Overview of the management of epidermolysis bullosa

INTRODUCTION — Epidermolysis bullosa (EB) is a heterogeneous group of hereditary mechanobullous diseases characterized by varying degrees of skin and mucosa fragility caused by mutations that affect skin structural proteins. There are four major types of EB, based upon the ultrastructural level of tissue cleavage in the skin: epidermolysis bullosa simplex (EBS), junctional epidermolysis bullosa (JEB), dystrophic epidermolysis bullosa (DEB), and Kindler epidermolysis bullosa (KEB) (table 1) [1-3]. Severity is determined by the level of blistering and type of mutation and is highly variable among subtypes of EB (table 2A-C).

There is no targeted therapy for EB, although this is an active area of investigation [4-6]. The management of patients with EB is largely supportive and includes wound care and prevention and treatment of complications.

This topic will provide an overview of the management of EB. The pathogenesis, clinical characteristics, and diagnosis of EB are discussed separately. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features" and "Diagnosis of epidermolysis bullosa".)

GENERAL PRINCIPLES

Supportive care — There is no specific therapy for most forms of epidermolysis bullosa (EB). Treatment is largely supportive and includes wound care, control of infection, nutritional support, and prevention and treatment of complications.

The management of patients with EB involves a multidisciplinary team usually composed of a dermatologist, an EB nurse with specialized expertise in wound care, primary care provider, occupational therapist, nutritionist, and social worker. Specialists, including gastroenterology, ophthalmology, nephrology, hematology, endocrinology, cardiology, pain management, psychiatry, genetics, plastic surgery, and specialized dentistry, are consulted as needed. This multidisciplinary approach is emphasized by published consensus recommendations for the management of inherited EB [7,8].

Care plans for patients with EB should be individualized according to age, severity, symptoms, complications, and patient priorities. We typically see patients with severe forms of EB, such as severe, generalized recessive dystrophic epidermolysis bullosa (RDEB) or junctional epidermolysis bullosa (JEB), at three- to six-month intervals. They often require inpatient multidisciplinary care. Patients with less severe forms of EB, such as localized epidermolysis bullosa simplex (EBS) or mild dominant dystrophic epidermolysis bullosa (DDEB), can be seen once a year in specialized outpatient clinics.

The burden for caregivers of children with severe forms of EB is enormous [9]. Support groups in the community, such as the Dystrophic Epidermolysis Bullosa Research Association, are important for caregivers of children with this chronic, debilitating disease.

Monitoring — Laboratory and imaging monitoring is an important aspect of the management of patients with EB. Patients with EB require regular monitoring for complications and sequelae. The laboratory and imaging tests and the frequency of these tests vary depending upon the type of EB and the presence of complications (table 3) [10].

MANAGEMENT DURING COVID-19 PANDEMIC — Recommendations for multidisciplinary care of epidermolysis bullosa (EB) during the coronavirus disease 2019 (COVID-19) pandemic were drafted by an international panel of experts [11]:

●Patients with a low risk of internal disease and cutaneous squamous cell carcinoma (cSCC; eg, patients with epidermolysis bullosa simplex [EBS], dominant dystrophic epidermolysis bullosa [DDEB], localized junctional epidermolysis bullosa [JEB]) may be followed by teledermatology visits and have laboratory tests as needed at local laboratories.

●Patients with a high risk of cSCC and cutaneous lesions suspicious for cSCC (eg, persistent, growing, or painful lesions) need to be seen in person, and the suspicious lesion should be biopsied.

●Surgical masks, gowns, visors/goggles, and gloves should be worn by all nursing and medical staff when consulting with patients with EB, for both patient and staff protection.

●Testing for COVID-19 using nasopharyngeal swabs should be performed only if necessary and with care to avoid frictional damage of the fragile nasal mucosa by using the most minimally invasive technique available. Testing should be aimed to avoid any unneeded pressure to any mucosal surface.

●For patients with EB and COVID-19 who are hospitalized, special care should be employed when applying cuffs for the measurement of blood pressure, securing intravenous lines, or intubating to avoid cutaneous and mucosal blistering and ulceration, with liberal use of lubricants (eg, petroleum jelly).

MANAGEMENT OF NEONATES — The early management of neonates with epidermolysis bullosa (EB) should be undertaken in a neonatal or pediatric unit with the expertise, staffing, and resources necessary to manage extensive erosions or potential complications related to widespread skin sloughing [12,13]. Expert nursing care is key to successful treatment of neonates with EB. Coordination of a multidisciplinary team involved in in-hospital management is essential and includes training parents/caregivers and nonspecialist nurses at other centers and organizing the child's return home. They should not have heel prick tests performed at birth, as this carries the risk of degloving of the heel. Blood should be taken by venipuncture instead.

Newborns presenting with skin lesions suspicious of EB should be handled with extreme care. They should be placed on a thick foam pad and the pad should be used for transporting the infant (eg, from the bed to the caregiver's arms). Heat may induce blisters in some neonates with EB; the risks and benefits of using an incubator must be determined individually.

If suction is necessary, a soft catheter should be chosen and minimal suction pressure exerted [14]. In newborns with severe dystrophic epidermolysis bullosa (DEB), over-zealous suction can strip the mucosa, resulting in scarring and earlier development of pharyngeal strictures.

There is still a difference of opinion on whether it is best to teach parents/caregivers how to bathe their baby and change the dressings from birth or whether to try to delay bathing until lesions present at birth have healed. The problem with delaying this important bonding and teaching is that babies and parents/caregivers can become averse to future bathing, which then leads to apprehension about bathing and may result in increased infections. Small babies are easy to bathe in warmed bags of normal saline in a baby bath, which is isotonic with the blood, thus avoiding stinging [15]. If delaying bathing is chosen, the erosions can be cleaned by gentle irrigation with warm sterile normal saline and covered with nonadherent dressings [16]. Dressings are changed on one limb at a time to prevent self-inflicted trauma from kicking the bare skin on the opposite limb if the infant is agitated during the change. (See 'Wound dressing' below.)

Disposable diapers can be used but should be lined with a soft material to reduce trauma from the elastic edges. Erosions on the diaper area can be protected by liberal application of a mixture of white soft paraffin and liquid paraffin in equal parts or petrolatum [14]. Specialized, nonadherent dressings (eg, Mepilex Transfer, Mepilex Lite) are also available for this purpose. More information is provided by the patient support group website. Clothing helps to prevent self-inflicted skin damage from kicking or rubbing. Clothes should be turned inside out to prevent skin damage from the seams.

