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NEJM Editorial

Volume 346:364-367 January 31, 2002 Number 5

Bullous Pemphigoid Therapy - Think Globally, Act Locally

Until now, systemic immunosuppressive agents, particularly oral corticosteroids, have been the standard treatment for bullous pemphigoid, which accounts for about 75 percent of cases of autoimmune blistering skin disease.1,2,3 Nearly two thirds of cases occur in persons 80 years of age or older.2,3 In France, whose population is one fifth that of the United States, about 500 new cases of bullous pemphigoid occur each year.2,3

Bullous pemphigoid can usually be distinguished from other blistering skin diseases on the basis of at least three of four criteria: the absence of atrophic scars, the absence of mucosal involvement, the absence of involvement of the head and neck, and an age of more than 70 years.4 Bullous pemphigoid is clinically and immunologically distinct from the pemphigus group of autoimmune intraepidermal diseases whose symptoms are usually erosions of the skin and mucous membranes rather than intact subepidermal blisters.5 The clinical and immunologic features of bullous pemphigoid and other less common autoimmune blistering skin diseases (herpes gestationis, linear IgA dermatosis, cicatricial pemphigoid, epidermolysis bullosa acquisita, bullous systemic lupus erythematosus, and chronis bullous disease of childhood) are summarized in Table 1 and Figure 1.

Table 1. Clinical Features and Antigenic Targets of Autoimmune Blistering Skin Diseases.

Figure 1. The Key Anchoring Elements at the Dermal-Epidermal Junction Associated with Autoimmune Blistering Diseases.

The dermal-epidermal junction has three major components: the basal keratinocyte, which includes the hemidesmosome-anchoring filament complex, the basement membrane, and the anchoring fibrils in the extracellular matrix of the papillary dermis. The hemidesmosomal plaque is the intracellular component of the hemidesmosome-anchoring filament complex. The components of the hemidesmosomal plaque include bullous pemphigoid antigen 1 (BPAG1), an intracellular member of the plectin family that links the hemidesmosomal plaque to the keratin filaments of the cytoskeleton of the basal cell and the intraepidermal components of the transmembrane proteins bullous pemphigoid antigen 2 (BPAG2) and 64 integrin. The anchoring filaments are the extracellular component of the hemidesmosome-anchoring filament complex. This complex includes the extracellular domain of BPAG2, 64 integrin, laminin-5, and LAD-1 (a 97-kD protein located in the lamina lucida), which attach the epithelial cells to the underlying basement membrane. The anchoring filaments together with the anchoring fibrils (type VII collagen) form adhesion complexes that link the intracellular cytoskeleton to the anchoring plaques in the papillary dermis. When autoantibodies against one of the key constituents of the dermal-epidermal junction trigger an autoimmune reaction, loss of adhesion, skin fragility, and subepidermal blisters result. In patients with bullous pemphigoid and herpes gestationis, an immunologically identical disease of pregnancy, the antibodies recognize one of four major epitopes clustered within the noncollagenous region of BPAG2, just outside the basal-cell membrane, termed NC16A. Antibodies directed against BPAG1 are often present in bullous pemphigoid. In patients with cicatricial pemphigoid, the C terminal of the collagenous portion of the BPAG2 molecule, located in the lamina densa, is usually targeted. The deeper location of the epitope in cicatricial pemphigoid is responsible for the more extensive scarring that occurs with this disorder than with bullous pemphigoid. These disorders illustrate that antibodies against different epitopes of a single protein structure can be associated with clinically different bullous diseases depending on the specific pemphigoid antigenic target. (Figure courtesy of Dr. Tamar Nijsten.)

Although clinical findings often lead to a correct diagnosis, positive histopathological studies - particularly direct immunofluorescence studies of perilesional skin demonstrating deposition of complement (C3) and immunoglobulins (IgG) in a linear pattern at the epidermal basement membrane - represent the usual diagnostic standard.6 Titers of circulating antibodies are diagnostically helpful but do not correlate well with disease activity; a therapeutic response occurs more rapidly than any change in antibody titers.

Loss of B-cell tolerance to bullous pemphigoid antigen 2, a 180-kD transmembrane molecule and a constituent of the hemidesmosome-anchoring filament complex, is probably the vital first step that induces an autoimmune response (Figure 1).7 The binding of the autoantibody to the antigen on the keratinocyte surface activates the classic complement pathway. These events stimulate mast-cell degranulation and induce keratinocytes to produce and secrete multiple inflammatory cytokines.8 The cytokines promote the occurrence of a polymorphic infiltrate in the upper dermis that includes many eosinophils. This infiltrate releases enzymes that are most likely responsible for cleavage at the dermal-epidermal junction.

The much higher incidence of bullous pemphigoid in the elderly distinguishes it from most other autoimmune diseases. A number of immunologic mechanisms, such as loss of tolerance and autoreactivity to additional antigens as a result of epitope spreading, may account for the development of autoimmunity so late in life. The importance of local factors in the formation of blisters together with the high risk associated with systemic immunosuppressive therapy in the elderly argues for the use of local rather than systemic therapy. High-potency topical corticosteroids have been used successfully for bullous pemphigoid that involves limited areas of the body. Topical corticosteroids are particularly effective in reducing cutaneous inflammation. Even when used extensively, such local therapy is probably safer than high-dose systemic corticosteroids.

