Epidermolysis Bullosa Treatment & Management

Skin involvement

Gene therapy

The FDA approved the first topical gene therapy for treatment of wounds in patients with dystrophic epidermolysis bullosa (DEB). It is indicated for the treatment of wounds in patients aged 6 months and older with dystrophic epidermolysis bullosa with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene. 

DEB is caused by mutation(s) in the COL7A1 gene, which results in reduced or absent levels of biologically active COL7. Patients with autosomal dominant DEB (DDEB) have lower than normal functional anchoring fibrils, and patients with recessive (RDEB) have no functional anchoring fibrils. COL7 molecules arrange themselves into long, thin bundles that form anchoring fibrils. Anchoring fibrils hold the epidermis and dermis together and are essential for maintaining skin integrity.  

Upon topical application to wounds, beremagene geperpavec can transduce both keratinocytes and fibroblasts. Once into the cells, it is deposited in the nucleus and transcription of the encoded human COL7A1 is initiated. Resulting transcripts allow for production and secretion of COL7 by the cell in its mature form. 

Approval was based on the phase 3 GEM clinical trial. For each patient, a primary wound pair was selected, with the wounds matched according to size, region, and appearance. The wounds within each pair were randomly assigned in a 1:1 ratio to receive weekly application of either beremagene geperpavec or placebo for 26 weeks. The primary end point was complete wound healing of treated as compared with untreated wounds at 6 months. Complete wound healing at 3 months occurred in 71% of the wounds exposed to beremagene geperpavec as compared with 20% of those exposed to placebo (P < 0.001). ^[21]   

Wound healing

This process is impaired by multiple factors including foreign bodies, bacteria, nutritional deficiencies, tissue anoxia, and aging. Exogenous agents contributing to impairment of wound healing include glucocorticoids and penicillamine. Optimizing wound healing in patients with epidermolysis bullosa (EB) involves controlling all of these factors. Patients with Herlitz junctional epidermolysis bullosa heal slowly, which may be because of a defect in laminin-332 (a protein involved intimately in keratinocyte adhesion and migration).

When a patient with epidermolysis bullosa is hospitalized for severe blistering, treat the blisters aggressively with wound and nutritional management. Regular whirlpool therapy can help with gentle cleansing and debridement of wounds. Whirlpool therapy is a helpful adjunct available in most hospitals and assists in the care of inpatients with epidermolysis bullosa.

Take great care to avoid trauma to the skin during transfers or additional blistering will occur, especially in patients with severe epidermolysis bullosa. Never apply tape to the skin of patients with epidermolysis bullosa.

Patients with severe epidermolysis bullosa require significant amounts of wound-care supplies, such as plain petroleum gauze, nonadhering gauze such as Adaptic or Telfa, petroleum jelly, antibiotic ointment, and self-adhering gauze. Be sure to prescribe sufficient quantities of these materials. Insurance companies and health maintenance organizations may neglect to cover these essential therapies. Physicians and social workers working together may need to advocate for their patients in this regard. 

A topical gel, Filsuvez (birch triterpenes), was approved by the FDA in December 2023 for treatment of wounds in patients aged 6 months and older with junctional and dystrophic epidermolysis bullosa. 

The approval was based on results from the phase 3 EASE study. Patients were randomized to receive either birch triterpenes (n = 109) or placebo (n = 114) and instructed to apply approximately 1 mm to all affected areas at each dressing change (every 1 to 4 days) for 90 days. 

At randomization, 1 wound was selected by the investigator as the target wound for the evaluation of the primary efficacy endpoint. The target wound was defined as a partial-thickness wound with a surface area of 10-50 cm² that was present for 21 days to 9 months before screening. Among patients treated with birch triterpenes, 41.3% had first complete closure of the target wound within 45 days compared with 28.9% of patients treated with placebo gel. ^[22]   

Infection

Extensive areas of denuded skin represent loss of the stratum corneum barrier to microbial penetration. Accumulation of serum and moisture on the surface enhances the growth of bacteria.

Patients with severe epidermolysis bullosa subtypes may have immunologic abnormalities, including decreased lymphocyte production or a poor nutritional status that lowers resistance to infections. Staphylococcus aureus and Streptococcus pyogenes are the usual causative organisms, but gram-negative infections with bacteria, such as Pseudomonas aeruginosa, also can occur. Patients also have increased susceptibility to developing sepsis.

Prevention of infection is the preferred strategy. With extensive areas of crusting and denudation, a strict wound care regimen should be followed. Such a regimen entails regular whirlpool therapy followed by application of topical antibiotics. The wound should be covered with semiocclusive nonadherent dressings. Do not apply adhesive tape directly to the skin. Self-adhering gauze or tape is a better choice for keeping dressings in place.

