eMedicine Specialties > Dermatology > Bullous Diseases

Pemphigus Herpetiformis

Author: Lawrence Chan, MD, Department Head and Director of Skin Immunology Research, Professor, Departments of Dermatology and Microbiology/Immunology, University of Illinois College of Medicine
Contributor Information and Disclosures

Updated: Oct 15, 2008

Introduction

Background

Pemphigus herpetiformis is a clinical variant of pemphigus that 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.

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. 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.1

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.

Frequency

United States

Pemphigus herpetiformis is a rare clinical variant of pemphigus. Frequency of occurrence remains undetermined.

International

Although frequency of occurrence 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.

Mortality/Morbidity

Pemphigus herpetiformis is not associated with significant mortality; however, the disease is associated with significant pruritus. Treatment regimens for the disease 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.2,3 In addition, pemphigus herpetiformis has been associated with prostate cancer development in one case.4

Race

Because pemphigus herpetiformis is rare, ethnic distribution is not determined yet. Because the disease 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.

Clinical

History

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

Physical

  • Patients affected with pemphigus herpetiformis usually present with erythematous, vesicular, bullous, or papular lesions.
  • Lesions often demonstrate a "herpetiform" pattern, which is manifested as a cluster of blisters on an inflammatory base.
  • Mucous membrane involvement is observed only occasionally. Oral erosion has been reported as a rare finding.
  • Occasionally, lesions resemble those found in dermatitis herpetiformis, bullous pemphigoid, linear IgA bullous dermatosis, pemphigus foliaceus, pemphigus erythematosus, or pemphigus vulgaris.

Causes

  • Pemphigus herpetiformis appears to be mediated by IgG autoantibodies targeting the interepidermal cell adhesion molecules desmoglein 1 or desmoglein 3.5,6,7 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.
  • Etiology in the neutrophil-dominant subset of pemphigus herpetiformis includes the following:
    • In a study of 2 patients, IgG autoantibodies that recognized desmoglein 1 (a predominant upper-epidermal protein) exclusively were found to co-localize with expression of IL-8 (a strong neutrophil chemokine) and neutrophilic infiltration at the upper epidermis of the patients' skin.
    • In the study of 2 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.8
  • 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.9
  • At least 2 reported patients with pemphigus herpetiformis had coexisting psoriasis,10 a chronic inflammatory dermatosis, raising a possible role of "epitope spreading" in the induction of pemphigus herpetiformis.11

More on Pemphigus Herpetiformis

Overview: Pemphigus Herpetiformis
Differential Diagnoses & Workup: Pemphigus Herpetiformis
Treatment & Medication: Pemphigus Herpetiformis
Follow-up: Pemphigus Herpetiformis
Multimedia: Pemphigus Herpetiformis
References
[ CLOSE WINDOW ]

References

  1. Amagai M, Tsunoda K, Suzuki H, Nishifuji K, Koyasu S, Nishikawa T. Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus. J Clin Invest. Mar 2000;105(5):625-31. [Medline].

  2. Kubota Y, Yoshino Y, Mizoguchi M. A case of herpetiform pemphigus associated with lung cancer. J Dermatol. Aug 1994;21(8):609-11. [Medline].

  3. Palleschi GM, Giomi B. Herpetiformis pemphigus and lung carcinoma: a case of paraneoplastic pemphigus. Acta Derm Venereol. 2002;82(4):304-5. [Medline].

  4. Marzano AV, Tourlaki A, Cozzani E, Gianotti R, Caputo R. Pemphigus herpetiformis associated with prostate cancer. J Eur Acad Dermatol Venereol. May 2007;21(5):696-8. [Medline].

  5. Brod C, Fierlbeck G, Metzler G, Sönnichsen K, Röcken M, Schaller M. [Desmoglein 1-negative, desmoglein 3-positive pemphigus herpetiformis with involvement of oral mucous membranes]. J Dtsch Dermatol Ges. Apr 2005;3(4):280-2. [Medline].

  6. Ishii K, Amagai M, Komai A, Ebihara T, Chorzelski TP, Jablonska S, et al. Desmoglein 1 and desmoglein 3 are the target autoantigens in herpetiform pemphigus. Arch Dermatol. Aug 1999;135(8):943-7. [Medline].

  7. Kubo A, Amagai M, Hashimoto T, Doi T, Higashiyama M, Hashimoto K, et al. Herpetiform pemphigus showing reactivity with pemphigus vulgaris antigen (desmoglein 3). Br J Dermatol. Jul 1997;137(1):109-13. [Medline].

  8. Verdier-Sevrain S, Joly P, Thomine E, Belanyi P, Gilbert D, Tron F, et al. Thiopronine-induced herpetiform pemphigus: report of a case studied by immunoelectron microscopy and immunoblot analysis. Br J Dermatol. Feb 1994;130(2):238-40. [Medline].

  9. Sanchez-Palacios C, Chan LS. Development of pemphigus herpetiformis in a patient with psoriasis receiving UV-light treatment. J Cutan Pathol. Apr 2004;31(4):346-9. [Medline].

  10. Morita E, Amagai M, Tanaka T, Horiuchi K, Yamamoto S. A case of herpetiform pemphigus coexisting with psoriasis vulgaris. Br J Dermatol. Oct 1999;141(4):754-5. [Medline].

  11. Chan LS, Vanderlugt CJ, Hashimoto T, Nishikawa T, Zone JJ, Black MM, et al. Epitope spreading: lessons from autoimmune skin diseases. J Invest Dermatol. Feb 1998;110(2):103-9. [Medline].

