Vesiculobullous Diseases of the Skin

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[edit] Vesiculobullous Diseases of the Skin

Lynne H. Morrison

The blistering diseases discussed in this chapter are immunologically mediated disorders that cause blisters, erosions, and erythema of both skin and mucous membranes. They are all uncommon. Although there are a variety of autoimmune bullous dermatoses, this chapter focuses on three major diseases—bullous pemphigoid, the major forms of pemphigus, and dermatitis herpetiformis. Patients with pemphigoid and pemphigus can be at risk for serious morbidity, especially if the disease becomes extensive; accurate diagnosis and early therapy are important issues in patient management. Bullous diseases can mimic one another not only clinically but also histologically. Therefore accurate diagnosis for all of these diseases requires a biospy for direct immunofluorescence (IF) studies to identify the presence of pathologic autoantibodies; biopsies for routine histology should be done.

[edit] BULLOUS PEMPHIGOID

[edit] Epidemiology

Bullous pemphigoid (BP) is an acquired bullous disease of the elderly. It is characterized histologically by subepidermal blisters and immunopathologically by deposition of autoantibodies and complement along the basement membrane zone (BMZ). Most patients also have circulating autoantibodies directed against the epithelial BMZ.^[1][2] The true incidence of BP is unknown, but according to estimates there is one case per 100,000 annually. The vast majority of BP patients are over 60 years old at the time of presentation. In general, men and women are equally affected, there is no racial or geographic predilection, and there is no known HLA association.

[edit] Pathophysiology

BP is considered an autoimmune disease mediated by autoantibodies directed against two antigens (the bullous pemphigoid antigens) in the BMZ of stratified squamous epithelia. These antigens are proteins thought to be important mediators of dermal to epidermal adhesion.^[1] Current evidence suggests the following hypothesis for subepidermal blister formation in BP:

• Initiating event: immunologic recognition of the BP antigens causes production of IgG class anti-BMZ antibodies.
  
• Attachment: autoantibodies attach to the pemphigoid antigen(s) in the BMZ.
  
• Complement activation: complement is activated, which generates the anaphylatoxins C3a and C5a.
  
• Inflammatory response: complement activation results in recruitment of eosinophils, mast cell degranulation, and release of multiple cytokines, histamine, and proteolytic enzymes. Injury to the BMZ is thought to be mediated by these enzymes and eventually produces dermal-epidermal separation.^[3]
  

[edit] History and Physical Examination

Most patients with BP present with a pruritic eruption. The degree of pruritus varies from nearly nonexistent to intense. A few patients have prolonged pruritus that precedes the clinical appearance of bullous lesions. Most patients with BP are not systemically ill, although elderly patients with extensive blistering can become debilitated. Most large series concluded that there is no increased incidence of malignancy in patients with BP compared with age-and sex-matched controls. Several medications and therapies have been associated with the onset of BP, including furosemide, sulfasalazine, phenoxymethylpenicillin, topical 5-fluorouracil (5-FU), and both ultraviolet B (UVB) and psoralen plus UVA (PUVA) phototherapy.^[3]

Frequently the earliest manifestation of BP includes erythematous macules, papules, and urticarial plaques that may have a serpiginous configuration. Subsequently, tense bullae arise on these erythematous lesions, as well as on normal skin (see Plate 6). These tense bullae make up the most characteristic clinical feature of BP. The blisters may be filled with clear fluid or may be hemorrhagic; when they rupture, they leave denuded areas that become encrusted. The erosions tend to not spread peripherally and generally heal without scarring.^[2][4]

[edit] Laboratory Studies/Diagnostic Procedures

Biopsies submitted for routine histology and for direct IF studies are essential in BP and other immunologically mediated blistering diseases. The most characteristic histologic finding is subepidermal separation with a mixed inflammatory infiltrate containing lymphocytes and eosinophils. Biopsies processed for IF studies show linear deposition of IgG and C3 along the BMZ. Biopsies taken for routine histology need to include part of the blister, whereas biopsies taken for IF studies should be from normal-appearing skin immediately adjacent to an urticarial lesion or a blister. Biopsies taken from blisters commonly give negative IF results. About 50% of patients show hypereosinophilia, and approximately 70% will have circulating anti-BMZ autoantibodies.

[edit] Differential Diagnosis

Differential diagnosis for BP can be found in Table 90-1.

