Pemphigus

Section 1 Aetiology and epidemiology
Pemphigus vulgaris is the most common variant of this condition, accounting for 70 per cent of all cases.

It is rare, with an overall incidence of 0.1-0.5 patients per 100,000 per year.¹ The condition is thought to have a strong genetic link to HLA class II alleles² and has a predilection for Ashkenazi Jews and people of Mediterranean and Asian descent.

It typically presents in middle age, although young Asians appear particularly susceptible. Incidence is equal in men and women.

Pemphigus vulgaris may also be associated with other immunological disorders, including thymoma, myasthenia gravis, rheumatoid arthritis, lupus erythematosus and pernicious anaemia.¹ It has been reported in association with Castleman's tumours³ and may coexist with bullous pemphigoid.⁴

Pathogenesis
The mechanism is loss of the normal cell-to-cell adhesion of keratinocytes in the epidermis (acantholysis).

This occurs through damage to connecting desmosomes by circulating IgG antibodies directed against the extracellular domains of the cadherin-type epithelial cell adhesion molecules, the desmogleins5 (so-called pemphigus antigens), which are localised within desmosomes. This immune deposition leads to intraepithelial vesicle formation.

The main antigen in pemphigus vulgaris is desmoglein 3 (pemphigus vulgaris antigen, Dsg3), which is found predominantly in the lower epidermis but is preferentially expressed in oral epithelium.⁶

However, half of pemphigus vulgaris patients also have autoantibodies to desmoglein 1 (pemphigus foliaceus antigen, Dsg1), which although present throughout the epidermis, primarily the upper layers, is only weakly expressed in mucosae.⁶

The relative distribution and proportion of the desmogleins expressed reflects the distribution of lesions seen clinically.

Rarer pemphigus antigens, including members of the desmocollin⁷ and desmoplakin⁸ families, are now thought to have an important role in pathogenesis, particularly in some of the rarer pemphigus subgroups, such as paraneoplastic pemphigus. Although a patient typically presents with a single pemphigus variant, there have been cases of transition from one to another, which may be related to differences in autoantibody expression.⁹

Radiotherapy is a known pemphigus inducer, and stress has recently been reported as a potential significant trigger for pemphigus flares. Dietary factors, such as garlic, have been postulated as a potential trigger.

In addition, the role of human herpes virus infections, such as HHV-8, in the initiation of pemphigus flares has been mooted, but the evidence is anecdotal.

Underlying neoplasia is a significant aetiological factor in the variant paraneoplastic pemphigus.¹⁰

Section 2 Clinical features
Pemphigus vulgaris invariably involves mucosae, with oral involvement seen in 50-70 per cent of patients.

Slow healing, ill-defined buccal or palatal erosions are typical; intact bullae are rare owing to the level of splitting suprabasally (see image above).

Painful and tender mouth lesions may prevent adequate food intake. Most patients develop cutaneous lesions, although months may elapse before skin involvement occurs.

Rarely, an acute generalised bullous eruption may be the presenting feature.

The skin lesions typically seen are flaccid, easily ruptured vesicles and bullae on normal skin or an erythematous base, leading to erosions and secondary crusting. The lesions tend not to be pruritic, but are painful and can be localised or widespread.

Pressure adjacent to a lesion to dislodge the epidermis from the dermis typically leads to the formation of an erosion (positive Nikolsky's sign). Typical sites of cutaneous involvement include the scalp, face, chest, axillae, umbilicus and groin.

The disease process is typically non-scarring, but post-inflammatory pigment change may be seen. Nail changes, including acute paronychia, subungual haematoma formation and dystrophy, have been reported.

Section 3 Diagnosis
Skin biopsy from a blister or erosion demonstrates separation of keratinocytes suprabasally, leading to a split just above the basal cell layer within the epidermis and vesicles containing acantholytic keratinocytes.

Direct immunofluorescence (IMF) is diagnostic, with IgG and often C3 deposited in lesional and paralesional skin in the intercellular substance of the epidermis. IgG1 and IgG4 are the most common subclasses.

Indirect IMF (serum) detects circulating pemphigus IgG autoantibodies in more than 80 per cent of patients. Serodiagnosis by ELISA reveals 95 per cent of pemphigus vulgaris patients have anti-Dsg3 antibodies and approximately 50 per cent have anti-Dsg1 antibodies.

Titres usually correlate with disease activity, so are a useful monitoring tool.

Without aggressive immunosuppressant therapy, the disease is invariably fatal, usually as a result of secondary sepsis. However, with corticosteroids, the mortality is now 5-15 per cent.¹¹

This depends in part on the extent of the disease and the immunosuppressant requirements. Morbidity is often related to complications of therapy.

Pemphigus vegetans
Pemphigus vegetans is a rare variant of pemphigus vulgaris, characterised by granulomatous, vegetating purulent plaques confined to flexures, the perioral area, scalp and neck.

