General Measures and Supportive Treatment

Owing to the similarity of this disease to inherited dystrophic epidermolysis bullosa, avoidance of trauma and wearing protective padding is recommended to reduce blistering. Sterile rupturing of bullae to release pressure from fluid and the use of nonstick dressings (ie, silicone or petroleum jelly gauze) is recommended for covering erosions. During procedures when the patient is unconscious, such as esophageal dilatations, care needs to be taken to not put too much pressure on blood pressure cuffs and nonstick tape should be used to minimize blistering. Appropriate oral antibiotics may be given in the setting of secondary bacterial infection.

Management of Mucosal Involvement

Mucosal involvement, especially of the ocular, oral, nasopharyngeal, esophageal, and genital mucosa, is often found in patients with EBA. The presence of mucosal involvement is a one of the main causes of disease morbidity.

In addition to the immunosuppressive treatment required to suppress the disease, patients may need specific treatment directed at involved mucosal sites.

Eye involvement is EBA may range from a mild conjunctivitis to symblepharon, trichiasis, and even cicatrizing conjunctivitis with scarring and blindness if left untreated. It is, therefore, imperative that EBA patients with ocular involvement be comanaged with an ophthalmologist to determine the response to the treatment modalities being given and to prescribe appropriate eye drops. Procedures such as repeated endoscopic esophageal dilatations are required under steroid cover if patients have esophageal strictures. There has been a case report of an adult male patient with EBA with recalcitrant disease for more than 13 years requiring repeated endoscopic dilatations due to esophageal strictures. He was covered with oral corticosteroids to reduce new blister formation that occurs after these procedures.

Ankyloglossia and microstomia are additional mucosal complications of EBA that require comanagement with a dentist who specializes in complex cases. Sometimes, teeth have to be removed as the mouth becomes smaller and the treatments given for osteopenia or osteoporosis can have negative effects on the jaw or teeth.

Medications Used in the Treatment of EBA

There have been no randomized controlled trials to assess the management of EBA because it is such a rare disease and includes various subtypes. The mainstay of treatment has been primarily systemic corticosteroids; however, the long-term immunosuppression required results in increased morbidity and mortality due to the known side effects of the drugs. EBA patients do not necessarily respond well to corticosteroids when compared with other autoimmune blistering diseases (AIBD), particularly patients that have mechanobullous EBA rather than inflammatory EBA. Various immunosuppressants have been used, with varying success. An algorithm has been suggested in a recent paper by a Japanese group. They suggest that mild EBA should be treated first with oral steroids 0.5 to 1.0 mg/kg/d with additional colchicine 50 to 100 mg/day and dapsone 100 to 300 mg/day, if required. Moderate EBA should be treated with a higher dose of oral steroids at 1.0 to 1.5 mg/kg/day with additional colchicine 100 to 200 mg/day. Finally, intractable EBA should be treated with the same treatment given to patients with moderate EBA, with the addition of one or a combination of steroid pulses, cyclosporine 3 to 6 mg/kg/day, plasmapheresis, intravenous immunoglobulin (IVIG), or rituximab. The median time to remission on combination treatment has been reported to range from 10 months in patients with classic EBA to 18 months in patients with bullous-pemphigoid–like EBA. The Cochrane Review of interventions for EBA found only 11 nonrandomized trials of treatments for EBA. The majority were on the use of prednisone in combination with colchicine, additional topical steroids, dapsone, azathioprine, sulfapyridine, and cyclosporine. There were also studies on the use of IVIG, as well as 8-methoxypsoralen, before leukapheresis that showed some improvement in the first few months but with recurrence. The investigators concluded that it is not possible to draw definite conclusions about the best treatments for EBA.

A review of articles on the treatment for EBA follows and a suggested algorithm is shown in Table 1 . It is clear, though, that monotherapy is often unsuccessful, and that a multimodality approach is often necessary. It is also prudent to weigh the benefits of these medications over their risks and the potential side effects of long-term immunosuppression.

Corticosteroids

Corticosteroids are still the mainstay in the treatment of EBA, with doses commonly ranging from 0.5 to 1.5 mg/kg/day. A study using high-dose methylprednisolone (>8 mg/day) for at least 1 month was shown to induce remission in 2 months, in contrast to remission in 12 months in those given low dose methylprednisolone (≤8 mg/day). The length of remission is unclear. Corticosteroids are often used in combination with dapsone in cases of childhood EBA, which has a different autoantibody profile, often to the triple helical collagen domain Superpotent topical corticosteroids in the form of clobetasol propionate cream have been used in a patient with EBA and chronic hepatitis C. A total of 40 g of cream was applied daily for 2 months with remission lasting for 8 years, with no increases in blood sugar and blood pressure.

