Elizabeth A. Abel MD1
Jean-Claude Bystryn MD2
1Clinical Professor of Dermatology, Stanford University School of Medicine
2Professor of Dermatology, New York University School of Medicine, Director, Melanoma Immunotherapy Clinic, NYU Kaplan Comprehensive Cancer Center
Elizabeth A. Abel, M.D., has received research support from Allergan Inc., Amgen, and Genentech.
Jean-Claude Bystryn, M.D., has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
Vesiculobullous diseases, which number more than 50, are characterized by fluid-filled blisters in the skin. Blisters smaller than 0.5 cm are called vesicles, and larger ones are called bullae. Vesicles and bullae are reaction patterns of skin to injury and thus can be caused by a wide variety of conditions.
Most primary vesiculobullous diseases are either immunologic or genetic. They are caused by autoimmune reactions to components of skin, by allergic reactions to external agents in which the skin is the major organ system affected, and by genetic conditions in which some components of the skin are missing or abnormal. The final common pathway is disadhesion: one or more of the structures that hold the skin together separate, and a fluid-filled cavity appears. The different diseases are classified by the structure or structures affected and the mechanism or mechanisms by which disadhesion occurs [see Table 1]. In this subsection, several paradigmatic vesiculobullous diseases are discussed in the context of a general diagnostic approach to the patient with blistering lesions.
Table 1 Differentiating Features and Standard Therapy for Selected Blistering Diseases
General Clinical Assessment
Diagnosis is based on clinical features, histologic findings, and immunologic findings. Clinical features of diagnostic importance include the following:
Table 2 Pathologic Typology of Blisters71
The most important histologic finding is the layer of skin where the blister forms. If the blister forms in the epidermis, does it form immediately above the basal cell layer or higher up (beneath the stratum corneum)? If it forms in the basement membrane zone, is it within the lamina lucida or below the lamina densa? The precise location may be determined by immunofluorescence or by electron microscopic procedures.
The most important immunologic finding is the presence or absence of abnormal circulating or tissue-fixed antibodies to skin. These are usually detected by immunofluorescence techniques: (1) indirect immunofluorescence to detect circulating antibodies and (2) direct immunofluorescence on skin biopsy specimens to detect tissue-fixed antibodies. Enzyme-linked immunosorbent assays (ELISAs) using purified antigens are now available to detect the antibodies that occur in some of the bullous diseases, such as pemphigus.
Definition and Pathogenesis
Pemphigus is characterized by blisters that arise within the epidermis and by a loss of cohesion of the epidermal cells (acantholysis) that results in the formation of clefts above the basal cell layer. Autoantibodies directed against adhesion molecules cause epidermal keratinocytes to separate, resulting in intraepidermal bullae. A recently proposed hypothesis holds that in pemphigus, the autoantibodies interact with cytokines, including tumor necrosis factor-α (TNF-α), to induce acantholysis via basal cell shrinkage.1 There are two types of pemphigus: deep (e.g., pemphigus vulgaris) and superficial (e.g., pemphigus foliaceus). They differ in the epidermal layers that are injured, in the clinical manifestations of the diseases, and in the associated immunologic abnormalities.2 In the deep forms, the blisters form immediately above the basal cell layer and are associated with autoantibodies to desmoglein 3; about half the cases are associated with antibodies to desmoglein 1 glycoprotein keratinocyte adhesion molecules.3 In the superficial forms, the bullae form immediately below the stratum corneum. The superficial forms of pemphigus are associated with antibodies to desmoglein 1.
Pemphigus vulgaris is the most common form of pemphigus. It can develop at any age but usually occurs in persons between 30 and 60 years of age. The disorder tends to affect persons of Mediterranean ancestry but can occur in persons of any ethnicity. Pemphigus is more common in persons with certain HLA allotypes. The occurrence of the disease in first-degree relatives, although rare, suggests an inherited susceptibility transferred as a dominant trait. However, other unknown factors are required for expression of the disorder in predisposed persons.4 Studies of HLA class II alleles in Japanese patients, as well as in other ethnic groups, show an association with HLA-DRB1*04 and HLA-DRB1*14 in patients with pemphigus vulgaris across racial lines.5
Pemphigus vulgaris usually, but not invariably, begins with chronic, painful, nonhealing ulcerations in the oral cavity [see Figure 1]. Bullae are rarely seen because they rupture easily, leaving ulcerated bases. The ulcerations are usually multiple, superficial, and irregular in shape. Any oral mucosal surface can be involved, but the most common sites are the buccal and labial mucosae, the palate, and the gingiva. The occurrence of multiple ulcerations differentiates these lesions from ulcerated malignant tumors of the oral cavity, which are usually single. A diagnosis of pemphigus is usually considered only after lesions have been present for weeks to months.