  12. Hashimoto T, Ogawa MM, Konohana A, Nishikawa T. Detection of pemphigus vulgaris and pemphigus foliaceus antigens by immunoblot analysis using different antigen sources. J Invest Dermatol. Mar 1990;94(3):327-31. [Medline].

  13. Ishii K, Amagai M, Hall RP, Hashimoto T, Takayanagi A, Gamou S, et al. Characterization of autoantibodies in pemphigus using antigen-specific enzyme-linked immunosorbent assays with baculovirus-expressed recombinant desmogleins. J Immunol. Aug 15 1997;159(4):2010-7. [Medline].

  14. American College of Rheumatology. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. American College of Rheumatology Task Force on Osteoporosis Guidelines. Arthritis Rheum. Nov 1996;39(11):1791-801. [Medline].

  15. Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med. Oct 26 2006;355(17):1772-9. [Medline].

  16. Amagai M, Klaus-Kovtun V, Stanley JR. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell. Nov 29 1991;67(5):869-77. [Medline].

  17. Barranco VP. Mixed bullous disease. Arch Dermatol. Aug 1974;110(2):221-4. [Medline].

  18. DeMento FJ, Grover RW. Acantholytic herpetiform dermatitis. Arch Dermatol. Jun 1973;107(6):883-7. [Medline].

  19. Dias M, dos Santos AP, Sousa J, Maya M. Herpetiform pemphigus. J Eur Acad Dermatol Venereol. Jan 1999;12(1):82-5. [Medline].

  20. Huhn KM, Tron VA, Nguyen N, Trotter MJ. Neutrophilic spongiosis in pemphigus herpetiformis. J Cutan Pathol. Jun 1996;23(3):264-9. [Medline].

  21. Jablonska S, Chorzelski TP, Beutner EH, Chorzelska J. Herpetiform pemphigus, a variable pattern of pemphigus. Int J Dermatol. Jun 1975;14(5):353-9. [Medline].

  22. Kuhl KA, Shofer FS, Goldschmidt MH. Comparative histopathology of pemphigus foliaceus and superficial folliculitis in the dog. Vet Pathol. Jan 1994;31(1):19-27. [Medline].

  23. Maciejowska E, Jablonska S, Chorzelski T. Is pemphigus herpetiformis an entity?. Int J Dermatol. Nov 1987;26(9):571-7. [Medline].

  24. Mahoney MG, Wang Z, Rothenberger K, Koch PJ, Amagai M, Stanley JR. Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris. J Clin Invest. Feb 1999;103(4):461-8. [Medline].

  25. Micali G, Musumeci ML, Nasca MR. Epidemiologic analysis and clinical course of 84 consecutive cases of pemphigus in eastern Sicily. Int J Dermatol. Mar 1998;37(3):197-200. [Medline].

  26. Nickoloff BJ, Karabin GD, Barker JN, Griffiths CE, Sarma V, Mitra RS, et al. Cellular localization of interleukin-8 and its inducer, tumor necrosis factor-alpha in psoriasis. Am J Pathol. Jan 1991;138(1):129-40. [Medline].

  27. O'Toole EA, Mak LL, Guitart J, Woodley DT, Hashimoto T, Amagai M, et al. Induction of keratinocyte IL-8 expression and secretion by IgG autoantibodies as a novel mechanism of epidermal neutrophil recruitment in a pemphigus variant. Clin Exp Immunol. Jan 2000;119(1):217-24. [Medline].

  28. Robinson ND, Hashimoto T, Amagai M, Chan LS. The new pemphigus variants. J Am Acad Dermatol. May 1999;40(5 Pt 1):649-71; quiz 672-3. [Medline].

  29. Santi CG, Maruta CW, Aoki V, Sotto MN, Rivitti EA, Diaz LA. Pemphigus herpetiformis is a rare clinical expression of nonendemic pemphigus foliaceus, fogo selvagem, and pemphigus vulgaris. Cooperative Group on Fogo Selvagem Research. J Am Acad Dermatol. Jan 1996;34(1):40-6. [Medline].

  30. Schröder JM. Cytokine networks in the skin. J Invest Dermatol. Jul 1995;105(1 Suppl):20S-24S. [Medline].

  31. Seitz CS, Staegemeir E, Amagai M, Rose C, Bröcker EB, Zillikens D. Pemphigus herpetiformis with an autoimmune response to recombinant desmoglein 1. Br J Dermatol. Aug 1999;141(2):354-5. [Medline].

  32. Shimizu K, Hashimoto T, Wang N, Watanabe K, Ohata Y, Kikuchi A, et al. A case of herpetiform pemphigus associated with autoimmune hemolytic anemia: detection of autoantibodies against multiple epidermal antigens. Dermatology. 1996;192(2):179-82. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

pemphigus herpetiformis, pemphigus, herpetiform pemphigus

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Lawrence Chan, MD, Department Head and Director of Skin Immunology Research, Professor, Departments of Dermatology and Microbiology/Immunology, University of Illinois College of Medicine
Lawrence Chan, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Association of Professors of Dermatology, Chicago Dermatological Society, Dermatology Foundation, Illinois State Medical Society, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Medical Editor

Smeena Khan, MD, Private Practice, Adult and Pediatric Dermatology Associates
Smeena Khan, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, University of Texas Health Science Center-San Antonio
Jeffrey Meffert, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Association of Military Dermatologists, and Texas Dermatological Society
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

RELATED EMEDICINE ARTICLES
 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.