Epidermolysis bullosa acquisita

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Epidermolysis bullosa acquisita

Lawrence S. Chan

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

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Epidermolysis bullosa acquisita is an uncommon, chronic, autoimmune blistering disease of the skin and mucous membranes. The disease primarily affects elderly individuals and occurs predominantly at trauma-prone skin areas (the non-inflammatory mechanobullous scarring subset) or widespread skin areas (the generalized inflammatory non-scarring subset). IgG (or rarely IgA) autoantibodies targeting the skin basement membrane component type VII collagen (anchoring fibrils) and minor physical trauma are the major contributing factors to the blistering process.

Management strategy

Epidermolysis bullosa acquisita, especially the non-inflammatory mechanobullous subset, is characteristically very resistant to conventional medical therapies. For an immune-mediated blistering disease associated with autoantibodies that target skin components, the logical approach is to modify the immune response to reduce the production and effect of the autoantibodies to their target skin component type VII collagen. However, no target-specific treatment is currently available. Thus the presently available non-target-specific immunosuppressants not only reduce the immune responses against self protein, but also suppress the patient’s immune defense to pathogens, resulting in a relative immunodeficiency. Therefore, when treating patients with this disease, every effort should be made to use anti-inflammatory rather than immunosuppressant agents, to use the lowest possible doses of immunosuppressant for the shortest duration, and to replace immunosuppressants with other anti-inflammatory medications whenever possible. A commonly used initial regimen is systemic corticosteroid with either mycophenolate mofetil or dapsone or both as a corticosteroid-sparing agent. For adult patients without significant medical problems, a combination of oral prednisone (1 mg/kg daily), mycophenolate mofetil (1–2 g daily), and dapsone (100–200 mg daily) can be started. Because of its rarity, no well-controlled clinical trial has been performed for epidermolysis bullosa acquisita. The following therapeutic guidelines are derived mainly from case reports of small groups or single patients.

Other therapeutic agents have been reported to be beneficial for this disease. Colchicine (1–2 mg daily) has been reported to significantly improve the disease. Cyclosporine (5–9 mg/kg daily) has been shown to be beneficial in reducing blister formation and speeding up healing. Intravenous immunoglobulin (IVIG) treatment (400 mg/kg daily) has also been demonstrated to reduce new blister formation and facilitate healing. In addition, extracorporeal photochemotherapy has been used successfully in some patients. Most recently, a monoclonal antibody against B-cell-specific target CD20 medically termed rituximab (usual dose 375 mg/m2 body surface area, multiple doses) has been shown to be quite effective in several cases of epidermolysis bullosa acquisita, considering the medication-resistant nature of the disease. At present the high cost and difficulty of obtaining insurance company approval are the major hindrances to the use of rituximab.

In addition to medical treatments, patients with this disease should be instructed to avoid physical trauma as much as possible. Vigorous rubbing of their skin and the use of harsh soaps and hot water should also be avoided. Patients should be instructed to care for open wounds promptly and to recognize local skin infection and seek medical attention when infection occurs.

Specific investigations

Congenital epidermolysis bullosa acquisita: vertical transfer of maternal autoantibody from mother to infant.

Abrams ML, Smidt A, Benjamin L, Chen M, Woodley D, Mancini AJ. Arch Dermatol 2011; 147: 337–41.

While epidermolysis bullosa acquisita rarely occurs in children, it has never been reported in an infant until now. This case, which occurred in an infant, should raise the awareness of maternally transferred epidermolysis bullosa acquisita by physicians when they encounter blistering disease in a neonate.

Physicians need to recognize the possibility of maternal transfer of autoantibodies and the transient nature of the blisters (with no need for systemic treatment). This case of naturally passive transfer disease further demonstrates the pathogenic role of the autoantibodies as was illustrated in animal model of epidermolysis bullosa acquisita.

First-line therapies

image Systemic corticosteroids D
image Mycophenolate mofetil E
image Dapsone D

Second-line therapies

image Intravenous immunoglobulin D
image Colchicine D
image Cyclosporine D

Severe, refractory epidermolysis bullosa acquisita complicated by an oesophageal stricture responding to intravenous immune globulin.

Harman KE, Whittam LR, Wakelin SH, Black MM. Br J Dermatol 1998; 139: 1126–7.