Figure 1. Painful ulcerations or erosions in the mouth may be present many months before the onset of generalized pemphigus vulgaris.
Skin lesions can also be the initial manifestation, beginning as small fluid-filled bullae on otherwise normal-looking skin. The blisters are usually flaccid because the thin overlying epidermis cannot sustain much pressure. Bullae therefore rupture rapidly, usually in several days, and may be absent when a patient is examined. Sharply outlined, coin-sized, superficial erosions with a collarette of loose epidermis around the periphery of the erosions may appear instead. The upper chest, back, scalp, and face are common sites of involvement, but lesions can occur on any part of the body. The condition progresses over weeks to months [see Figure 2]. Sites often overlooked include the periungual areas (in which disease manifests itself as painful, erythematous, paronychial swelling), the pharynx and larynx (characterized by pain on swallowing and by hoarseness), and the nasal cavity (characterized by nasal congestion and a bloody mucous discharge, which is particularly noticeable upon blowing the nose in the morning). Although the mucous membranes are typically involved in pemphigus vulgaris, a rare variant marked by blisters and erosions in the skin only, without mucosal involvement, has recently been identified.6
Figure 2. Flaccid bullae of pemphigus vulgaris have broken down to form erosions and crusts, particularly under the breasts.
A characteristic feature of all severe active forms of pemphigus is the Nikolsky sign, in which sliding firm pressure on normal-appearing skin causes the epidermis to separate from the dermis. A recent study demonstrated that the Nikolsky sign is highly specific for the diagnosis of pemphigus.7 The sign is elicited most easily on clinically uninvolved skin adjacent to an active lesion.
If left untreated, the erosions and bullae of pemphigus vulgaris gradually spread, involving an increasing surface area, and can become complicated by severe infections and metabolic disturbances. Before the advent of corticosteroids, pemphigus was almost invariably fatal—approximately 75% of patients died within a year.8 However, as better techniques have permitted the diagnosis of earlier, milder forms of the disease, the prognosis has improved significantly.9 Mild forms may regress spontaneously, and the progression of even the most severe forms can be reversed in most cases. With treatment (see below), lesions normally heal without scarring. Most patients treated for pemphigus will experience a partial remission within 2 to 5 years. They can then be maintained lesion-free with minimal doses of corticosteroids (approximately 15 mg of prednisone daily). In a longitudinal study of outcome in 40 patients with pemphigus vulgaris, 45% experienced a complete and long-term remission after 5 years, and 71% experienced such a remission after 10 years. Patients in remission remained lesion-free without any therapy.10 The hyperpigmentation that is commonly associated with pemphigus usually resolves after several months.
In pregnancy, pemphigus appears to be associated with an increased incidence of premature delivery and fetal death.11 The lesions of pemphigus can appear on the skin of the neonate; however, they normally resolve spontaneously in several weeks.
Pemphigus foliaceus is the second most common form of pemphigus. It usually begins with small (approximately 1 cm), pruritic, crusted lesions resembling corn flakes on the upper torso and face. The crusts are easily removed, leaving chronic, superficial erosions.
Over weeks to months, the condition progresses, with an increasing number of lesions appearing on the upper torso, face, and scalp. In extensive cases, lesions develop over the entire body, become confluent, and can progress to an exfoliative erythroderma. In contrast to the deep forms of pemphigus, oral involvement in pemphigus foliaceus is very rare.
The prognosis of untreated pemphigus foliaceus is more favorable than that of pemphigus vulgaris. The lesions of pemphigus foliaceus are not as deep, and there is less chance for infection, fluid loss, and metabolic disturbance. Although pemphigus foliaceus is less severe, the doses of medications required for control are similar to those used for pemphigus vulgaris. There are two clinical variants: pemphigus erythematosus and fogo selvagem. Pemphigus erythematosus (also known as Senear-Usher syndrome) has features of lupus erythematosus. Fogo selvagem (Portuguese for “wild fire”; also known as endemic pemphigus and Brazilian pemphigus) [see Table 1] may be triggered by exposure to one or more environmental antigens.12
Both pemphigus vulgaris and pemphigus foliaceus can exist in a latent form and be unmasked by the use of certain drugs. Pemphigus that continues after a patient stops using a drug is referred to as triggered, whereas lesions that clear soon after withdrawal are referred to as induced. Although drug-related pemphigus is uncommon, its possibility must be excluded in all patients with newly diagnosed disease. The clinical, histologic,13 and immunofluorescence abnormalities14 of drug-induced pemphigus are similar to those of the idiopathic variety. However, pemphigus caused by drugs containing a sulfhydryl radical (thiol drugs) is clinically distinct from pemphigus caused by nonthiol drugs. The presence or absence of a sulfhydryl radical appears to influence both the type of pemphigus that is expressed and the prognosis of the drug-induced condition. Thiol drugs are more likely to induce pemphigus foliaceus, which is more likely to regress spontaneously when the drug is discontinued [see 2:VI Cutaneous Adverse Drug Reactions]. Nonthiol drugs are more likely to trigger pemphigus vulgaris, which can persist even after the drug is stopped.
