, 3 months to 10 years, 4 [80%] female) exhibited increased laminin 332 in the dermal-epidermal junction. By 1 month, 7 of 9 wounds in patients receiving low-dose intravenous gentamicin and all wounds in patients receiving high-dose intravenous gentamicin exhibited at least 50% wound closure. By 3 months, 8 of 9 wounds in patients receiving low-dose gentamicin and all wounds in patients receiving high-dose intravenous gentamicin exhibited greater than 85% closure. All 3 patients who were evaluated with EBDASI showed a decrease in total activity scores that met minimal clinically important differences 1 month after treatment. All 5 patients completed the study, and no ototoxic effects, nephrotoxic effects, or anti-laminin 332 antibodies were detected. CONCLUSIONS AND RELEVANCE: In this nonrandomized clinical trial, intravenous gentamicin therapy was associated with induced readthrough of nonsense variants in patients with JEB, restored functional laminin 332 in their skin, and wound closure during the 3-month study period. Although long-term safety and efficacy requires further evaluation, a single cycle of intravenous gentamicin may be a safe and readily available therapy in the short term for this population of patients with JEB. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT03526159 and NCT04140786.

A Novel Phenotype of Junctional Epidermolysis Bullosa with Transient Skin Fragility and Predominant Ocular Involvement Responsive to Human Amniotic Membrane Eyedrops.

Junctional epidermolysis bullosa (JEB) is a clinically and genetically heterogeneous skin fragility disorder frequently caused by mutations in genes encoding the epithelial laminin isoform, laminin-332. JEB patients also present mucosal involvement, including painful corneal lesions. Recurrent corneal abrasions may lead to corneal opacities and visual impairment. Current treatments are merely supportive. We report a novel JEB phenotype distinguished by the complete resolution of skin fragility in infancy and persistent ocular involvement with unremitting and painful corneal abrasions. Biallelic LAMB3 mutations c.3052-5C>G and c.3492_3493delCG were identified as the molecular basis for this phenotype, with one mutation being a hypomorphic splice variant that allows residual wild-type laminin-332 production. The reduced laminin-332 level was associated with impaired keratinocyte adhesion. Then, we also investigated the therapeutic power of a human amniotic membrane (AM) eyedrop preparation for corneal lesions. AM were isolated from placenta donors, according to a procedure preserving the AM biological characteristics as a tissue, and confirmed to contain laminin-332. We found that AM eyedrop preparation could restore keratinocyte adhesion in an in vitro assay. Of note, AM eyedrop administration to the patient resulted in long-lasting remission of her ocular manifestations. Our findings suggest that AM eyedrops could represent an effective, non-invasive, simple-to-handle treatment for corneal lesions in patients with JEB and possibly other EB forms.

Gentamicin Induces Laminin 332 and Improves Wound Healing in Junctional Epidermolysis Bullosa Patients with Nonsense Mutations.

Generalized severe junctional epidermolysis bullosa (GS-JEB) is an incurable and fatal autosomal recessively inherited blistering skin disease caused by mutations in the LAMA3, LAMB3, or LAMC2 genes. Most of these mutations are nonsense mutations that create premature termination codons that lead to impaired production of functional laminin 332, a protein needed for epidermal-dermal adherence. Gentamicin induces readthrough of nonsense mutations and restores the full-length protein in various genetic diseases. Using primary keratinocytes from three GS-JEB patients, we showed that gentamicin induced functional laminin 332 that reversed a JEB-associated, abnormal cell phenotype. In a subsequent open-label trial involving the same patients, we examined whether 0.5% gentamicin ointment applied topically to open skin wounds could promote nonsense mutation readthrough and create new laminin 332 in the patients' skin. Gentamicin-treated wounds exhibited increased expression of laminin 332 at the dermal-epidermal junction for at least 3 months and were associated with improved wound closure. There were no untoward side effects from topical gentamicin. The newly induced laminin 332 did not generate anti-laminin 332 autoantibodies in either the patients' blood or skin. Gentamicin readthrough therapy may be a treatment for GS-JEB patients with nonsense mutations.

Leading edge: emerging drug, cell, and gene therapies for junctional epidermolysis bullosa.

INTRODUCTION: Junctional epidermolysis bullosa (JEB) is a rare inherited genetic disorder with limited treatments beyond palliative care. A major hallmark of JEB is skin blistering caused by functional loss or complete absence of major structural proteins of the skin. Impaired wound healing in patients with JEB gives rise to chronic cutaneous ulcers that require daily care. Wound care and infection control are the current standard of care for this patient population. AREAS COVERED: This review covers research and clinical implementation of emerging drug, cell, and gene therapies for JEB. Current clinical trials use topical drug delivery to manipulate the inflammation and re-epithelialization phases of wound healing or promote premature stop codon readthrough to accelerate chronic wound closure. Allogeneic cell therapies for JEB have been largely unsuccessful, with autologous skin grafting emerging as a reliable method of resolving the cutaneous manifestations of JEB. Genetic correction and transplant of autologous keratinocytes have demonstrated persistent amelioration of chronic wounds in a subset of patients. EXPERT OPINION: Emerging therapies address the cutaneous symptoms of JEB but are unable to attend to systemic manifestations of the disease. Investigations into the molecular mechanism(s) underpinning the failure of systemic allogeneic cell therapies are necessary to expand the range of effective JEB therapies.