SKIN AND WOUND CARE

Bathing — Bathing in normal water is painful for patients with severe forms of epidermolysis bullosa (EB) and open wounds. In our clinical experience, pain is greatly reduced by bathing with salt water that approximates isotonic saline for bathing. For neonates, warmed bags of normal saline may be used in small baby bathtubs. Normal saline baths can also be prepared by dissolving approximately one kg (two pounds) of pool salt in a full tub (approximately 40 gallons [160 L]) of warm water [15]. Pool salt is less expensive than table salt and available commercially. In one retrospective, observational study including 21 patients (11 with recessive dystrophic epidermolysis bullosa [RDEB]), saltwater baths significantly reduced pain and pain medication use in most patients [17]. Reduction of body odor and skin exudate were additional beneficial effects.

Wound dressing — Nonstick or nonadherent silicone dressings and foam dressings that absorb exudates are ideal as primary dressings for EB wounds. They can be covered with absorbent padding and left in place for several days. Using expensive nonstick dressings as a secondary layer is unnecessary, costly, and offers no additional benefit. Removal of adherent dressings can be facilitated by soaking in the bath, which is the easiest way to painlessly remove them. The recommended dressings for specific subtypes of EB are listed in the tables (table 4A-C) [16]. (See "Basic principles of wound management", section on 'Wound dressings'.)

In patients with wounds covering large areas of the body, dressing change is laborious, time consuming, and may be painful [18]. The frequency of change depends upon the patient's preference, time availability, amount of exudate, and presence of infection. Wounds with bacterial colonization or frank infection may require more frequent changes and specific types of dressings (table 5). (See 'Prevention and management of infection' below.)

In addition to tub soaks, measures to reduce the discomfort associated with wound care include [16] (see 'Bathing' above):

●Turning off fans before removing dressings to reduce pain from circulating air

●Cutting templates for dressing specific wounds or body areas

●Cutting all dressings before starting the dressing change

●Using tubular bandage rather than tape to cover dressings and hold them in place

Novel topical wound therapies

Topical gene therapy (beremagene geperpavec) — In May 2023, beremagene geperpavec (B-VEC) was approved by the US Food and Drug Administration for the treatment of wounds in patients six months of age and older with dystrophic epidermolysis bullosa (DEB) due to variants in the type VII collagen alpha 1 chain gene (COL7A1) [19]. B-VEC is a replication-defective and nonintegrating, modified herpes simplex virus 1 vector that is topically applied to deliver a functional version of the COL7A1 gene directly to skin cells. Treatment with B-VEC seeks to restore the production of type VII collagen in patients with DEB.

●Administration – B-VEC is applied to selected wounds in evenly spaced droplets once weekly [19].

●Efficacy – The efficacy of B-VEC was first evaluated in a phase 1/2, intrapatient, comparison trial in nine adult and pediatric patients with DEB [20]. At 12 weeks, complete wound closure (reduction in wound area from baseline ≥95 percent) was observed in 83 percent of the wounds treated with B-VEC compared with 14 percent of the wounds treated with placebo. In many cases, the wound-healing duration was longer than six months. The therapy was well tolerated with repeated dosing; adverse effects were mild and included fever, rash, and itching.

In a subsequent intrapatient, phase 3, randomized trial, selected wound pairs in 31 patients with DEB (median age 16 years, range 1 to 44 years) were treated with B-VEC or placebo for six months [21]. At six months, complete wound healing occurred in 67 percent of the wounds treated with B-VEC compared with 22 percent of those treated with placebo. Sustained wound closure at three and six months after stopping treatment was observed in 50 percent of wounds exposed to B-VEC versus 7 percent of those exposed to placebo. Adverse events occurred in 58 percent of patients and were, in most cases, mild or moderate in severity (pruritus, chills). Cutaneous squamous cell carcinoma (cSCC) occurred in three patients at wound sites not exposed to B-VEC.

Oleogel-S10 (birch triterpenes) — In June 2022, the European Medicines Agency approved oleogel-S10 for the treatment of partial-thickness wounds associated with DEB and junctional epidermolysis bullosa (JEB) in patients six months and older [22]. Oleogel-S10 was also approved by the United Kingdom Medicines and Healthcare products Regulatory Agency in September 2022 and by the US Food and Drug Administration in December 2023 [23]. Oleogel-S10 is a sterile gel for topical use containing 10% birch triterpenes formulated with sunflower oil that acts at various stages of the wound-healing process, including modulation of inflammatory mediators, keratinocyte migration, and differentiation stimulation [24]. A phase 2 trial conducted in Europe demonstrated improved would healing in EB [25]. A subsequent large, international, phase 3 trial evaluated oleogel-S10 in 223 patients with DEB or JEB with a target partial-thickness wound 10 to 50 cm² in size and lasting 21 days to 9 months [26]. The primary outcome was the proportion of the target wound showing within 45 days. At 45 days, complete healing was achieved in 41 percent of target wounds in the oleogel-S10 group versus 29 percent in the vehicle group (relative risk [RR] 1.44, 95% CI 1.01-2.05; number needed to treat [NNT] 8). Adverse events (eg, increase in wound size or wound reopening) occurred with similar frequency in the active treatment and vehicle groups and were, in most cases, mild or moderate.

Foot care — Foot blistering from friction or minor trauma is common in all types of EB. While leaving the roof intact, rupture of blisters at their lowest point to allow gravitational drainage is recommended. Some prefer sterile scissors. In addition to regular wound care, podiatric consultation (preferably with a podiatrist with experience in EB) and use of molded orthotics, appropriate socks (eg, silver fiber socks, bamboo socks, double layer socks), and soft, ventilated, well-fitting footwear to minimize trauma and blistering is recommended. Shoes that have comfortable fit, appropriate length and width, rounded toe, plenty of room for the toes, flexibility, laces or straps to keep the foot from slipping, and flat or absent seams are recommended [27].

Prevention and management of infection — Bacterial colonization of EB wounds, usually with Staphylococcus sp., Streptococcus sp., and Pseudomonas aeruginosa, is common [28,29]. Wounds that are "critically colonized" (ie, active multiplication of organisms without invasion) or frankly infected fail to heal [30-33]. In addition to nonhealing, clinical signs of critical colonization include increased exudate, red, friable tissue, debris, and smell. Wounds that are frankly infected present with increased size and depth, erythema/edema of surrounding skin, and increased exudate and smell. Systemic signs (eg, lymphadenopathy, fever, malaise) also may be present.

In critically colonized wounds, the bacterial load can be reduced with topical agents, including diluted bleach baths or compresses, topical antiseptics, and topical antibiotics [34]. Bacterial cultures of critically colonized wounds are not routinely performed. If required, cultures should be obtained before starting topical antimicrobial treatments.