Tumors

SCC often arises in chronic cutaneous lesions in patients with epidermolysis bullosa. SCC often occurs at multiple primary sites, which is especially true for patients with recessively inherited epidermolysis bullosa.

In the non–epidermolysis bullosa population, cutaneous SCC arises most frequently in sun-exposed areas and primarily affects individuals with skin types I and II after the fourth decade of life.

In contrast, the distribution of cutaneous SCC in patients with recessively inherited epidermolysis bullosa is different. In recessively inherited epidermolysis bullosa, SCC affects all skin types, does not show a predilection for sun-exposed sites, and peak incidence begins to increase dramatically in the second and third decades of life.

Careful surveillance of nonhealing areas is very important.

GI management

The most disabling complication is esophageal lesions, which are found in Hallopeau-Siemens and inverse recessively inherited epidermolysis bullosa subtypes, Dowling-Meara, letalis epidermolysis bullosa simplex subtypes, and all junctional epidermolysis bullosa forms except localized and progressiva/neurotropica. These lesions are managed in several ways. One medical approach is to use phenytoin and oral steroid elixirs to reduce the symptoms of dysphagia. In addition, if oral candidiasis is present, an anticandidal medication is helpful.

Eye lesions

Patients with epidermolysis bullosa simplex, particularly those with the Weber-Cockayne and Dowling-Meara subtypes, can experience recurrent blepharitis in 1 or both eyes along with bullous lesions of the conjunctivae.

Patients with junctional epidermolysis bullosa and Hallopeau-Siemens dystrophic epidermolysis bullosa can experience corneal ulcerations, corneal scarring, obliteration of tear ducts, and eyelid lesions.

Cicatricial conjunctivitis also can occur in patients with the recessively inherited epidermolysis bullosa Hallopeau-Siemens subtype.

Corneal erosions are treated supportively with application of antibiotic ointment and use of cycloplegic agents to reduce ciliary spasm and provide comfort. Avoid using tape to patch the eye because of frequent blistering of the skin under the adhesive.

Chronic blepharitis can result in cicatricial ectropion and exposure keratitis. Moisture chambers and ocular lubricants are used commonly for management. This disorder also has been treated with full-thickness skin grafting to the upper eyelid; however, complete correction is difficult to obtain. ^[23]

Oral care

Good dental hygiene is essential for patients with epidermolysis bullosa, and regular visits to the dentist are recommended. If possible, a dentist familiar with epidermolysis bullosa should be consulted. Despite their best efforts, many patients with junctional epidermolysis bullosa and dystrophic epidermolysis bullosa develop dental caries because of enamel defects. In addition, significant oral mucosal involvement can accompany severe forms of junctional epidermolysis bullosa and dystrophic epidermolysis bullosa. Avoid harsh mouthwashes containing alcohol. Normal saline rinses can help gently clean the mucosal surfaces.

Research therapies

Potential protein, cell, and gene therapies are advancing. Model systems using these approaches show promise for significant advances in future therapies.

In protein therapy, the missing or defective protein is produced in vitro by recombinant methods and applied directly to blistered skin. Protein therapy may be most useful in epidermolysis bullosa subtypes involving a defect or deficiency in type VII collagen because this protein appears to have a long half-life in the body. ^{[24, 25]}

In gene therapy, the goal is to deliver genes targeted to restore normal protein production. Beremagene geperpavec, the first gene therapy approved by the FDA, is a nonlethal form of junctional epidermolysis bullosa has been successful in long-term studies. This was accomplished using a retroviral gene transfer system, using ex vivo gene transfer and grafting corrected keratinocytes back onto the patient. ^[26]

Clinical trials

Gene therapy for nonlethal junctional epidermolysis bullosa has been performed and shown to be efficacious in a small trial of one patient. In this trial, cultured patient keratinocytes received a normal copy of the LAMB3 gene through retroviral delivery, then the corrected cells were grafted back to areas of the patient’s skin. Analysis over 1 year showed continued high expression of laminin-332 and a clinical absence of blistering.

In one clinical trial at the University of Minnesota, bone marrow transplantation was used as the mechanism of delivery of corrective cells. In this trial, recessively inherited epidermolysis bullosa patients undergo bone marrow ablation and immunosuppression. Complications included mortality in approximately 30% of patients; however, some efficacy was demonstrated in blistering phenotype and collagen VII expression in the skin.