There are two subtypes, the severe Neumann pemphigus vegetans and the more benign Hallopeau type. Histology demonstrates suprabasal acantholysis with intraepidermal abscesses comprising acantholytic cells and eosinophils; direct IMF shows intercellular IgG.

Pemphigus foliaceus
Pemphigus foliaceus accounts for 10-20 per cent of cases and is less severe than pemphigus vulgaris.¹² It represents the superficial form of pemphigus, with acantholysis in the epidermal granular layer.

Bullae are therefore very rare, with lesions consisting of erythematous erosions and patches with associated crusting most commonly on the scalp, face, chest and upper back.

Oral/mucosal lesions are rare, reflecting the predominance of circulating autoantibodies to Dsg1, rather than Dsg3.¹³ IMF (direct and indirect) is usually identical to that seen in pemphigus vulgaris.

Pemphigus foliaceus is a chronic but benign condition that responds well to treatment and may resolve with time.

Endemic pemphigus foliaceus is a form common in rural parts of South America, especially Brazil.¹⁴ It may be environmentally triggered, possibly by an insect-borne infectious agent.

Clinically, histologically and immunopathologically, it is identical to pemphigus foliaceus.

Drug-induced cases
Several drugs have been implicated in inducing or exacerbating pemphigus. These include those containing a sulfhydryl group (so-called thiol drugs), such as penicillamine and captopril, and non-thiol drugs, such as rifampicin, penicillins, cephalosporins, diclofenac, nifedipine and ACE inhibitors.¹⁵

Thiol drug-induced pemphigus appears to resolve after cessation of the offending agent in about half of cases. Non-thiol drug cases recover spontaneously in only 15 per cent.¹⁵

Neoplastic disease
Paraneoplastic pemphigus resembles pemphigus vulgaris and erythema multiforme clinically and histologically, with severe mucous membrane involvement, erosions and often, palmoplantar targetoid lesions.

It presents in two-thirds of cases with underlying neoplasia,¹⁰ including B-cell lymphoproliferative disorders, carcinomas, thymoma and sarcomas.

In the remainder, the neoplasm postdates the eruption.

Antibodies are predominantly against the desmoplakin antigen family and therapy is often ineffective, despite treatment of the malignancy. Death is usually secondary to sepsis, or respiratory or multi-organ failure.

Section 4 Treatment
Topical and intralesional steroids often have a role in localised forms of pemphigus and antibiotics (topical/oral) are frequently used to treat secondary infection. Good oral hygiene is essential.

Systemic glucocorticoids remain the mainstay of treatment. Regimens differ according to the clinician, but the most common is prednisolone (1-1.5mg/kg/day) until new blisters have stopped appearing, followed by gradual titration of the dose to the lowest that maintains control.

In severe cases, higher doses are required, but are frequently associated with side-effects, despite the use of gastric and bone protection. In such cases, IV pulses of 1g methylprednisolone (initially monthly) or 100mg dexamethasone may be safer.¹⁶

Steroid-sparing agents
Steroid-sparing immunosuppressive agents are usually used in conjunction with glucocorticoids to limit the steroid dose and associated side-effects. Azathioprine (2.5mg/kg/day) is frequently used and often continued for many months after steroid therapy has been tapered and stopped.¹¹

Cyclophosphamide (1-3mg/kg/day) in combination with steroids is very effective and can also be used as pulse therapy with methylprednisolone (initially monthly) and then less frequently as the disease improves.¹⁶ Remission may be maintained with low-dose oral therapy.

Mycophenolate mofetil (2-3g/day), a newer steroid-sparing agent, is frequently used.¹⁷ Other agents include methotrexate (oral or IM), ciclosporin (5mg/kg/day) and gold (oral or IM), both in conjunction with steroids and dapsone.

Plasmapheresis to reduce antibody titres in patients who are poorly controlled, and high-dose IV immunoglobulin (2g/kg) are alternative therapies; the effect of the latter is rapid but temporary.

A relatively new agent, the anti-CD20 chimeric monoclonal antibody rituximab (given as an infusion), has recently been shown to be effective in severe cases resistant to conventional therapy, either in combination with IV immunoglobulins or as monotherapy.^{18, 19}

However, owing to potentially serious side-effects, its use should be restricted to the most severe types of the disease.

Monitoring of disease activity should be both clinical and immunological (antibody titres), but adverse effects that are often the result of immunosuppressive therapy must be detected early to prevent morbidity and mortality.

• The authors would like to thank the dermatology and medical photography departments, and consultant clinical scientist Dr Edward Davies, of King's College Hospital, London, for kind permission to publish the photographs.

• This article was originally published in MIMS Dermatology. To subscribe visit: www.hayreg.co.uk

References

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19. Joly P, Mouquet H, Roujeau J et al. A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med 2007; 357: 545-52.

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