Bleach baths are prepared by diluting 100 mL of bleach in an adult-sized bathtub. Patients are soaked in the bath for 10 minutes and then rinsed with lukewarm water.

Topical antiseptic agents include chlorhexidine, benzalkonium chloride, and silver sulfadiazine. However, prolonged use of silver preparations over large wounds may induce systemic silver toxicity (argyria) and a slate-gray metallic skin discoloration. (See "Basic principles of wound management", section on 'Antiseptics and antimicrobial agents' and "Topical agents and dressings for local burn wound care", section on 'Antimicrobial agents'.)

Topical antibiotics (eg, mupirocin, fusidic acid) should be used in moderation to avoid the emergence of antibiotic-resistant bacteria. If used, different agents should be rotated every two to six weeks to minimize the induction of bacterial resistance [32].

Wounds with frank infection usually require systemic antibiotics. The choice of antibiotic therapy should be based on bacterial culture and antibiogram results.

PAIN AND ITCH MANAGEMENT — Pain is a constant feature of epidermolysis bullosa (EB) and an important management issue. Pain may be inherent (eg, from skin blisters and wounds, oral or corneal erosions, dental problems, etc) or elicited by bathing or dressing change. A comprehensive approach to EB pain management is summarized in the table (table 6) [35].

For mild to moderate pain, analgesics (eg, paracetamol, acetaminophen) can be used alone or in conjunction with a nonsteroidal anti-inflammatory drug [36]. For more severe pain, opioids (eg, codeine, morphine) or anxiolytics (eg, diazepam, lorazepam, midazolam) may be required [35]. Gabapentin and pregabalin may be used as adjuvant therapy for severe chronic pain [34,37]. (See "Pain in children: Approach to pain assessment and overview of management principles".)

Opioids may be used topically to provide analgesia without adverse effects or induction of tolerance [38]. A preparation of 10 mg of morphine sulfate mixed with 15 g of hydrogel can be applied directly to open wounds at dressing changes. Nonaddictive topical cannabinoids are also in use by patients with EB, and they appear to reduce pain. However, clinical trials are necessary to determine their effectiveness.

Chronic pruritus is a prominent debilitating feature of EB [39]. Measures that may be helpful include antihistamines, antidepressants, and oral gabapentin or pregabalin.

In a small, eight-week, randomized trial of 14 patients with EB, serlopitant (an investigational oral neurokinin 1 antagonist) was not more effective than placebo in reducing the average itch score measured by an 11-point numeric rating scale [40]. However, a larger number of patients in the serlopitant group had an itch score reduced by ≥3 points compared with the placebo group. Due to these encouraging results, a larger, randomized trial of serlopitant for the treatment of pruritus in patients with EB is underway (NCT03836001).

Use of more than one agent may be needed. The daily application of emollients all over the skin, including unaffected areas, may also be beneficial. Oral pain can be reduced by rinsing the mouth with coating products (eg, sucralfate) or topical anesthetics [41].

MANAGEMENT OF NUTRITIONAL COMPROMISE — All patients with severe forms of epidermolysis bullosa (EB), particularly recessive dystrophic epidermolysis bullosa (RDEB) or junctional epidermolysis bullosa (JEB), have nutritional compromise and require nutritional support. Major causes of macro- and micronutrient deficiency include:

●Oral, oropharyngeal, and/or gastrointestinal complications (eg, ulcerations, strictures, painful defecation) that limit nutritional intake and/or nutrient absorption

●Hypercatabolic state due to chronic inflammation and infection of skin lesions

●Nutrient loss due to loss of fluid and blood through cutaneous and mucosal lesions

Principles of evaluation and management of nutritional compromise in children with severe EB are discussed below [42,43].

Evaluation — The nutritional status of children with severe forms of EB can be evaluated by the Tool to Help Identify Nutritional Compromise (THINC), a scoring system based upon the child's height, weight, and gain or loss of weight in the previous six months; gastroenterologic aspects (eg, tethered tongue, dysphagia, painful defecation, presence of a gastrostomy tube); and dermatologic aspects (eg, body surface area of denuded skin, skin infection) [44].

Nutritional support — The aims of nutritional support include [42,44,45]:

●Alleviating the stress associated with feeding difficulties

●Addressing macro- and micronutrient deficiencies (eg, hypoproteinemia, zinc or selenium deficiency)

●Promoting normal bowel function and alleviating painful defecation

●Promoting optimal growth rates for age, sex, and sexual maturation

●Promoting optimal immune status and wound healing

●Promoting mobility and quality of life

Breastfeeding is recommended for infants with EB. Supplementation with a more nutrient-dense formula may be necessary if breast feeding is not possible or weight gain is poor [42]. In infants with failure to thrive, temporary supplemented feeding using nasogastric (NG) tubes may be necessary. However, NG tubes should not be used for more than six to eight weeks, since they can cause mucosal trauma and scarring. (See "Infant benefits of breastfeeding" and "Poor weight gain in children younger than two years in resource-abundant settings: Management".)

A gastrostomy tube (G-tube) may be beneficial for children with severe dystrophic epidermolysis bullosa (DEB) who require long-term supplementation [46,47]. (See "Enteral feeding: Gastric versus post-pyloric", section on 'Gastric feeding' and "Overview of enteral nutrition in infants and children", section on 'Long-term needs'.)

Placement of a G-tube is indicated in the following circumstances:

●Growth rate is lower than expected despite nutritional interventions

●Eating and drinking are aversive or painful

●Supplements or medications are refused

●Meal times are increasingly stressful and protracted

●Esophageal dilation does not alleviate the above issues

Patients with impaired gastric emptying, intractable gastro-esophageal reflux, and risk of aspiration may benefit from jejunal feeding with partially hydrolyzed feeds. (See "Enteral feeding: Gastric versus post-pyloric", section on 'Post-pyloric feeding'.)

Children receiving enteral feeding should be encouraged to maintain oral sucking and swallowing skills. Maintaining oral ability is important for social eating and development later in life.

Micronutrients — The serum levels of micronutrients such as iron, zinc, selenium, vitamin B12, vitamin A, and folate should be checked at regular intervals (3 to 6 months for iron, 12 months for vitamins and trace elements) (table 3) [10]:

●Iron – Iron levels are frequently low in severe forms of EB due to chronic blood loss from cutaneous and visceral wounds and reduced intake. Iron deficiency usually is treated with oral iron; liquid formulations are generally more acceptable than tablets for young children. If oral iron is not tolerated or inadequately absorbed, iron should be given intravenously. (See "Iron deficiency in infants and children <12 years: Treatment".)

●Calcium and vitamin D – Children with RDEB often have a low bone mineral density for age and increased risk of fractures [48]. (See 'Osteopenia and osteoporosis' below.)