Table 90-1 Differential Diagnosis of Bullous Pemphigoid

[edit] Management

Determining the severity of the disease and identifying the patient's other medical problems are important in choosing a therapeutic agent. Systemic corticosteroids are still the mainstay of therapy in generalized BP. The majority of patients can be controlled with prednisone 40 to 80 mg/day. In general, mild disease usually responds to lower doses of prednisone than does moderate or severe disease. Once the disease is under control the goal of therapy is to taper the prednisone and eventually maintain the patient on alternate-day therapy to minimize long-term steroid side effects. In patients with mild to moderate disease or those who are not tolerating prednisone, dapsone or tetracycline would be reasonable alternative therapies. Most patients respond well to corticosteroids, but those who do not or those who require high doses may need the addition of azathioprine or methotrexate.^[1][2][5]

[edit] PEMPHIGUS

The term pemphigus refers to a group of chronic blistering skin diseases (Table 90-2, Table 90-3, and Table 90-4) in which autoantibodies are directed against keratinocytes resulting in loss of epidermal cell-to-cell adhesion—a process termed acantholysis. This loss of epidermal cell cohesion causes intraepidermal blisters. In all types of pemphigus, IgG autoantibodies are bound in a characteristic pattern around the cell membrane of affected cells and are also found in patients' serum. The three major forms of pemphigus are pemphigus vulgaris (PV), with suprabasilar acantholysis (i.e., the split occurring above the basal or lowest layer of epidermal cells); pemphigus foliaceus (PF), with acantholysis in the superficial layers of the epidermis; and paraneoplastic pemphigus (PNP), which shows suprabasilar acantholysis and the histologic features of erythema multiforme and is seen in association with underlying malignant neoplasms.^[2][4]

Table 90-2 Differential Diagnosis of Pemphigus Vulgaris

Table 90-3 Differential Diagnosis of Pemphigus Foliaceus

Table 90-4 Differential Diagnosis of Paraneoplastic Pemphigus

Both PV and PF have further variants that are not reviewed here. Each major form is associated with distinct autoantibodies that are directed against specific epithelial proteins that have been shown to be pathogenic.

[edit] Epidemiology

PV is the most common form of the disease and generally occurs during the fourth to sixth decades of life. It occurs worldwide with an annual incidence of about 0.1 to 0.5 per 100,000 population and is more common in the Jewish population. There is an increased incidence of HLA-DR4, HLA-DR6, and HLA-DR10 haplotypes. In the presteroid era, the disease had a nearly 100% mortality at 5 years. Currently, the mortality from PV is approximately 10% and often due to side effects of therapy. PF is generally less life-threatening than PV, which is likely due to the more superficial nature of the lesions.^[1][4] Patients with PNP often have a high mortality rate with refractory cutaneous lesions.

[edit] Pathophysiology

Each major form of pemphigus is characterized by specific autoantibodies of the IgG class directed against epithelial desmosomal proteins. In PV and PF the antigens are found only in stratified squamous epithelia, whereas in PNP the antigens are found in all types of epithelia. The autoantibodies in each form of the disease are capable of reproducing the disease clinically and histologically, both in vivo and in vitro, indicating their pathogenicity.^[1][6] Attachment of autoantibodies to desmosomal proteins is thought to be the first step in pathogenesis and is followed by acantholysis. The mechanism of acantholysis is not certain but some data suggest that binding of the autoantibody may induce release of proteolytic enzymes from epidermal cells. Antibodies alone in the absence of complement can induce acantholysis, although complement may augment the process. Other mechanisms, including the direct effect of the IgG autoantibodies on desmosomal integrity and cell adhesion, may also be important in the pathogenesis of this disease.

[edit] History and Physical Examination

PV is the most common form of pemphigus. Many patients present with painful oral erosions, which can precede the cutaneous lesions by weeks or months. Typically, oral lesions are painful and irregularly bordered erosions that extend peripherally, are persistent, and heal slowly. Other mucous membranes may be involved but less commonly than the oral mucosa. Patients who present with only cutaneous lesions eventually have mucous membrane involvement in almost all cases. Cutaneous lesions usually appear as flaccid bullae or erosions with a predilection for the scalp, face, upper trunk, axillae, and groin (Plate 72). The lesions may develop on normal skin or on erythematous base. They rupture easily to produce painful, red, weeping erosions that extend at the edges. It is not uncommon to see only erosions in these patients, as the fragile blisters break quite easily.^[1][6][2] The ability to easily dislodge epidermis adjacent to an erosion with lateral pressure is referred to as a Nikolsky's sign and indicates active disease with potential to progress. When disease activity increases, large areas of a patient's skin can become denuded, resembling a burn patient, with marked susceptibility to secondary infection and fluid and electrolyte imbalance. Sepsis is a common cause of death in patients with widespread disease.

Patients with PF have a different clinical appearance than those with PV. PF usually presents with scaling, crusted lesions on the upper trunk and face, and patients rarely, if ever, have oral lesions. The primary lesions are flaccid, extremely fragile bullae that rupture to produce shallow erosions with subsequent scaling and crusting with relatively little weeping. They are not usually found intact. Mortality from this form of pemphigus is usually quite low.

