Bullous pemphigoid

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Bullous pemphigoid

Michelle Scott and Victoria P. Werth

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

image

Courtesy of Katherine Evans

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease that mainly affects elderly patients, although childhood cases do occur. Subepidermal blistering is mediated by activation of complement and release of tissue-destructive proteases following IgG autoantibody complex formation with hemidesmosomal antigens BPAg1 (BP230) and BPAg2 (BP180 or collagen XVII). IgE autoantibodies to BPAg2 have also been identified in the majority of patients and have been shown to be pathogenic. The clinical hallmarks of the eruption are tense bullae with either generalized or localized distribution; however, variants, including urticarial, vesicular, vegetative, erythrodermic, and nodularis, have been described. Pruritus associated with BP can be severe and adversely affect quality of life. Mucosal involvement with small blisters or erosions may exist in a minority of patients. Although there can be relapses and exacerbations, BP is generally self-limiting, with remission in most adults by 5 years, and more rapidly in children. Mortality can be high in patients with poor overall health and advanced age.

Management strategy

The Cochrane Skin Group updated its review on the treatment of BP in 2011. The review focused on evidence from 10 randomized controlled trials to help guide physicians with treatment. While the quality of evidence from the majority of the trials was limited by small sample size and lack of blinding, two of the 10 studies were large and included more than half of the participants in the review (Joly 2002, Joly 2009). The reviewers concluded that very potent topical steroids are effective and safe in the treatment of BP, and milder regimens are effective in moderate BP. Doses of prednisolone >0.75 mg/kg/day show no added benefit over lower doses and have an increased incidence of adverse effects. The data also showed that topical clobetasol propionate 0.05% cream (40 g/day) was as effective as oral corticosteroids in controlling disease and associated with fewer side effects. These are the only recommendations with strong evidentiary support.

Patients with localized disease may be successfully treated with clobetasol propionate 0.05% or intralesional corticosteroids. Those with generalized disease in which topical therapy is not feasible can be treated with prednisone, 0.5–0.75 mg/kg/day, depending on disease severity and considering the overall health of the patient. The risks of both short- and long-term systemic corticosteroid therapies are well known and are heightened in the elderly patient population. Every effort should be made to find the minimum dosage of systemic corticosteroids required to suppress disease. With only a few exceptions, all elderly patients started on systemic corticosteroids should also start calcium, vitamin D, and bisphosphonate therapy. All patients on systemic corticosteroids should be screened for tuberculosis and have their blood pressure and serum glucose levels followed closely.

Tetracyclines combined with nicotinamide can be used for patients unable to tolerate or who have contraindications to corticosteroids. If gastrointestinal side effects manifest, minocycline may be substituted. Tetracycline or Doxycycline alone has also been used in one case with success.

Azathioprine is a second-line alternative that may be used alone or as a corticosteroid-sparing agent in more severe disease. Owing to genetic polymorphisms in the expression of thiopurine methyltransferase (TPMT), the enzyme that metabolizes azathioprine, a TPMT level prior to initiating treatment may assist the physician in appropriate dosing. Azathioprine has a slow onset of action and should be started in conjunction with corticosteroids during the acute stage. Patients usually respond within 3 to 4 weeks of initiation. Mycophenolate mofetil, an immunosuppressant, is an effective corticosteroid-sparing agent in BP. It is generally well tolerated and does not carry the risk of liver toxicity seen with azathioprine. Dapsone is particularly useful when histologic examination reveals a predominance of neutrophils. Methotrexate is another corticosteroid-sparing agent that may be useful in BP. It is given in a weekly, low-dosage protocol in a similar manner to psoriasis therapy.

For severe and refractory BP, a variety of immunosuppressive and immunomodulatory therapies have demonstrated efficacy, including intravenous immunoglobulin, chlorambucil, pulsed intravenous corticosteroids, cyclophosphamide, cyclosporine, etanercept, rituximab, daclizumab, omalizumab.

An international consensus on the definition of end-points and a disease severity measure for studies in BP was recently published, and should allow for better comparisons between studies in the future (Definitions and outcome measures for bullous pemphigoid: Recommendations by an international panel of experts. Murrel DF, Daniel BS, Joly P, Borradori L, Amagai M, Hashimoto T, et al. J Am Acad Dermatol 2012; 66: 479–5).

Specific investigations

First-line therapies

image Clobetasol propionate 0.05% B
image Systemic corticosteroids B
image Tetracycline and nicotinamide B
image Minocycline C
image Tetracycline E

A comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a multicenter randomized study.

Joly P, Roujeau JC, Benichou J, Delaporte E, D’Incan M, Dreno B, et al. J Invest Dermatol 2009; 129: 1681–7.

This non-blinded, randomized study stratified 312 patients to moderate or extensive disease and compared treatment with clobetasol proprionate cream in a mild regimen (10–30 g/day for 4 months) to a standard regimen (40 g/day with tapering over 12 months). The mild regimen was as effective as the standard regimen in both moderate and extensive disease. There was a 70% reduction in the cumulative dose of topical steroids with the mild regimen, and there were fewer adverse effects. The mild regimen reduced the risk of death or life threatening side effects in patients with moderate BP.

