Pemphigus Herpetiformis 

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

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]

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.

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]

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]

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]

 

Presentation

History

Patients affected with pemphigus herpetiformis usually have a subacute onset of disease. Approximately half the patients experience severe pruritus.

Physical Examination

Patients affected with pemphigus herpetiformis usually present with erythematous, vesicular, bullous, or papular lesions.[26] Pemphigus herpetiformis lesions often demonstrate a "herpetiform" pattern, which is manifested as a cluster of blisters on an inflammatory base.

Distribution is typically generalized and most prominent on trunk and limbs. However, atypical and localized distributions have been reported. Two cases of localized distribution described grouped pustules on the dorsum of the feet and unilateral preauricular involvement.[27] Mucous membrane involvement in pemphigus herpetiformis is observed only occasionally. Oral erosion has been reported as a rare finding of pemphigus herpetiformis.

Occasionally, pemphigus herpetiformis lesions resemble those found in dermatitis herpetiformis, bullous pemphigoid, linear IgA bullous dermatosis, pemphigus foliaceus, pemphigus erythematosus, or pemphigus vulgaris.

During the clinical course of the disease, manifestations may remain herpetiform in nature or evolve into other pemphigus types such as pemphigus foliaceus or pemphigus vulgaris.[28] However, patients may also initially present with pemphigus foliaceus or pemphigus vulgaris and later exhibit a more herpetiform clinical picture.[29, 30]

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

To establish a diagnosis of pemphigus herpetiformis, perform the following tests: histopathology on newly blistered skin, direct immunofluorescence (DIF) on periblistered skin, and indirect immunofluorescence (IIF) of the patient's sera on monkey esophagus substrate.

Histopathology of pemphigus herpetiformis

Histopathology documents the acantholytic process and inflammatory cell infiltration (eosinophils, neutrophils, or both) that characterize pemphigus herpetiformis. Eosinophilic spongiosis is the most frequently reported histologic finding. Other characteristic features include intraepidermal or subcorneal neutrophilic and eosinophilic microabscesses. It is estimated inflammatory cell infiltration is mixed in 60% of cases, with the remainder exhibiting either predominantly eosinophilic (20%) or neutrophilic (20%) involvement.[28] Acantholytic cells are more prominent in other pemphigus types such as pemphigus vulgaris, but are usually visualized in pemphigus herpetiformis. Note the image below.

Histopathologic examination of a blister lesion ob Histopathologic examination of a blister lesion obtained from a patient with pemphigus herpetiformis shows a subcorneal blistering process, acantholysis, and neutrophilic infiltrate.

Direct immunofluorescence in pemphigus herpetiformis[31]

See the image below. DIF documents the immunologic nature of pemphigus herpetiformis. DIF usually detects the presence of IgG with or without C3 deposition around cell surfaces of keratinocytes in the patient's skin. The optimal location for the skin biopsy used in this study is adjacent to a blister or an inflammatory papule.

Direct immunofluorescence microscopy performed on Direct immunofluorescence microscopy performed on a skin biopsy specimen obtained from a patient with pemphigus herpetiformis detects immunoglobulin G deposits on the epithelial cell surfaces but sparing the basal layers.

Indirect immunofluorescence in pemphigus herpetiformis

IIF confirms the presence in the patient's serum of IgG-circulating autoantibodies that bind to epidermal cell surfaces. In some patients, IgG autoantibodies predominantly bind to the upper part of the epidermis; in other patients, IgG autoantibodies bind to the entire epidermis. The titer of autoantibodies often parallels the clinical level of activity of pemphigus herpetiformis and often is helpful in following the patient's disease activity after the diagnosis has been established.

Imaging Studies

Patients with pemphigus herpetiformis who have associated pulmonary symptoms should undergo routine chest radiography. CT scanning may also be needed.

Other Tests

Immunoblotting in pemphigus herpetiformis[32]

Immunoblotting documents specific skin desmosomal components, in a denatured form, that are recognized by the patient's IgG autoantibodies. Most patients with pemphigus herpetiformis have IgG autoantibodies that recognize desmoglein 1, a desmosomal protein predominantly located in the upper epidermis. In a minority of patients with pemphigus herpetiformis, IgG autoantibodies were detected to desmoglein 3, a desmosomal protein predominantly located in the lower epidermis.

Enzyme-linked immunosorbent assay in pemphigus herpetiformis[33]

Similar to immunoblotting, enzyme-linked immunosorbent assay (ELISA) detects the specific protein component (usually in recombinant nondenatured form) recognized by the patient's IgG autoantibodies. ELISA usually is more sensitive than immunoblotting in detecting the protein recognized by autoantibodies.

Immunoprecipitation in pemphigus herpetiformis

Immunoprecipitation has the same function as immunoblotting but is more difficult to perform. Immunoprecipitation detects the native form of the target antigen rather than the denatured form of the antigen.

