Pemphigus Herpetiformis

Updated: Nov 16, 2018
  • Author: Blanca Anais Estupiñan; Chief Editor: William D James, MD  more...
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Overview

Background

Pemphigus herpetiformis is a rare autoimmune bullous skin disorder that is considered a clinical variant of pemphigus. Classically, it combines the clinical features of dermatitis herpetiformis with the immunopathologic features of pemphigus. Previously, pemphigus was described using various terms, including herpetiform pemphigus, acantholytic herpetiform dermatitis, pemphigus controlled by sulfapyridine, and mixed bullous disease. Because pemphigus herpetiformis is a clinical variant of pemphigus, it may be more appropriately described with a term that begins with the general group term (pemphigus), followed by a term for the variant subset (herpetiformis), similar to the terms for other pemphigus variants, such as pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, and pemphigus vegetans. [1, 2]

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Pathophysiology

Pemphigus herpetiformis appears to be mediated by the immunoglobulin G (IgG) class of autoantibodies that target the skin epidermis desmoglein components. Most patients demonstrate autoantibodies to desmoglein 1, a desmosomal component predominantly located in the upper epidermis, while a minority of patients demonstrates autoantibodies to desmoglein 3, which is predominantly located in the lower epidermis, and, most recently, desmocollin. [3, 4, 5] The ability of desmoglein 3 to induce an experimental model of pemphigus after transfer of splenocytes from desmoglein 3-immunized desmoglein 3-knockout mice to Rag-2 immunodeficient mice further supports the role of desmogleins as autoantigens. Histologically demonstrated eosinophil and/or neutrophil infiltration into the epidermis may be relevant pathogenically in the disease process of pemphigus herpetiformis. [6]

In the neutrophil-dominant subset, epidermal cells secrete a neutrophil chemokine interleukin 8 (IL-8), which apparently is induced by IgG autoantibodies to desmoglein and may be responsible for the recruitment of neutrophils to the epidermis, resulting in the subsequent blistering process.

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Etiology

Pemphigus herpetiformis appears to be mediated by IgG autoantibodies targeting the interepidermal cell adhesion molecules desmoglein 1 or desmoglein 3. [7, 8, 9] Other less commonly seen target antigens include desmocollin 1, desmocollin 3, and an unidentified 178-kd protein. [10, 11] In many cases, the target antigens are the same as those seen in classic variants of pemphigus. It is likely that antibodies in pemphigus herpetiformis bind to epitopes of desmogleins 1 and 3 and desmocollins 1 and 3, leading to a different clinical presentation. A 2012 study supports this hypothesis through its discovery of a broader epitope distribution in pemphigus herpetiformis than seen in pemphigus vulgaris. [12] However, unlike typical pemphigus vulgaris, significant numbers of inflammatory cells, eosinophils, neutrophils, or mixed eosinophils and neutrophils infiltrate pemphigus herpetiformis lesional skin. The roles of inflammatory cells, particularly eosinophils, in the pathogenesis of pemphigus herpetiformis require further investigation.

Regarding the etiology in the neutrophil-dominant subset of pemphigus herpetiformis, in a study of two patients, IgG autoantibodies that recognized desmoglein 1 (a predominant upper-epidermal protein) exclusively were found to co-localize with expression of interleukin (IL)–8 (a strong neutrophil chemokine) and neutrophilic infiltration at the upper epidermis of the patients' skin. In the study of two patients, the purified IgG fraction of the patients' sera induced IL-8 secretion from normal cultured human keratinocytes. Purified IgG from one of these patients also induced the cytoplasmic expression of IL-8 in normal cultured human keratinocytes. Thus, in the neutrophil-dominant subset of pemphigus herpetiformis, it seems that IgG autoantibodies targeting desmoglein 1 were responsible for neutrophil recruitment to the epidermis as a result of inducing epidermal-cell IL-8 expression and secretion. Once at the epidermis, infiltrating neutrophils may result in blisters by releasing their proteases.