The most commonly implicated agents in drug-related pemphigus are thiol drugs such as penicillamine and captopril. Other responsible drugs include sulfur-containing drugs such as penicillins and cephalosporins. These undergo metabolic changes to form thiol groups and are termed masked thiol drugs. Nonthiol drugs that contain an amide group (e.g., dipyrone and enalapril) can provoke a disease that is indistinguishable from spontaneously occurring pemphigus vulgaris.14
Epidemiologic features of fogo selvagem in rural areas of Brazil suggest that the production of pathologic antibodies to desmoglein 1 is linked to exposure to one or more environmental antigens.12
Paraneoplastic Mixed Bullous Disease
Paraneoplastic pemphigus is an autoimmune disease of the skin and oral mucosa that develops in patients with an underlying neoplasm. It is characterized by large, tense bullae. A rare lymphoproliferative disorder known as Castleman tumor is a common subtype of paraneoplastic pemphigus in China.15 Unfortunately, standard treatments for autoimmune blistering diseases fail in most cases. Paraneoplastic pemphigus shares clinical features of both pemphigus and severe erythema multiforme.16
Familial benign chronic pemphigus, or Hailey-Hailey disease, is an autosomal dominant disorder marked by multiple vesicles on inflammatory bases in skin subject to friction or pressure, such as intertriginous areas. In addition to pharmacologic treatment (see below), therapy includes keeping involved areas dry and free of friction.
Histologic and Immunologic Findings
The diagnosis should always be confirmed by histopathologic examination and immunofluorescence studies.17 Biopsies for pemphigus and all other bullous diseases should be performed at the edge of a lesion, so as to include clinically uninvolved adjacent skin. Acantholysis (the separation of keratinocytes from each other) is the fundamental abnormality in all forms of pemphigus.
All forms of pemphigus are associated with circulating and tissue-fixed intercellular (IC) autoantibodies that react against cell-surface keratinocyte antigens. The detection of these antibodies is very helpful in establishing the diagnosis, because they rarely appear in other conditions. Circulating IC autoantibodies are detected by indirect immunofluorescence assays on serum, and tissue-fixed IC autoantibodies are detected by direct immunofluorescence on skin biopsies. In both cases, the autoantibodies cause a lacelike pattern of fluorescence within the epidermis. Low titers of IC autoantibodies may also be present in burns, fungal infections, and allergic drug reactions. Antibodies against ABO blood group antigens, which are present in approximately 5% of the normal population, are the most common cause of false positive tests for IC autoantibodies. Tissue-fixed IC autoantibodies are present in lesions and adjacent normal skin in approximately 90% of patients with pemphigus and are more sensitive and specific for the diagnosis of pemphigus than are circulating IC autoantibodies. The most common autoantibodies are IgG, but IgM and IgA (with or without C3) may also be deposited.
Initial therapy is determined by the extent and rate of progression of lesions. Localized, slowly progressive disease can be treated with intralesional injections of corticosteroids (triamcinolone acetonide, 10 to 20 mg/ml) or topical application of high-potency corticosteroids. New lesions that continue to appear in increasing numbers can be controlled in some cases with low-dose systemic corticosteroids (prednisone, 20 mg/day). Patients with extensive or rapidly progressive disease are treated with moderately high doses of corticosteroids (prednisone, 70 to 90 mg/day). This dose is rapidly escalated every 4 to 14 days in 50% increments until disease activity is controlled, as evidenced by an absence of new lesions and the disappearance of skin pain or itching. If the disease remains active despite high doses of corticosteroids (e.g., prednisone, 120 to 160 mg/day), one of the following approaches should be considered for rapid control:
No comparative studies have yet evaluated the relative effectiveness of these procedures. On the basis of such limited experience, IVIg may be preferred because it has fewer side effects than the other procedures and is associated with a significantly higher response rate. Once disease activity is controlled, the patient is maintained on the type and dose of medications required to establish control until approximately 80% of lesions are healed. Therapy should not be tapered while new lesions are appearing.
