Chapter 10 Vesiculobullous disorders
1. What is the difference between a vesicle and a bulla?
If the blister is less than 5 mm in diameter, it is referred to as a vesicle; if it is 5 mm or larger, it is called a bulla. Some dermatologists require that blisters be 1 cm before using the term bulla. The term vesiculobullous disorder is often used clinically since some patients may have both vesicles and bullae.
2. How are the bullous diseases defined?
Bullous diseases are characterized by blisters. Blisters are defined as circumscribed skin lesions containing fluid. They may arise at various depths in the epidermis and dermis and are sometimes classified on the basis of the depth of skin involved. One broad classification divides blisters into those that develop within the epidermis (intraepidermal) versus those that develop below the epidermis (subepidermal) (Table 10-1). Some blistering disorders develop because of autoantibodies directed against a component of the epidermis or basement membrane zone, or they develop because of structural defects of these components. Refer to Fig. 10-1 for the location of these components in normal skin as they are discussed during questions.
4. How do you approach a patient who presents with an acute onset of a vesiculobullous eruption?
The patient history is very important in the initial evaluation of blisters. If the onset of lesions was acute, exposure to contact allergens, arthropods, phototoxic and other drugs or chemicals, trauma, and infectious agents should be queried. Certain chronic vesiculobullous diseases may have an acute onset but may then persist or recur and become chronic (Table 10-2).
5. Which skin findings are helpful in evaluating a patient with blisters?
Several features of vesiculobullous lesions are important to note, including the distribution, symmetry, involvement of mucosal surfaces, and associated lesions (such as erosions, ulcers, and crusts). Additional types of skin lesions, such as urticarial lesions, should be noted. In bullous pemphigoid, urticarial lesions often precede the development of blisters. In some vesiculobullous diseases such as dermatitis herpetiformis, secondary excoriations may be the only lesions visible, with no intact blisters.
| INTRAEPIDERMAL BLISTERS | SUBEPIDERMAL BLISTERS |
|---|---|
Table 10-2. Acute versus Chronic Onset of Vesiculobullous Eruption
| ACUTE | CHRONIC |
|---|---|
The character of the blisters also may provide useful information. Flaccid blisters may indicate a more superficial blistering process than is seen with tense blisters. However, factors other than the depth of the blister are important, including site (blisters on acral skin, which has a thick stratum corneum, are often tense even when superficial) and the specific disease process (in toxic epidermal necrolysis, the blistering is subepidermal, but vesicles and bullae are usually flaccid with large sheets of skin sloughing).
7. Which tests are most useful in evaluating vesiculobullous diseases?
Most of the tests helpful in determining the cause of vesiculobullous eruptions are performed on the blister itself. When infectious causes are being considered, appropriate cultures (aerobic bacteria, viruses, fungi) may be obtained, and smears from the blisters may be stained for bacteria, dermatophytes, or the multinucleate giant cells of herpes virus infections. For noninfectious vesiculobullous diseases, a skin biopsy is often a useful test.
8. How should a skin biopsy of a vesiculobullous eruption be performed?
The lesion for biopsy should be an early lesion, to avoid secondary changes that might make the diagnosis more difficult. A small, intact blister is a good choice, as the entire lesion and some of the surrounding skin can be removed in one piece. If a punch biopsy technique is used, it is important to avoid rupturing the blister. A small excisional biopsy is a good choice and minimizes the possibility of rupturing the blister. The specimen should be placed in 10% formalin and processed for routine histologic examination. Clinical information, including the age and sex of the patient, a description of the lesions, associated symptoms, and any exacerbating factors, should be provided, along with a differential diagnosis based on the clinical examination.
9. When are special tests necessary to diagnose blistering diseases of the skin?
In addition to routine histology, a skin biopsy for direct immunofluorescence is often helpful in diagnosing the immunobullous diseases (Table 10-4). Direct immunofluorescent technique uses fluorescent, tagged antibodies that are directed against IgG, IgA, IgM, C3, and fibrin; these antibodies fluoresce when illuminated with a fluorescent microscope (Fig. 10-2). For precise diagnosis of the inherited forms of epidermolysis bullosa, electron microscopy studies may be necessary. Other tests are indicated in specific circumstances, such as urine porphyrin tests when porphyria cutanea tarda is being considered, and zinc levels when acrodermatitis enteropathica is possible.
