Approach
The general goal of treatment is to decrease or stop blister formation, to promote healing of existing blisters and erosions, and to control the associated pruritus. The patient should be maintained with the minimal dose of medication necessary to keep the disease process under control.
Widespread disease
Systemic corticosteroids
Therapy must be individualized for each patient. Unless contraindicated, for all patients with widespread skin disease, systemic corticosteroids are the mainstay of treatment and should be initiated as soon as skin biopsies and blood draws have been performed.[30] Most patients will respond rapidly to therapy and stop developing new blisters within 1 or 2 weeks of starting treatment.
High doses are associated with high mortality and morbidity, so lower doses and a shorter duration of treatment is optimal. The initial dose is maintained until new blister formation ceases. It is then slowly tapered over 6 to 9 months.
Corticosteroids should be used with caution, due to adverse effects, especially in the older population. Starting doses of prednisone >0.75 mg/kg/day may not give additional benefit. Lower doses may be adequate to control disease and reduce the incidence and severity of adverse reactions.[38]
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Combination therapy
The addition of antibiotics is considered for corticosteroid-sparing if long-term use is anticipated.[37][9] If antibiotics such as tetracycline plus niacinamide are added, corticosteroids may be tapered and stopped more rapidly (over several months).
Niacinamide is used in combination with antibiotics and appears to have anti-inflammatory properties. It may act as a histamine receptor antagonist and has also been reported to inhibit eosinophil and neutrophil chemotaxis and secretion.[39] Niacinamide lacks the vasodilator, gastrointestinal, hepatic, and hypolipemic actions of niacin. As such, niacinamide has not been shown to produce the flushing, itching, and burning sensations of the skin as is commonly seen when large doses of niacin are given orally.[40] On successful treatment of blisters, the antibiotics and niacinamide should be slowly tapered over several months to avoid a relapse.[37]
Cyclosporine can be added to the combination therapy as a corticosteroid-sparing drug; the systemic corticosteroids would then be slowly tapered over weeks to months while the patient continues taking antibiotics. A slow corticosteroid taper depends on the patient's starting dose and duration of therapy, and is adjusted to the clinical response of the patient once the disease process is stable.
The evidence for benefit with cyclosporine is conflicting, even with relatively high doses, and responses mainly occurred in patients treated with concomitant oral corticosteroids.[37]
Contraindication to corticosteroids
Patients with contraindications to corticosteroids may be treated with dapsone; a combination of a tetracycline and niacinamide; or immunosuppressive drugs, such as azathioprine or methotrexate.[30]
Dapsone is used especially if patients have a neutrophil-rich infiltrate. It is contraindicated in glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency predisposes to hematologic adverse effects of dapsone and should be excluded in predisposed races.[37] In the US, black males are most commonly affected, with a prevalence of approximately 10%. Methotrexate is considered in patients with concomitant psoriasis and bullous pemphigoid in the hands of practitioners with experience using antimetabolites. Methotrexate should include folic acid or leucovorin as part of the regimen.
Localized disease
Localized disease may be successfully managed with high-potency topical corticosteroids, with or without occlusion.[35][41] Thus, disease is controlled while avoiding systemic adverse effects. Widespread application of potent topical corticosteroids (such as fluorinated corticosteroids) over a large body surface area may result in significant systemic absorption, and should be avoided. Use of occlusion enhances absorption of the topical corticosteroid, so it should be limited to small body surface areas and only several days at a time.
Individual case reports described a response to topical treatment with tacrolimus, a calcineurin inhibitor. Topical tacrolimus causes more local irritation than topical corticosteroids, but it may be useful as an alternative in localized and limited disease without the disadvantage of causing skin atrophy.[37]
Treatment-resistant patients
Immunosuppressants
If the patient requires high doses of systemic corticosteroids for maintenance or is not showing a clinical response, other immunosuppressive (corticosteroid-sparing) agents, such as azathioprine, mycophenolate, or cyclosporine, may be added.[38][9]
Adjuvant azathioprine and mycophenolate may be similarly effective, but mycophenolate may have significantly less liver toxicity according to one randomized controlled trial.[42] There is currently insufficient evidence to recommend routine addition of azathioprine to systemic corticosteroids. Because of its side effects, azathioprine should be considered as an adjunctive treatment to prednisone only when response has been inadequate and the disease is not suppressed, or where the side effects of existing therapy are unacceptable.[37]
The evidence for benefit with cyclosporine is conflicting, even with relatively high doses, and responses mainly occurred in patients treated with concomitant oral corticosteroids.[37]
Other therapies for severe generalized disease include cyclophosphamide and methotrexate.[35] These may be used as alternatives to corticosteroids. Methotrexate is considered in patients with concomitant psoriasis and bullous pemphigoid, in the hands of practitioners with experience using antimetabolites. Methotrexate should include folic acid or leucovorin as part of the regimen.
Other treatments
Intravenous immunoglobulin (IVIG) and plasmapheresis are used if all other treatment options fail. The total published experience of IVIG in bullous pemphigoid is small and suggests that it is of limited value. It produced some dramatic but short-lived responses.[43] To establish the exact role of IVIG in the management of bullous pemphigoid, large-scale controlled studies with defined entry criteria, objectives, end points, and long-term follow-up are required.[44]
Rituximab alone or the combination of rituximab and intravenous immunoglobulin or immunoadsorption appears to be advantageous in severe cases.[45][46][47][48]
The effectiveness of the addition of plasma exchange to systemic corticosteroids has not been established.[41]
Childhood bullous pemphigoid
Childhood bullous pemphigoid usually follows a self-limited course with appropriate therapy of topical or oral corticosteroids.[37] However, if longer therapy is required or corticosteroids are not adequately treating symptoms, erythromycin with niacinamide is used instead. In treatment-resistant cases, there are reports of success with dapsone, cyclosporine, chlorambucil, and high-dose intravenous methylprednisolone therapy. In most patients, remission is achieved within the first year.
Symptom control
Itch is usually controlled with the use of oral sedating antihistamines, such as hydroxyzine or diphenhydramine.
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