Cuprimine

Blistering skin conditions are often seen in primary care practice. Common causes include contact allergens, infections and arthropod bite reactions. Autoimmune bullous diseases are encountered infrequently, but they have important noncutaneous associations. Previously, the diagnosis of autoimmune blistering diseases was based on clinical features. However, it is now possible to precisely define individual diseases based on the location of disease antigens in the ultrastructural components of the skin.

Approach to Blistering Conditions

The history of the patient with a blistering condition should be directed at identifying exposures to environmental allergens and insects (Table 1). It is also important to document the patient's medications, particularly topical preparations such as neomycin (Neosporin) or diphenhydramine, as well as occasionally used laxatives and antibiotics.

TABLE 1

Evaluation of Acute Blistering Conditions

1. Evaluate for exposure to insects and pets. 2. Document use of prescription and over-the-counter drugs. 3. Look for patterns of contact dermatitis. 4. Look for patterns of burn, friction or trauma. 5. Evaluate for mucosal disease. 6. Examine primary blisters. 7. Evaluate for diabetes, systemic lupus erythematosus, thyroid disease, porphyria and celiac disease.

The physical examination should focus on the distribution, extent and morphology of the lesions. The location may indicate the cause of blistering. Contact dermatitis is suggested by focal involvement, linear lesions and, usually, erythematous vesicular patches (Figure 1). Bullae limited to the lower legs suggest bite reactions, most often from fleas (Figure 2). Tense bullae on the soles may indicate dyshidrosis or dermatophytosis. In dyshidrosis, small deep vesicles also are present, while in dermatophytosis, the blister roof shows fungal hyphae on potassium hydroxide examination. Symmetric truncal and widespread blisters strongly suggest an autoimmune etiology.

The onset of contact dermatitis or a bite reaction is usually acute. In contrast, autoimmune blistering disorders may have an indolent or intermittent course. Antecedent pruritus and/or mucosal involvement are features of autoimmune disease.

Erythema multiforme and fixed drug reactions may be difficult to distinguish from other blistering diseases. The course of these reactions is either acute or episodic, and their characteristic dusky-purple plaques may have necrotic central blisters.

Patients with persistent blistering who do not have a history of allergen or insect exposure should be evaluated for autoimmune etiologies. New intact blisters and the surrounding skin should be examined for the detachment of adjacent epidermis with lateral pressure (Nikolsky's sign). The presence of accompanying urticarial plaques, erythematous or vesicular patches, crusts and erosions, and milia or scarring can be helpful in directing the diagnosis. The ocular and oral mucosa should be examined for asymptomatic erosions and scarring.

If the history and the physical examination suggest a nonautoimmune origin of blistering, a biopsy should not be performed. A biopsy will not distinguish between exogenous and nonautoimmune blistering.

Autoimmune Blistering Diseases

Immunologically induced blistering diseases are caused by direct antibody, immune complex or complement deposition. The clinical characteristics of the condition depend largely on the epidermal or subepidermal level that is targeted.

Autoimmune blistering diseases include pemphigus, bullous pemphigoid, cicatricial pemphigoid, herpes (pemphigoid) gestationis, epidermolysis bullosa acquisita, bullous systemic lupus erythematosus, dermatitis herpetiformis and linear immunoglobulin A (IgA) bullous dermatosis. While these conditions usually are clinically distinct, they can resemble one another closely. Therefore, the diagnosis of any autoimmune bullous disease requires immunohistologic confirmation. Since the various blistering diseases have different complications and responses to therapy, a definitive diagnosis is essential.

PEMPHIGUS

Pemphigus Vulgaris. The worldwide incidence of pemphigus vulgaris is 0.1 to 0.5 cases per 100,000 population. The disease is more common among Ashkenazi Jews than in other populations. Men and women are equally affected.[1] Pemphigus is caused by immunoglobulin G (IgG) antibodies directed against desmoglein 3 in skin and mucosal desmosomes, with splitting occurring in the suprabasilar layer.