Combined supplementation of calcium and vitamin D is required even in patients with adequate intake of milk and milk products, since chronic inflammation and infection can adversely affect bone turnover and gastrointestinal complications may interfere with absorption (see "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Malabsorption and other medical conditions'):

●Zinc – Zinc is essential for wound healing and immune function. Since most plasma zinc is bound to albumin, zinc levels may be low in patients with hypoalbuminemia. If supplementation is required for young children, the liquid form is preferable and daily doses may be split into two to reduce nausea. (See "Zinc deficiency and supplementation in children", section on 'Recommended intake'.)

●Selenium – Supplementation with selenium and L-carnitine supplements is indicated in children with RDEB [42]. In these patients, low levels of selenium and carnitine may play a role in the development of dilated cardiomyopathy [49]. (See "Overview of dietary trace elements", section on 'Deficiency' and "Causes of dilated cardiomyopathy", section on 'Trace elements'.)

●Vitamins – If vitamin intake is not optimal, an age-appropriate multivitamin supplement is recommended. However, the total vitamin intake (particularly of vitamin A) should not exceed the recommended safe upper limits. In children with severe EB, vitamin supplementation up to 150 to 200 percent of normal national recommendations is considered safe [42]. Vitamin supplementation is given orally in most cases. Children with feeding difficulties or esophageal strictures may need intravenous supplementation. (See "Dietary recommendations for toddlers and preschool and school-age children", section on 'Vitamin and mineral supplements'.)

Related problems

Anemia — In patients with EB, anemia develops as a result of chronic inflammation, blood loss from cutaneous and mucosal wounds, and malabsorption of iron and other micronutrients from the gastrointestinal tract [50]. (See "Anemia of chronic disease/anemia of inflammation" and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)

Parenteral iron supplementation may be necessary for patients who are unable to tolerate oral iron supplements [51]. Treatment with erythropoietin plus parenteral iron may be beneficial in severely anemic patients [52,53]. Transfusions may be required for rapid correction of anemia. (See "Treatment of iron deficiency anemia in adults", section on 'Intravenous iron' and "Anemia of chronic disease/anemia of inflammation", section on 'ESAs'.)

Osteopenia and osteoporosis — Bone mineral density is decreased in most patients with RDEB and JEB due to reduced mobility, poor nutritional status, and low 25-hydroxyvitamin D levels [54-57]. In a study of 72 patients (57 adults) from the Australasian Epidermolysis Bullosa Registry who underwent dual-energy x-ray absorptiometry (DXA) scan, the prevalence of osteoporosis was 75 percent among patients with RDEB and JEB. Fifty percent of patients with epidermolysis bullosa simplex (EBS) and 30 percent of those with dominant dystrophic epidermolysis bullosa (DDEB) had osteopenia [56].

Annual screening with DXA scans is suggested for detecting osteopenia and osteoporosis [48,54]. Studies have shown that even patients with EBS have a higher incidence of osteopenia and osteoporosis than age-matched controls, presumably because their exercise levels are usually chronically reduced by blistering of the feet [55,56]. (See "Screening for osteoporosis in postmenopausal women and men".)

In patients with decreased bone density, calcium and vitamin D supplementation (oral or by intramuscular injection) should be commenced and the serum bone profile monitored. In patients who have experienced spinal crush fractures or other fractures, additional therapies (including denosumab and zoledronic acid) should be considered in conjunction with an endocrinologist. Bisphosphonates are not usually easily taken by patients with EB and esophageal problems unless they have a gastrostomy. If there is renal impairment as well and parathyroid hormone is raised, calcitriol is often needed. (See 'Micronutrients' above and "Etiology and treatment of calcipenic rickets in children", section on 'Nutritional rickets' and "Bone health and calcium requirements in adolescents", section on 'Calcium intake' and "Calcium and vitamin D supplementation in osteoporosis".)

GENETIC CONSULTATION — Affected families should be offered genetic consultation so that they can better understand their reproductive risks and options, such as prenatal diagnosis and preimplantation genetic testing. Affected individuals and family members may benefit from updated genetic consultation prior to their reproductive years.

PREGNANCY AND CHILDBIRTH — Only a few studies have reported the outcomes of pregnancy and childbirth in patients with epidermolysis bullosa (EB) [58-60]. This limited evidence suggests that females with EB, including the more severe subtypes, can have successful pregnancies and deliveries. Consensus-based guidelines that provide recommendations for improving the preconception, pregnancy, childbirth, and postpartum management of females affected with EB have been published [61]. They provide detailed guidance for the care of patients with EB who desire to plan a pregnancy. Main recommendations include:

●Discuss and evaluate vulvovaginal manifestations as part of routine care of a female patient with EB, dependent on EB subtype, and offer preconception genetic counseling

●Offer prenatal testing for couples at reproductive risk of severe forms of EB, including carriers of autosomal dominant subtypes.

●Engage a multidisciplinary team early during pregnancy for females with severe forms of EB

●Discuss mode of childbirth and prepare a birth plan

●Offer vaginal birth as the preferred mode of delivery for females with all EB subtypes

●Provide modified skin care during labor and epidural placement including padding of monitoring equipment, avoid prolonged pressure, use nonadhesive tape and dressings

●Avoid instrumental vaginal delivery to minimize local skin trauma

●Discuss breastfeeding and options to avoid nipple trauma

MANAGEMENT OF EXTRACUTANEOUS COMPLICATIONS — The management of extracutaneous complications of severe forms of epidermolysis bullosa (EB) requires consultation with appropriate specialists. Modified approaches are often needed to avoid further tissue damage.

Ocular lesions — Ocular involvement in EB ranges from mild conjunctival irritation to severe blistering and scarring of conjunctiva, cornea, and eyelids leading to symblepharon and progressive visual impairment (table 7) [62-65]. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Eye'.)

For conjunctival irritation, regular use of preservative-free ocular lubricants is generally sufficient. Corneal erosions are treated with antibiotic ointments. Less common approaches used in severe cases include the application of amniotic membranes or cell sheets derived from autologous oral or limbal epithelium and corneal transplants [64]. In junctional epidermolysis bullosa (JEB)-laryngo-onycho-cutaneous syndrome, where there is a higher risk of blindness from conjunctival inflammation, thalidomide has been successfully used in at least one patient [66].

Chronic blepharitis can result in cicatricial ectropion and exposure keratitis. Conservative treatment includes moisture chambers and topical lubricants. Patients who do not improve with conservative treatment may require full-thickness skin grafting to the upper eyelid.

A large proportion of children with EB has clinically significant refractive errors and strabismus requiring orthoptic and ophthalmic surveillance [65]. (See "Refractive errors in children" and "Evaluation and management of strabismus in children".)