Rituximab is an anti-CD20 chimeric monoclonal antibody that is approved for use in non-Hodgkin lymphoma. In a recent trial in which rituximab was given in combination with IVIg to 11 patients with refractory pemphigus vulgaris, the combined therapy produced rapid resolution of lesions and clinical remission lasting from 22 to 37 months.22 Eventually, it was possible to discontinue all treatment for all the patients in the study. Side effects were mild, and no serious infections occurred.
The role of adjuvants in the treatment of pemphigus remains controversial. Because of a lack of controlled studies, it is not known whether the potential benefits of adjuvants outweigh the additional toxicities.5 Indications for adjuvant therapy include the presence of relative contraindications to systemic corticosteroids, development of serious corticosteroid side effects, and repeated flares of disease activity that make it undesirable to reduce corticosteroid doses.10 Because adjuvants require 4 to 6 weeks to become effective, they are not used to control active, rapidly progressive disease.
Adjuvant treatments for pemphigus include a variety of cytotoxic and immunosuppressive agents, such as cyclophosphamide, azathioprine, cyclosporine, methotrexate, and mycophenolate mofetil.23 Mycophenolate mofetil may be preferred as an alternative to azathioprine because it is nonhepatotoxic and possibly more efficacious. Dapsone, anti-inflammatory agents (e.g., gold), antimalarials, and certain antibiotics (e.g., tetracycline and minocycline) are also used for adjuvant therapy.
The immediate cause of bullous pemphigoid (BP) appears to be an autoantibody response to the 180 kd (BP180) and 230 kd (BP230) basement membrane zone antigens.24 Passive transfer of these antibodies into animals can cause lesions of the disease25; anti-BP180 autoantibodies have been found to be a poor prognostic factor in a study of 94 elderly patients.26
BP is a nonscarring, subepidermal blistering disease that is characterized by recurrent crops of large, tense blisters arising from urticarial bases. Lesions normally appear on the torso and flexures, particularly on the inner thighs. Blisters can range in size from a few millimeters to several centimeters [see Figure 3]. They are usually filled with a clear fluid, but they can be hemorrhagic. Erosions are much less common than in pemphigus, and the Nikolsky sign is negative. A characteristic feature is that multiple bullae usually arise from large (palm-sized or larger), irregular, urticarial plaques. This is in contrast to the bullae of erythema multiforme (see below), in which a single bulla arises from the center of a smaller (coin-sized) urticarial base.
Figure 3. Tense bullae characteristically occur in bullous pemphigoid.
In acute flares of BP, bullae may arise from normal-appearing skin. Oral lesions occur in 10% to 25% of patients; ocular involvement, however, is rare. Without treatment, the disease may become very extensive.
BP is a sporadic disease that occurs mainly in the elderly but can occur at any age and in any race. It has been reported in a 2-month-old infant.27 Precipitating factors include trauma, burns, ionizing radiation, ultraviolet light, and certain drugs. In a case-control study of 116 incident cases, neuroleptics and diuretics—particularly aldosterone antagonists—were more commonly used by patients who developed BP than by control subjects.28 BP has also been associated with use of the loop diuretic furosemide.29 There is still controversy as to whether BP is associated with an increased incidence of cancer30; however, correlations between flare in disease activity and recurrence of underlying cancer suggest such an association in individual patients.
BP is characterized by spontaneous remissions followed by flares in disease activity that can persist for years. Even without therapy, BP is often self-limited, resolving after a period of many months to years. The disease is nonetheless serious, particularly in older patients who have been treated with high doses of oral corticosteroids.31 Mortality is low in younger persons but is significant in the elderly. In one study of patients older than 68 years, nearly a third died of the disease or its complications (mainly sepsis and cardiovascular disease) within 1 year.26
Histologic and Immunologic Findings
The earliest lesion of BP is a blister arising in the lamina lucida, between the basal membrane of keratinocytes and the lamina densa. This is associated with loss of anchoring filaments and hemidesmosomes. Histologically, there is a superficial inflammatory cell infiltrate and a subepidermal blister without necrotic keratinocytes. The infiltrate consists of lymphocytes and histiocytes and is particularly rich in eosinophils. There is no scarring.
Approximately 70% to 80% of patients with active BP have circulating antibodies to one or more basement membrane zone antigens. Immunofluorescence microscopy is essential in making the diagnosis of BP. On direct immunofluorescence, the antibodies are found to be deposited in a thin linear pattern; and on immune electron microscopy, they are detected in the lamina lucida. By contrast, the antibodies to basement membrane zone antigens that are present in the skin of patients with systemic lupus erythematosus are deposited in a granular pattern.