Pemphigus vulgaris is characterized by widely scattered flaccid bullae and erosions on the face, scalp, upper body and intertriginous areas (Figures 3 and 4). The blisters rupture easily, and the adjacent epidermis detaches with lateral pressure. Painful gingival erosions are present in 50 to 70 percent of patients, and the erosions often precede the skin blistering by months[2,3] (Figure 5).

An association exists between pemphigus and thymoma, with or without myasthenia gravis. Years after the onset of the skin disease, Kaposi's sarcoma and lymphoreticular malignancies may develop, possibly because of immunosuppressive therapy. Other malignancies occur at the same rates as for age-matched populations.[4]

Drug-Induced Pemphigus. Penicillamine (Cuprimine, Depen) and captopril (Capoten) may induce pemphigus, usually a superficial form (pemphigus foliaceus), which often remits with discontinuation of the drug. Other medications, including rifampin (Rifadin, Rimactane), penicillin, cephalexin (Biocef, Keflex), progesterone, gold, piroxicam (Feldene) and phenobarbital may unmask latent typical pemphigus vulgaris, which often does not remit.[5]

Paraneoplastic Pemphigus. Severe mucosal erosions and polymorphous skin lesions suggestive of erythema multiforme have recently been described in patients with lymphoma. Antibodies to epithelial antigens desmoplakin 1, desmoplakin 3 and bullous pemphigoid antigen 2 are detectable. The widespread blistering is difficult to control, with few favorable outcomes documented.[6]

Therapy. Pemphigus can cause extensive loss of epidermis, which is accompanied by fluid loss and an increased risk of infection. Before the introduction of corticosteroids, the mortality rate for pemphigus was between 60 and 90 percent. Corticosteroids, antibiotics and modern wound care have reduced this mortality rate to between 5 and 15 percent.[7]

Pemphigus is treated with prednisone in a dosage of 1.0 to 2.5 mg per kg per day The drug is tapered slowly to avoid relapse, which is common.

Adjuvant agents, including azathioprine (Imuran), cyclophosphamide (Cytoxan), cyclosporine (Neoral, Sandimmune), methotrexate and gold are frequently needed, as is plasmapheresis.

Even with aggressive treatment, the blistering may be slow to cease, and healing of erosions is often delayed because of the high-dose steroid therapy. Patients with extensive blistering may require admission to a burn unit for wound care, electrolyte monitoring and infection control.

PEMPHIGOID

Among the autoimmune blistering conditions, bullous pemphigoid is a relatively common subepidermal blistering disease that affects older men and women equally. Antibodies are directed against components of the basal keratinocyte hemidesmosome, a 230-kilodalton (kd) antigen (bullous pemphigoid antigen 1) and a 180-kd antigen (bullous pemphigoid antigen 2).

In pemphigoid, tense blisters form on inflamed or noninflamed skin. However, unlike in pemphigus, the pemphigoid blisters do not spread (Figure 6). Erythematous plaques resembling urticaria may precede the blisters. Intertriginous areas are particularly affected. Oropharyngeal involvement is rare, a feature that distinguishes pemphigoid from pemphigus. Pemphigoid tends to follow a benign course of spontaneous healing and recurrence.

The incidence of diabetes and psoriasis is increased in patients with bullous pemphigoid.[8,9] Furosemide (Lasix) has been reported to cause this blistering disease. Studies have found cancer to be no more common in patients with pemphigoid than in age-matched control subjects.[10,11]

Conditions with tense bullae that need to be differentiated from pemphigoid include contact dermatitis, bullous bite reactions, diabetic bullae, porphyria cutanea tarda and epidermolysis bullosa acquisita.

