Treatments Of Choice For Bullous Pemphigoid

S.M. Cooper MD and F. Wojnarowska, MD

Department of Dermatology, Oxford Radcliffe Hospital, Oxford, UK

ABSTRACT

Bullous pemphigoid (BP) is the most frequently occurring autoimmune blistering disease in Europe and North America. Although it is primarily a disease of the elderly, children and young adults can also develop it. The aim of treatment is to suppress the clinical signs and symptoms of BP without over-treating the patient, because BP tends to spontaneously remit in most patients within approximately 5 years. Mild or localized disease may respond to super-potent topical corticosteroids alone or in combination with tetracyclines with or without niacinamide. More severe or generalized disease usually requires systemic treatment with prednisolone (dose range from 20-70mg/d). Additional immunosuppressant therapy is necessary for more refractory disease.

Key Words: bullous pemphigoid, autoimmune disease

Clinical Presentation and Diagnosis of Bullous Pemphigoid

BP is a non-scarring blistering disease.^1,2 Tense blisters may arise on normal appearing skin or on erythematous plaques. Blistering may be widespread or occur in one site, typically a flexural site. The involvement of mucous membranes occurs in approximately half of patients. Occasionally an urticarial or eczematous rash may precede blister formation by months or years.

Diagnosis is made by considering the clinical picture, histology and immunofluorescence results. Atypical biopsy of a new blister shows a subepidermal cleft with a mixed dermal inflammatory infiltrate containing many eosinophils. Direct immunofluorescence of perilesional skin reveals linear deposits of IgG and/or C3 (rarely IgA, IgM or IgE), and indirect immunofluorescence of serum or blister fluid demonstrates linear IgG at the basement membrane zone.

Principles of Treatment

There are few randomized, controlled trials of therapy for BP, thus information comes mostly from case series, case reports and clinical experience. There are still many unanswered questions. Clinicians differ in their approach to management. Here, we outline our approach:

BP is self-limiting, usually remitting within 5 years, thus it is important not to overtreat the disease. Many of the drugs for BP are potentially hazardous. Drug interactions and side effects are more frequent in the elderly, so that the treatment may be more dangerous than the disease. We favor the use of the minimum doses of systemic therapy to control the disease, modifying the treatment on an individual basis, taking account of the age and general health of the patient and the extent of the disease. Some will have more aggressive disease and need significant immunosuppression. Once control of BP has been achieved, treatment can be gradually tapered off. In practice, treatment should be reduced whenever the disease has been well controlled for a month. It is not necessary to completely suppress all blister formation. The occurrence of an occasional blister ensures that the patient is not being over treated.

Mechanisms of Treatment

Treatments for bullous pemphigoid comprise three categories: antiinflammatories, immunosuppressants, and immune-modulators. Anti-inflammatory drugs, e.g., corticosteroids and antibiotics aim to suppress the inflammatory process. Immunosuppressant drugs aim to suppress the production of circulating pathogenic antibodies and include high dose corticosteroids, azathioprine, methotrexate, ciclosporin and cyclophosphamide. Intravenous immunoglobulin is an immune modulator.

Systemic Steroids

The use of systemic corticosteroids is well established although optimum treatment doses are still a subject of debate. Initial treatment doses should take disease severity into account. In localized or mild disease 20mg/d of prednisolone (0.3 mg/kg/d) is sufficient, and for moderate disease 40mg/d or 0.6mg/kg/d. Higher doses of 50-70mg or 0.75-1.0mg/kg/d are indicated in severe disease. Treatment with more than 30mg of prednisolone (0.75 mg/kg) daily is associated with significant mortality and must be tapered as soon as possible.³ However, more severe disease may take longer to come under control. It is important to consider prevention of osteoporosis when steroid treatment is commenced.

Topical Steroids

Topical superpotent steroids, e.g., clobetasol proprionate 0.05% have a role in treating localized and mild-to-moderate generalized disease.4 In localized and sometimes in generalized disease this treatment alone may suffice. Topical steroids can be a useful adjunct to systemic treatment in severe disease, aiding control of symptoms.

Antibiotics and Nicotinamide

Antibiotics and niacinamide (nicotinamide) are useful first line treatments that may spare some patients from immunosuppressant therapy.⁵ Tetracyclines (oxytetracycline, minocycline or doycycline) may be prescribed as sole agents or in combination with niacinamide. In local or mild disease, tetracyclines may provide disease control without resorting to systemic prednisolone. In moderate disease, tetracyclines in combination with prednisolone may have a steroid sparing action. We use minocycline (50-100mg/d) or oxytetracycline (500-1000mg/d) when minocycline-induced pigmentation is a problem. Tetracycline is not suitable in renal impairment and doxycycline and minocycline should be avoided in liver impairment. Erythromycin is another option that may be particularly effective in children.⁶

Table 1: Therapies used for various stages of BP.

The combination of tetracycline and niacinamide may confer some additional benefit to tetracycline alone.⁷ Niacinamide is started at 500mg/d and then gradually increased to 1,500- 2,500mg/d over several weeks. The principal side effect is gastrointestinal upset, but gradual building of the dose helps tolerance of the drug. It is important that therapy, with any of these agents, is withdrawn gradually, over months, to prevent relapse.

Azathioprine

Azathioprine (up to 2.5mg/kg/d) in combination with systemic steroids has a steroid sparing effect, but is associated with increased morbidity and mortality.⁸ Prior measurement of thiopurine methyltransferase activity identifies those at greater risk of developing myelosuppression and also those in whom larger doses may be necessary. We only use azathioprine when response to prednisolone is inadequate.