Two less common subepidermal blistering diseases that are closely related to BP are cicatricial mucous membrane pemphigoid and herpes gestationis [see Table 1]. Cicatricial pemphigoid is characterized by blisters that tend to heal with scarring.32 Although mucosal surfaces are the primary site in most patients, skin lesions are occasionally localized to the head and neck or are disseminated. Complications of cicatricial pemphigoid include entropion, corneal ulcerations and other ocular problems, esophageal strictures, and scarring. The differential diagnosis of BP also includes dermatitis herpetiformis and acquired epidermolysis bullosa (see below). Scar formation in mucous membrane pemphigoid and acquired epidermolysis bullosa can lead to major disability.33
Treatment of BP is generally similar to that of pemphigus.34 The differences are as follows: (1) BP normally, but not invariably, responds to lower doses of systemic corticosteroids (alone or in combination with other oral or topical agents), with most patients improving on prednisone at a dosage of 80 mg/day or less; (2) in an open prospective study of 18 cases, low-dose methotrexate was shown to be effective for maintenance of clinical remission induced by initial short-term use of potent topical steroids35; and (3) BP is more likely to respond to dapsone36 or to the combination of tetracycline and niacinamide.37,38 Mycophenolate mofetil has also proved useful in the treatment of BP.39 Considering that the prognosis of untreated BP is better than that of pemphigus, side effects of treatment are of greater concern. Two small studies of severe ocular mucous membrane pemphigoid suggest that this condition responds more favorably to treatment with cyclophosphamide in combination with prednisone, whereas dapsone suppresses some cases of mild to moderate disease.33 In a recent study, three patients with mucous membrane pemphigoid—all with oral involvement and one with severe ocular disease—responded to twice-weekly subcutaneous injections of the TNF-α blocker etanercept.40 Coexisting bullous pemphigoid and psoriasis have also been successfully treated with etanercept.41
Dermatitis herpetiformis (DH) is a rare vesiculobullous disease characterized by intensely pruritic, small vesicles that are grouped in small clusters and typically appear on the extensor aspects of the extremities and on the buttocks, scalp, and back. The condition is believed to be an immune-mediated disorder and is associated with abnormal granular deposits of IgA at the basement membrane zone. It is sometimes associated with asymptomatic, gluten-sensitive, spruelike enteropathy. The disease is chronic, with periods of exacerbation and remission. Lesions may clear if patients follow a strict gluten-free diet.
Linear IgA dermatosis [see Table 1] is an uncommon subepidermal autoimmune blistering disease that may clinically resemble DH or erythema multiforme (see below). It is characterized by linear deposition of IgA at the dermoepidermal junction. The exact pathogenesis of linear IgA disease is unknown, but several cases have been reported in association with inflammatory bowel disease, use of drugs such as vancomycin, malignancy, connective tissue diseases, and infections.42
The cause of DH is unknown. It may be related to gluten-sensitive celiac disease; there is a strong association between the two conditions, and they share a similar genetic basis (both are associated with HLA-B8 and HLA-DR3). DH is thought to result from an abnormal IgA immune response to an unidentified antigen (possibly found in gluten) that contacts the gut. Skin lesions may result from deposition of immune complexes against this antigen in skin.
Skin lesions of DH are polymorphic. They usually begin as small, very pruritic urticarial papules or vesicles that are grouped in a herpetiform pattern [see Figure 4]. Actual vesicles or other primary lesions are rarely seen because they are excoriated by patients' scratching. The distribution of lesions is characteristic: they occur most commonly on the elbows, knees, buttocks, scapular area, and scalp. Sometimes, lesions are scattered over the entire body. The lesions tend to appear suddenly and symmetrically, sometimes after ingestion of large amounts of gluten. Lesions heal, leaving hyperpigmentation; scarring may result from scratching or secondary infection. Involvement of mucous membranes is rare.
Figure 4. Dermatitis herpetiformis, an extremely pruritic eruption, commonly presents as excoriated, grouped papulovesicles, often in a symmetrical distribution.
The disease is twice as common in men as in women. It predominantly affects persons between the ages of 20 and 50 years. There may be an associated patchy duodenal and jejunal atrophy that resembles the gluten-sensitive enteropathy of adult celiac disease.43,44 The enteropathy is usually asymptomatic and, like celiac disease, responds to gluten restriction. Because celiac disease is associated with gastrointestinal lymphoma, there is concern that the same may be true for DH. However, although lymphomas of the small intestine have been reported in DH,45 the association appears to be rare.
