Diagnostic Hallmarks

Distribution: oral mucous membranes and upper trunk

Multiple shallow erosions that heal unusually slowly

Biopsy: acantholytic intraepidermal bulla

Immunofluorescent studies: immunoglobulin G (IgG) deposited in the intracellular space around epidermal cells.

Clinical Presentation

The bullae of pemphigus vulgaris arise from normal-appearing skin, there is essentially no surrounding inflammation. The blisters are also extraordinarily fragile. Consequently, intact bullae are found only during the first day or two of their existence. Thereafter, the blister roof is broken, leaving a bright-red or crusted shallow erosion that requires weeks or months to heal. The initial lesions are usually found on the upper trunk and back, but since new lesions develop faster than old ones heal, there is gradual extension elsewhere with special predilection for the face, groin, and axillae. The prominence of these crusted erosions often suggests eczematous disease and obscures the fact that the patient has, in fact, a bullous condition.

Oral mucous membrane lesions are practically always present, and they frequently precede the appearance of the cutaneous lesions by weeks to months. These oral lesions begin as blisters, but they, too, quickly break down to form shallow erosions. These erosions are much larger in diameter than the ones found in patients with oral herpes simplex infection and oral aphthae. Characteristically, the posterior mouth is involved. The accompanying discomfort interferes with eating, and the resultant malnutrition contributes to the extreme debilitation that develops in untreated patients.

A suspected clinical diagnosis must be confirmed by biopsy. Light microscopy reveals a characteristic suprabasilar intraepidermal vesicle with loss of epidermal cell cohesion (acantholysis). Direct immunonuorescent studies carried out on perilesional skin demonstrate a pathognomonic pattern of IgG deposition in a network-like pattern surrounding the epidermal cells. Complement components are sometimes present. More than 90% of patients will also have specific circulating autoantibodies. These antibodies can be demonstrated on indirect immunofluorescent study. The titer of these antibodies roughly corresponds to the severity of the disease. Thus, reduction in the antibody titer can be used as one indication of response to therapy.

Atypical Presentations

Pemphigus joliaceus is a form of pemphigus in which the intraepidermal clefting occurs high in the epidermis rather than just above the basal layer. Patients with pemphigus foliaceus develop erosions that are more superficial than those found in pemphigus vulgaris. Oral involvement is less often present, and patients do not become as debilitated. Some patients with pemphigus foliaceus have a considerable degree of facial erythema and may also have a variety of lupus-like autoantibodies. The combination of these findings is known as pemphigus erythematosus (Senear-Usher syndrome). A form of pemphigus found in Brazil (fogo selvagem) has epidemiologic features that suggest an infectious etiology. Paraneoplastic pemphigus is a recently described form of pemphigus that occurs concomitantly with lymphoma or other types of malignancy. The histology shows acantholysis similar to that of pemphigus vulgaris, but the clinical features, because of fairly marked erythema around the blisters, simulate erythema multiforme bullosum.

Course and Prognosis

Pemphigus begins most commonly in mid to late adult life. It is a chronic, severely debilitating disease that, if left untreated, inevitably leads to death. With vigorous, early treatment the mortality rate is approximately 10%. Other autoimmune diseases are found with unexpected frequency in patients with pemphigus, and a rather small, but probably significant, number of patients have thymomas. Pathogenesis

Pemphigus is an autoimmune disease in which specific IgG antibodies and, sometimes, complement components are deposited at the precise site of epidermal cell damage; these same antibodies are regularly found in the circulation. Moreover, the antibodies, when isolated and injected into a suitable substrate, cause an epidermal lesion identical with that found in the original disease. The acantholysis caused by these antibodies appears to develop as a result of the release of proteolytic enzymes. This process does not appear to require, though it may be optimized by, the activation of complement. The 85- and 130-kD antigens responsible for this autoimmune reaction are one or another of several proteins that make up adherence junctions, such as the desmosomes, responsible for the adherence of adjacent epidermal cells. Genetic factors as reflected by the presence of certain HLA antigens and a high incidence in certain Jewish populations are probably also important. Perhaps most interesting of all is the observation that some medications, most notably penicillamine and captopril, can induce in certain individuals a disease indistinguishable from idiopathic pemphigus.

Therapy

The landmark studies of Lever 35 years ago proved that pemphigus need not inevitably lead to death. He showed that very high doses of orally administered steroids (prednisone 120-240 mg/day) would almost always bring the disease under control. Unfortunately, the required long-term, high-dose administration of steroids causes its own morbidity and mortality. In fact, the mortality associated with pemphigus today is mostly due to drug toxicity rather than to the disease itself. There are several ways in which this potential toxicity can be minimized. In some patients, once initial response is obtained, it is possible to convert their steroids to an alternate day schedule and for others the steroid dose can be greatly reduced through the addition of steroid-sparing immunosuppressive agents such as methotrexate, azathioprine, or cyclophosphamide. In patients with relatively mild disease it is sometimes possible to obtain remission through long-term administration of gold salts. Other therapies sometimes used include pulsed IV methylprednisolone, plasmaphoresis, and oral cyclosporine.

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