Fig. 61.1
Severe scarring lesions in EBA. (a) Flexion contractures of the fingers, (b) loss of nails, (c) erosions, synechia, and webbing of esophagus observed by endoscopy, (d) end-stage ocular involvement in a LAD-like form of child. (e) Computed tomography scan showing synechia and stenosis of trachea (Courtesy of Pr M Brauner)
61.2 Medications Used in the Treatment of EBA
61.2.1 Anti-inflammatory Agents (Dapsone, Colchicine, Sulfapyridine/Sulfasalazine)
This group of drugs is ideal due to their milder side effects compared with other medications.
61.2.1.1 Dapsone
Dapsone can help some EBA patients, especially those with neutrophils in their dermal infiltrate [4, 9, 18, 45, 60, 74, 76]. It has been one of the first drugs used in EBA as systemic corticosteroids. The first cases reported efficacy at doses up to 200–300 mg/day. In more recent publications, efficiency alone was observed at varying doses (25–300 mg/day) in both adults [74, two cases] and children [18, five cases]. In his review of the literature of IgA-mediated EBA including 82 cases, Vodegel showed that the majority responded to dapsone [74]. The effectiveness of dapsone is difficult to interpret when it is associated, usually at lower doses, with other treatments [4, 9, 45, 76].
61.2.1.2 Sulfasalazine
61.2.1.3 Colchicine
Colchicine is the first-line drug for EBA therapy for Gupta et al. [25]. The mechanism of action of colchicine has not been well defined; however, the drug is thought to reduce the production of antibodies and inhibit antigen presentation to T cells. The efficacy of colchicine in EBA was reported for the first time in 1989 (after dapsone) [6]. Since then, over more than 20 years, only nine cases of successful treatment have been reported in both classical and inflammatory clinical presentations of EBA [3, 17, 49, 69]. Colchicine has been used at doses of 0.5–2 mg/day as monotherapy in seven cases or in combination with other immunosuppressants. Note that Cunningham described four patients for whom colchicine was effective but also four failures [17]. All authors reported the good long-term tolerance of this treatment, except the digestive intolerance; diarrhea makes it problematic for some patients to obtain a high enough dose for a therapeutic response and led to a cessation of treatment in some cases [17]. In the situation where EBA is associated with Crohn’s disease, the use of colchicine is contraindicated.
61.2.2 Systemic and Local Corticosteroids
61.2.2.1 Systemic Corticosteroids
The interest in using systemic corticosteroids in the treatment of EBA is controversial. For some authors, they are still the mainstay, with doses commonly ranging from 0.5 to 1.5 mg/kg/day [26, 29, 30, 32, 34]. A study of 19 patients treated with colchicine 1.2 mg/day, dapsone 100 mg/day, and methylprednisolone (≤8 mg/day if less than 10 % body involvement and >8 mg/day if more than 10 % body involvement) has shown that the group treated with high-dose (>8 mg) methylprednisolone achieved remission earlier (median time to remission: 3 months) than a group treated with low-dose (≤8 mg) methylprednisolone (median time to remission: 12 months), irrespective of clinical type (p = 0.003) [32].
For others and in our experience, corticosteroids are inefficient as monotherapy, in particular in EBA patients with the classical mechanobullous form [6, 25, 40]. High doses of systemic glucocorticoids alone may have some effectiveness in EBA with the inflammatory BP-like or LAD-like forms [25], but they induce later a corticosteroid dependence in certain cases [70]. Systemic corticosteroids may be effective in combination with dapsone in children [9, 76] or adults [4].
61.2.2.2 Local Corticosteroids
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 diabetes nor hypertension [1].
61.2.3 Immunosuppressive Agents (Cyclosporine, Mycophenolate Mofetil, Others)
These medications are often used as adjuvants to systemic corticosteroids, colchicine, and dapsone. Bear in mind that there is an enormous bias in the medical literature toward reporting positive rather than negative outcomes when reading the following paragraphs.
