Pemphigus

Pemphigus, derived from the Greek 'pemphix' (bubble) describes a group of autoimmune disorders in which there is blistering of the skin and/or mucosal surfaces. The term used to include most bullous eruptions but improved diagnostic tests have allowed a reclassification of bullous diseases. The bullae are superficial and confined to the epidermal layer. This is contrast to bullous pemphigoid where bullae are subepidermal.

Three major variants of the disorder have been described, each with characteristic clinical and immunological features:

• Pemphigus vulgaris (PV) is the most common subset or variant and accounts for 70% of cases of pemphigus.
• Pemphigus foliaceus (PF) is characterised by lesions which occur only in the skin and associated with antibodies to desmoglein 1 (DSG1).
• Pemphigus herpetiformis, IgA pemphigus, paraneoplastic pemphigus and IgG/IgA pemphigus are rarer forms.^[1]

Pathophysiology

• The particular autoimmune characteristic associated with pemphigus was first described in the 1960s. Essentially this is the identification of circulating IgG autoantibodies to antigens on the surface of keratinocytes.^[2]
• These pathogenic IgG autoantibodies bind to transmembrane desmosomal proteins of keratinocytes called desmogleins. The binding process results in loss of cell to cell adhesion, causing acantholysis and the production of superficial bullae in the epidermal layer. These superficial bullae rupture easily.^[3]
• An immunogenetic predisposition is now well established.^[4]
• The acantholysis occurs with or without complement activation. If complement is activated then this process may trigger release of inflammatory mediators and T-cell activation.
• The cell surface desmogleins are principally DSG3, but 50-60% also have antibodies to DSG1.
• The circulating IgG autoantibodies may be of both the IgG1 and IgG4 variety and disease activity correlates with the titre of antibodies.

Epidemiology

• Pemphigus vulgaris (PV) is by far the most common variant of pemphigus. Even this variant is rare. UK incidence has been claimed to be rising and is estimated to be 0.68 per 100,000 person years. Incidence is higher in women and in older age groups.^[5]
• The exact prevalence and incidence depends on the population studied reflecting the immunogenetics of pemphigus:
  • PV is seen in all races but more frequently in Asian populations and in Ashkenazi Jews.
  • HLA-DRB1*0402 is associated with the disease in Ashkenazi Jews and DRB1*1401/04 and DQB1*0503 in non-Jewish patients of European or Asian descent.^[3]
• PV may occur at any age, but is most commonly seen between the ages of 30 and 70 years. In adolescents, girls are more often affected than boys.
• The majority of affected children and adolescents have mucocutaneous disease.^[6]
• Pemphigus, like pemphigoid, appears to be triggered by environmental factors. Such factors include:
  • Drugs (for example, penicillamine, captopril, rifampicin).
  • Burns.^[7]
  • Stress.
  • Hormones and pregnancy.
  • Vaccinations.
  • UV light.
  • X-rays.
  • Tumours.
  • Nutritional factors.^[3]
• Removal of the trigger factor does not bring about resolution of the condition.

Presentation

General features

• Skin lesions:^[3]
  • Skin blisters are flaccid rather than tense. Intact blisters may not be found.
  • Lesions can extend easily and become large.
  • Blisters appear on normal or erythematous skin.
  • Affected skin is painful but very rarely pruritic (contrast with bullous pemphigoid).
  • Fluid in the blisters may be turbid.
  • Vegetating lesions (excess granulation and crusting) may be found in intertriginous areas.
  • Nail lesions may occur (paronychias, nail dystrophies and subungal haematomas).
• Mucous membranes:
  • Bullae in the mouth are rarely intact.^[8]
  • Lesions are usually irregular and poorly defined.
  • Lesions are painful and heal very slowly.
  • The oral cavity is most often affected (almost all patients). Gingival, buccal and palatine lesions occur.
  • Lesions may extend to cause hoarseness.
  • Eating and drinking may become very uncomfortable.
  • Other mucous membranes (conjunctivae, oesophagus and genitalia) may be involved.

Specific features

• Pemphigus vulgaris (PV):
  • Most commonly presents with painful erosions or blisters on the oral mucosa, and these oral lesions may occur up to four months before skin lesions become evident.
  • Occasionally, the lesions will remain confined to the mouth.
  • A small number of patients will present with cutaneous blistering first; however, all will go on to develop oral lesions.
• Pemphigus foliaceus (PF):

  Pemphigus foliaceus

  

  • Presents with lesions on the skin only, and these patients will not go on to develop oral blisters.
• Paraneoplastic pemphigus (PNP):
  • It may present in patients who are already known to have an underlying neoplasm such as the B-cell lymphoproliferative disorders (eg, non-Hodgkin's lymphoma and chronic lymphocytic leukaemia).
  • It may present with mucocutaneous lesions before any underlying tumour has been diagnosed.
  • Patients present with painful ulcers on their mucous membranes, generalised polymorphic blistering and lichenoid skin lesions.