Histologic and Immunologic Findings
Two characteristic laboratory features of DH are used for diagnosis. First, the disease is characterized histologically by accumulations of neutrophils and eosinophils in microabscesses at the tips of dermal papillae. In more severe cases, edema appears and can progress to subepidermal blisters appearing just below the lamina densa. Second, granular deposits of IgA are found at the basement membrane zone in almost all patients. These are often associated with granular deposits of C3 and, occasionally, of IgG and IgM. When found alone, IgA is one of the most sensitive and specific diagnostic markers for DH. When IgA is found with deposits of IgG, IgM, or C3, immune complex vasculitis and systemic lupus erythematosus are added to the differential diagnosis. Although basement membrane zone deposits of IgA alone also occur in linear IgA disease,46 the deposits in that condition are linear rather than granular. There are no circulating antibodies to normal skin components in DH.
DH responds rapidly and dramatically to sulfones. Dapsone at a dosage of 100 to 200 mg/day is most commonly used for treatment. Glucose-6-phosphate dehydrogenase (G6PD) deficiency must be excluded before starting therapy, because lack of this enzyme can result in severe drug-induced anemia. Sulfapyridine at a dosage of 1 to 3 g/day in divided doses (or sulfamethoxypyridazine) can be used in patients who cannot tolerate dapsone. Doses of these drugs are gradually reduced to the lowest amount that will suppress pruritus and the development of new lesions. As indicated, patients also respond to a gluten-free diet; however, such diets are difficult to follow. Nevertheless, even a partial decrease in gluten intake will result in a decreased requirement of sulfones and should therefore be encouraged.
Erythema multiforme is an acute, recurrent, self-limiting disease that affects all age groups and races. It is characterized by the sudden eruption of crops of lesions, which represent a cell-mediated hypersensitivity reaction of the skin and mucous membranes to a variety of precipitating factors, including infectious agents and drugs [see Table 3].47 Recent or recurrent infection with herpes simplex virus is a principal risk factor for erythema multiforme.48
Table 3 Precipitating Factors in Erythema Multiforme
Lesions may be localized or widespread and may affect both the skin and the mucous membranes. The eruption often occurs bilaterally and symmetrically on the extensor surfaces of the extremities and on both the dorsal and the volar areas of the hands and feet. Lesions vary from well-defined, red or purple, edematous macules and papules to vesicular or bullous lesions that may ulcerate, encrust, erode, and become infected. A target lesion consisting of a papule or vesicle surrounded by a region of normal skin and a halo of erythema at the periphery [see Figure 5] is characteristic.
Figure 5. Target lesions are characteristic of erythema multiforme.
Stevens-Johnson syndrome is a severe form of erythema multiforme that is usually disseminated, fulminant, and multisystemic [see Figure 6]. The syndrome may be accompanied by high fever, malaise, chills, headache, tachycardia, tachypnea, and prostration. Drugs are more commonly the underlying etiologic agent than infection. Some of these include long-acting sulfonamides (particularly trimethoprim-sulfamethoxazole), anticonvulsants, barbiturates, and nonsteroidal anti-inflammatory drugs. The mucous membranes in the mouth, the anus, and the vagina contain round or oval erythematous macules that form vesicles, bullae, and ulcers. Ocular lesions are bilateral yellowish-gray papules that often ulcerate and become secondarily infected, resulting in conjunctivitis. Ocular involvement has produced blindness.
Figure 6. Stevens-Johnson syndrome is a fulminating form of erythema multiforme associated with marked mucocutaneous involvement, eye involvement, and severe constitutional symptoms.
Toxic epidermal necrolysis (TEN) is potentially fatal because of detachment of large areas of epidermis. TEN is considered by some to be a form of erythema multiforme, usually a reaction to medication. However, the absence of immune reactants within the blood vessels in the skin and the paucity of dermal inflammation have led some researchers to consider TEN a separate disease.
Staphylococcal scalded skin syndrome also causes large areas of epidermal necrosis. This syndrome, which results from toxins produced byStaphylococcus aureus,49 is sometimes confused with TEN [see Table 1].
Histologic and Immunologic Findings
Characteristic cutaneous histologic findings of erythema multiforme include subepidermal edema, bulla formation, epidermal cell necrosis, and a deep perivascular inflammatory infiltrate composed of mononuclear cells involving vessels in the upper dermis. The chemokine profile, with dominance of lymphocytic attractant chemokines at the dermoepidermal junction, is a feature of the interface dermatitis.50 There are no specific immunofluorescence findings and no circulating antibodies, although direct immunofluorescence may show granular deposits of C3 and fibrin at the dermoepidermal junction and deposits of IgM, C3, and fibrin in the dermal blood vessels.