Oral and dental lesions

Oral hygiene — Gentle tooth brushing with a soft, small brush is possible in all patients with EB, even those with severe mucosal involvement. Mouth rinses with normal saline can be used for gentle cleaning of the mucosal surfaces.

Dental treatment — A preventive program with strict oral hygiene instructions for patients and parents/caregivers along with frequent professional cleaning and fluoride therapy is of key importance [67].

Dental care should be provided with great caution to patients with JEB or recessive dystrophic epidermolysis bullosa (RDEB) who have severe mucosal fragility, varying degrees of ankyloglossia, vestibule obliteration, and microstomia.

These patients require a modified approach for dental treatments, which includes [68-70]:

●Lubrication of lips, oral mucosa, gloves, and instruments with petroleum jelly, glycerin, or methylcellulose

●Avoidance of contact of suction tips with mucosal surface

●Drainage or incision of oral bullae to avoid spreading

●Avoidance of lateral traction and compression to prevent tissue sloughing

Patients with generalized enamel hypoplasia may require staged restoration of dentition with full crowns with or without dental implants to improve appearance and feeding ability [71]. Impression taking may be cumbersome in patients with microstomia. Custom-made gel or acrylic application trays are usually needed.

Tooth extractions should be performed by atraumatic techniques (eg, mucosal incisions) to prevent the formation of bullae. Hemostasis is obtained by applying gentle pressure with gauze packs. Sutures may or may not be used.

Perioperative complications include mucosal sloughing or blistering. Post-operative complications are rare and healing of oral tissues including alveolar sockets generally occurs in one to two weeks.

Orthodontic treatment is generally tolerated by patients with EB [69]. In patients with RDEB and microstomia, serial extractions during the appropriate stage of dental development can prevent dental crowding.

Anesthesia for dental procedures is most often local. However, conscious sedation or general anesthesia may be necessary for more extensive procedures in patients with severe forms of EB. (See "Procedural sedation in children: Approach".)

Delayed puberty — Delayed onset of puberty and reduced pubertal growth is common in children with severe EB [57]. Abnormalities in the secretion of gonadotropin releasing hormone (GnRH), growth hormone (GH), and insulin-like growth factor-1 (IGF-1) result from a multiplicity of factors, including chronic inflammation and malnutrition [48,72].

If delayed puberty is suspected, basal serum levels of luteinizing hormone, follicle stimulating hormone, and estradiol (in girls) or testosterone (in boys) should be obtained. Bone age can be assessed by radiographs of the left hand and wrist. (See "Approach to the patient with delayed puberty", section on 'Initial testing'.)

Hormonal treatment for puberty induction should be evaluated on a case-by-case basis in collaboration with a pediatric endocrinologist. (See "Approach to the patient with delayed puberty", section on 'Therapy'.)

Esophageal strictures — Esophageal strictures are a frequent complication and a major cause of poor nutrition in RDEB and JEB. They occur most often in the upper third of the esophagus and may be present even in the absence of dysphagia [73].

Esophageal strictures are managed by esophageal dilation using endoscopic balloon dilators or fluoroscopy-guided, over-the-guidewire hydrostatic balloon dilators [74-76]. (See "Endoscopic interventions for nonmalignant esophageal strictures in adults".)

Multiple procedures are often required because of recurrence. In a retrospective, multicenter study of 125 patients observed over 17 years, patients experienced a median of two (interquartile range one to seven months) stricture episodes, with a median interval between dilations of seven months (interquartile range 4 to 12 months) [77].

Despite esophageal dilation, some patients present with significant failure to thrive and require the placement of a gastrostomy tube for supplemental enteral feeding [74]. These can be reversed later in life if the patient reaches a normal weight. (See "Enteral feeding: Gastric versus post-pyloric", section on 'Gastric feeding' and "Overview of enteral nutrition in infants and children", section on 'Long-term needs'.)

Mitten deformity — Pseudosyndactyly or "mitten" deformity of the hands and feet is a major complication of RDEB, occurring in over 95 percent of affected patients [78]. Pseudosyndactyly results from repeated blistering and scarring of the hands that initially induces obliteration of the web spaces and with time leads to the encasement of the entire distal extremity in an epidermal cocoon (picture 1). (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Severe recessive dystrophic epidermolysis bullosa'.)

Surgery is indicated when loss of hand function compromises the patient's independence [79]. Ideally, surgery should be performed when the patient's skin, medical, and nutritional conditions are optimal. The aims of surgery include:

●Providing simple pinch grip and grasp, by releasing the first web space and flexion contractures

●Allowing independent finger movement, by releasing pseudosyndactyly

●Improving the appearance of the hand

Postoperative use of custom-made splints and hand therapy are important to maintain the benefits of surgery [80]. Patients are educated about measures to prevent the loss of web spaces such as using nonadherent bandages or dressings (eg, petroleum jelly gauze) and wearing rings [79]. However, despite optimal postoperative care, contractures recur within two to five years [81].

Repeat surgery is planned on a case-by-case basis. Since the thumb contributes to the majority of hand function, the release of the first web space alone produces significant functional improvement. Many patients can cope well merely with the release of the dominant thumb. There is an isolated report of successful use of CO₂ laser to treat pseudosyndactyly [82].

In a preclinical study using mouse models of RDEB, mice treated with oral losartan (an angiotensin II receptor blocker antihypertensive agent that inhibits the transforming growth factor-beta scarring pathway) did not develop mitten forepaw deformity and had significantly longer digits than the mice in the placebo group [83]. A phase 1/2 trial is underway in patients with RDEB in Germany (EudraCT Number: 2015-003670-32).

Squamous cell carcinoma — Squamous cell carcinoma (SCC) arising in chronic wounds is the most serious complication and a major cause of death for patients with RDEB [84]. Comprehensive clinical practice guidelines for the diagnosis and management of SCC in patients with EB have been provided by an international multidisciplinary group of experts, based upon the best available evidence and clinical experience [85]:

●Surveillance and diagnosis – At-risk patients with EB should have regular clinical surveillance for SCC. Full body skin examinations every three to six months are recommended between ages 10 and 16 and every three months after age 16. Digital pictures taken at each appointment may be useful for comparison during follow-up visits [84].

Any skin areas that are suspicious for SCC (eg, nonhealing, painful wounds) should be biopsied for histopathologic examination (picture 2A-B). Suspicious areas include wounds that do not heal in four weeks or more, rapid wound growth resembling exuberant granulation tissue, deep ulcers with raised borders, hyperkeratotic areas in a wound, and abnormally painful wounds.