The patient had the non-inflammatory mechanobullous subset of disease and esophageal stricture, and was refractory to prednisone (up to 80 mg daily), dapsone (100 mg daily), cyclophosphamide (150 mg daily), and azathioprine (3 mg/kg daily). The patient was treated with courses of IVIG (0.4 g/kg daily) on 5 consecutive days at 4- to 6-week intervals as a monotherapy, resulting in a dramatic fall in the circulating titers of anti-basement membrane IgG autoantibodies, reduction of new blister formation, and disappearance of dysphagia. However, not all patients reported in the literature responded to this treatment. The major disadvantage of this regimen is the high cost.

Colchicine for epidermolysis bullosa acquisita.

Cunningham BB, Kirchmann TT, Woodley DT. J Am Acad Dermatol 1996; 34: 781–4.

Four patients with the non-inflammatory mechanobullous subset of disease, some refractory to prednisone treatment, were treated with oral colchicine (1–2 mg daily), with or without the addition of cyclophosphamide (50 mg daily). In all patients there was substantial clinical improvement in the reduction of skin fragility and spontaneous blister formation. An initial dose of 0.4–0.6 mg daily is recommended, with an increase by 0.6 mg daily each week until diarrhea develops. The patients are instructed to take the highest tolerable doses. Other than diarrhea, the long-term administration of colchicine (up to 4 years) was well tolerated. The side effect of diarrhea, however, makes it questionably suitable for those patients who have associated inflammatory bowel disease.

Third-line therapies

image Anti-CD20 antibody (rituximab) D/E

Successful adjuvant treatment of recalcitrant epidermolysis bullosa acquisita with anti-CD20 antibody rituximab.

Schmidt E, Benoit S, Brocker E-B, Zillikens D, Goebeler M. Arch Dermatol 2006; 142: 147–50.

The patient, who had both skin and oral mucosal involvement, was not controlled with prednisolone (up to 250 mg/day), dapsone (150 mg/day), and subsequently azathioprine (up to 175 mg/day), and colchicine (2.5 mg/day). The regimen was changed to rituximab g weekly infusion (375 mg/m2 body surface area) for 4 consecutive weeks, with continuous use of azathioprine (175 mg/day) and colchicine (2.5 mg/day) and reducing doses of prednisolone. The patient’s lesions completely healed in 11 weeks post rituximab infusion, allowing the tapering of systemic steroid, colchicine, and azathioprine. Fourteen weeks after the discontinuation of colchicine and prednisolone, the patient remained in clinical remission. No complication was reported except an event of deep vein thrombosis.

A successful therapeutic trial of rituximab in the treatment of a patient with recalcitrant, high-titre epidermolysis bullosa acquisita.

Crichlow SM, Mortimer NJ, Harman KE. Br J Dermatol 2006; 156: 194–6.

A patient with both oral mucosal and skin lesions and a high titer of IgG autoantibodies to skin basement membrane zone (indirect immunofluorescence titer up to 1 : 3200) was treated with conventional therapeutic agents (prednisolone up to 60 mg/day, mycophenolate mofetil 2 g/day, and subsequently IVIG infusions (2 g/kg body weight/month) without much success. Moreover, the patient could not tolerate azathioprine (due to liver toxicity) or cyclosporine (owing to nephrotoxicity and hypertension). In the mean time, the patient’s conditions were worsening, with increasing autoantibody titer and involvement of the esophagus. Therefore, weekly rituximab infusions (375 mg/m2 body surface area) were then given to the patient along with mycophenolate mofetil (2 g/day) and prednisolone (30 mg/day). The patient had slow but progressive improvement of the lesions and all were healed 5 months after starting rituximab. One year after the rituximab treatment the patient was still in partial remission, suffering only occasional trauma-induced blisters, and the autoantibody titer fell to 1 : 10.

Epidermolysis bullosa acquisita following bullous pemphigoid, successfully treated with anti-CD20 monoclonal antibody rituximab.

Wallet-Faber N, Franck N, Matteux F, Mateus C, Gilbert D, Carlotti A, et al. Dermatology 2007; 215: 252–5.