Dapsone and Sulfonamides

The role of dapsone⁹ and sulfonamides is unclear, however they may have a role in BP unresponsive to first line agents. Glucose- 6-phosphate dehydrogenase deficiency should be excluded in atrisk racial groups. There is an increased likelihood of side effects in the elderly.

Other Treatments

Experience with cyclophosphamide, methotrexate, ciclosporin, mycophenolate mofetil and chlorambucil is very limited. Cyclophosphamide treated patients have a high mortality so this treatment is only appropriate in very refractory disease. Methotrexate may be especially useful if there is coexistent psoriasis. The role of ciclosporin and mycophenolate mofetil is undetermined, as no large series have been reported. Intravenous immunoglobulins can give dramatic but transient relief of symptoms but appear to have no long-term benefits.¹⁰ Plasmapheresis (plasma exchange) may have a role in refractory disease.

Conclusion

It is important that patients with bullous pemphigoid are followed regularly while being treated. Treatment must be regularly reviewed and attempts made to reduce, and ultimately withdraw all treatment if possible. We usually attempt to reduce treatment every 1-2 months if the disease is well controlled. While blistering in most patients is easily controlled, a few patients have very resistant disease, which is therapeutically challenging.

References

1. Wojnarowska F, Eady RAJ and Burge SM. Bullous eruptions. In: Champion RH, Burton JL, Ebling FJG, Eds. Textbook of Dermatology 6th Edition, Oxford:Blackwell pp. 1817-98 (1998).
2. Korman NJ. Bullous pemphigoid. The latest in diagnosis, prognosis and therapy. Arch Dermatol 134 (9):1137-41 (1998 Sep).
3. Korman NJ. Bullous pemphigoid. The latest in diagnosis, prognosis and therapy. Arch Dermatol 134 (9):1137-41 (1998 Sep).
4. Zimmermann R, Faure M, Claudy A. [Prospective study of treatment of bullous pemphigoid by a class I topical corticosteroid]. Ann Dermatol Venereol 126(1):13-6 (1999 Jan) [article in French].
5. Hornschuh B, Hamm H, Wever S, et al. Treatment of 16 patients with bullous pemphigoid with oral tetracycline and niacinamide and topical clobetasol. J Am Acad Dermatol 36(1):101-3 (1997 Jan).
6. Altomare G, Capella GL, Fracchiolla C, Frigerio E. Treatment of bullous pemphigoid with erythromycin: a reappraisal. Eur J Dermatol 9(7):583-5 (1999 Oct-Nov).
7. Fivenson DP, Breneman DL, Rosen GB, Hersh CS, Cardone S, Mutasim D. Nicotinamide and tetracycline therapy of bullous pemphigoid. Arch Dermatol 130(6):753-8 (1994).
8. Guillaume J-C, Vaillant L, Bernard P, et al. Controlled trial of azathioprine and plasma exchange in addition to prednisolone in the treatment of bullous pemphigoid. Arch Dermatol 129(9):49-53 (1993 Jan).
9. Bouscarat F, Chosidow O, Picard-Dahan C, et al. Treatment of bullous pemphigoid with dapsone: retrospective study of thirty-six cases. J Am Acad Dermatol 34(4):683-4 (1996 Apr).
10. Harman KE, Black MM. High-dose intravenous immune globulin for the treatment of autoimmune blistering diseases: an evaluation of its use in 14 cases. Br J Dermatol 140(5):865-74 (1999 May).

Garlic Supplements Can Impede HIV
Medication

Investigators from the US National Institutes of Health (NIH) observed that garlic supplements sharply reduce blood levels of the anti-HIV drug saquinavir.^*

For the first three days of the study, nine healthy HIV-negative volunteers received doses of saquinavir, a protease inhibitor that is effective at slowing the progression of HIV infection. After three days, they were also given garlic caplets twice daily for 3 weeks. Analysis of blood samples showed a 51% reduction in the average overall levels of saquinavir when compared to baseline levels.

Even after a 10-day “wash-out” period, when the volunteers again used only the protease inhibitor for 3 days, their average saquinavir levels were still approximately 35% lower than baseline.

Exactly how garlic supplements disrupt the uptake of saquinavir is unclear. Garlic has a reputation as a natural cholesterol fighter, which has made it popular with HIV+ patients whose cholesterol levels have risen as a result of their HIV medications. The investigators also suspected a strong possibility of a drug interaction because both garlic and protease inhibitors share the same metabolic pathway.

^*Piscitelli SC, Burstein AH, Welson N, Gallicano KD, Falloon J. The effect of garlic supplements on the pharmacokinetics of Saquinavir. Clin Infect Dis 34(2):234-8 (2002 Jan).

Once-Daily, Non-Sedating Antihistamine Clarinex1 Now Available in the US

Clarinex® 5 mg. tablets (desloratidine, Schering-Plough) are now available by prescription throughout the US. This nonsedating antihistamine provides 24-hour relief and was approved by the US FDA in December 2001, for the treatment of seasonal allergic rhinitis in adults and children >12 years of age. Schering-Plough also received an approvable letter from the US FDA for this product for the treatment of chronic idiopathic urticaria (CIU), or hives of unknown cause. Clarinex® is similar to Schering-Plough’s Claritin®, but is believed to be more effective, faster acting, and have milder side-effects.

In clinical trials, this product provided significantly greater symptom relief than placebo with a low incidence of side effects, which included pharyngitis, dry mouth, somnolence and fatigue. However the indidence rate was similar to that found with the placebo.

Source: Schering-Plough Corporation