Multiple biopsies should be taken from the edges of a lesion, and the position of each biopsy within the lesion should be carefully recorded with a clinical diagram or digital photograph. Biopsy specimen should be examined by an experienced pathologist, given the difficulty in distinguishing SCC from granulation tissue or pseudoepitheliomatous hyperplasia.

●Surgical treatment and staging – Wide local excision with 2 cm margins is considered the treatment of choice for SCCs confirmed by histopathologic examination. Mohs micrographic surgery and rush paraffin sections ("slow Mohs") are alternative methods that allow complete margin examination and a more precise removal of the tumor while preserving the uninvolved tissue [86]. Limitations to the use of Mohs surgery in patients with EB include the difficulty in tissue handling, due to the intrinsic fragility of EB skin, and in differentiating SCC from pseudoepitheliomatous hyperplasia in frozen sections [86]. (See "Mohs surgery".)

Preoperative localized imaging studies, including magnetic resonance imaging (MRI), computerized tomography (CT) scan, or ultrasonography, are helpful in assessing local invasion. Locally invasive lesions (eg, lesions involving vessels, nerves, tendons, or bones) that are not amenable to wide local excision may require amputation.

Because of the aggressive nature of SCC associated with EB, patients with invasive tumors should undergo staging evaluation. Imaging studies of chest, abdomen, and pelvis are generally performed by ultrasonography, CT scan, or MRI. Positron emission tomography scans can also be used to determine the extent and presence of hematogenous or lymphatic metastases. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma", section on 'Staging'.)

●Nonsurgical treatments – Patients with locally advanced or metastatic disease may be treated with adjunctive radiotherapy or chemotherapy. Radiotherapy may be useful to reduce the primary tumor size prior to surgical excision or may be used as a palliative treatment for the primary tumor if surgery is not feasible and for subcutaneous, lymph nodes and distant metastases [87]. Radiation doses as low as 2 Gy per fraction should be used in patients with EB to minimize the risk of severe desquamation and skin ulceration.

Conventional chemotherapeutic agents, including cisplatin, fluorouracil, taxol, and methotrexate, have been used in the past in a few patients with advanced SCC with some benefit [88]. Cetuximab, a monoclonal antibody against the epidermal growth factor receptor (EGFR), has been used successfully in a few patients with EB [89,90]. Other nonsurgical treatment modalities include electrochemotherapy [91] and photodynamic therapy [92].

Punch grafting for chronic ulcers — Punch grafting has been successfully used in a few patients with laminin 332-deficient junctional epidermolysis bullosa non-Herlitz (JEB-nH) for the treatment of chronic, deep ulcers on the extremities [93]. This technique may potentially be useful in patients with RDEB as well.

EXPERIMENTAL THERAPIES — Research related to the treatment of epidermolysis bullosa (EB) is focused on the development of new surgical techniques as well as on gene-, protein-, and cell-based molecular therapies targeting specific gene defects in severe forms of EB, such as recessive dystrophic epidermolysis bullosa (RDEB) and junctional epidermolysis bullosa Herlitz (JEB-H) [4,94-99]. New anti-inflammatory topical agents for several forms of EB are under investigation. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Molecular pathogenesis'.)

Although most of these targeted approaches, including culturing/grafting revertant mosaic keratinocytes [100], gene editing/engineering, and inducible pluripotent stem cells [101,102], are still in a preclinical stage of development, some have been evaluated in small clinical trials [5,84,94-99].

Gene therapy — Gene therapy strategies include genomic locus transfer, cDNA transfer, ex vivo gene transfer, and in vivo gene transfer [6]. Functional correction of gene expression by spliceosome-mediated ribonucleic acid (RNA) trans-splicing (SMaRT) appears to be promising for RDEB, epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), and autosomal dominant epidermolysis bullosa simplex (EBS) [103-107].

Cutaneous gene therapy

●Expanded autologous keratinocytes transduced with retroviral vector containing unmutated COL7A1 (EB-101) – The safety and efficacy of genetically corrected autologous epidermal grafts for the treatment of RDEB is being evaluated in an ongoing phase 1/2 clinical trial (NCT01263379), whose preliminary results have been published [108]. In this study, autologous RDEB keratinocytes isolated from biopsy samples were transduced with a retroviral vector containing full-length human COL7A, assembled into epidermal sheet grafts, and applied to six wounds on four patients with severe RDEB. The primary safety outcomes were recombinant viral infection, cancer, and autoimmune reaction. Expression of type VII collagen was assessed by immunofluorescence microscopy or immunoelectron microscopy on graft biopsy samples, and by level of wound healing at 3, 6, and 12 months after transplantation. Type VII collagen expression at the dermal-epidermal junction was demonstrated on the graft sites in 9 of 10 biopsy samples at three months and in 5 of 12 samples at 12 months. A 75 percent or greater wound healing was demonstrated in 20 of 24 grafts at one month and in 12 of 24 at 12 months. All grafts were well tolerated and no serious adverse events were reported. Transient tissue-bound and circulating antibodies to type VII collagen were detected in one patient.

Based on the preliminary results of this trial [108], the US Food and Drug Administration and the European Medicines Agency have granted the orphan drug designation for the gene therapy using ex vivo-expanded autologous keratinocytes transduced with retroviral vector containing the COL7A1 gene (also called EB-101) for patients with RDEB [109].

●Expanded autologous keratinocytes transduced with retroviral vector containing unmutated LAMB3 – Genetically modified autologous cultured skin grafts have been used for the treatment of a seven-year-old boy with generalized junctional epidermolysis bullosa (JEB) presenting with complete epidermal loss on approximately 80 percent of the total body surface area [110]. The skin grafts, obtained by culturing the patient's keratinocytes from a nonblistered area transduced with a retroviral vector containing the nonmutated LAMB3 gene, were applied to all denuded body surfaces. One month after grafting, epidermal regeneration was stable and complete. During a follow-up period of 21 months, the regenerated epidermis adhered firmly to the underlying dermis, even after induced mechanical stress, and did not form blisters. The absence of blisters was confirmed by histopathologic examination of multiple skin biopsies taken at 4, 8, and 21 months after grafting.

Cell-based therapies — Cell-based therapies include fibroblast therapy and bone marrow transplantation [4]:

●Intradermal allogenic fibroblast injection – Type VII collagen is synthesized in culture by epidermal keratinocytes and dermal fibroblasts. Following studies in murine models of RDEB, it was hypothesized that the injection of normal fibroblasts in the dermis of patients with RDEB could restore collagen synthesis and reduce skin fragility. Because fibroblasts are similar to mesenchymal stromal cells and have a low potential to activate the host's immune system, they are ideal candidates for cell-based therapies for RDEB [95]:

•In a small, uncontrolled open study, five patients with RDEB received a single intradermal injection of allogenic fibroblasts [111]. Increased expression of type VII collagen at the dermal-epidermal junction was noted at two weeks and up to three months after the injection, although the allogeneic fibroblasts were not detectable at the injection site. The mechanisms underlying the upregulation of collagen synthesis in these patients is unknown and may involve the expression of cytokines such as the heparin binding-EGF-like growth factor (HB-EGF) [112].