Therapy. Compared with pemphigus, bullous pemphigoid is more responsive to systemic corticosteroid therapy. Limited and generalized pemphigoid may be controlled with a combination of tetracycline and niacinamide.[12]

CICATRICIAL PEMPHIGOID

Cicatricial pemphigoid is a chronic blistering disease that affects the mucous membranes and the skin. It has an unknown incidence, and it may be an underdiagnosed disease. Cicatricial pemphigoid is known to be more common in older women. The targeted basement-membrane zone antigens include, among others, bullous pemphigoid antigen 2 and epiligrin.[13]

Oral mucosal lesions occur in up to 100 percent of patients with cicatricial pemphigoid, with ocular disease affecting 61 to 80 percent of patients.[13] Smooth-bordered erosions of the gingivae and the buccal mucosae are less painful than the erosions of pemphigus. The lesions heal with scarring.

Ocular involvement (Figure 7) begins as fibrosis and loss of the redundant mucosa. This leads to symblepharon (adhesion between the tarsal and bulbar conjunctiva), entropion (inward turning of the eyelid) and trichiasis (ingrown eyelashes). Trauma to the cornea from the lashes may lead to corneal scarring.[13]

Skin involvement is usually limited to isolated blisters on the upper body. Cicatricial pemphigoid may be limited to subclinical desquamative gingivitis for years. However, as ocular involvement ensues, the disease course is relentless, and the fibrosis usually leads to blindness.[13]

Cicatricial pemphigoid must be distinguished from numerous conditions that are associated with both oral erosions and skin blistering. Conjunctival scarring similar to that seen in cicatricial pemphigoid may occur after long use of ophthalmic glaucoma medicines. This drug-induced condition is referred to as "pseudopemphigoid."[14]

Therapy. Cicatricial pemphigoid is resistant to therapy. Severe disease is treated with systemic corticosteroids. Frequently cyclophosphamide is administered for 18 to 24 months. Ocular lesions must not be treated surgically while the disease is active, or severe scarring may occur.

HERPES (PEMPHIGOID) GESTATIONIS

Herpes (pemphigoid) gestationis is a subepidermal blistering disease that is related to bullous pemphigoid. It usually occurs in the second trimester and has an incidence of approximately two cases per 100,000 pregnancies.[15] The target antigen is bullous pemphigoid antigen 2. The relationship of herpes gestationis to pregnancy and exogenous estrogens, both of which may induce this blistering disease, is unexplained.

Herpes gestationis begins as erythematous patches with clustered tense vesicles and bullae at the umbilicus. The disease then spreads peripherally to the proximal limbs. Pruritus is pronounced, and peripheral eosinophilia may be present. The disease wanes towards the end of pregnancy but often flares at delivery. Blistering may recur in 25 percent of affected women who subsequently use oral contraceptives.[15] The disease may also occur with subsequent pregnancies.

Stillbirths have been reported in women with herpes gestationis, but the incidence is no higher than in unaffected women with infants of the same birth weight.[16] Compared with the general population of pregnant women, patients with herpes gestationis have a higher incidence of concurrent autoimmune disease, including Hashimoto's thyroiditis, and pernicious anemia. Graves' disease subsequently develops in 11 percent of patients with herpes gestationis.[16]

The initial localized eruption of herpes gestationis may suggest contact dermatitis. Another dermatosis, pruritic urticarial papules and plaques of pregnancy (PUPPP), usually occurs in the third trimester and is characterized by the development of urticarial lesions in the striae. Bullae formation is rare in PUPPP, and immunofluorescence testing is negative.

Therapy. Prednisone controls blistering during pregnancy in most patients with herpes gestationis. Dapsone is also used.

EPIDERMOLYSIS BULLOSA ACQUISITA

Epidermolysis bullosa acquisita is a rare autoimmune disease with a variable onset and no radal or sexual predilection. The target antigen of the disease is type VII collagen, which forms the anchoring fibrils connecting the basement membrane to the dermis.

Classic epidermolysis bullosa acquisita resembles dystrophic epidermolysis bullosa, a congenital defect of anchoring fibrils. The skin is fragile. Blisters and scars form on the dorsal hands and feet, the knees and the elbows, but they do not form spontaneously elsewhere. The disease follows a chronic course, with partial remissions and progressive . The mouth, eyes, esophagus and larynx may be severely affected.

