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).
• Paraneoplastic pemphigus (PNP) presents in association with a tumour (which may be occult).

• 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.
• 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.^4,5
• 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.

• PV is by far the most common variant of pemphigus. Even this variant is rare.
• PV incidence ranges from 0.5 to 3.2 cases per 100,000. 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.
  • Lower incidences are reported in populations where there are fewer people of Jewish or Mediterranean origin. For example, Finland has a low prevalence of 0.76 per million population.
  • An endemic form of PF exists in Brazil and Colombia where it is known as "fogo selvagem".
• There is an apparent association of PV with certain HLA class II alleles (DR6 and DR4). The HLA association is probably the most important predisposing factor.⁶
• 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.
• Pemphigus, like pemphigoid, appears to be triggered by environmental factors. Such factors include:
  • Drugs (for example, penicillamine, captopril, rifampicin)
  • Burns⁷
  • Stress
  • Hormones and pregnancy
  • Vaccinations
  • UV light
  • X-rays
  • Tumours
  • Nutritional factors³
• Removal of the trigger factor does not bring about resolution of the condition.

General features

• Skin lesions:
  • 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.
  • 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

• PV:
  • Most commonly presents with painful erosions or blisters on the oral mucosa, and these oral lesions may occur up to 4 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.
• PF:
  
  
  • Presents with lesions on the skin only, and these patients will not go on to develop oral blisters.
• PNP:
  • It may present in patients who are already known to have an underlying neoplasm such as the B-cell lymphoproliferative disorders (e.g. 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 mucus membranes, generalised polymorphic blistering and lichenoid skin lesions.

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

• Aphthous ulcers
• Crohn's disease
• Herpetic lesions
• Bullous pemphigoid⁸
• Impetigo
• Hailey-Hailey disease (familial benign pemphigus)⁹
• Pemphigus herpetiformis
• Pemphigus erythematosus
• Erythema multiforme
• Lichen planus (bullous forms)
• Drug-induced pemphigus
• Pemphigus IgA

A person in whom a diagnosis of pemphigus is being considered should have the following investigations performed prior to being given any treatment.¹⁰

• General tests:
  • Full blood count and differential count
  • Urea and electrolytes
  • Liver function tests
  • Random blood glucose measurement
  • Antinuclear antibody
  • Chest X-ray
  • 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 PV.¹¹
  • 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.

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

There are differences of opinion on diagnosis and treatment, which require more research.¹¹

General measures

• Patients with painful oral lesions should be advised to have soft diets and use soft toothbrushes.
• Topical analgesics or anaesthetics may give some symptomatic relief.

Medical care

Current treatments are aimed mainly at suppression of the immune system and are associated with significant adverse events. Better understanding of the pathophysiology means that newer therapies have been proposed and are being evaluated. Such therapies include intravenous immunoglobulin, plasmapheresis, immunoadsorption, extracorporeal photochemotherapy and biological agents. There are also experimental therapies involving, for example, DSG3 peptides.¹²

• The initial aim of treatment is to induce remission followed by a period of maintenance therapy using the lowest possible drug doses which maintain disease control.
• Patients with only mild oral disease may be managed with topical therapy alone, e.g.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 within 6-8 weeks. The dose of steroid used varies with the severity of the disease, from 40 mg per day in mild cases up to 100 mg per day in severe cases. Once remission is achieved, a step down regime is followed to find the lowest possible dose which will allow control to be maintained.
• Steroid-sparing agents are sometimes used in an attempt further to reduce the dose, e.g. azathioprine, cyclophosphamide, methotrexate, gold, mycophenolate mofetil^13,14 and ciclosporin. Steroid with cyclophosphamide may be emerging as the best combination in PV.^15,16
• Intravenous immunoglobulin may be used to induce remission in resistant cases, or used as adjuvant therapy.
• Plasma exchange and extracorporeal photopheresis have also been used with some success as adjuvant therapy in severe and/or resistant cases.
• Patients should be followed up routinely until all treatment has been stopped, and the patient remains in remission.

• 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).

Untreated, the mortality associated with PV was 75%. The use of corticosteroids and adjuvant drugs has reduced the mortality rate to less than 10%, although many will suffer 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. If patients survive the first five years of disease the prognosis is particularly good (most deaths occur in the early years of the disease). The outlook is worst in elderly patients and patients with extensive disease.

1. Zeina B; Pemphigus vulgaris; emedicine, 2009. Includes pictures
2. Anhalt GJ, Diaz LA; Pemphigus vulgaris--a model for cutaneous autoimmunity. J Am Acad Dermatol. 2004 Jul;51(1 Suppl):S20-1.
3. Nousari HC, Anhalt GJ; Pemphigus and bullous pemphigoid. Lancet. 1999 Aug 21;354(9179):667-72. [abstract]
4. Tron F, Gilbert D, Mouquet H, et al; Genetic factors in pemphigus. J Autoimmun. 2005 Jun;24(4):319-28. [abstract]
5. Tron F, Gilbert D, Joly P, et al; Immunogenetics of pemphigus: an update. Autoimmunity. 2006 Nov;39(7):531-9. [abstract]
6. Gazit E, Loewenthal R; The immunogenetics of pemphigus vulgaris. Autoimmun Rev. 2005 Jan;4(1):16-20. [abstract]
7. Brenner S, Wohl Y; A burning issue: burns and other triggers in pemphigus. Cutis. 2006 Mar;77(3):145-6.
8. Chan L; Bullous pemphigoid; emedicine, 2008. Includes pictures
9. Burge SM; Hailey-Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol. 1992 Mar;126(3):275-82. [abstract]
10. Harman KE, Albert S, Black MM; Guidelines for the management of pemphigus vulgaris. Br J Dermatol. 2003 Nov;149(5):926-37. [abstract]
11. Mimouni D, Nousari CH, Cummins DL, et al; Differences and similarities among expert opinions on the diagnosis and treatment of pemphigus vulgaris. J Am Acad Dermatol. 2003 Dec;49(6):1059-62. [abstract]
12. Perez OA, Patton T; Novel therapies for pemphigus vulgaris: an overview. Drugs Aging. 2009;26(10):833-46. doi: 10.2165/11316810-000000000-00000. [abstract]
13. Mimouni D, Anhalt GJ, Cummins DL, et al; Treatment of pemphigus vulgaris and pemphigus foliaceus with mycophenolate mofetil. Arch Dermatol. 2003 Jun;139(6):739-42. [abstract]
14. Beissert S, Werfel T, Frieling U, et al; A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of pemphigus. Arch Dermatol. 2006 Nov;142(11):1447-54. [abstract]
15. Mahajan VK, Sharma NL, Sharma RC, et al; Twelve-year clinico-therapeutic experience in pemphigus: a retrospective study of 54 cases. Int J Dermatol. 2005 Oct;44(10):821-7. [abstract]
16. Olszewska M, Kolacinska-Strasz Z, Sulej J, et al; Efficacy and safety of cyclophosphamide, azathioprine, and cyclosporine (ciclosporin) as adjuvant drugs in pemphigus vulgaris. Am J Clin Dermatol. 2007;8(2):85-92. [abstract]

• Guidelines for the management of pemphigus vulgaris, British Association of Dermatologists (2003)