In vitro studies suggest that different immunopathogenic processes may be involved in herpes-mediated erythema multiforme and the drug-mediated forms of the disease.51
Erythema multiforme eruptions may recur without warning, despite preventive measures. It is therefore important to identify and eliminate underlying causes. Mild cases are treated symptomatically with topical glucocorticoids and topical anti-inflammatory, antipruritic, or antibiotic preparations. Oral acyclovir may be effective in the prophylaxis of recurrent postherpetic erythema multiforme. In more severe cases, treatment with prednisone, 40 to 120 mg/day in divided doses, is indicated. If the eyes are involved, prompt ophthalmologic consultation should be obtained. Patients with large areas of epidermal necrosis (e.g., those with Stevens-Johnson syndrome) may require specialized intensive care, such as in a burn unit. Administration of IVIg reportedly produced a positive response in children with Stevens-Johnson syndrome in one study; no new blisters developed within 24 to 48 hours of treatment, and rapid recovery ensued.52
Early treatment with high-dose IVIg has also been reported to be safe and effective in improving survival of patients with TEN.53 However, there is no standard treatment of TEN that can be used as a basis for comparative studies.54
Epidermolysis bullosa (EB) comprises a group of genetically-based disorders with an estimated incidence of 19.6 per 1 million live births.55There are more than 20 different phenotypes of EB, which may be inherited as an autosomal recessive trait. These disorders are characterized by blistering and erosions that arise after minor skin trauma or friction and heal with or without scarring. The extent of involvement ranges from localized blisters (e.g., on the palms and soles) to severe widespread sloughing of the skin, with a risk of severe morbidity and mortality from secondary infection, fluid and electrolyte imbalance, anemia, or other complications. Several genitourinary complications, including urethral meatal stenosis, urinary retention, and hydronephrosis, have also been associated with EB.56
EB is classified primarily on the basis of an ultrastructural level of skin cleavage in the basement membrane zone [see Figure 7]. Three major subtypes include EB simplex or epidermolytic (intraepidermal), junctional EB (intra-lamina lucida), and dystrophic or dermolytic EB (sub-lamina densa). Electron microscopy examination localizes the lesions to a specific layer.57 Because this technology may not be widely available, immunofluorescence mapping with monoclonal antibodies can be used to target components of the basement membrane layers such as BP antigen (basal cell layer), laminin (lamina lucida), and type IV collagen (lamina densa).58 The prenatal diagnosis may be made by immunocytochemical probes for antigenic components of the basement membrane in fetal skin biopsy, such as in the junctional EB pyloric atresia syndrome.59
Figure 7. Three major forms of epidermolysis bullosa (EB) have been recognized: EB simplex, in which a split occurs within the basal cell layer; junctional EB, which is characterized by separation within the lamina lucida; and dystrophic EB, in which separation occurs below the basement membrane zone.
Epidermolysis Bullosa Simplex
There are three major forms of EB simplex.60 The most common type is a mild autosomal dominant form that appears at birth or shortly thereafter as either localized or generalized blisters that do not usually result in scarring. A second type is Weber-Cockayne disease, which can be either localized or generalized. In the localized form, blisters appear acrally on the palms and soles during childhood or adolescence. In the generalized form, disease activity is usually greater in a warm climate.
The Dowling-Meara variant (EB herpetiformis) is a less common form of EB simplex that presents as severe generalized blistering in infancy; it resembles recessive junctional and dystrophic EB. EB herpetiformis becomes less severe with age.
Junctional Epidermolysis Bullosa
Junctional EB is a recessively inherited group of disorders that exhibit a decreased number of hemidesmosomes and hypoplasia of hemidesmosomes, as revealed by electron microscopy, and separation at the level of the lamina lucida. Mucosal involvement and dystrophic nails are common. The most severe form, EB letalis, occurs within the first few days or months of life and has a high mortality. Patients with EB letalis have a high incidence of respiratory arrest at an early age because of laryngeal and tracheal involvement. Less severe forms of junctional EB exhibit severe generalized blistering at birth that gradually improves. Esophageal strictures may develop.
Dystrophic Epidermolysis Bullosa
There are two forms of dystrophic EB that are inherited in an autosomal dominant fashion. Hyperplastic EB dystrophica (Cockayne-Touraine syndrome) appears in early infancy or childhood as serosanguineous blisters, predominantly on extensor aspects of the lower extremities, in association with nail dystrophy. The albopapuloid type of EB dystrophica is characterized by white papules that develop during adolescence on the trunk or extremities; however, blistering is present in the perinatal period. In both forms, ultrastructural examination reveals sublaminal dermal separation, with abnormalities in anchoring fibrils or a decrease in their number.
Recessive forms of EB dystrophica appear during the neonatal period as severe serosanguineous blistering that is either localized to sites of skin trauma or generalized. Milium formation is uncommon, but lesional scarring may result. Other complications include dental abnormalities, nail dystrophy or loss, digital fusion, flexion contractures, and esophageal strictures [see Figure 8]. Growth retardation, malnutrition, and chronic anemia also occur. Patients with recessive EB dystrophica are at increased risk for squamous cell carcinoma, with a high incidence of fatal metastases.