•In the first randomized controlled study involving five adult patients with severe generalized RDEB, 38 symmetric wounds (with one wound in each pair serving as an untreated control) were randomized to local injections of cultured allogenic fibroblasts in a crystalloid suspension solution with 2% albumin or injections of suspension solution with 2% albumin alone [113]. All injected wounds healed more rapidly than noninjected wounds, without difference between the cultured allogenic fibroblasts and vehicle. In three patients, an increased type VII collagen expression at the dermoepidermal junction and the appearance of anchoring fibrils on electron microscopy examination was noted in both fibroblast and placebo injection sites.

•A similar randomized controlled trial evaluated the effects of allogenic fibroblasts injection into the margins of chronic erosions in 11 patients with RDEB [96]. Twenty-nine erosions were randomized to either a single injection of fibroblasts or normal saline vehicle. Fibroblast injections produced a statistically significant greater reduction in the erosion area, time to healing, and proportion of wounds healed than vehicle only at seven days, but for the rest of the study, there was no significant difference between the two groups.

●Stem cell therapy – Stem cell therapy with allogeneic bone marrow transplantation is based upon the observation that bone marrow pluripotent stem cells can reprogram to keratinocytes and home to the skin [5,98,114-118]. In a murine model of RDEB, donor cells producing type VII collagen were detected at the dermal-epidermal junction in the recipient's skin [115]:

•Stem cell therapy has been evaluated in a small clinical trial including seven children with RDEB [5]. All children underwent immuno-myeloablative chemotherapy followed by allogenic stem-cell transplantation. Two children died from complications associated with the procedure. All the surviving children achieved improved wound healing and reduced blistering between 30 to 130 days after transplantation. Because of the high mortality associated with bone marrow transplantation with myeloablation, there is a need of further studies evaluating less aggressive, nonmyeloablative, preparative regimens in patients with EB. (See "Preparative regimens for hematopoietic cell transplantation".)

•Bone marrow allogenic, nonhematopoietic mesenchymal stem cells (MSCs) have also been shown to promote healing of chronic wounds and reduce the formation of new blisters after systemic administration in 14 patients with RDEB [119]. Treatment with a skin-derived allogenic MSC population (ATP-binding cassette subfamily B member 5 [ABCB5]⁺ MSC) with immunomodulatory, anti-inflammatory, and tissue-healing properties was evaluated in a phase 1/2 trial in 18 patients with RDEB aged 4 to 36 years [120]. At 12 weeks, treatment was associated with reductions in the Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) score and Instrument for Scoring Clinical Outcome of Research for Epidermolysis Bullosa-clinician (iscorEB-c) score, as well as with a reduction of itch and pain. Treatment-related adverse events included mild lymphadenopathy in one patient and hypersensitivity reaction in two patients, all of which resolved with treatment withdrawal. Based on the results of this trial, ABCB5⁺ MSCs, referred to as allo-APZ2-EB, has been granted orphan drug designation by the US Food and Drug Administration and the European Medicines Agency. A larger and longer-term randomized trial is needed to confirm the efficacy and safety of ABCB5⁺ MSCs.

Protein replacement therapy — Protein replacement therapy for RDEB has been evaluated in preclinical studies using animal models [121]. It consists in delivering recombinant type VII collagen, locally or systemically, to skin wounds where the protein is defective or missing [95,122]. The feasibility of recombinant protein therapy is supported by the observation that type VII collagen is long lived and the intradermal injection of human type VII collagen into mouse models of RDEB (COL7A1 null mice) can reverse the blistering phenotype and restore the expression of type VII collagen at the basal membrane zone for several weeks [123,124].

A subsequent study showed that intravenously injected human recombinant type VII collagen homes to full thickness skin wounds of nude mice and to the skin of COL7A1 null mice, incorporates into the dermoepidermal junction, and restores the anchoring fibrils and the dermal-epidermal adherence [125]. Although protein replacement therapy represents a promising pathway toward clinical application, further research is needed to determine the efficacy and safety of this approach for patients with RDEB [126,127].

Premature termination codon read-through drugs — Gentamicin and some newer medications are capable of enabling the skipping or ignoring of premature termination codon mutations in patients with recessive diseases. At least 25 percent of patients with RDEB have one or two premature termination codon mutations in the COL7A1 gene. Almost 100 percent of these were misread in vitro by gentamicin, resulting in almost complete type VII collagen production in vitro.

A small, pilot study of topical and intradermal gentamicin was conducted in RDEB in which both treatments improved wound healing without affecting the kidneys or hearing [128]. Two open-label studies of intravenous gentamicin 7.5 mg/kg/day for 14 days were conducted in RDEB and JEB over three months. In the RDEB study, four patients with RDEB and nonsense mutations showed increased type VII collagen production and improved wound healing and clinical status with no toxicities [129]. In the JEB study, three patients who had nonsense mutations in either LAMB3 or LAMA3 had improved wound healing and function and neither ototoxicity nor nephrotoxicity after one and three months. The EBDASI overall activity score was reduced. No autoantibodies against laminin 332 developed [130].

Readthrough therapy (intravenous gentamicin) — Gentamicin has the property to induce ribosomal readthrough of premature termination codons, thus allowing the expression of the absent or deficient protein. Intravenous gentamicin has been used as a readthrough therapy for intermediate and severe JEB caused by nonsense variants in LAMA3 and LAMB3 and for EBS-MD (caused by a homozygous nonsense variant in PLEC) [131,132]:

●In a clinical trial, five children, two with intermediate JEB and three with severe JEB and confirmed nonsense variants in LAMA3 or LAMB3 in one or two alleles, were treated with intravenous gentamicin 7.5 mg/kg daily for 14 days (low dose) or 10 mg/kg daily for 24 days (high dose) [131]. After treatment, all patients showed increased laminin 332 expression in the dermal-epidermal junction. At three months, eight of nine monitored wounds in patients receiving low-dose gentamicin and all monitored wounds in patients receiving high-dose gentamicin exhibited greater than 85 percent closure. No nephrotoxicity or ototoxicity was noted.

