Pemphigus

Bullous disorders of immunological origin

In pemphigus and pemphigoid, the damage is done by autoantibodies directed at molecules that norm ally bind the skin.

This type of mechanism has not yet been proven for dermatitis herpetiformis; but the characteristic deposition of immunoglobulin (Ig) A in the papillary dermis, and an association with a variety of autoimmune dis-orders, both suggest an immunological basis for the disease.

Pemphigus

Pemphigus is severe and potentially life-threatening. There are two main types. The most common is pemphigus vulgaris, which accounts for at least three-quarters of all cases, and for most of the deaths. Pemphigus vegetans is a rare variant of pemphigus vulgaris. The other important type of pemphigus, superficial pemphigus, also has two variants: the generalized foliaceus type and localized erythema-tosus type. A few drugs, led by penicillamine, can trigger a pemphigus-like reaction, but autoanti-bodies are then seldom found. Finally, a rare type of pemphigus (paraneoplastic pemphigus) has been described in association with a thymoma or an under-lying carcinoma; it is characterized by unusually severe mucosal lesions.

Cause

All types of pemphigus are autoimmune diseases in which pathogenic IgG antibodies bind to antigens within the epidermis. The main antigens are des-moglein 3 (in pemphigus vulgaris) and desmoglein 1 (in superficial pemphigus). Both are cell-adhesion molecules of the cadherin family (see Table 2.5), found in desmosomes. The antigen–antibody reaction interferes with adhesion, causing the keratinocytes to fall apart.

Presentation

Pemphigus vulgaris is characterized by flaccid blisters of the skin (Fig. 9.2) and mouth (Fig. 9.3) and, after the blisters rupture, by widespread painful erosions. Most patients develop the mouth lesions first. 

Shearing stresses on normal skin can cause new erosions to form (a positive Nikolsky sign). In the vegetans variant (Fig. 9.4), heaped up cauliflower-like weeping areas are present in the groin and body folds. The blisters in pemphigus foliaceus are so superficial, and rupture so easily, that the clinical picture is dominated more by weeping and crusting erosions than by blisters. In the rarer pemphigus erythematosus, the facial lesions are often pink, dry and scaly.

Course

The course of all forms of pemphigus is prolonged, even with treatment, and the mortality rate of pemphigus vulgaris is still at least 15%. Superficial pemphigus is less severe. With modern treatments, most patients with pemphigus can live relatively normal lives, with occasional exacerbations.

Complications

Complications are inevitable with the high doses of steroids and immunosuppressive drugs that are needed to control the condition. Indeed, side-effects of treat-ment are now the leading cause of death. Infections of all types are common. The large areas of denuda-tion may become infected and smelly, and severe oral ulcers make eating painful.

Differential diagnosis

Widespread erosions may suggest a pyoderma, impetigo, epidermolysis bullosa or ecthyma. Mouth ulcers can be mistaken for aphthae, Behçet’s disease or a herpes simplex infection.

Investigations

Biopsy shows that the vesicles are intraepidermal, with rounded keratinocytes floating freely within the blister cavity (acantholysis). Direct immunofluorescence  of adjacent normal skin shows intercellular epidermal deposits of IgG and C3 (Fig. 9.5). The serum from a patient with pemphigus contains antibodies that bind to the desmogleins in the desmosomes of normal epidermis, so that indirect immunofluorescence  can also be used to confirm the diagnosis. The titre of these antibodies correlates loosely with clinical activ-ity and may guide changes in the dosage of systemic steroids.

Treatment

Because of the dangers of pemphigus vulgaris, and the difficulty in controlling it, patients should be treated in a specialized unit. Resistant and severe cases need very high doses of systemic steroids, such as prednis-olone  80–320 mg/day, and the dose is dropped only when new blisters stop appear-ing. Immunosuppressive agents, such as azathioprine or cyclophosphamide and, recently, mycophenylate mofetil, are often used as steroid-sparing agents. New and promising approaches include plasmapheresis and intravenous immunoglobulin as used in other auto-immune diseases. Treatment needs regular follow-up and is usually prolonged. In superficial pemphigus, smaller doses are usually needed, and the use of top-ical corticosteroids may help too