Many patients previously diagnosed with pemphigoid have antibodies against type VII collagen. Thus, they actually have an inflammatory variant of epidermolysis bullosa acquisita. Unlike in the classic form of the disease, tense blisters form spontaneously over the body (Figure 8) without skin fragility or scarring. However, progression the inflammatory variant to the chronic scarring form is common.[17] The inflammatory variant is perhaps three or four times more common than classic epidermolysis bullosa acquisita.[18]

Acral epidermolysis bullosa acquisita resembles inherited epidermolysis bullosa or porphyria cutanea tarda. The inflammatory variant resembles bullous pemphigoid, bullous systemic lupus erythematosus or, if mucosal disease predominates, cicatricial pemphigoid. Epidermolysis bullosa acquisita, bullous pemphigoid and cicatricial pemphigoid often lack circulating antibodies and may require special direct immunofluorescence testing to differentiate them.

Therapy. Epidermolysis bullosa acquisita is noted for its resistance to therapy. Corticosteroids and dapsone are often ineffective. Besides other immunosuppressant drugs, extracorporeal photochemotherapy, high-dose immune globulin and colchicine have been used to treat patients with this disorder.[19]

BULLOUS SYSTEMATIC LUPUS ERYTHEMATOSUS

Bullous lupus occurs in the setting of active systemic lupus erythematosus. Most patients are young black women. As in epidermolysis bullosa acquisita, type VII collagen is the target antigen, but skin fragility and scarring do not occur in bullous systemic lupus erythematosus.

The vesiculobullous eruption occurs mostly on sun-exposed skin, particularly on the face, lips and arms (Figure 9). The lesions are usually grouped in erythematous patches. In most patients, remission without complications occurs after the lupus flare subsides.[20]

The clustered vesicles of bullous systemic lupus erythematosus may resemble those of dermatitis herpetiformis. If the vesicles are larger and widespread, they may resemble the lesions of bullous pemphigoid or epidermolysis bullosa acquisita. Histologically, bullous systemic lupus erythematosus closely resembles dermatitis herpetiformis, which makes both the history and immunofluorescence testing essential for an accurate diagnosis.

Therapy. Patients with bullous systemic lupus erythematosus usually respond promptly to dapsone, but the disease recurs quickly after the drug is discontinued.[21]

DERMATMS HERPETIFORMIS

Dermatitis herpetiformis is an intensely pruritic, papulovesicular blistering disorder characterized by IgA deposits at the dermoepidermal junction. The disorder is more common in men and northern European populations, and it is uncommon in blacks.

The eruption of dermatitis herpetiformis is symmetric, involving the elbows, extensor forearms, knees, buttocks and, often, the upper back and scalp (Figure 10). The primary lesions are papulovesicles, which are often grouped on erythematous bases, as in herpes. However, because of the characteristic intense pruritus, sometimes only excoriations are found.

Gluten enteropathy occurs in 15 percent of patients with dermatitis herpetiformis, and over 85 percent of patients have evidence of celiac disease on biopsy of the small bowel. The role of gluten in dermatitis herpetiformis is not known, but the elimination of gluten from the diet leads to a reduction of Iga in the skin.[22] Dermatitis herpetiformis is strongly associated with HLA-DR3/HLA-B8, and the association of HLA DQw2 and enteropathy in dermatitis herpetiformis is nearly 100 percent.[23]

The incidence of hypochlorhydria, atrophic gastritis and pernicious anemia is increased in patients with dermatitis herpetiformis. Hyperthyroidism and hypothyroidism are more common in patients with this blistering disorder, and thyroid auto-antibodies are frequently detectable. Exacerbation of dermatitis herpetiformis has been reported in patients receiving thyroid replacement therapy and in those with thyrotoxicosis.[24] The incidence of lymphoma is increased in patients with dermatitis herpetiformis is similar to the rate of lymphoma noted in celiac disease.

Intense pruritus with papulovesicles suggests dermatitis herpetiformis. However, if only excoriations are found, scabies or idiopathic pruritus may be suspected. Papulovesicles with intense pruritus may also occur in bullous pemphigoid, bullous systemic lupus erythematosus, epidermolysis bullosa acquisita or linear IgA bullous dermatosis.

