Elsevier

Clinics in Dermatology

Volume 31, Issue 4, July–August 2013, Pages 374-381
Clinics in Dermatology

Pemphigus: Etiology, pathogenesis, and inducing or triggering factors: Facts and controversies

https://doi.org/10.1016/j.clindermatol.2013.01.004Get rights and content

Abstract

Pemphigus includes a group of autoimmune bullous diseases with intraepithelial lesions involving the skin and Malpighian mucous membranes. Pemphigus vulgaris (PV), the most frequent and representative form of the group, is a prototypical organ-specific human autoimmune disorder with a poor prognosis in the absence of medical treatment.

The pathomechanism of PV hinges on autoantibodies damaging cell–cell cohesion and leading to cell–cell detachment (acantholysis) of the epidermis and Malpighian mucosae (mainly oral mucosa). A controversy exists about which subset of autoantibodies is primarily pathogenic: the desmoglein-reactive antibodies or those directed against the acetylcholine receptors of the keratinocyte membrane.

The onset and course of PV depend on a variable interaction between predisposing and inducing factors. Genetic predisposition has a complex polygenic basis, involving multiple genetic loci; however, the genetic background alone (“the soil”), although essential, is not by itself sufficient to initiate the autoimmune mechanism, as proven by the reports of PV in only one of two monozygotic twins and in only two of three siblings with an identical PV-prone haplotype. The intervention of inducing or triggering environmental factors (“the seed”) seems to be crucial to set off the disease. The precipitating factors are many and various, most of them directly originating from the environment (eg, drug intake, viral infections, physical agents, contact allergens, diet), others being endogenous (eg, emotional stress, hormonal disorders) but somehow linked with the subject’s lifestyle. As to certain drugs, their potential of provoking acantholysis may be implemented by their interfering with the keratinocyte membrane biochemistry (biochemical acantholysis) and/or with the immune balance (immunologic acantholysis). Viral infections, especially the herpetic ones, may trigger the outbreak of PV or simply complicate its clinical course. The precipitating effect might be due to interferons and other cytokines released by the host as a consequence of the viral attack, which overactivate the immune response. Inductions of PV by physical agents (ultraviolet or ionizing radiation, thermal or electrical burns, surgery and cosmetic procedures), contact allergens (in particular, organophosphate pesticides), dietary factors (eg, garlic, leek, onion, black pepper, red chili pepper, red wine, tea), and emotional stress are rare, but well-documented events.

The possible intervention of the environment in the outbreak of PV has been overlooked in the past, but nowadays clinicians perceive it more frequently. The assumption that genetic factors alone are not sufficient to cause the outbreak of the disease, inevitably instills the idea that PV may not occur spontaneously, but always results from an interaction between an individual predisposing genetic background and environmental precipitating factors, often concealed or apparently harmless.

Introduction

Pemphigus, a word derived from the Greek πέμφιξ-ίγος (read pemphix-igos) meaning blister (or bulla, from the Latin), refers to a group of autoimmune bullous diseases characterized by widespread blistering and erosions of the skin and mucous membranes. There are six main variants of pemphigus: pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceus, pemphigus erythematosus, paraneoplastic pemphigus, and drug-induced pemphigus. This contribution focuses only on pemphigus vulgaris (PV), which is the most frequent and representative form of the pemphigus group, as well as a prototypical organ-specific human autoimmune disease. Its incidence is estimated at one to five cases per 1 million inhabitants per year but is much higher in some Ashkenazi Jewish populations and in Eastern countries, such as India, Malaysia, China, and Japan. It involves both men and women with a mean age between 40 and 60 years, although some cases have been described in children.1

Initial lesions consist in cell–cell detachment (acantholysis) in the deep part of the epithelium, just above the basal layer (suprabasal acantholysis), resulting in a splitting that gives rise to blister formation (intraepithelial bulla). In two-thirds of cases, the oral mucosa is the site of onset and the disease may remain confined there for several months (oral pemphigus). Intact bullae are quite an uncommon finding in the mouth, where painful and poorly healing erosions represent the hallmark lesions. Skin involvement usually occurs subsequently, with flaccid blisters evolving into erosive areas. Lesions often appear on the trunk, intertriginous areas (axillar, inframammary, and inguinal regions), and scalp, but every site may be involved. Pruritus and the degree of pain are variable. Other stratified squamous epithelial mucosal surfaces (pharynx, larynx, esophagus, conjunctiva, urethra, cervix, anal mucosa) also may be affected in patients with more severe disease.

If left untreated, PV becomes generalized (new crops of bullae appear anywhere, more and more areas of skin present eroded and crusted), the outcome often being fatal within 1 to 3 years due to uncontrolled fluid and protein loss or opportunistic infection. The use of systemic steroids and immunosuppressants has completely modified the natural course and dramatically improved the prognosis of the disease. Currently, the mortality rate of PV is estimated at 5% to 10%1; however, although mortality from PV is low, deaths from treatment side effects or complications are not rare.

Section snippets

Etiopathogenesis

Beutner and Jordon found the key to the etiopathogenesis of pemphigus in 1964.2 They demonstrated antibodies directed against an intercellular antigen of Malpighian epithelia (skin and mucous membranes) in sera of patients with pemphigus. Clinical and experimental observations (Table 1) proved that these antibodies are pathogenic, being the “culprit” and not simply the “witness” of the acantholytic phenomenon.

Much is known but much remains controversial about the exact nature and molecular

Genetic background (the soil)

The existence of a complex polygenic basis, involving multiple genetic loci, is clearly established for PV. Most of these loci still remain unknown, being twin and adoption studies unavailable because of the low prevalence of the disease among the general population. Additional support to this genetic basis comes from the increased incidence of autoimmunity disorders in PV patients (autoimmunity comorbidity) and in their blood relatives, who may be affected by type 1 diabetes, autoimmune

Inducing or triggering factors (the seed)

In the majority of patients with pemphigus, no inducing agent seems to exist and the disease apparently starts in a spontaneous manner (spontaneous or idiopathic pemphigus); however, in several cases, a meticulous clinical history detects the presence, often just a slight hint, of facilitating factors (induced or triggered pemphigus).

Induced pemphigus proper refers to a condition where exogenous factors, very often thiol drugs (eg, penicillamine or captopril), play such a major role for the

A provocative question

The possible intervention of the environment in the outbreak of PV is ever more perceived by clinicians. In fact, there are some reports of induced or triggered pemphigus claiming more than one environmental factor as causal or precipitating agent (eg, penicillamine and captopril acting simultaneously37), two viral infections (common cold and herpes simplex labialis) treated with a combination drug composed of paracetamol, caffeine, chlorpheniramine maleate and phenylephrine HCl,38 surgical

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