Table 10-3. Characteristic Distribution of Vesiculobullous Diseases
| DISEASE | CHARACTERISTIC DISTRIBUTION |
|---|---|
| Acrodermatitis enteropathica | Acral, periorificial |
| Allergic contact dermatitis | Reflects pattern of contact; often linear |
| Bullous dermatophyte infection | Feet, hands |
| Bullous diabeticorum | Distal extremities |
| Bullous pemphigoid | Flexural areas, lower extremities |
| Cicatricial pemphigoid | Eyes, mucous membranes |
| Dermatitis herpetiformis | Elbows, knees, buttocks |
| Erythema multiforme | Acral areas, palms, soles, mucosa |
| Hailey-Hailey disease | Intertriginous areas, neck |
| Hand, foot, and mouth disease | Mouth, palms, fingers, soles |
| Herpes zoster | Dermatomal distribution |
| Linear IgA bullous dermatosis (childhood type) | Groin, buttocks, perineum |
| Pemphigus vulgaris | Oral mucosa, other sites |
| Pemphigus foliaceus | Head, neck, trunk |
Table 10-4. Direct Immunofluorescence Findings of Vesiculobullous Diseases
| DISEASE | TARGET ANTIGEN | DIRECT IMMUNOFLUORESCENCE FINDINGS |
|---|---|---|
| Bullous pemphigoid | BP180, BP230 | Linear C3, IgG at DEJ |
| Bullous SLE | COL7A1 | Linear/granular IgG, other Igs at DEJ |
| Cicatricial pemphigoid | BP180, LAM5, and others | Linear C3, IgG, IgA at DEJ |
| Dermatitis herpetiformis | eTG | Granular IgA, C3 in upper dermis (see Fig. 10-1) |
| Epidermolysis bullosa acquisita | COL7A1 | Linear IgG, IgA, other Igs at DEJ |
| Herpes gestationis | BP180 | Linear C3, IgG at DEJ |
| Linear IgA bullous dermatosis | BP180, COL7A1, LAD | Linear IgA, C3 at DEJ |
| Pemphigus foliaceus | DSG1 | IgG, C3 in intercellular spaces |
| Pemphigus vulgaris | DSG3 (mucous membrane only) DSG3 and DSG1 (mucous membrane and skin) |
IgG, C3 in intercellular spaces |
| IgA pemphigus | DSC1, DSG1, DSG3 | IgA in intercellular spaces |
| Paraneoplastic pemphigus | DSG1, DSG3, DP1, DP2, BP180, BP230, EP, PP, γ-catenin, plectin, 170 kD, DSC2, DSC3 | IgG, C3 in intercellular spaces, DEJ |
| Porphyria cutanea tarda | None (not antibody mediated) | Homogenous IgG at DEJ and around vessels |
| Anti–p200 pemphigoid | 200-kD antigen | IgG, C3 at DEJ |
| Anti–p105 pemphigoid | 105-kD antigen | IgG, C3 at DEJ |
DEJ, Dermal–epidermal junction; Ig, immunoglobulin; C3, third complement component.
Zillikens D: Diagnosis of autoimmune bullous skin diseases, Clin Lab 54:491–503, 2008.
10. How are specimens obtained for direct immunofluorescence?
Generally, this specialized testing would be ordered by a dermatologist, as the selection of an appropriate laboratory and proper handling of the tissue are essential to an accurate result. For most immunobullous diseases, tissue for direct immunofluorescence testing is obtained from skin next to a blister, and it is either frozen immediately in liquid nitrogen or placed in a transport medium such as Michel’s media. It should never be placed in formalin; direct immunofluorescence testing involves identifying immunoglobulins and complement deposited in the skin. These molecules may be altered by formalin.
11. For which vesiculobullous diseases are indirect immunofluorescence helpful?
It is most commonly used in pemphigus vulgaris (less commonly in bullous pemphigoid), epidermolysis bullosa acquisita, and cicatricial pemphigoid. This procedure identifies antibodies present in the circulation; therefore, serum is submitted for evaluation. It is most commonly used to obtain an antibody titer to help monitor disease activity. Again, only a few laboratories perform this testing routinely, so consultation with the laboratory prior to obtaining the specimen is recommended to ensure appropriate handling of the specimen. Enzyme-linked immunosorbent assay (ELISA) testing for these same serum antibodies has now become commercially available and is both sensitive and specific. ELISA has largely replaced indirect immunofluorescent studies as the study of choice for antibody titers and for detecting certain antibodies such as BP180, BP230, desmoglein 1, and desmoglein 3 in blistering diseases.
