Pemphigus - A Treatment Update

Sue Jessop; Nonhlanhla P. Khumalo

Disclosures

Am J Clin Dermatol. 2009;9(3):147-154. 

In This Article

Abstract

Pemphigus is an uncommon but potentially life-threatening chronic autoimmune bullous disorder. Antibodies are directed against antigens (desmoglein 1 and 3) in the desmosomes linking keratinocytes and against acetylcholine receptors. Conventional treatment with high-dose corticosteroids, sometimes with adjuvant immunosuppressive agents, may be associated with very serious adverse effects. There is an urgent need to establish the evidence for the safest and most effective form of treatment. A literature review has revealed 11 controlled (9 randomized) trials of treatment for pemphigus. The numbers of participants in the individual trials are small and the data cannot be pooled as they evaluate different forms of treatment. The results of these trials suggest that very high doses of corticosteroids, either as pulse therapy or in daily dosage, are not superior to moderate daily doses. Based on evidence from the available trials, addition of an immunosuppressive agent generally does not appear to offer substantial benefit in terms of clinical response. However, a recent study demonstrated a significant reduction in corticosteroid requirements among patients receiving immunosuppressive agents. Newer therapies, such as biologic agents (in particular rituximab), calcineurin inhibitors, or immunoadsorption appear promising but there are inadequate controlled trials to establish their role clearly. Initial open-label studies suggest that specific peptide immunotherapy may offer a safe and novel approach to the treatment of pemphigus in the future. At present, treatment of an individual patient with pemphigus requires clinical judgment and should not be based purely on guidelines or on the inadequate available evidence alone. There is an urgent need for large randomized, controlled, multicenter trials of treatment in patients with pemphigus.

Background

Pemphigus is an uncommon, autoimmune blistering disorder characterized by the presence of flaccid blisters of the skin and/or mucous membranes. It may occur at any age (peak 50–60 years).[1] In the newborn it is thought to result from passive placental transfer of pathogenic antibodies from the maternal circulation. Neonatal pemphigus is usually self-limiting, resolving with the disappearance of maternal antibodies.[2,3]

The recognized forms of this disease are pemphigus vulgaris (PV), pemphigus vegetans, pemphigus foliaceus (PF), IgA pemphigus, and paraneoplastic pemphigus. This article reviews only the literature relating to the two most common types (PV and PF – including endemic forms).

Epidemiology and Etiology

Accurate prevalence figures are limited but it has long been recognized that PV has a relatively high prevalence in people from the Mediterranean area and among those of Jewish ancestry.[1] The two common forms, PV and PF, show a variation in relative prevalence from one geographic area to another. PF is known to have an extraordinarily high prevalence in parts of Tunisia and Brazil (the endemic, so-called 'fogo selvagem,' form of the disorder).[4] A genetic predisposition (HLA-DRB1*0102) has been identified.

Clinical Features

PV is characterized by the presence of flaccid blisters that rupture easily, leading to erosions and crusts. Without treatment the blisters tend to spread, showing little tendency to heal spontaneously. Skin and mucosal surfaces are often both involved, although pemphigus may initially remain at one site for months to years.[5]

PF is a more superficial condition in which the cleft occurs in the outer layers of the epidermis and frequently leads to erosive or crusted lesions rather than blisters.[6]

Impact of Disease and Natural History

Lesions in pemphigus can be anything from uncomfortable to extremely painful, particularly when mucosae are involved. Secondary candidal infection of the mucous membranes is common and contributes to discomfort. Secondary bacterial infection is a major hazard in patients with impaired barrier function, and the risk is enhanced by the use of high-dose corticosteroids and immunosuppressive drugs. Many of the symptoms experienced by patients with pemphigus are secondary to the therapy. The psychosocial impact of pemphigus can be extreme, with painful mucosae and frequently visible skin lesions and changes in body image resulting from corticosteroid effects.[7]

Reported mortality rates for pemphigus vary but recent figures indicate an average of around 6%, with many of the deaths being due to sepsis.[8,9] Severe disease and death appear to be more prevalent during the first year of the disease.[9,10] Retrospective analysis of mortality in historical cohorts suggests that the prognosis has improved since the introduction of corticosteroids, even though these agents may enhance the risk of infection.[11] In a review of the results of 77 published studies, Carson et al.[12] highlighted the changing mortality pattern and explored the possible relationship between mortality and corticosteroid therapy. However, improved survival may have complex underlying causes, including improved infection control and intensive medical care.

Herbst and Bystryn[9] reviewed the pattern of remission in 40 patients with PV. They identified four patterns of illness in their cohort: rapid responders, slow responders, patients with persistent intermittent disease, and patients with refractory disease.

Pathogenesis

Loss of adhesion of keratinocytes is the fundamental abnormality in both PV and PF. The pathogenic role of pemphigus antibodies has been well established both in humans with the disorder and in animal models.[13,14]

Antibodies (generally IgG) are usually directed against transmembrane glycoproteins of the keratinocyte membrane, desmoglein (Dsg) 1 or 3, or against acetylcholine receptors.[15] These components of the desmosomes are critical to cell-to-cell adhesion in the epidermis. The antibodies are thought to produce acantholysis by inducing apoptotic and oncotic pathways, as demonstrated in in vivo and in vitro studies.[16] The cleft forms in the superficial levels of the epidermis in PF and suprabasally in PV, with resultant separation of epidermal cells. Clinical reports of the successful use of nicotine and nicotinamide have suggested a possible role for the acetylcholine axis in epidermal cell adhesion.[17] This finding is supported by work in experimental animals, where carbachol inhibited acantholysis.

Diagnosis

A diagnosis of PV or PF should be considered in patients presenting with non-healing superficial blisters, erosions, or crusts. Light microscopy of involved skin (preferably from a biopsy of a small intact blister) characteristically shows a suprabasal cleft, with acantholysis. Immunofluorescent studies of adjacent skin identify the target antigens in the desmosomes, displaying pericellular epidermal IgG fluorescence. Indirect immunofluorescence studies of serum can detect circulating antibodies against Dsg-1 and/or Dsg-3 and confirm the diagnosis.[18,19]

Activity and Severity Scores

Several clinical scoring systems have been used in the assessment and monitoring of oral and cutaneous pemphigus. Previous scoring systems used in autoimmune blistering disorders have been reviewed by Pfutze et al.,[20] who have also proposed a new combined score, the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS).

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