Figure 8. Recessive dystrophic epidermolysis bullosa may cause severe scarring and syndactyly.
Prenatal diagnosis of recessive dystrophic EB may be made by fetoscopy and skin biopsy; ultrastructural analysis of the tissue reveals dermolytic blister formation. An alternative method for prenatal diagnosis of recessive dystrophic EB involves testing of chorionic villus samples for mutation and haplotype analysis of the type VII collagen gene.61
Supportive treatment of EB is directed toward promotion of wound healing and prevention of complications. Daily skin care may include wet dressings or whirlpool baths, antibiotic ointment, and nonadhesive dressings, such as fine-mesh gauze (N-terface). A multidisciplinary approach that includes genetic counseling, psychological or psychiatric counseling, and support systems for the patient and family is essential, particularly for managing the severe forms of the disease.
Acquired Epidermolysis Bullosa
Acquired epidermolysis bullosa, or epidermolysis bullosa acquisita (EBA), is a trauma-induced blistering disorder in adults who have no genetic basis for the disease. Both circulating and tissue-bound IgG anti-basement membrane zone anti-bodies may be demonstrated by immunohistology. The blisters develop below the epidermis and heal with atrophic scars and malformation. They are usually confined to the extremities at sites of mechanical trauma. Oral lesions and nail dystrophy may be associated with EBA. Underlying malignant, autoimmune, and inflammatory diseases may be associated with this condition. The presence of ulcerative colitis or Crohn disease in approximately 30% of cases suggests that EBA should be included among the extraintestinal manifestations of inflammatory bowel disease.62
The diagnosis is made by excluding other bullous disorders, particularly BP (see above) and porphyria cutanea tarda. Immunoelectron microscopy may be used as an additional diagnostic aid, although this technique may not be widely available. Direct immunofluorescence with the use of salt-split skin to separate the lamina lucida aids in the differential diagnosis. With this method, the IgG antibodies appear on the dermal side of the split specimens in EBA and on the epidermal side in pemphigoid.63 The antigen of EBA has been identified as the globular carboxyl terminus of type VII procollagen,64 a major constituent of anchoring fibrils.16 EBA may also be triggered by certain drugs, such as penicillin, cephalosporins, diclofenac, and captopril.65 A successful trial of rituximab in the treatment of recalcitrant EBA has recently been reported.66 In another recent trial, patients with severe EBA responded to combined therapy with immunoadsorption and rituximab.67
Differential Diagnosis of Vesiculobullous Disorders
The major forms of bullous diseases occurring on an autoimmune or inherited basis have been discussed. The differential diagnosis includes a number of additional conditions in which vesicles or bullae are less common or appear secondary to other disease processes.
Acantholytic blisters occur in keratosis follicularis (Darier disease) as well as in pemphigus. Such blisters are a histologic rather than a clinical finding. Darier disease is an autosomal dominant disorder that manifests as greasy papules and plaques on seborrheic areas and in the flexures; almost all patients have nail abnormalities. Unlike pemphigus vulgaris, Darier disease is most effectively treated with oral retinoids.68
A fixed drug eruption may produce localized bullae that appear after ingestion of a particular drug [see 2:VI Cutaneous Adverse Drug Reactions]. Eczematous dermatitis results in spongiotic vesicles caused by intercellular edema [see 2:IV Eczematous Disorders, Atopic Dermatitis, and Ichthyoses]. This is manifested clinically by large bullae in acute allergic contact dermatitis triggered by poison ivy or poison oak. Systemic lupus erythematosus [see 15:IV Systemic Lupus Erythematosus] occasionally produces bullae by causing degeneration of basal cells.
A bullous eruption on the dorsa of the hands and other sun-exposed sites in patients receiving long-term hemodialysis may resemble porphyria cutanea tarda [see 9:VII The Porphyrias].69 Porphyrin levels are usually within normal limits. Intraepidermal or subepidermal bullae, primarily on the extremities, may be a cutaneous sign of diabetes mellitus.70 Bacterial infections of the skin, such as impetigo, may be associated with subcorneal bulla formation. Bullae may occur on the feet in patients with severe dermatophytosis.
Various viral infections, including varicella (chickenpox), herpes simplex, and herpes zoster, also must be considered in the differential diagnosis [see 2:VII Fungal, Bacterial, and Viral Infections of the Skin, 7:XXVI Herpesvirus Infections, and 7:XXXIII HIV and AIDS]. Lastly, blisters from physical trauma, burns, or cold must also be considered.
Editors: Dale, David C.; Federman, Daniel D.