Mortality rates are significantly higher among patients with bullous pemphigoid than among similar persons without bullous pemphigoid,9 but the clinical course of the disease is highly variable. Although ultraviolet light may precipitate bullous pemphigoid, other precipitating factors or strongly associated diseases have not been determined. Spontaneous remissions are infrequent, although remissions after therapy do occur. Oral corticosteroid treatment, which has been the standard treatment for widespread disease until now, is responsible for much of the excess mortality and morbidity among patients with bullous pemphigoid. The variable course of the disease makes uncontrolled trials particularly unreliable in determining the efficacy of treatment. Previously, Guillaume and colleagues demonstrated that a well-controlled and reasonably powered study of bullous pemphigoid therapy was feasible.10 Although their trial demonstrated that neither azathioprine nor plasmapheresis adds substantially to the effects of oral corticosteroids, the publication of its results has not greatly changed either the recommendations of experts or clinical practice.10 On the basis of clinical experience alone, new systemic therapies, including very costly ones such as intravenous immune globulin, continue to be advocated.11

In this issue of the Journal, Joly et al.1 report that large quantities of high-potency topical corticosteroids (40 g per day initially) applied to the entire body surface were safer and more effective in controlling extensive bullous pemphigoid than oral corticosteroids. Patients with extensive disease who were treated topically had shorter hospitalizations, with more rapid control of disease, fewer severe complications, and lower mortality rates, than those who were treated systemically with prednisone in a dose of 1 mg per kilogram of body weight per day. The incidence of severe adverse events that were probably related to corticosteroid use was dramatically reduced. Among those with less severe bullous pemphigoid, mortality was similar regardless of whether they were treated with oral corticosteroids (at a lower dose of 0.5 mg per kilogram per day) or the same topical regimen those with more extensive disease received, but total days of hospitalization and the number of severe adverse events typically associated with corticosteroids were lower in topically treated patients. However, adverse events and death were more frequent than would be expected in a comparable group of persons without bullous pemphigoid, suggesting that the elderly tolerate poorly even moderate doses of oral corticosteroids as well as the large quantities of high-potency topical corticosteroids used in this study.

Although they are not without risk, topical corticosteroids should now be the treatment of choice for bullous pemphigoid. Particularly when the disease is not extensive, smaller quantities of high-potency topical corticosteroids than were used in this study might control bullous pemphigoid and reduce treatment-related morbidity.

A well-controlled clinical trial of bullous pemphigoid therapy is feasible.1,10 Before other expensive, complex, or potentially toxic treatments are adopted, each should undergo a similarly robust evaluation.

Will this less expensive and safer approach to treatment be widely adopted here in the United States? Perhaps not. Our health care and social systems are not supportive of therapies that require extensive topical treatment. In Europe, inpatient care of skin disease is still widely available. In the United States, few hospitals provide specialized inpatient care for skin disease. In this country, many patients with bullous pemphigoid are not hospitalized, and those who are hospitalized remain in the hospital less than half as long as similar patients in France. In the United States, access to and payment for long-term intensive nursing for skin diseases are limited. Medicare reimbursement for the evaluation and management of complex and chronic diseases is low. Without intensive nursing or family support, many elderly and frail patients may be unable to adhere to a regimen that requires topical therapy. Elderly patients, in whom bullous pemphigoid is most likely to develop and who are most likely to benefit from topical therapy, probably lack the political and economic power to prompt this logistically difficult change in medical practice.

In contrast to the situation in France, where this study was conducted, the economics of clinical research and medical care in the United States also makes such clinical innovation difficult here. Since the results of studies of this type are unlikely to provide an economic benefit to the health care industry, it is difficult to obtain funding for them. Pharmaceutical companies lack incentives to compare two generic drugs, and there are no obvious sources of support for complex, multicenter studies that critically assess "old" therapies for old persons. Joly et al. have provided important information that can improve the outcome in elderly patients with bullous pemphigoid. The combined efforts of patients, their families, and health care providers are needed to translate these findings into routine clinical practice.12

Robert S. Stern, M.D.

Beth Israel Deaconess Medical Center

Boston, MA 02215

References

1.Joly P, Roujeau JC, Benichou J, et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med 2002;346:321-327.

2.Bernard P, Vaillant L, Labeille B, et al. Incidence and distribution of subepidermal autoimmune bullous skin diseases in three French regions. Arch Dermatol 1995;131:48-52.

3.Jung M, Kippes W, Messer G, Zillikens D, Rzany B. Increased risk of bullous pemphigoid in male and very old patients: a population-based study on incidence. J Am Acad Dermatol 1999;41:266-268.

4.Vaillant L, Bernard P, Joly P, et al. Evaluation of clinical criteria for diagnosis of bullous pemphigoid. Arch Dermatol 1998;134:1075-1080.

5.Stanley JR. Pemphigus. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick's dermatology in general medicine. 5th ed. Vol. 1. New York: McGraw-Hill, 1999:654-66.

6.Jordon RE, Beutner EH, Witebsky E, Blumental G, Hale WL, Lever WF. Basement zone antibodies in bullous pemphigoid. JAMA 1967;200:751-758.

7.Xu L, Robinson N, Miller SD, Chan LS. Characterization of BALB/c mice B lymphocyte autoimmune responses to skin basement membrane component type XVII collagen, the target antigen of autoimmune skin disease bullous pemphigoid. Immunol Lett 2001;77:105-111.

8.Chen R, Ning G, Zhao M-L, et al. Mast cells play a key role in neutrophil recruitment in experimental bullous pemphigoid. J Clin Invest 2001;108:1151-1158.

9..Roujeau J-C, Lok C, Bastuji-Garin S, Mhalla S, Enginger V, Bernard P. High risk of death in elderly patients with extensive bullous pemphigoid. Arch Dermatol 1998;134:465-469.

10.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 1993;129:49-53.

11.Ahmed AR. Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol 2001;45:825-835.

12.Grol R. Improving the quality of medical care: building bridges among professional pride, payer profit, and patient satisfaction. JAMA 2001;286:2578-2585.