61.2.3.1 Cyclosporine
Another drug for consideration in EBA therapy is the immunosuppressant cyclosporine. Studies have shown that a number of EBA patients have responded to cyclosporine [7, 13, 14, 16, 24, 25, 35, 41, 45, 47, 53, 77]. This immunosuppressant has been the subject of the largest number of publications tending to show its effectiveness and superiority over other conventional immunosuppressants. Fifteen cases have been reported. Connolly and Sander were the firsts to report in 1987 a patient with EBA who was resistant to corticosteroid and low doses of dapsone and successfully treated by adjunction of cyclosporine [14]. In the early publications, cyclosporine was used at high doses (6 mg/kg/day) and always in combination with corticosteroids. More recently, cyclosporine has been used successfully without corticosteroids and at a lower dose (4 mg/kg/day) [47]. The effectiveness when it was reported can be very fast such as in 2–3 weeks [14, 24, 47]. However, the use of cyclosporine may be limited by long-term toxicity, and in some reports, it is noted as previously tested ineffective drug as well as many others [68].
61.2.3.2 Mycophenolate Mofetil
61.2.3.3 Other Immunosuppressants
Other immunosuppressants (methotrexate, azathioprine, cyclophosphamide) are sometimes cited in the literature reviews, but in the original articles, they are noted as previously tested ineffective treatments.
61.2.4 Rituximab and Other Biologic Agents
61.2.4.1 Rituximab (cf Chap. 53)
Rituximab, a CD-20 monoclonal antibody, has become increasingly popular in refractory mucocutaneous autoimmune diseases, such as pemphigus vulgaris, and has been tried as an adjuvant agent in many EBA patients refractory to all therapies listed above [12, 15, 33, 37, 39, 43, 46, 51, 52, 57, 61, 62, 66, 75]. The standard dose of 375 mg/m2 of body surface area was given at weekly intervals for 4 weeks in all the patients except two [46, 61], in combination with other immunosuppressants, systemic corticosteroids or not [43]. Rituximab has also been used in combination with immunoadsorption [37, 39, 57]. Currently, 19 cases treated with rituximab have been reported. Complete remission was achieved in 15 cases and partial remission in two, 3–6 months after the first infusion of rituximab, allowing a gradual withdrawal of previous treatments. In one case of use in combination with immunoadsorption, the results are less conclusive [57]. Death occurred 1 week after the first infusion of rituximab in one patient [52]. A relapse occurred in four of the five cases reported by Le Roux et al. [43]. It was controlled by a second course of rituximab in three cases and led to death in the fourth. The two deaths were secondary to pneumonia and occurred in patients already under heavy immunosuppressive treatments, and causation was difficult to establish.
61.2.5 Intravenous Immunoglobulins (IVIG)
IVIG is another treatment modality for EBA patients. Currently, reports of its use in 26 patients suggest success in treating recalcitrant EBA [2, 8, 11, 20, 23, 27, 28, 31, 36, 44, 50, 55, 56, 58, 67, 71]. Treatment by IVIG is generally given at doses of 2 g/kg over 3–5 days. It was administered as monotherapy in eight patients and in combination with systemic corticosteroids in eight and allowed gradually the withdrawal of earlier treatments (corticosteroids, dapsone, and others) over a 5–9-month period (mean 7.2) in ten. None of these patients had received both IVIG and rituximab. Improvement usually occurred in 4–6 months. In the series of Ahmed [2], the patients were in complete remission off therapy, after 30–52 months (mean 38.8) of treatment by IVIG. There is a case report suggesting that monthly cycles of low dose, 40 mg/kg daily for 5 days, can help to induce long-term remission [36].
61.2.6 Plasmapheresis and Extracorporeal Photochemotherapy (ECP)
ECP or photopheresis is used in the treatment of a variety of autoimmune bullous diseases, graft-versus-host disease, Sézary syndrome, and mycosis fungoides and has been shown to be effective in a small number of recalcitrant cases of EBA. A total of nine EBA patients treated with ECP have been reported in the literature [5, 10, 22, 54, 63]. One cycle of ECP consisted of two sessions on two consecutive days. The number of ECP cycles varied from 3 to more than 72, at 2–8-week intervals. The overall response was observed in eight (89 %) of the nine patients, with complete remission in five (56 %) (three on minimal therapy and two off therapy). Time to complete remission was short: 6–8 weeks of treatment with a follow-up of at least 3 months, except in one patient who needed 24 weeks of ECP. ECP allowed the withdrawal of earlier treatments in three cases. Complete remission was maintained while ECP spacing in one case with a follow-up of 8 years [5]. Circulating autoantibodies to the basement membrane were no longer detected after ECP treatment in the five patients with positive tests when ECP was started. No significant adverse effects were noted except in one patient [54]. The limitations of this treatment are its cost and the need to have a good venous access.