PNP is a recently described variant in which the vast majority of patients have a recognized or occult malignant neoplasm, most often non-Hodgkin's lymphoma, thymomas, or hematologic malignancies.^[3][1] Patients can have a polymorphous skin eruption that consists of large areas of erythema, bullae, and lesions resembling erythema multiforme. A consistent clinical finding is painful oral erosions often accompanied by an erosive conjunctivitis. Pulmonary and gastrointestinal tract involvement has been identified in some patients with PNP.

[edit] Laboratory Studies/Diagnostic Procedures

Skin biopsies for routine histopathology and IF are essential for accurate diagnosis.^[4][5] PV histopathologically shows suprabasilar intraepidermal blister formation with acantholysis. In PF, the intraepidermal split is higher up on the plane of the epidermis, often within the granular layer just below the stratum corneum. The remainder of the epidermis stays attached to the BMZ. PNP characteristically shows a combination of suprabasilar acantholysis similar to PV, vacuolar interface change, and keratinocyte necrosis, which is similar to erythema multiforme.

Skin biopsies processed for direct IF in all three types of pemphigus show deposition of IgG autoantibodies and often, complement within the intercellular spaces of the epithelium. Biopsies from patients with PNP may also have linear or granular deposition of complement along the BMZ.

Obtaining indirect IF studies on a patient's serum and looking for the presence and titer of pemphigus autoantibodies are also useful for diagnosis management of pemphigus patients and can help differentiate PNP from other forms of pemphigus.^[3]

[edit] Management

The mainstay of therapy for both PV and PF is corticosteroids, usually in the form of oral prednisone. The goal of therapy is to control the disease at the lowest possible dose of prednisone. When the disease is severe, achieving control in a hospital setting is appropriate. For severe disease, higher doses of prednisone, generally 80 mg a day or greater, is necessary to get the disease under control. Less severely affected patients can be started on lower doses. Once the disease is under control, the prednisone is tapered, if possible, to an alternate-day regimen. The goal is to control the disease at the lowest possible alternate-day dose of prednisone or discontinue prednisone if possible. This is a chronic disease, and although remission with therapy is possible, the disease generally recurs at some point after treatment has been discontinued. It is not unusual for PV patients to need immunosuppressive medications in addition to prednisone for control. Those most often used include azathioprine, cyclophosphamide, and gold and may be used in patients who are not responding well to higher doses of corticosteroids or not tolerating side effects of steroids. They can also be used as steroid-sparing agents.^[1][2][4]

It is important early in the course of the disease to initiate osteoporosis evaluation and prevention therapies, since these patients are often subjected to long-term corticosteroid therapy.

[edit] DERMATITIS HERPETIFORMIS

[edit] Epidemiology

Dermatitis herpetiformis (DH) is a chronic, severely pruritic papulovesicular eruption distributed symmetrically over extensor areas, characterized by deposition of IgA in the upper dermis, and associated with a gluten sensitivity. DH usually has an onset between the second and fourth decades, with a male/female ratio of 3×2. The prevalence of DH in the United States is unknown; however, the prevalence in Utah has been estimated at 15×100,000. Scandanavian and Anglo-Saxon populations have a relatively high prevalence of DH, but it is uncommon in African-Americans and Asians. Patients with DH have an associated gluten-sensitive enteropathy that is present in the vast majority of patients but is most often asymptomatic. As in patients with isolated gluten-sensitive enteropathy, there is an increased frequency of the HLA-B8 antigen, which is noted in 80% to 90% of DH patients.^[1][6] The frequency in the normal population is 20% to 30%. There is also an increased frequency of HLA-DR3 and HLA-DQW2 haplotypes.

[edit] Pathophysiology

The precise pathophysiology of DH is unknown. Features that suggest an immunologic basis include the presence of IgA in the upper dermis in essentially all patients, as well as marked HLA associations. The disease has not been clearly shown to be an immune complex–mediated process nor has pathogenicity of IgA autoantibodies been demonstrated. The association of a gluten-sensitive enteropathy and presence of granular IgA in the skin suggest that gluten may act as an antigen, inducing an abnormal mucosal permeability with subsequent production of IgA either locally in the gut mucosa or systemically. This IgA could then bind to the skin as either a cross-reacting antibody or possibly an immune complex. Gluten has been proposed as the dietary antigen important in producing the disease. A strict gluten-free diet controls both the cutaneous and gastrointestinal manifestations.^[6][5] An alternative hypothesis is that a gluten-induced intestinal defect may allow passage of other dietary antigens that then could incite production of IgA that subsequently binds to the skin.