Antiinflammatory Agents: Dapsone, Colchicine, Sulfapyridine, or Sulfasalazine

This group of drugs exerts their antiinflammatory effects via their antineutrophil action and are ideal owing to fewer side effects. Dapsone at doses of 25 to 100 mg/day or 1to 2mg/kg/day has been used successfully in combination with topical and systemic corticosteroids in both adults and children with EBA.

Colchicine has been used to treat EBA at doses of 0.5 to 2 mg/day as a monotherapy or in combination with other immunosuppressants. Response was seen as early as 2 weeks in some patients. Sulfapyridine, sulfasalazine, and mesalazine have also been given with some benefit in some EBA patients, with clinical response within a few weeks for some patients. In addition, it was possible to wean them off other immunosuppressive treatments.

The authors have personal experience of an EBA patient with ulcerative colitis who has been in complete remission of his EBA on low-dose sulfasalazine for many years. Long-term control with this medication is unclear, and it is often used in conjunction with other immunosuppressives such as prednisone or cyclophosphamide.

Immunosuppressive Agents: Cyclosporine, Mycophenolate, Mofetil, and Others

These medications are often used as immunosuppressive adjuvants to systemic corticosteroids, colchicine, and dapsone. Dose ranges for cyclosporine have been reported at 4 to 9 mg/kg with remission in recalcitrant case of EBA.

Mycophenolate mofetil (MMF) has been administered at 1 to 2 mg/kg/day in case of adult and pediatric EBA, with varying responses. There have reports of azathioprine, cyclophosphamide, and gold, as additional adjuvants in small studies.

IVIG

IVIG is used as an off-label treatment for AIBD including EBA. It is generally given at doses of 2 g/kg over 3 to 5 days, and reports of its use in fewer than 20 patients have suggested success in treating recalcitrant EBA. It is either administered as a monotherapy with doses of 1 to 2 g/kg or in combination with systemic corticosteroids.

There is a small study suggesting that 7-month cycles of low-dose, 40 mg/kg/day for 5 days can help induce long-term remission, as seen in a patient with recalcitrant EBA of 7 years duration. Another paper reports high-dose IVIG at 1 g/kg over 3 days given at monthly intervals achieved remission in 18 months. IVIG has also been administered subcutaneously at a dose of 0.9 g/kg/month in divided doses over 5 days, as an immunomodulation therapy in a patient with severe EBA.

Rituximab

Rituximab, a CD-20 monoclonal antibody has become increasingly popular in refractory mucocutaneous autoimmune disease such as pemphigus vulgaris, and has been trialed in a small group of EBA patients. There are seven patients reported in literature, with five patients showing improvement, one without improvement, and another dying of septicemia.

The standard dose of 375 mg/m ² of body surface area given at weekly intervals for 4 weeks was used in patients with recalcitrant EBA, and mostly in combination with other immunosuppressives such as MMF and systemic corticosteroids. Rituximab has also been used successfully in combination with immunoadsorption, and various papers suggest that the depletion of memory B-cells parallels the decline in titers of circulating antibasement membrane zone antibodies.

Other Biologic Agents

One paper examined the use of daclizumab, a humanized monoclonal antibody to the α–subunit of the high-affinity interleukin-2 receptor also known as CD25 or Tac. Three patients received between 6 and 12 intravenous infusions of daclizumab, given at 1 mg/kg at 2 to 4 week intervals. One patient with inflammatory disease had a favorable response without complications. The two remaining patients with dermolytic disease did not respond. Reports have suggested the potential use of tumor necrosis factor (TNF-α) inhibitors, such as infliximab, in the treatment of EBA.

Plasmapheresis and Extracorporeal Photochemotherapy (Photopheresis)

Plasmapheresis has been suggested as an adjunct to conventional treatments in recalcitrant EBA. Adjuvant extracorporeal photochemotherapy (ECP), that is, ECP with administration of 8-methoxypsoralen before plasmapheresis, has been shown to induce partial-to-complete remission after three to six cycles of ECP in a small number of recalcitrant cases of EBA.