Clinical trials in England and Australia have found some short-term benefits of allogenic fibroblast injections into the wounds of recessive dystropic epidermolysis bullosa patients. ^{[27, 28]}

Another clinical trial, performed at Stanford University, consisted of retroviral-mediated type VII collagen gene transfer to keratinocytes. ^[29] In this trial, patient keratinocytes are treated with a type VII collagen gene in a retrovirus, and the cells are grafted back to the patient. Analysis of four patients treated with six type VII collagen gene corrected grafts each showed that the approach was both safe and effective, with clinical improvement and type VII collagen expression still present in many grafted sites, even after assessment at 1 year.

Clinical trials of autologous collagen VII overexpressing fibroblast injections in recessive dystropic epidermolysis bullosa patients are currently taking place at both Stanford University and King’s College, London.

GI management

Esophageal dilation has been helpful in relieving strictures. Removal of esophageal strictures by colonic interposition has proved effective in cases of advanced disease. Gastrostomy tube insertion has been effective in providing nutrition to individuals with esophageal strictures.

Surgical restoration of the hand  ^[30]

Mitten deformity of the hand occurs frequently in patients with the Hallopeau-Siemens dystrophic epidermolysis bullosa subtype. Repeated episodes of blistering and scarring eventually result in fusion of the web spaces. As a result, fine manipulative skills and digital prehension are lost. Surgical procedures can correct this deformity, but a high rate of recurrence is seen with mitten pseudosyndactyly. Typically, the dominant hand has earlier recurrence. Recurrence appears to be delayed by the prolonged use of splinting in the interphalangeal spaces at night.

Surgical excision of SCC

Invasive aggressive SCC is a particularly troubling complication of recessively inherited epidermolysis bullosa. When detected, excision of the carcinoma is indicated. Both Mohs and non-Mohs surgical approaches have been used.

Endotracheal tube placement

Perform this procedure with extra care in patients with epidermolysis bullosa. Optimally, consult an anesthesiologist experienced in the care of patients with epidermolysis bullosa. ^[31]

Skin equivalents

Human keratinocytes cultured atop dermal equivalents are commercially available; they have been useful in facilitating healing of erosions in persons with epidermolysis bullosa and in improving the overall quality of life of these patients. ^[32] These are allografts, in that the cells do not derive from the patient themselves but from another unidentified donor. These allografts are eventually rejected by immunocompetent hosts such as patients with epidermolysis bullosa. However, before they are rejected, they are believed to produce cytokines that facilitate the wound healing process and stimulate reepithelialization of the patients' wounds. Skin equivalent therapy represents an effective short-term therapy for treating chronic nonhealing wounds associated with epidermolysis bullosa. Claims that allografts produce a permanent cure for epidermolysis bullosa are unsubstantiated.

Genetic counseling

Genetic information provided by mutation analyses on epidermolysis bullosa candidate genes provides an immediate benefit to families of patients with epidermolysis bullosa. Siblings of a patient identified as a proband with recessively inherited epidermolysis bullosa that are considering children often want to know whether they carry the mutant allele.

Most importantly, prenatal diagnosis of epidermolysis bullosa in affected families currently is a genetic-based protocol, providing that the patient identified as the original proband has had mutational analysis or identification of the defective gene. Currently, fetal skin biopsies and fetoscopy, with their increased risk of pregnancy loss, can be avoided by analyzing either a chorionic villus sample as early as 8-10 weeks or amniotic fluid in the second trimester. The development of highly informative intragenic and flanking polymorphic DNA markers in epidermolysis bullosa candidate genes, together with rapid screening of genetic hotspots, make genetic screening of high-risk pregnancy a viable option. Preimplantation diagnosis has also been performed in epidermolysis bullosa cases.

Increased needs

Extensive cutaneous injury is associated with marked alterations in both hemodynamic and metabolic responses, requiring increased caloric and protein intake for recovery. The burn patient has been studied extensively from both of these perspectives. Studies confirm that the development of nutritional deficiencies inhibits successful wound healing and the body's return to a normal hemodynamic and metabolic profile.

Impediments to intake and absorption

Oropharyngeal and GI lesions greatly threaten the nutritional well being of patients with epidermolysis bullosa. Complications include oral blistering, abnormal esophageal motility, strictures, dysphagia, diarrhea, malabsorption, and dental problems. Nutritional assessment taking these factors into account is essential for replenishing the malnourished patient.

Inactivity as a result of pain and scarring can cause contractures to form. Physical therapy can be helpful in reducing limb and hand contractions and in maintaining the range of motion.

Prevention of trauma to the skin reduces blistering. Padding of limbs helps reduce unnecessary trauma. A soft mechanical diet helps reduce oral and esophageal erosions.

Implementation of proper wound and nutritional care is critical to the outpatient care of epidermolysis bullosa. Home health care providers familiar with skin care, nutrition, and physical therapy can be helpful. Education of patient and family members is essential.