Therapy. Dermatitis herpetiformis persists many years, with illness, stress and variations in diet provoking exacerbations. Dapsone is remarkably effective in patients with this disorder, and it sometimes relieves pruritus within hours of initial administration. A gluten-free diet, which is difficult for patients to follow, leads to the eventual clearance of dermatitis herpetiformis, but when patients resume a regular diet, the disorder recurs. However, gluten restriction does reduce the required dose of dapsone.

ADULT AND CHILDHOOD LINEAR IGA

BULLOUS DERMATOSIS

Linear Iga bullous dermatosis is a rare subepidermal vesiculobullous disease. Since this disease was for,some time considered a variant of dermatitis herpetiformis or pemphigoid, its true incidence is not known. The hallmark of the disorder is the linear deposition of IgA along the basement membrane and, in some cases, the presence of a circulating 97-kd antibasement membrane antibody.[25]

Annular groups of blisters resembling "clusters of jewels" are highly characteristic of linear IgA bullous dermatosis.[26] The blisters represent bullae forming around a crusted healing lesion (Figure 11).

Therapy. Linear IgA bullous dermatosis usually responds to dapsone, but the dosage may need to be higher than in dermatitis herpetiformis. Corticosteroids and other immunosuppressants have been used to treat resistant cases.

Final Comment

In almost an instances, nonautoimmune blistering conditions can be identified by the history and the physical examination, with no need for biopsy. In fact, the histology of allergic reactions and autoimmune bullous diseases may be indistinguishable without immunofluorescence. Therefore, a biopsy is not performed if an exogenous cause is suspected. In such cases, removal of the offending agent is the effective treatment.

If an exogenous cause for a blistering condition is not found, a medical assessment should be performed. The review of systems should focus on ocular and oral symptoms, antecedent pruritus, diarrhea or weight loss, and symptoms of systemic lupus erythematosus, diabetes and thyroid disease (Table 2).

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Once the list of possible causes has been narrowed, specimens for histologic and immunohistochemical testing are required to establish a definitive diagnosis. Because the types of tissue required for routine pathology and immunopathology are different and vary with the disease, the laboratory evaluation should be performed by a physician with experience in blistering diseases. Accurate diagnosis requires proper dermatopathologic interpretation and laboratory personnel experienced in immunofluorescence techniques.

The management of autoimmune blistering diseases ranges from simple interventions to an extensive evaluation of multiple systems plus aggressive treatment. Close medical monitoring is required when prolonged immunosuppressant drug therapy is necessary, especially in elderly patients. Periodic evaluations by ophthalmologic, dental and other specialists should be coordinated by a primary physician who is familiar with the late complications of the particular autoimmune blistering disease.

REFERENCES

[1.] Becker BA, Gaspari AA. Pemphigus vulgaris and vegetans. Dermatol Clin 1993;11:429-52.

[2.] Bean SF, Halubar K, Gillett RB. Pemphigus involving the eyes. Arch Dermatol 1975;111:1484-6.

[3.] Goldberg NS, Weiss SS. Pemphigus vulgaris of the esophagus in women. J Am Acad Dermatol 1989;21 (5 Pt 2):1115-8.

[4.] Younus J, Ahmed AR. The relationship of pemphigus to neoplasia. J Am Acad Dermatol 1990;23(3 Pt 1):498-502.

[5.] Mutasim DF, Pelc NJ, Anhalt GJ. Drug-induced pemphigus. Dermatol Clin 1993;11:463-71.

[6.] Anhalt GJ, Kim SC, Stanley JR, Korman NJ, Jabs DA, Kory M, et al. Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med 1990;323:1729-35.

[7.] Ahmed A, Moy R. Death in pemphigus. J Am Acad Dermatol 1982;7:221-8

[8.] Chuang TY, Korkij W, Soltani K, Clayman J, Cook J. Increased frequency of diabetes mellitus in patients with bullous pemphigoid: a case-control study. J Am Acad Dermatol 1984;11:1099-102.