12. List the most common blistering diseases due to external agents.
• Allergic contact dermatitis: Direct contact with allergens may cause an acute, pruritic vesicular eruption in the areas of contact. When it is due to plants such as poison ivy, the pattern is often linear, corresponding to areas where the the skin brushes the plant. The diagnosis can usually be made on the basis of history and clinical findings, particularly exposure to the offending agent. Skin biopsy for routine histologic examination may be helpful in difficult cases (see also Chapter 9).
• Bullous drug eruptions: A number of drugs can produce characteristic vesiculobullous eruptions through toxic, immunologic, idiopathic, or phototoxic/photoallergic mechanisms (see also Chapter 14).
• Miliaria crystallina: Superficial, fragile vesicles develop as eccrine sweat ducts become obstructed. Predisposing factors include high fever and occlusion, as well as sunburn. Clinical findings are usually diagnostic, but occasional cases require a skin biopsy.
• Blisters caused by physical agents: Heat, cold, chemicals, friction, pressure, and radiation (second-degree sunburn) may induce blisters. These can generally be identified readily by history and physical examination.
14. What is epidermolysis bullosa?
This is a group of diseases with inherited defects in the skin that result in blistering spontaneously or after minor trauma. Many subtypes have been described (Table 10-6):
• Epidermolysis bullosa simplex, an autosomal dominant trait, begins at birth or early in childhood, with blisters due to mild trauma that heal without scarring.
• Junctional epidermolysis bullosa also typically begins at birth and may present with generalized blistering. The blisters occur at the dermal–epidermal junction and are due to molecules involved in anchoring the epidermis to the dermis. This type of epidermolysis bullosa may be inherited as an autosomal recessive trait.
• Dystrophic epidermolysis bullosa may be autosomal dominant or recessive in inheritance. It ranges from mild to severe blistering that can be disfiguring. It is due to a defect in the dermal anchoring fibrils (type VII collagen).
| ERUPTION | OFFENDING DRUG(s) |
|---|---|
| Bullous pemphigoid | Tetracycline, furosemide, ibuprofen and other nonsteroidal antiinflammatory drugs (NSAIDs), captopril, penicillamine, and other antibiotics |
| Erythema multiforme | Anticonvulsants, barbiturates, sulfonamides, NSAIDs, antibiotics |
| Linear IgA bullous dermatosis | Vancomycin, lithium, captopril, antibiotics |
| Phototoxic drug eruption | Psoralens, thiazides, furosemide, fluoroquinolones, doxycycline (and other TCNs), sulfonamides |
| Porphyria-like drug eruption | Furosemide, tetracycline, naproxen |
| Toxic epidermal necrolysis and Stevens-Johnson syndrome | Anticonvulsants, sulfonamides, NSAIDs, allopurinol, antiretrovirals |
TCNs, tetracyclines.
Table 10-6. Subtypes of Epidermolysis Bullosa
| DISEASE | DEFECT | LEVEL OF SPLIT |
|---|---|---|
| EB simplex | Keratins 5 and 14 | Basal keratinocytes |
| EB simplex with muscular dystrophy EB simplex with pyloric atresia EB simplex, Ogna type EB simplex, Dowling-Meara type |
Plectin | Intracytoplasmic plaque of hemidesmosome |
| Junctional EB, Herlitz Junctional EB, non-Herlitz (GABEB) Junctional EB with pyloric atresia |
Laminin components α3, β3, α2 BP180 (COLXVIIa1) Laminin components α3, β3, γ2 Integrins α6, β4 |
Lamina densa/lucida interface Lamina lucida Lamina densa/lucida interface Lamina lucida/hemidesmosome |
| Dystrophic EB | Type VII Collagen (COL VIIa1) | Sublamina densa |
For all types of epidermolysis bullosa, skin biopsies for routine histology (sometimes with immunoperoxidase stains to type IV collagen to detect the level of the split), as well as electron microscopy, are often required for diagnosis. Referral to a center specializing in epidermolysis bullosa is optimal, and also the National Epidermolysis Bullosa Registry (telephone: 919-966-2007) may be contacted. The mechanobullous diseases are covered in detail in Chapter 6.
15. Describe the other genetic blistering diseases.
• Acrodermatitis enteropathica: This condition may be autosomal recessive or acquired and is due to a deficiency of zinc. Cutaneous findings include scaling and vesicles in a periorificial and acral distribution associated with alopecia. Diarrhea is often present. This disorder occurs in infants, especially premature infants, and alcoholics (acquired form) or other patients with impaired gastrointestinal absorption of zinc. Skin biopsy and serum zinc levels are helpful diagnostic tests. Deficiencies of essential fatty acids and amino acids may also cause acrodermatitis enteropathica.