Second-line therapies

image Azathioprine B
image Mycophenolate mofetil B
image Dapsone C
image Methotrexate C

Third-line therapies

image Intravenous immunoglobulin (IVIG) C
image Chlorambucil + prednisolone C
image Pulse intravenous corticosteroids D
image Cyclophosphamide + pulse intravenous corticosteroids E
image Cyclophosphamide E
image Cyclosporine E
image Etanercept E
image Rituximab E
image Daclizumab E
image Omalizumab E

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Bullous pemphigoid

Michelle Scott and Victoria P. Werth

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

image

Courtesy of Katherine Evans

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease that mainly affects elderly patients, although childhood cases do occur. Subepidermal blistering is mediated by activation of complement and release of tissue-destructive proteases following IgG autoantibody complex formation with hemidesmosomal antigens BPAg1 (BP230) and BPAg2 (BP180 or collagen XVII). IgE autoantibodies to BPAg2 have also been identified in the majority of patients and have been shown to be pathogenic. The clinical hallmarks of the eruption are tense bullae with either generalized or localized distribution; however, variants, including urticarial, vesicular, vegetative, erythrodermic, and nodularis, have been described. Pruritus associated with BP can be severe and adversely affect quality of life. Mucosal involvement with small blisters or erosions may exist in a minority of patients. Although there can be relapses and exacerbations, BP is generally self-limiting, with remission in most adults by 5 years, and more rapidly in children. Mortality can be high in patients with poor overall health and advanced age.

Management strategy

The Cochrane Skin Group updated its review on the treatment of BP in 2011. The review focused on evidence from 10 randomized controlled trials to help guide physicians with treatment. While the quality of evidence from the majority of the trials was limited by small sample size and lack of blinding, two of the 10 studies were large and included more than half of the participants in the review (Joly 2002, Joly 2009). The reviewers concluded that very potent topical steroids are effective and safe in the treatment of BP, and milder regimens are effective in moderate BP. Doses of prednisolone >0.75 mg/kg/day show no added benefit over lower doses and have an increased incidence of adverse effects. The data also showed that topical clobetasol propionate 0.05% cream (40 g/day) was as effective as oral corticosteroids in controlling disease and associated with fewer side effects. These are the only recommendations with strong evidentiary support.

Patients with localized disease may be successfully treated with clobetasol propionate 0.05% or intralesional corticosteroids. Those with generalized disease in which topical therapy is not feasible can be treated with prednisone, 0.5–0.75 mg/kg/day, depending on disease severity and considering the overall health of the patient. The risks of both short- and long-term systemic corticosteroid therapies are well known and are heightened in the elderly patient population. Every effort should be made to find the minimum dosage of systemic corticosteroids required to suppress disease. With only a few exceptions, all elderly patients started on systemic corticosteroids should also start calcium, vitamin D, and bisphosphonate therapy. All patients on systemic corticosteroids should be screened for tuberculosis and have their blood pressure and serum glucose levels followed closely.

Tetracyclines combined with nicotinamide can be used for patients unable to tolerate or who have contraindications to corticosteroids. If gastrointestinal side effects manifest, minocycline may be substituted. Tetracycline or Doxycycline alone has also been used in one case with success.

Azathioprine is a second-line alternative that may be used alone or as a corticosteroid-sparing agent in more severe disease. Owing to genetic polymorphisms in the expression of thiopurine methyltransferase (TPMT), the enzyme that metabolizes azathioprine, a TPMT level prior to initiating treatment may assist the physician in appropriate dosing. Azathioprine has a slow onset of action and should be started in conjunction with corticosteroids during the acute stage. Patients usually respond within 3 to 4 weeks of initiation. Mycophenolate mofetil, an immunosuppressant, is an effective corticosteroid-sparing agent in BP. It is generally well tolerated and does not carry the risk of liver toxicity seen with azathioprine. Dapsone is particularly useful when histologic examination reveals a predominance of neutrophils. Methotrexate is another corticosteroid-sparing agent that may be useful in BP. It is given in a weekly, low-dosage protocol in a similar manner to psoriasis therapy.

For severe and refractory BP, a variety of immunosuppressive and immunomodulatory therapies have demonstrated efficacy, including intravenous immunoglobulin, chlorambucil, pulsed intravenous corticosteroids, cyclophosphamide, cyclosporine, etanercept, rituximab, daclizumab, omalizumab.

An international consensus on the definition of end-points and a disease severity measure for studies in BP was recently published, and should allow for better comparisons between studies in the future (Definitions and outcome measures for bullous pemphigoid: Recommendations by an international panel of experts. Murrel DF, Daniel BS, Joly P, Borradori L, Amagai M, Hashimoto T, et al. J Am Acad Dermatol 2012; 66: 479–5).

Specific investigations

First-line therapies

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image Clobetasol propionate 0.05% B