[9.] Grattan CE. Evidence of an association between bullous pemphigoid and psoriasis. Br J Dermatol 1985;113:281-3.

[10.] Stone SP, Schroeter AL. Bullous pemphigoid and associated malignant neoplasms. Arch Dermatol 1975;111:991-4.

[11.] Lindelof B, Islam N, Eklund G, Arfors L. Pemphigoid and cancer. Arch Dermatol 1990; 126:66-8.

[12.] Berk MA, Lorincz AL. The treatment of bullous pemphigoid with tetracydine and niacinamide. A prelirainary report. Arch Dermatol 1986;122:670-4.

[13.] Mutasim DF, Pelc NJ, Anhalt GJ. Cicatricial pemphigoid. Dermatol Clin 1993;11:499-510.

[14.] Anhalt GJ, Morrison LH. Pemphigoid: bullous, gestational and cicatricial. Curr Probl Dermatol 1989; 1:125-56.

[15.] Shornick JK. Herpes gestationis. Dermatol Clin 1993;11:527-33.

[16.] Shornick JK, Black MM. Fetal risks in herpes gestationis. J Am Acad Dermatol 1992;26:63-8.

[17.] Briggaman RA, Gammon WR. Epidermolysis bullosa acquisita and other acquired blistering diseases manifesting autoimmunity to type VII collagen. Curr Probl Dermatol 1991;111:47-74.

[18.] Woodley DT, Briggaman RA, Gammon WT. Review and update of epidermolysis bullosa acquisita. Semin Dermatol 1988;7:111-22.

[19.] Fine JD. Management of acquired bullous skin diseases. N Engl J Med 1995;333:1475-84.

[20.] Gammon WR, Briggaman RA. Epidermolysis Bullosa acquisita and bullous systemic lupus erythematosus. Diseases of autoimmunity to type VII collagen. Dermatol Clin 1993;11:53547.

[21.] Hall RP, Lawley TJ, Smith HR, Katz SI. Bullous eruption of systemic lupus erythematosus. Dramatic response to dapsone therapy. Ann Intern Med 1982;97:165-70.

[92.] Leonard JN, Fry L. Treatment and management of derrnatitis herpetiformis. Clin Dermatol 1991;9:403-8.

[23.] Hameed A, Ahmed AR. MHC regulation of immune responses. Dermatol Chn 1993;11:391-8.

[24.] Smith EP, Zone JJ. Dermatitis herpetiformis and linear IgA bullous dermatosis. Dermatol Clin 1993; 11:511-26.

[25.] Zone JJ, Taylor TB, Kadunce DP, et al. IgA antibodies in chronic bullous disease of childhood react with a 97 kDa basment membrane zone protein. J Invest Dermatol 1996;106:1277-80.

[26.] Edwards S, Wojnarowska F, Armstrong LM. Chronic bullous disease of childhood with oral mucosal scarring. Clin Exp Dermatol 1991;16:41-3.

The Authors

BRUCE RYE, M.D. is chnical instructor in the Department of Derniatology at the University of Alabama School of Medicine at Birmingham. He is also in private clinical and surgical dermatology practice at Tennessee River Dermatology, Florence, Ala. Dr. Rye received his medical degree from University of South Alabama College of Medicine, Mobile. In addition, he completed internal medicine training at the University of Vermont, Burlington, and dermatology training at the University of Alabama-Birmingham.

J. MICHAEL WEBB, M.D. is clinical instructor in the Department of Dermatology at the University of Alabama School of Medicine-Birmingham. Dr. Webb also is in private clinical and surgical dermatology practice with Tennessee River Dermatology. After earning his medical degree from the University of Alabama School of Medicine at Birmingham, he completed training in internal medicine and dermatology at the University of Alabama-birmingham.

Address correspondence to Bruce Rye, M.D., Tennessee River Dermatology, 2471 Helton Dr., Florence, AL 35630.

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