In the eosinophil-dominant subset of pemphigus herpetiformis, eosinophilic involvement has not been investigated yet.

One report of a patient with pemphigus herpetiformis has been associated with use of medication (thiopronine). A detailed mechanism is not delineated. [13]

One patient with pemphigus herpetiformis had a history of psoriasis and developed the pemphigus disease shortly after a course of ultraviolet light treatment, raising a possible role of ultraviolet light in the induction of pemphigus herpetiformis. [14]

At least two reported patients with pemphigus herpetiformis had coexisting psoriasis, [15] a chronic inflammatory dermatosis, raising a possible role of "epitope spreading" in the induction of pemphigus herpetiformis. [16]

In one case report, an acute, concurrent eruption of pemphigus herpetiformis and sarcoidosis was described. [17] The temporal and disease severity relationships suggested the two disease processes may share a common link. IL-8, a neutrophil chemotactic factor, has increased activity in both diseases. The pathogenesis of pemphigus herpetiformis includes up-regulation of IL-8 on keratinocytes, causing neutrophil-induced blister formation, while sarcoidosis causes a systemic increase of IL-8 through activation of T helper-2 cells during granuloma formation. Additionally, phosphorylation of p28 leads to an intracellular signaling cascade involved in both inflammatory diseases as well as psoriasis.

Pemphigus herpetiformis may also demonstrate autoantibodies targeting antigen (or antigens) other than the typical desmoglein proteins (desmoglein 1 or 3). [18]

A patient with pemphigus herpetiformis, manifested by prominent skin involvement with no oral mucosal involvement, demonstrated autoantibodies to desmoglein 3, in contrast with what would typically be seen with this antibody. [19]

Pemphigus herpetiformis may also present with lesions characteristic of the inflammatory stage of heritable pretibial dystrophic epidermolysis bullosa. [20]

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Epidemiology

Frequency

Pemphigus herpetiformis is a rare clinical variant of pemphigus. Frequency of occurrence remains undetermined. Although frequency of occurrence of pemphigus herpetiformis is not determined, pemphigus herpetiformis has been reported in Europe, Japan, and the United States. In a large study conducted in Eastern Europe, 15 patients (7.3%) with pemphigus herpetiformis were found among 205 patients with pemphigus. In a smaller study conducted in Italy, 5 patients with pemphigus herpetiformis were found among 84 patients with pemphigus. Therefore, pemphigus herpetiformis accounts for approximately 6-7% of pemphigus in European populations.

Race

Because pemphigus herpetiformis is rare, ethnic distribution is not determined yet. Because pemphigus herpetiformis occurs in the United States, Europe, and Asia, it does not appear to have a specific ethnic predominance.

Sex

Because pemphigus herpetiformis is rare, sex distribution has yet to be defined clearly. Studies in the literature do not appear to support a sex predilection.

Age

The age of onset for pemphigus herpetiformis ranges from 30-80 years, with a mean age of onset of 60 years. Moutran et al describes an unusual case of onset at age 6 years successfully treated with dapsone. [21] One case report describes transplacental transmission of pemphigus herpetiformis to an otherwise healthy infant with subsequent resolution after age 3 weeks. [22]

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Prognosis

The prognosis for pemphigus herpetiformis usually is excellent. Pemphigus herpetiformis is not associated with significant mortality; however, pemphigus herpetiformis is associated with significant pruritus. Treatment regimens for pemphigus herpetiformis may cause significant adverse effects that must be monitored closely by the patient's physicians. Severe pruritus is noted in approximately one half of patients affected with pemphigus herpetiformis. At least 2 cases of pemphigus herpetiformis have been reported to occur in association with lung cancer. Whether this association was coincidental is not clear. [23, 24] In addition, pemphigus herpetiformis has been associated with prostate cancer development in one case. [25]

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