• Bullous congenital ichthyosiform erythroderma (epidermolytic hyperkeratosis): This autosomal dominant disease presents with diffuse erythema at birth, with later development of flaccid bullae, and still later with furrowed hyperkeratosis. The defect is in keratins 1 and 10. The diagnosis is by skin biopsy and family history, in addition to clinical findings and disease course.
• Hailey-Hailey disease (benign familial pemphigus): In this autosomal dominant disorder, blisters, erosions, and crusts develop in the intertriginous areas. These may begin early in life or later. The intraepidermal blisters form secondary to a loss of cohesion between keratinocytes (acantholysis). The underlying defect is in ATP2C1, which encodes a calcium pump. Secondary bacterial infections are common. A diagnosis is established by routine skin biopsy.
• Incontinentia pigmenti: This X-linked disease is seen predominantly in females; affected males usually die in utero. It begins in neonatal life, with vesicles occurring in a whorled pattern. Later, verrucous lesions develop, and finally, hyperpigmented patches appear. Skin biopsy is a helpful diagnostic test.
17. Describe the clinical findings in bullous diabeticorum.
Bullous diabeticorum is characterized by tense bullae that arise spontaneously on the distal extremities in patients with both insulin-dependent and non–insulin-dependent diabetes. The course is chronic and recurring. The diagnosis is made by the clinical findings and skin biopsy. Although the histologic findings are not specific, they may help to rule out other bullous diseases.
18. What is the cause of pellagra?
Pellagra is a nutritional disorder caused by a deficiency of niacin, which results in dermatitis, dementia, and diarrhea. The dermatitis may occur in a photodistribution, consisting of vesicles, papules, erosions, and hyperpigmentation. The diagnosis is by clinical findings, as biopsy is nondiagnostic. In developed countries, patients at risk for pellagra include alcoholics and those on isoniazid therapy.
Key Points: Vesiculobullous Disorders
1. Vesiculobullous disorders can often be distinguished by the clinical history, distribution, and location of the split (superficial versus deep blister).
19. What is the difference between porphyria cutanea tarda and pseudoporphyria?
Porphyria cutaneous tarda is clinically characterized by skin fragility, tense blisters, scarring, and milia in sun-exposed areas, particularly the dorsal hands (Fig. 10-3). Patients have decreased levels of uroporphyrinogen decarboxylase, sometimes due to alcoholic liver disease or to drugs such as estrogen and iron. Hypertrichosis may develop on the face. The diagnosis is established by skin biopsy for routine histology, as well as porphyrin studies, including a 24-hour urine collection for uroporphyrins. Other porphyrias, including variegate porphyria and hereditary coproporphyria, may present with identical cutaneous findings, and should be separated from porphyria cutanea tarda on the basis of associated clinical findings and complete porphyrin studies. Direct immunofluorescence of the skin may be a helpful test for porphyria but does not distinguish one type from another. Pseudoporphyria demonstrates similar cutaneous findings but porphyrin studies are normal. It is associated with uremia, hemodialysis, and some drugs, especially, nonsterioidal antiinflammatory drugs (NSAID)s.
21. What is the difference between bullous pemphigoid and cicatricial pemphigoid?
Bullous pemphigoid (IgG directed against BP180 and BP230) is a chronic autoimmune bullous disease that most commonly affects older adults. The primary lesions may be urticarial plaques or tense bullae (Fig. 10-4). Lesions occur particularly on the flexural surfaces but may be widespread. Blisters form crusts and may heal with pigmentary changes, but not scarring. The oral mucosa is sometimes affected, but lesions in this area are usually minor. Cicatricial pemphigoid (IgG or IgA directed against multiple antigens at the basement membrane zone, including BP180) is a chronic autoimmune blistering disorder associated with scarring of mucosal surfaces. It primarily affects the elderly, with some patients having blisters on the cutaneous surface. In both diseases, the diagnosis is established by correlating the clinical findings with routine histologic examination of lesional skin, direct immunofluorescence of perilesional skin, and indirect immunofluorescence or ELISA testing of serum.
