Pemphigus Foliaceus

Updated: Feb 13, 2017
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

Pemphigus foliaceus (PF) is generally a benign variety of pemphigus. It is an autoimmune skin disorder characterized by the loss of intercellular adhesion of keratinocytes in the upper parts of the epidermis (acantholysis), resulting in the formation of superficial blisters. It is typified by clinical involvement of healthy-appearing skin that blisters when rubbed (the Nikolsky sign; commonly but incorrectly spelled Nicholsky), a finding named after Dr Piotr Nikolsky, who first described this sign in 1896. [1] Pemphigus foliaceus is characterized by a chronic course, with little or no involvement of the mucous membranes.

Pierre Louis Alphee Cazenave, founder of the first journal dedicated entirely to dermatology, documented the first description of pemphigus foliaceus in 1844 in this journal. The description was of a 47-year-old woman who consulted him at l'Hopital Saint Louis in Paris for a generalized eruption of several years' duration. Nikolsky described lateral extension of the preexisting erosion due to lifting up the collarette (and when applying a lateral pressure to the clinically intact skin), whereas Asboe-Hansen described extension of the intact blister due to pressure that is applied to its roof.

Pemphigus foliaceus has the following 6 subtypes: pemphigus erythematosus (PE), pemphigus herpetiformis (PH), endemic pemphigus foliaceus, endemic pemphigus foliaceus with antigenic reactivity characteristic of paraneoplastic pemphigus (but with no neoplasm), immunoglobulin A (IgA) pemphigus foliaceus, and drug-induced pemphigus foliaceus. See Pemphigus Erythematosus; Pemphigus Herpetiformis; Pemphigus, Paraneoplastic; and Pemphigus, IgA for more information.

Senear and Usher originally described PE in 1926 as an unusual type of pemphigus with features of lupus erythematosus. PE (also known as Senear-Usher syndrome) is best viewed as a localized form of pemphigus foliaceus. Chorzelski et al [2] determined its immunopathology in 1968.

Another pemphigus foliaceus variant with pruritic, flaccid vesicles in an annular pattern has been characterized as IgA pemphigus foliaceus, with antibodies of IgA class providing the basis for diagnosis.

Jablonska and associates [3] coined the term pemphigus herpetiformis for the pemphigus foliaceus variant that often begins as small clusters of pruritic papules and vesicles mimicking dermatitis herpetiformis.

Endemic pemphigus foliaceus, or fogo selvagem (formerly known as Brazilian pemphigus foliaceus because it is evident mainly in the river valleys of rural Brazil), has also been described in Columbia, El Salvador, Paraguay, Peru, and Tunisia. Fogo selvagem (Portuguese for wild fire) displays immunopathologic findings of pemphigus and a distinctive epidemiology suggestive of a disorder triggered by an infectious insect-borne agent (see Fogo Selvagem). [4] A focus of endemic pemphigus foliaceus also exists in El Bagre, Columbia and shares features with Senear-Usher syndrome but occurs in an endemic fashion. [5, 6] Heterogeneous antigenic reactivity was observed as in paraneoplastic pemphigus but with no evidence of association with neoplasia. This endemic pemphigus disease in El Bagre had immunologic features similar to pemphigus foliaceus or erythematosus.

Chorzelski et al in 1999 [7] described paraneoplastic pemphigus with cutaneous and serologic features of pemphigus foliaceus in a patient with an underlying lymphoma. The authors are not aware of any similar patients with these highly unusual findings.

Drug-induced pemphigus foliaceus is mostly associated with penicillamine, nifedipine, or captopril, medications with a cysteinelike chemical structure.

A transition from pemphigus vulgaris (PV) to pemphigus foliaceus, or vice versa, is not likely. However, in the experience at the Medical University of Warsaw, PV in the remission period may resemble pemphigus foliaceus. About 7% of patients with pemphigus foliaceus may have the initial features of PH. This figure was 35% in patients with endemic pemphigus foliaceus in Tunisia (see Pemphigus Vulgaris). The pivotal contributions of Jean-Claude Bystryn have been summarized. [8]

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Pathophysiology

Superficial blisters in pemphigus foliaceus are induced by immunoglobulin G (IgG) (mainly IgG4 subclass) autoantibodies directed against a cell adhesion molecule, desmoglein 1 (160 kd), expressed mainly in the granular layer of the epidermis. Desmoglein 1 is also a major autoantigen in cases of PH, suggesting that most cases of both PE and PH are clinical variants of pemphigus foliaceus. The mechanism of acantholysis induction by specific autoantibodies may involve phosphorylation of intracellular proteins associated with desmosomes. Complement activation does not play a pathogenic role in pemphigus foliaceus. A polyclonal mixture in pemphigus foliaceus patients of anti-Dsg1 IgG antibodies enhances pathogenic activity for blister formation, with not only pathogenic antibodies, but also nonpathogenic antibodies, contributing to blister formation. [9]

Antibodies against desmoglein 3 are also present in patients with paraneoplastic pemphigus (PNP), a severe condition associated with various antibodies against different components of the cell adhesion complex. Other target antigens, including the acetylcholine receptor, have also been postulated to be relevant in the pathogenesis of pemphigus foliaceus. [10, 11, 12, 13]

Cholinergic control of epidermal cohesion may be important. [14] The regulation of keratinocyte cell-to-cell and cell-matrix adhesion is an important biological function of cutaneous acetylcholine. Progress in therapy of pemphigus using cholinergic drugs supports this concept.