●In a single case report, a female patient with EBS-MD plectin deficiency due to a biallelic nonsense variant in PLEC1 received intravenous gentamicin 7.5 mg/kg/day for 14 consecutive days in 2019 and 2020 [132]. Both treatments were followed by increased plectin protein expression lasting five months, with improvement of nasal mucosal lesions and respiratory and neuromuscular parameters. No nephrotoxic or ototoxic effects were noted.

The repurposed use of gentamicin for the treatment of JEB is promising. It may provide relief of symptoms and improve quality of life for patients with severe JEB [133]. However, limitations to the use of such therapy include its low readthrough efficiency (ie, modest increase in the production of the defective protein), requiring repeated high-dose treatments with increased potential for bacterial resistance, nephrotoxicity, and ototoxicity [134].

PROGNOSIS — The risk of death among patients with epidermolysis bullosa (EB) differs markedly by EB subtype in terms of specific cause and magnitude of risk [135]. Most children with EB who survive the first 12 to 24 months of life will live at least into adulthood if meticulous, aggressive medical care is provided. In particular, advances in wound care have greatly reduced the risk of death from sepsis in patients with extensive wounds.

Epidermolysis bullosa simplex — The prognosis for patients with localized epidermolysis bullosa simplex (EBS) is favorable. Patients have a normal life expectancy and in most cases are able to live a normal life. In contrast, patients with generalized EBS Dowling-Meara experience inflammatory flares throughout their life. Children with the rare, recessive forms of EBS (eg, autosomal recessive lethal acantholytic EBS, EBS-pyloric atresia with extensive aplasia cutis) usually do not survive beyond the first year of life.

Junctional epidermolysis bullosa — Most patients with junctional epidermolysis bullosa Herlitz (JEB-H) and junctional epidermolysis bullosa non-Herlitz (JEB-nH) do not survive past infancy [135-137]. In one study, 19 of 22 children with JEB-H died before age 1 [136]. Sepsis, failure to thrive, and respiratory failure are the major causes of death.

Dystrophic epidermolysis bullosa — With improved nutritional support, wound care, and management of complications, patients with recessive dystrophic epidermolysis bullosa (RDEB) usually survive to their early 30s to 40s. Metastatic squamous cell carcinoma and renal failure are major causes of death. Patients with dominant dystrophic epidermolysis bullosa (DDEB) generally survive to adulthood with few complications.

Kindler epidermolysis bullosa — Patients with Kindler epidermolysis bullosa (KEB) generally have a good prognosis. However, they have increased photosensitivity and are at risk of developing skin cancer, particularly squamous cell carcinoma [138]. (See "Kindler epidermolysis bullosa", section on 'Prognosis and follow-up'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Epidermolysis bullosa".)

SUMMARY AND RECOMMENDATIONS

●General principles – The management of patients with epidermolysis bullosa (EB) is largely supportive and involves a multidisciplinary team, usually composed of a dermatologist, an EB nurse, a primary care provider, an occupational therapist, a nutritionist, and a social worker. Specialty teams (eg, ophthalmology, nephrology, hematology, endocrinology, cardiology, pain management, plastic surgery, specialized dentistry) are consulted as needed. (See 'Introduction' above and 'General principles' above.)

●Management of the neonate with epidermolysis bullosa – The early management of neonates with EB should be undertaken in a neonatal or pediatric unit with the expertise, staffing, and resources necessary to manage extensive erosions or potential complications related to widespread skin sloughing. Since heat may induce blisters, the risks and benefits of using an incubator must be determined individually. Bathing should be delayed until the lesions present at birth have healed. (See 'Management of neonates' above.)

●Wound care:

•Dressing – Wounds should be dressed with nonadherent silicone dressings, foam dressings that absorb exudates, and nonadherent silicone-based tape (table 4A-C). Diluted bleach baths or compresses, topical antiseptics, and topical antibiotics are used to reduce the bacterial load in wounds with critical bacterial colonization. Frankly infected wounds usually require systemic antibiotics. (See 'Wound dressing' above and 'Prevention and management of infection' above.)

•Novel topical therapies – Novel topical wound treatments include topical gene therapy with beremagene geperpavec (B-VEC; an inactive viral vector carrying a functional version of the COL7A1 gene), approved in 2023 by the US Food and Drug Administration for the treatment of wounds in patients ≥6 months with dystrophic epidermolysis bullosa (DEB), and oleogel-S10 (a 10% birch triterpenes gel that promotes wound healing), approved in Europe and in the United Kingdom for the treatment of partial-thickness wounds in patients with DEB and junctional epidermolysis bullosa (JEB). (See 'Topical gene therapy (beremagene geperpavec)' above and 'Oleogel-S10 (birch triterpenes)' above.)

●Pain control – Pain control is an important aspect of the management of patients with EB (table 6). For mild to moderate pain, analgesics (eg, paracetamol, acetaminophen) can be used alone or in conjunction with a nonsteroidal anti-inflammatory drug. For severe pain, opioids or anxiolytics may be required. (See 'Pain and itch management' above.)

●Nutrition – All patients with severe forms of EB have nutritional compromise and require nutritional support and ongoing weight checks, including home visits if necessary. Anemic patients require iron supplementation with or without erythropoietin. Calcium and vitamin D supplementation should be initiated in patients with evidence of osteopenia or osteoporosis. (See 'Management of nutritional compromise' above and 'Related problems' above.)

●Management of extracutaneous manifestations:

•Ocular lesions – Conjunctival irritation, corneal erosions, and chronic blepharitis are generally treated conservatively with ocular lubricants and ointments. Severe cases may require autologous transplantation of limbal epithelium or allogenic corneal transplantation. (See 'Ocular lesions' above.)

•Oral and dental lesions – Oral hygiene should be encouraged with gentle tooth brushing and normal saline rinses. Dental treatments require a modified approach to limit local trauma and tissue damage. (See 'Oral and dental lesions' above.)

•Esophageal strictures – Esophageal strictures are treated with fluoroscopy-guided hydrostatic balloon dilation. Recurrence is common, and repeated treatments may be needed. (See 'Esophageal strictures' above.)

•Pseudosyndactyly – Pseudosyndactyly with loss of hand function may be corrected by surgical release of the first web space and flexion contractures. (See 'Mitten deformity' above.)

•Cutaneous squamous cell carcinoma – Squamous cell carcinoma is treated with wide local excision or Mohs surgery. Locally invasive lesions may require amputations. (See 'Squamous cell carcinoma' above.)

●Prognosis – The risk of death among patients with EB differs markedly by EB subtype in terms of specific cause and magnitude of risk. Most children with EB who survive the first 12 to 24 months of life will live at least into adulthood if meticulous, aggressive medical care is provided.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Lizbeth Intong-Wheeler, MD, who contributed to an earlier version of this topic review.