Differential diagnosis

The differential diagnoses will include other blistering eruptions of the skin and mucous membranes:

• Aphthous ulcers (oral lesions).
• Herpetic lesions.
• Bullous pemphigoid.
• Impetigo.
• Hailey-Hailey disease (familial benign pemphigus).
• Pemphigus herpetiformis.
• Pemphigus erythematosus.
• Lichen planus (bullous forms).
• Drug-induced pemphigus.
• Pemphigus IgA.

Investigations

A person in whom a diagnosis of pemphigus is being considered should have the following investigations performed prior to being given any treatment.^[9]

General tests

• FBC and differential count.
• U&Es.
• LFTs.
• Random blood glucose measurement.
• Antinuclear antibody.
• CXR.
• Urinalysis for blood, protein and sugar.
• Blood pressure measurement.
• Bone densitometry.

Specific diagnostic tests

Differences of opinion are apparent amongst experts around the world on how best to diagnose and treat pemphigus vulgaris (PV):^[10]

• Skin biopsy should be from the edge of a blister and preferably examined fresh rather than in transport media (risk of false-negative results).
• A skin or mucosal biopsy is sent for histological examination and immunofluorescence (direct and indirect).
• Enzyme-linked immunosorbant assays (ELISAs) may be performed for DSG1 and DSG3 antibodies in serum.

Associated diseases

Pemphigus is associated with other autoimmune diseases. It has been reported in association with myasthenia gravis.

Management

There are differences of opinion on diagnosis and treatment, which require more research.^[11] General measures include advising patients with painful oral lesions to have soft diets and use soft toothbrushes. Topical analgesics or anaesthetics may give some symptomatic relief.

Current treatments are aimed mainly at suppression of the immune system and are associated with significant adverse events. Treatment is in three phases: control, consolidation and maintenance.

Control

• Patients with only mild oral disease may be managed with topical therapy alone - eg, beclometasone sprayed directly from an asthma aerosol inhaler, or the use of hydrocortisone lozenges.
• The majority of patients are treated using systemic corticosteroid therapy which usually results in full remission.^{[12, 13]}
• If high-dose steroids do not seem to be working, plasmapheresis can be used to remove antibodies. It is normally done three times a week, removing about 2L of plasma each time. It is most effective if given with a cytotoxic drug (eg, azathioprine or cyclophosphamide) to prevent concentrations of antibody increasing afterwards. Plasmapheresis can be complicated by severe infections, and this limits its use.
• Intravenous immunoglobulin may be used to induce remission in resistant cases, usually with a cytotoxic therapy like azathioprine. It works by selectively and rapidly decreasing circulating concentrations of pathogenic antibodies.

Consolidation and maintenance

Once remission is achieved, a step-down regime is followed to find the lowest possible dose which will allow control to be maintained. Treatment should not be tapered until most lesions (about 80%) have healed, to reduce the chances of a subsequent flare in disease activity. The aim is, eventually, to discontinue all systemic medication.

• Steroid-sparing agents are sometimes used in an attempt to further reduce the dose - eg:
• Azathioprine
• Cyclophosphamide
• Methotrexate* 
• Gold
• Mycophenolate mofetil^[14]
• Dapsone^[15]
• Ciclosporin

*Methotrexate should not be given to patients who are on high doses of corticosteroids, since this combination has been associated with sepsis.

• Rituximab given with intravenous immunoglobulin has also been successfully used in cases which resist standard treatments.^[16]
• Plasma exchange and extracorporeal photopheresis have also been used with some success as adjuvant therapy in severe and/or resistant cases.
• There are also novel, experimental therapies evolving, such as DSG3 peptides.^[17]

Patients should be followed up routinely until all treatment has been stopped, and the patient remains in remission.

Complications

• Secondary infection, particularly of skin lesions, may delay healing and increase scarring.
• Malignancies from immunosuppression.
• Growth impairment in children (corticosteroids and immunosuppressants).
• Leukaemia and lymphomas (treatments causing prolonged immunosuppression).
• Osteoporosis and adrenal insufficiency (from corticosteroids).

Prognosis

Untreated, the mortality associated with pemphigus vulgaris (PV) was 75%. The use of corticosteroids and adjuvant drugs has reduced the mortality rate significantly. It has been reported as 12% in the UK, with a 3 x higher risk of death compared with age-matched controls.^[5]

Many experience serious side-effects from the drugs used, and many of the deaths occurring today are as a result of infection due to the immunosuppressive effects of the treatment. The outlook is worst in elderly patients and patients with extensive disease.