Precipitating factors include medications and ultraviolet light radiation. It has been suggested that both enhanced autoantibody epidermal binding and preferential neutrophil adhesion to UV-irradiated epidermis contribute to acantholysis development in photo-induced pemphigus foliaceus. Radiation therapy may also flare pemphigus foliaceus in those with it. [15, 16, 17]

Endemic pemphigus foliaceus seems to have an environmental cause. The prevalence of antibodies against desmoglein 1 is high in people residing in endemic areas of Brazil, with disease onset preceded by a sustained antibody response due to an as yet unknown environmental factor.

Genetic factors predispose to the development of pemphigus foliaceus. The HLA-DRB1*01:02 allele and the HLA-DRB1*01-DQA1*01-DQB1*05 haplotype had the strongest linkage among 86 pemphigus foliaceus patients from southeastern Brazil. [18] The role of genetic factors is evident in fogo selvagem in which a strong association exists with some human leukocyte antigen DRB1 (HLA-DRB1) haplotypes, including DRB1*0404, 1402, 1406, and 1401. In France, persons with DRB1*0102 and 0404 are at an increased risk of pemphigus foliaceus.

Pemphigus trigger factors have been meticulously analyzed by Ruocco and Ruocco, [19] who have delineated an exhaustive list and stressed the need to detect environmental provoking or precipitating factors. As a superb memory device to facilitate thorough patient evaluation, Ruocco [20] has cleverly observed that PEMPHIGUS should encourage the physician to consider pesticides (PE), malignancy (M), pharmaceuticals (P), hormones (H), infectious agents (I), gastronomy (G), ultraviolet light (U), and stress (S).

Rarely, a change in pemphigus subtype may occur, accompanied by qualitative and quantitative changes in the anti-Dsg autoantibody profile as detected using antigen-specific enzyme-linked immunosorbent assays (ELISAs). Thus, the antibody profile defines the clinical phenotypes of pemphigus, and that intermolecular "epitope spreading" may be the immunological mechanism underlying a shift between pemphigus foliaceus and PV. [21]

It has been suggested that polymorphisms in the 2q33 and 3q21 chromosomal regions influence susceptibility to pemphigus foliaceus. [22]

Scientific evidence links interactions between thymoma function, thymoma, and pemphigus, often associating loss of self-tolerance and the presence of autoimmunity. [23] The association of pemphigus foliaceus and thymoma is noteworthy.

Endemic pemphigus foliaceus in Tunisia has merited analysis. Unlike in North America and Japan, in Tunisia IgG autoantibodies against Dsg1 are commonly detected in healthy individuals. [24] In a Tunisian study, these IgG autoantibodies against Dsg1 were generally against pre-Dsg1 and/or C-terminal domains of Dsg1 in healthy Tunisians.

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Epidemiology

Frequency

The incidence of pemphigus foliaceus varies depending on the population studied. Pemphigus foliaceus is rare and sporadic worldwide. In contrast to PV, no predominance of pemphigus foliaceus is found in Jews and in people of Mediterranean descent. An increased incidence of pemphigus foliaceus was noted in Tunisian women (6.6 cases per million per year), whereas, in Western Europe, the incidence of pemphigus foliaceus is about 0.5-1 case per million per year. [25]

Endemic pemphigus foliaceus, or fogo selvagem, occurs with a high frequency in central and southwestern Brazil and in Colombia. The Terena reservation in Brazil has a prevalence of 3.4% of the population. In endemic regions of Brazil, as many as 50 cases per million per year are seen. [26] Other foci may be present in the Maghreb; one was described in Morocco.

Race

Pemphigus foliaceus has been described in all races.

Sex

In general, the prevalence of pemphigus foliaceus in men and women is about equal; however, in the Sousse region of Tunisia, an overwhelming predominance of women are affected. The peak incidence of endemic pemphigus foliaceus in women aged 25-34 years in the Sousse region of Tunisia is 15.5 cases per million per year. In El Salvador, a similar female and age predisposition may also be evident.

Age

The mean patient age at onset of pemphigus foliaceus is about 50-60 years; however, it may occur at any age, from infancy onward. [27] Fogo selvagem often occurs in children, young adults, and genetically related family members. The mean patient age at onset is about 20-30 years. The peak incidence of endemic pemphigus foliaceus occurs in women aged 25-34 years in the Sousse region of Tunisia. An increased incidence in genetically related family members does not appear to exist.

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Prognosis

Pemphigus foliaceus tends to persist for months to years. Pemphigus foliaceus may coexist with thymoma, myasthenia gravis, lupus erythematosus, and other autoimmune bullous diseases.

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