 

Treatment

Medical Care

Pemphigus herpetiformis is responsive to anti-inflammatory and immunosuppressive medications. Dapsone is the drug of choice if the patient tolerates the treatment. Among its many anti-inflammatory actions, dapsone has been shown to decrease neutrophil migration, which may lessen the immune response seen in pemphigus herpetiformis.[34]

In severe cases of pemphigus herpetiformis that do not respond to conventional treatments (systemic corticosteroid and immunosuppressives), also consider using a monoclonal antibody anti-CD20 (rituximab), which has specific actions against B lymphocytes.[35] Rituximab has shown very good clinical efficacy for patients with pemphigus vulgaris, a form of pemphigus that is usually more severe than pemphigus herpetiformis. One report noted success with the combination of rituximab and intravenous immune globulin.[36]

The disease activities of pemphigus herpetiformis rarely require hospitalization. In a few patients, short-term hospitalization (< 10 d) may be helpful.

Activity

No specific activity restrictions are indicated for pemphigus herpetiformis patients; however, advise patients to avoid injury during the active disease period.

Prevention

For pemphigus herpetiformis patients who are treated with systemic corticosteroid for longer than 1 month, combined calcium and vitamin D supplements should be instituted to prevent osteoporosis. The dosage and frequency of these supplements are stated in the 1996 recommendations established by the American College of Rheumatology Task Force.[37]

Long-Term Monitoring

The disease activities of pemphigus herpetiformis range from mild to moderate. During the active disease period, provide follow-up care for patients on a monthly outpatient basis. These visits ensure that (1) patients are responding clinically to prescribed medications and (2) patients experience no serious adverse effects that require a change of medications. Typically, follow-up visits are not needed for patients in clinical remission and not on treatment.

 

Medication

Medication Summary

Because pemphigus herpetiformis is a rare variant of pemphigus, comprehensive therapeutic studies of large numbers of patients have not taken place. The following treatment options are taken from the personal experiences of physician-investigators with a small number of patients.

In general, dapsone is the drug of choice for pemphigus herpetiformis treatment. Other anti-inflammatory and immunosuppressive medications are also effective.

Anti-inflammatories

Class Summary

Because pemphigus herpetiformis lesions are characterized by prominent infiltration of inflammatory cells, anti-inflammatory medication may inhibit the functions of these cells, therefore improving disease conditions.

Dapsone (Avlosulfon)

Dapsone's mechanism of action is similar to that of sulfonamides, in which competitive antagonists of PABA prevent the formation of folic acid, inhibiting bacterial growth. Dapsone is used alone or in conjunction with other anti-inflammatory medications or immunosuppressives for pemphigus herpetiformis.

Prednisone (Deltasone)

Prednisone is an immunosuppressant used for the treatment of autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. Taken alone, or in conjunction with other anti-inflammatory or immunosuppressive medications, it is useful for controlling pemphigus herpetiformis.

Immunosuppressives

Class Summary

Pemphigus herpetiformis is an autoimmune disease; immunosuppressives are useful in suppressing autoimmune response.

Azathioprine (Imuran)

Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease the proliferation of immune cells, which results in lower autoimmune activity. Azathioprine is usually used as a supplement to anti-inflammatory medication; it is useful in controlling pemphigus herpetiformis.

Biological Response Modulator

Class Summary

The agents in this class target specific antigens in carcinoma cells and induce cytotoxicity. Rituximab is used off-label for steroid-refractory pemphigus herpetiformis.

Rituximab (Rituxan)

Rituximab is a genetically engineered chimeric murine/human monoclonal antibody against human CD20, a molecule present in normal and malignant B lymphocytes. It is described in case reports as a promising biological treatment for B-lymphocyte–mediated diseases (eg, pemphigus vulgaris).

 

Questions & Answers

Overview

What is pemphigus herpetiformis?

What is the pathophysiology of pemphigus herpetiformis?

What causes pemphigus herpetiformis?

What is the prevalence of pemphigus herpetiformis?

What are the racial predilections of pemphigus herpetiformis?

What are the sexual predilections of pemphigus herpetiformis?

Which age groups have the highest prevalence of pemphigus herpetiformis?

What is the prognosis of pemphigus herpetiformis?

Presentation

Which clinical history findings are characteristic of pemphigus herpetiformis?

Which physical findings are characteristic of pemphigus herpetiformis?

DDX

What are the differential diagnoses for Pemphigus Herpetiformis?

Workup

Which lab tests are performed in the workup of pemphigus herpetiformis?

Which histologic findings are characteristic of pemphigus herpetiformis?

Which direct immunofluorescence findings are characteristic of pemphigus herpetiformis?

Which indirect immunofluorescence findings are characteristic of pemphigus herpetiformis?

What is the role of imaging studies in the workup of pemphigus herpetiformis?

What is the role of immunoblotting in the workup of pemphigus herpetiformis?

What is the role of ELISA in the workup of pemphigus herpetiformis?

What is the role of immunoprecipitation in the workup of pemphigus herpetiformis?

Treatment

How is pemphigus herpetiformis treated?

Which activity modifications are used in the treatment of pemphigus herpetiformis?

How is osteoporosis prevented in pemphigus herpetiformis?

What is included in the long-term monitoring of patients with pemphigus herpetiformis?

Medications

What is the role of medications in the treatment of pemphigus herpetiformis?

Which medications in the drug class Biological Response Modulator are used in the treatment of Pemphigus Herpetiformis?

Which medications in the drug class Immunosuppressives are used in the treatment of Pemphigus Herpetiformis?

Which medications in the drug class Anti-inflammatories are used in the treatment of Pemphigus Herpetiformis?