Plasmapheresis, via lowering plasma anti-collagen seven autoantibodies, has also been reported as a treatment for EBA patients [21].
61.2.7 Local Treatments and General Measures
The management of the EBA, as do inherited dystrophic epidermolysis bullosa (see Chap. 42) and mucous membrane pemphigoid (see Chap. 59), requires various local treatments.
Briefly, sterile rupturing of cutaneous bullae to release pressure from fluid has to be performed, and the use of nonstick dressings (i.e., silicone or Vaseline gauze) is recommended for covering erosions. Adhesive tapes are prohibited. Antiseptic mouthwashes (0.2 % chlorhexidine), steroid mouthwashes (e.g., betamethasone phosphate 2-mg tablets dissolved in 10-mL water), or paste with topical steroids (e.g., betamethasone dipropionate 0.05 % mixed with Orabase) and anesthetics (e.g., lidocaine gel) can be used to reduce inflammation and accelerate healing of erosions and for pain relief. In ocular EBA, preservative-free artificial tears are necessary to moisturize the ocular surface because of sicca syndrome that develops after conjunctival scarring. Corticosteroid eye drops are usually inefficient. Trichiasis has to be treated by eyelash extractions. Surgical procedures such as oral mucosal graft for a lid malposition or endoscopic dilatations for esophageal strictures must be performed under immunosuppressive treatment or complete control of the disease. General measures include wearing padded clothing, avoidance of trauma, and good oral hygiene with regular brushing of teeth and dental care.
61.3 Principles of Management
The treatment of EBA is dictated by the extent and severity of cutaneous and mucous membrane involvement and the medical specifics of the patient. Mild and moderate disease is defined by cutaneous lesions occurring only on the distal extremities, with or without oral or nasal mucosa involvement, and without any stenosis. Severe disease is characterized by any stenosis or involvement of the following sites: ocular, pharyngeal, esophageal, and laryngeal mucosae. To weigh the benefits of the medications with their potential side effects is necessary. All the medications except dapsone are off-label treatment.
There have been no randomized controlled trials to assess the management of EBA, since it is such a rare disease and includes various subtypes. The Cochrane review of interventions for EBA found only 11 non-randomized trials of treatments for EBA [34]. 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 ECP showing some improvement in the first few months but with recurrence. The authors concluded that it is not possible to draw definite conclusions about the best treatments for EBA.
An algorithm has been suggested in a recent paper by a Japanese group which suggests that mild EBA should be treated first with oral steroids 0.5–1.0 mg/kg/day with additional colchicine 50–100 mg/day and dapsone 100–300 mg/day if required. Moderate EBA should be treated with a higher dose of oral steroids at 1.0–1.5 mg/kg/day with additional colchicine 100–200 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 3–6 mg/kg/day, plasmapheresis, intravenous immunoglobulins (IVIG), or rituximab [30].
Based on the analysis of the literature and their own experience, a French group of experts at the request of the High Authority of Health of their country has published treatment guidelines for EBA [59]. In the initial treatment of mild or moderate forms and for maintenance treatment, they recommended as a monotherapy or in combination dapsone, sulfasalazine, or colchicine. In the severe or recalcitrant forms, the recommended first-line drug is cyclosporine (3–5 mg/kg/day) and the second rituximab, IVIG, or ECP. Unlike the Japanese, they did not recommend the use of corticosteroids, except in very specific situations, such as rapidly progressive ocular lesions or respiratory distress associated with laryngeal edema. Indeed the benefit/risk balance in favor of corticosteroids is unfavorable. In our experience systemic corticosteroids are less effective than cytotoxic drugs in the treatment of EBA and have unacceptable long-term side effects.
61.4 Conclusion
Although deemed very difficult to treat, mild forms precociously diagnosed of EBA can go into complete remission with minimal treatment. Some studies on the use of rituximab, IVIG, and ECP appear promising in severe and recalcitrant forms. In order to establish an evidence-based management of EBA, multicenter randomized controlled trials of treatments are now mandatory. In addition, because the high cost of rituximab, IVIG, and ECP is of concern to healthcare provider, comparative studies of the overall cost of treatment by these agents versus conventional immunosuppressants are necessary.
References
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