[edit] History and Physical Examination

Patients with DH typically have severe pruritus, often described as having a stinging or burning quality. The onset of pruritus commonly precedes the onset of new lesions by several hours. The typical primary lesion of DH is a erythematous papule or papulovesicle. Patients quite often excoriate the primary lesions quickly so that when they are examined only secondary changes of excoriations and crusts are apparent. The configuration of lesions is grouped or “herpetiform” with an erythematous base. Usually, the eruption of DH is very characteristic with symmetric involvement of extensor surfaces including elbows, knees, sacrum, upper back and shoulders, and posterior neck (Plate 73). Mucous membranes are characteristically spared. Oral involvement should raise suspicion of other immunobullous diseases. Because of the frequent lack of intact primary lesions, the diagnosis should be based on characteristic distribution. Although the activity of the disease may wax and wane, DH is generally a lifelong disease with spontaneous remissions considered rare.^[1][6][4]

Patients frequently have a gluten-sensitive enteropathy, which is often clinically asymptomatic. Only 15% of DH patients have symptomatic malabsorption. Approximately 20% to 30% of patients show deficiencies of iron or folate, resulting in a mild anemia.^[5] The enteropathy can be diagnosed by small intestinal biopsies showing varying degrees of villous atrophy and lymphocytic infiltrate, but this procedure is generally not warranted.

DH is associated with a variety of clinical diseases and serologic abnormalities, some of which are autoimmune in nature. Several investigators found an increased incidence of thyroid abnormalities in patients with DH, reporting an incidence of 5% to 34% of patients with thyroid disease and 20% to 48% with antithyroid antibodies.^[1][4] Several studies found the presence of antigastric parietal cell antibodies in 10% to 25% of patients with DH, and a small number of these individuals will develop pernicious anemia.^[4][5] Hypochlorhydria and atrophic gastritis has been identified in 50% to 70% of individuals with DH.

An important association with DH is the increased frequency of malignancy, particularly gastrointestinal lymphoma. Leonard and associates evaluated 109 patients with DH and found a 6.4% incidence of malignancy over 12 years, giving a relative risk of 2.38. Three of seven patients who developed malignancy had a lymphoma, giving a 3.00 relative risk for that specific malignancy.^[1][4][5]

[edit] Laboratory Studies/Diagnostic Procedures

The diagnosis is most reliably established by direct IF biopsies taken from clinically normal-appearing skin immediately next to an area of inflammation or vesicle. These studies should be correlated with histologic findings and clinical picture. Histologically DH shows a subepidermal blister with infiltration of neutrophils in the papillary tips. Perilesional skin biopsies processed for direct IF studies show pathognomonic findings of granular deposition of IgA in papillary tips and along the dermal-epidermal junction.^[2][4] Indirect IF studies typically are negative. Antiendomesial antibodies have been found in a number of these patients and tend to correlate with severity of underlying gastrointestinal abnormality. An iron deficiency anemia or folate deficiency anemia resulting from malabsorption may be noted in some patients, and appropriate laboratory testing should be done to evaluate these manifestations.

[edit] Differential Diagnosis

The diseases most likely to be confused with DH are linear IgA bullous dermatosis and BP. Linear IgA bullous dermatosis generally occurs after puberty and presents with heterogenous clinical features. Some cases are indistinguishable clinically from true DH. Unlike DH, however, mucous membranes are affected in up to 50% of patients with linear IgA bullous dermatosis. Pruritus is not as consistent a feature of linear IgA bullous dermatosis as in patients with DH. The disease tends to have exacerbations and remissions similar to DH; spontaneous resolution is noted in approximately one-third of the cases. There is no known association between linear IgA bullous dermatosis and gluten-sensitive enteropathy.

[edit] Management

There are two approaches to therapy for patients with DH. One is adherence to a strict gluten-free diet and the other is medical therapy, usually with dapsone.^[1][4][5] Most patients can completely control their cutaneous disease with dapsone, 100 mg/day. Dapsone does not alter any morphologic changes noted in the intestine or change gastrointestinal symptoms, but it does control cutaneous manifestations of DH quite well. Patients who are glucose-6-phosphate dehydrogenase (G6PD)-deficient develop severe anemia on dapsone; screening for G6PD levels should be performed before initiating therapy with dapsone. Less common side effects of dapsone include toxic hepatitis, sensory and motor neuropathy, infectious mononucleosis–like syndrome, and agranulocytosis. Because of these potential side effects, complete blood counts and liver functions should be routinely monitored, more often early in therapy and less frequently later in the course of therapy.

Patients following a strict gluten-free diet may be able to significantly reduce the dose of dapsone needed to control the disease or control the eruption entirely by diet alone. This diet corrects the abnormality of the small bowel and results in a decrease or loss of cutaneous deposits of IgA. Adherence to this diet is difficult and requires support from a dietitian, as well as family members. The clinical benefits of a strict gluten-free diet may not be seen for up to 2 years.

[edit] REFERENCES