Epidermolysis Bullosa Treatment & Management

Skin involvement

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 5 (a protein involved intimately in keratinocyte adhesion and migration).

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. Recent studies on the pathogenesis of SCC in recessively inherited epidermolysis bullosa patients suggest that it arises from retained expression of the type VII collagen NC1 domain.^[12] Type VII collagen is required for Ras-driven human epidermal tumorigenesis.

Careful surveillance of nonhealing areas

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^[13]

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.

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. Also see the clinical guideline summary, Guideline on management of dental patients with special health care needs, from the American Academy of Pediatric Dentistry Council on Clinical Affairs.^[14]

Research therapies

Potential future therapies include protein and gene therapies. 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.^{[15, 16]}

In gene therapy, the goal is to deliver genes targeted to restore normal protein production. Gene therapy for one patient with a nonlethal form of junctional epidermolysis bullosa has been successful at the 1-year mark. This was accomplished using a retroviral gene transfer system, using ex vivo gene transfer and grafting corrected keratinocytes back onto the patient.^[17]

Molecular therapy ^{[18, 19, 20, 21]}

Gene therapy for non-lethal 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 patient skin. Analysis over one year showed continued high expression of laminin 5 and a clinical absence of blistering.

Two clinical trials for treatment of recessive dystrophic epidermolysis bullosa are currently underway. In one center at the University of Minnesota, bone marrow transplantation is used as the mechanism of delivery of corrective skin cells. In this trial, recessively inherited epidermolysis bullosa patients undergo bone marrow ablation and immunosuppression. The other clinical trial, which is being performed at Stanford University, consists of retroviral mediated type VII collagen gene transfer. In this trial patient skin cells are treated with type VII collagen gene in a retrovirus, and the cells are grafted back to the patient. Both studies are currently in progress and no peer reviewed scientific data are currently available.

Surgical management can include the following:

• 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^[22] : 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.^[23]
• 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.^[24] 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.

Nutritional management includes the following:

• 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.