An interesting patient who initially developed bullous pemphigoid, but who upon subsequent flare manifested a generalized skin and mucosal (oral and genital) blistering disease that was confirmed as epidermolysis bullosa acquisita by target antigen identification. The initial success of treatment (combined prednisone 1.5 mg/kg/day and azathioprine 100 ng/day) did not last long as the reduction of prednisone resulted in rapid worsening of the condition, further complicated by a life-threatening Legionella pneumonophila infection. Furthermore, the patient could not tolerate mycophenolate mofetil. Therefore, rituximab (375 mg/m2 body surface area) was initiated on a weekly interval for 4 consecutive weeks, resulting in dramatic improvement of the patient’s condition. At 10 months’ follow-up post rituximab initiation the patient had only a few visible blisters.

Treatment-resistant classical epidermolysis bullosa acquisita responding to rituximab.

Sadler E, Schafleitner B, Lanschuetzer C, Laimer M, Pohla-Gubo G, Hametner R, et al. Br J Dermatol 2007; 157: 417–19.

A patient with both skin and multiple mucosal (oral, esophageal, and laryngeal) lesions and failed to respond to multiple conventional immunosuppressive medications subsequently responded to rituximab. Over a 6-year period the patient failed to show complete clinical response to methylprednisolone (up to 5 mg/kg/day), azathioprine (up to 2.5 mg/kg body weight), cyclosporine (up to 9 mg/kg/day), mycophenolate mofetil (up to 30 mg/kg/day), cyclophosphamide (500 mg/m2 body surface area IV, followed by 1 mg/kg/day orally), colchicine (up to 1.5 mg/day), IVIG (up to 2.5 g/kg body weight/cycle), gold (1 mg/kg/week IV, followed by IM and oral preparations), and daclizumab (1 mg/kg body weight, six infusions over 3 weeks). Therefore, a regimen of reduced dose of rituximab (144 mg/m2 infusion per week for 5 weeks) along with azathioprine (2 mg/kg/day) was given; the patient tolerated the treatment without any side effects or infections. A remarkable improvement was noticed 4 weeks after the initiation of rituximab treatment, and all medications were subsequently discontinued. Two years after all medications were tapered, the patient’s disease activity remained at a very low level.

Clinical response of severe mechanobullous epidermolysis bullosa acquisita to combined treatment with immunoadsorption and rituximab (anti-CD20 monoclonal antibodies).

Niedermeier A, Eming R, Pfutze M, Neumann CR, Happel C, Reich K, et al. Arch Dermatol 2007; 143: 192–8.

Two patients affected by the mechanobullous type of epidermolysis bullosa acquisita were treated with combined immunoadsorption (daily treatment for 8 consecutive days) and rituximab (375 mg/m2 body surface area/week for total of 4 weeks). Mycophenolate mofetil (1–3 g/day) was given continuously during this period. In both patients treatment with multiple medications, including cyclosporine, azathioprine, dapsone, dexamethasone pulse, and cyclophosphamide pulse, was unsuccessful. One patient achieved near complete clinical resolution, but the other could only obtain stable disease status. This report illustrates the treatment-resistant nature of this disease.

Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin.

Ahmed R, Spigelman Z, Cavacini LA, Posner MR. N Engl J Med 2006; 355: 1772–9.

In this largest series of autoimmune blistering skin disease rituximab study, 11 patients affected by pemphigus vulgaris were treated with a combined regimen of rituximab and IVIG (three weekly cycles of rituximab at 375 mg/m2 body surface area, followed by a dose of IVIG (2 g/kg), then by four monthly cycles of (one dose of rituximab and one dose of IVIG). Nine patients had rapid clearing of lesions and were subsequently in remission lasting from 22 to 37 months, and all other immunosuppressants were tapered off before the ending of rituximab treatment. No complication or infection was reported. The absence of infection reported in this study may be due to the addition of IVIG in this protocol, as IVIG (IgG antibodies from another individual who likely had been immunized and developed immunity against common pathogens) would be helpful in defending the IVIG-receiving and B lymphocyte-depleted patients against those pathogens.

Although this study was not conducted for epidermolysis bullosa acquisita, it seems that combined rituximab and IVIG would give the best clinical outcomes: high remission rate and low complication rate. The high cost could be a prohibitive factor.

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