Attenuation of Severe Generalized Junctional Epidermolysis Bullosa by Systemic Treatment with Gentamicin.

Severe generalized junctional epidermolysis bullosa (JEB), a lethal genodermatosis, is mainly caused by premature termination codons (PTCs) in one of the three genes encoding the anchoring protein laminin-332. Only symptomatic treatment has been established; overcoming PTCs by aminoglycosides may represent an interesting alternative. This retrospective study aimed at assessing for the first time the clinical effects of systemic gentamicin application in infants with severe generalized JEB. Five patients, homozygous or compound-heterozygous for PTCs in the gene LAMB3, were treated with gentamicin which was administered intravenously or by intramuscular injection at doses of 7.5 mg/kg/d for three weeks. Skin biopsies were investigated by immunofluorescence analyses. Clinical effects of the medication were recorded with a parent questionnaire and by assessing weight-for-age charts. Gentamicin application was well tolerated, long hospitalization was not required. Low levels of laminin-332 could be detected in a skin sample obtained after treatment. Gentamicin had a positive impact on skin fragility and daily life in four patients but did not influence weight gain and failed to reverse the lethal course of the disease. Gentamicin injections should be considered regularly in cases of severe generalized JEB caused by PTCs as they may attenuate JEB symptoms without impeding quality of life.

Palliative Sedation with Oral Medicines in an Infant with Generalized Severe Junctional Epidermolysis Bullosa.

Generalized severe junctional epidermolysis bullosa is a rare mechanobullous skin disorder that is uniformly fatal. We present the case of an infant who received palliative pain management and ultimately proportionate palliative sedation. However, because of the extent of the patient's skin disease, we were unable to provide palliative medication through parenteral routes. We discuss the provision of enteral palliative sedation, including the pharmacology, and creative use of medications to achieve sufficient palliation in this difficult and unique situation.

Responsiveness of nonHerlitz junctional epidermolysis bullosa to topical gentian violet.

BACKGROUND: Gentian violet (GV), a mixture of crystal violet and methyl violet, a dye belonging to the di- and triaminophenylmethanes class and has been widely used for its bactericidal and fungicidal properties. To date, there have been no reports of long-term therapeutic use of GV in epidermolysis bullosa (EB). METHODS: Two brothers with nonHerlitz junctional epidermolysis bullosa (JEB) aged 12 and 14 tried topical GV to one lower leg with conventional silicone dressings and this was compared with leaving the other leg with silicone dressings alone, over 4 weeks. Wounds were photographed and measured using Visitrak analysis. Pain, ooze, and appearance were assessed using visual analog scales (VAS) scales and Quality of life using Dermatology Life Quality Index and QOLEB (2) tools. RESULTS: The side treated with dressings and GV reduced to 14.9 cm(2) (-20.74%) and to 9.5 cm(2) (-56.62%) for dressings alone in the older brother (EB-012) and to 4.2 cm(2) (+20%) and 12.5 cm(2) (-7%) for the younger brother (EB-011) in ulcer size, respectively. Both patients did complain of stinging on the sites treated within a few days. QOL measures and VAS scores did not show any significant change. CONCLUSIONS: GV may be considered to be a therapeutic option for ulcers in nH-JEB patients and potentially other EB subtypes. A formal randomized controlled trial and long-term safety study of GV in EB is recommended.

Bullous pemphigoid in a patient with suspected non-Herlitz junctional epidermolysis bullosa.

A 56-year-old man with lifelong trauma-induced blisters, nail dystrophy and dental enamel hypoplasia presented with a new spontaneous blistering eruption. Clinicopathologically, he had evidence of both an inherited and an acquired blistering disorder: non-Herlitz junctional epidermolysis bullosa (nHJEB) and bullous pemphigoid (BP). HIstological examination of a skin biopsy found reduced (but not absent) collagen XVII in nonlesional skin, in vivo bound anticollagen XVII antibodies in perilesional skin, and prominent eosinophils in perilesional and lesional skin, with subepidermal blistering. Circulating anticollagen XVII antibodies were also present. Treatment with oral corticosteroids and mycophenolate mofetil led to clinical control of the BP but had no effect on the mechanobullous blistering. Our patient is unusual in that his skin retains some labelling for collagen XVII rather than having the complete absence of immunoreactivity expected in patients with generalized nHJEB. Moreover, we were unable to identify any pathogenic mutations in the COL17A1 gene encoding collagen XVII (or in other EB-associated basement membrane genes). It is plausible that the long-term consequences of basement membrane disruption in our patient, perhaps associated with atypical inherited COL17A1 pathology, might result in a conformationally altered and more immunogenic protein with the subsequent development of anticollagen XVII antibodies and BP as a secondary pathology.