22. How do pemphigus vulgaris and pemphigus foliaceus differ?
Pemphigus vulgaris (IgG directed against DSG3 and DSG1) is a chronic blistering disease that typically affects adults and usually begins in the oral mucosa. Flaccid vesicles and bullae develop on the face, scalp, neck, chest, groin, and intertriginous areas. These are often tender rather than pruritic. Generalized involvement may occur, and pemphigus vulgaris may be life-threatening. Pemphigus foliaceus (IgG directed against DSG1 only) is a more superficial form of pemphigus and is generally not as severe as the vulgaris type. Patients develop very superficial vesicles and bullae, typically on the scalp, face, upper chest, and back. Because the blisters are very superficial, they often rupture, and secondary changes of scale, crust, and erosions may be the only findings present. For both varieties, the diagnosis is made by routine histologic exam of an early blister, as well as by direct immunofluorescence of perilesional skin and indirect immunofluorescence of patient serum.
23. Linear IgA bullous dermatosis occurs in two different clinical situations. What are they?
One occurs in early childhood and has been termed chronic bullous disease of childhood. Pruritic, urticarial blisters, often sausage-shaped or like a string of pearls, develop on the buttocks and perineal areas, as well as the trunk and extremities (Fig. 10-5). Mucosal lesions are common. The adult form often occurs in the elderly and may be associated with drugs such as vancomycin. Skin lesions may resemble bullous pemphigoid or dermatitis herpetiformis. Diagnosis is by routine histologic exam of an early blister, direct immunofluorescence of perilesional skin, or indirect immunofluorescence to detect IgA antibodies directed against the basement membrane zone of skin.
24. Describe the clinical findings in dermatitis herpetiformis.
Dermatitis herpetiformis is an autoimmune disease due to IgA autoantibodies directed against tissue transglutaminase. Dermatitis herpetiformis, an extremely pruritic condition, most commonly begins in early adult life and is characterized by symmetrically distributed papules and vesicles that develop on the elbows, knees, buttocks, extensor forearms, scalp, and, sometimes, face and palms (Fig. 10-6). In some patients, the lesions are generalized and severe. Patients may have an associated gluten-sensitive enteropathy, though it is seldom symptomatic. The diagnosis is established by routine histologic exam of an early blister and direct immunofluorescence of nonlesional skin (IgA is seen in the dermal papillae) (see Fig. 10-2). Scratching may destroy all intact blisters for skin biopsy, and thus direct immunofluorescence may be a particularly helpful diagnostic test. Serologic testing for antiendomysial/eTG antibodies and antigliadin antibodies is also a useful screening test.
25. Does herpes gestationis have anything to do with herpes viruses?
No. Herpes gestationis, also called gestational pemphigoid, is a rare, autoimmune blistering disease with IgG autoantibodies directed against BP180 (type XVII collagen), which is an important component of the hemidesmosome. It is seen in pregnant women, typically beginning in the second trimester. Lesions often begin in the periumbilical area and may initially be urticarial. Later, tense vesicles and bullae develop, which may resemble bullous pemphigoid. The disease may flare after delivery and may recur in subsequent pregnancies. The pregnancy should be monitored, because premature births as well as small-for-gestational-age infants have occurred in some patients. The diagnosis is made from clinical findings, routine histology of an early blister or urticarial lesion, and direct and indirect immunofluorescence tests.
26. What is bullous systemic lupus erythematosus?
Bullous SLE is a rare blistering eruption that has been reported primarily in patients with established SLE. In most cases, autoantibodies are directed against type VII collagen that is found in the basement membrane zone. Vesicles and bullae may develop on inflamed or noninflamed skin. In some patients, the lesions may resemble bullous pemphigoid, and in others, epidermolysis bullosa acquisita. The diagnosis is made on the basis of clinical findings, routine histologic exam (which may show findings similar to those seen in dermatitis herpetiformis), and immunofluorescence studies including direct, indirect, and a special split-skin indirect immunofluorescence test.
27. What is epidermolysis bullosa acquisita?
Epidermolysis bullosa acquisita is an autoimmune bullous disease with autoantibodies directed against type VII collagen in the basement membrane zone. In this disease, vesicles and bullae follow trauma and tend to occur on areas with frictional trauma, such as the fingers, knees, and elbows. Mucosal lesions are common. As with bullous SLE, diagnosis is by clinical findings, routine histology, direct immunofluorescence, indirect immunofluorescence, and split-skin indirect immunofluorescence testing.
Lehman JS, Camilleri MJ, Gibson LE: Epidermolysis bullosa acquisita: concise review and practical considerations, Int J Dermatol 48:227–235, 2009.
