Vesiculobullous Diseases Part 3

Clinical features

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, edema-tous 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.

Stevens-Johnson syndrome is a severe form of erythema mul-tiforme that is usually disseminated, fulminant, and multisys-temic [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.

Toxic epidermal necrolysis (TEN) has a potentially fatal outcome 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 re-actants within the blood vessels in the skin and the paucity of dermal inflammation have led other 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 by Staphylococcus aureus,39 is sometimes confused with TEN [see Table 1].

Table 3 Precipitating Factors in Erythema Multiforme

Viral diseases

Herpes simplex

Hepatitis

Influenza A

Vaccinia

Mumps

Fungal diseases

Dermatophytoses

Histoplasmosis

Coccidioidomycosis

Bacterial diseases

Hemolytic streptococcal infections

Tuberculosis

Leprosy

Typhoid

Collagen vascular disorders

Rheumatoid arthritis

Systemic lupus erythematosus

Dermatomyositis

Allergic vasculitis

Polyarteritis nodosa

Malignant tumors

Carcinoma

Lymphoma after radiation therapy

Hormonal changes

Pregnancy

Menstruation

Drugs

Penicillins

Sulfonamides

Barbiturates

Salicylates

Halogens

Phenolphthalein

Miscellaneous

Rhus dermatitis

Dental extractions

Mycoplasma pneumoniae infection

Histologic and immunologic findings

Characteristic cutaneous histologic findings of erythema mul-tiforme 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.40 There are no specific immuno-fluorescence 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 multi-forme and the drug-mediated forms of the disease.41

Treatment

Erythema multiforme eruptions may recur without warning, despite preventive measures. It is therefore important to identify and eliminate underlying causes. Mild cases are treated sympto-matically 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 predni-sone, 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.

Target lesions are characteristic of erythema multiforme.

Figure 5 Target lesions are characteristic of erythema multiforme.

Early treatment with high-dose IVIg has been reported to be safe and effective in improving survival of patients with TEN.42 However, there is no standard treatment of TEN that can be used as a basis for comparative studies.43

Epidermolysis Bullosa

Epidermolysis bullosa (EB) comprises a group of genetically based disorders with a prevalence of approximately one in 500,000 persons. There 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. 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.

Stevens-Johnson syndrome is a fulminating form of erythema multiforme associated with marked mucocutaneous involvement, eye involvement, and severe constitutional symptoms.

Figure 6 Stevens-Johnson syndrome is a fulminating form of erythema multiforme associated with marked mucocutaneous involvement, eye involvement, and severe constitutional symptoms.

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 (in-traepidermal), junctional EB (intra-lamina lucida), and dystrophic or dermolytic EB (sub-lamina densa). Electron microscopy examination localizes the lesions to a specific layer.44 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).45 The prenatal diagnosis may be made by im-munocytochemical probes for antigenic components of the basement membrane in fetal skin biopsy, such as in the junctional EB pyloric atresia syndrome.46

Epidermolysis bullosa simplex

There are three major forms of EB simplex.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 dystroph-ic 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 hypopla-sia 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 #]. 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.

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.

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.

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 in the type VII collagen gene.48

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.

A national registry has been established by the Dystrophic Epidermolysis Bullosa Research Association of America (http://www.debra.org) to collect epidemiologic data, to assess economic and social aspects of EB, and to register patients willing to participate in various research protocols.

Recessive dystrophic epidermolysis bullosa may cause severe scarring and syndactyly.

Figure 8 Recessive dystrophic epidermolysis bullosa may cause severe scarring and syndactyly.

Acquired epidermolysis bullosa

Acquired epidermolysis bullosa, or epidermolysis bullosa ac-quisita (EBA), is a trauma-induced blistering disorder in adults who have no genetic basis for disease. Both circulating and tissue-bound IgG anti-basement membrane zone antibodies 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.49

The diagnosis is made by excluding other bullous disorders, particularly BP (see above) and porphyria cutanea tarda. Immu-noelectron 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.50 The antigen of EBA has been identified as the globular carboxyl terminus of type VII procollagen,51 a major constituent of anchoring fibrils.12 EBA may also be triggered by certain drugs, such as penicillin, cephalosporins, diclofenac, and captopril.52

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.

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 spongiot-ic 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 erythemato-sus [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:V The Porphyrias].54 Por-phyrin levels are usually within normal limits. Intraepidermal or subepidermal bullae, primarily on the extremities, may be a cutaneous sign of diabetes mellitus.55 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:XXX1II HIV and AIDS]. Lastly, blisters from physical trauma, burns, or cold must also be considered.

Next post:

Previous post: