You are in: eMedicine Specialties > Dermatology > BULLOUS DISEASES Pemphigus HerpetiformisArticle Last Updated: Sep 8, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  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 is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Investigative Pathology, Federation of American Society of Experimental Biology, Illinois State Medical Society, and Society for Investigative Dermatology Editors: Smeena Khan, MD, Private Practice, Adult and Pediatric Dermatology Associates; Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA; Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, Medicine, University of Texas Health Science Center-San Antonio; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System Author and Editor Disclosure Synonyms and related keywords: herpetiform pemphigus INTRODUCTIONSection 2 of 11
  BackgroundPemphigus 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 vegetans, and pemphigus erythematosus. PathophysiologyPemphigus 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. 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. FrequencyUnited StatesPemphigus herpetiformis is a rare clinical variant of pemphigus. Frequency of occurrence remains undetermined. InternationalAlthough 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/MorbidityPemphigus 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. RaceBecause 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. SexBecause pemphigus herpetiformis is rare, sex distribution has yet to be defined clearly. Studies in the literature do not appear to support a sex predilection. AgeThe age of onset for pemphigus herpetiformis ranges from 30-80 years, with a mean age of onset of 60 years. CLINICALSection 3 of 11
HistoryPatients affected with pemphigus herpetiformis usually have a subacute onset of disease. Approximately one half of patients experience severe pruritus. Physical
Causes
DIFFERENTIALSSection 4 of 11
Bullous Pemphigoid Dermatitis Herpetiformis Pemphigus Erythematosus Pemphigus Foliaceus Pemphigus Vulgaris
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| Drug Name | Dapsone (Avlosulfon) |
|---|---|
| Description | Mechanism of action is similar to that of sulfonamides, in which competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth. Used alone or in conjunction with other anti-inflammatory medication or immunosuppressives for pemphigus herpetiformis. |
| Adult Dose | 100 mg PO qd or 50 mg PO bid |
| Pediatric Dose | >10 years: 25-50 mg/d PO single dose or 25-50 mg/d PO bid; consult pediatrician before prescribing |
| Contraindications | Absolute: Documented hypersensitivity Relative: G-6-PD deficiency (especially in African Americans, persons of Middle Eastern heritage, Asians), significant cardiopulmonary disease, significant hematologic disease, sulfa allergy (cautious use may be attempted; cross-reactivity is relatively rare and mild) |
| Interactions | Trimethoprim, probenecid, and folic acid antagonists (eg, pyrimethamine, methotrexate) increase levels; activated charcoal, PABA, and rifampin decrease levels; may increase hemolysis with sulfonamides and hydroxychloroquine |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Perform weekly CBC counts (first mo), then perform CBC counts monthly (6 mo), then semiannually; discontinue if significant reduction in platelets, leukocytes, or hematopoiesis is seen; methemoglobin reductase deficiency, G-6-PD deficiency, or hemoglobin M because of high risk for hemolysis and Heinz body formation; patients exposed to other agents or conditions (eg, infection, diabetic ketosis) capable of producing hemolysis; peripheral neuropathy can occur (rare); phototoxicity may occur when exposed to UV light |
| Drug Name | Sulfapyridine |
|---|---|
| Description | Sulfa drug with similar function to dapsone in controlling pemphigus herpetiformis. Competitive antagonist of PABA. |
| Adult Dose | 500 mg PO bid; increase by 1 g q 1-2 wk until disease is controlled; control may require 1-4 g/d |
| Pediatric Dose | 35 mg/kg PO bid, not to exceed 100 mg/kg/d; consult pediatrician before prescribing |
| Contraindications | Documented hypersensitivity; slow acetylators may require smaller doses or more gradual initial dosage adjustment |
| Interactions | Bioavailability of digoxin is reduced by sulfapyridine; recommended interval of 2-3 h between administrations |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Idiosyncratic reactions (eg, hypersensitivity pneumonitis, a lupuslike syndrome, pancreatitis, toxic hepatitis) may occur; agranulocytosis occurs rarely; immune and nonimmune hemolytic anemia develop; nonimmune hemolytic anemia is more common in G-6-PD–deficient patients; folate deficiency may occur secondary to impaired absorption; nephrolithiasis may occur as with other sulfa drugs; toxic epidermal necrolysis has been reported with medications containing sulfa groups; check CBC and LFT monthly for 5 mo, then q6wk thereafter |
| Drug Name | Prednisone (Deltasone) |
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| Description | Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production. Taken alone, or in conjunction with other anti-inflammatory or immunosuppressive medications, is useful for controlling pemphigus herpetiformis. |
| Adult Dose | 20-60 mg PO qam; taper over 2-4 wk as symptoms resolve; alternatively, 0.5-2 mg/kg/d; taper as condition improves; single morning dose is safer for long-term use, but divided doses have more anti-inflammatory effect |
| Pediatric Dose | 4-5 mg/m2/d PO, or 0.05-2 mg/kg PO; taper over 2 wk as symptoms resolve; consult pediatrician before prescribing |
| Contraindications | Absolute: Systemic fungal infection, herpes simplex keratitis, hypersensitivity (usually with corticotropin, occasionally with IV forms) Relative: Hypertension, active TB, CHF, prior psychosis, positive purified protein derivative test result, glaucoma, severe depression, diabetes mellitus, active peptic ulcer disease, cataracts, osteoporosis, recent bowel anastomosis, pregnancy |
| Interactions | Increased levels occur with ketoconazole, erythromycin, clarithromycin, estrogens, and birth control pills; decreased levels occur with aminoglutethimide, phenytoin, phenobarbital, rifampin, cholestyramine, and ephedrine; levels of potassium-depleting diuretics (potentiates potassium loss and digitalis toxicity) and cyclosporine increase; levels of isoniazid, insulin (resistance is induced), and salicylates decrease; monitor anticoagulant therapy and theophylline levels |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Use lower dose in hypothyroidism, liver disease, and obesity (decreased cortisol-binding globulin [CBG] and increased free fraction of steroid); pregnancy, hyperthyroidism, and concurrent estrogen therapy may increase CBG levels; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use; alternate-day therapy does not prevent bone loss (appropriate monitoring and prophylaxis for osteoporosis continues to evolve) |
Pemphigus herpetiformis is an autoimmune disease; immunosuppressives are useful in suppressing autoimmune response.
| Drug Name | Azathioprine (Imuran) |
|---|---|
| Description | Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity. Usually used as supplement to anti-inflammatory medication; is useful in controlling pemphigus herpetiformis. |
| Adult Dose | 1 mg/kg qd/bid (empiric) or by TPMT level; increase by 0.5 mg/kg q4wk until response, not to exceed 2.5 mg/kg/d TPMT testing not entirely reliable; involves testing activity of TPMT activity in RBCs, which correlates with systemic TPMT activity; functional enzyme test has been shown to have variability between test sites, and kits may contain varying amounts of enzyme inhibitor; starting at low doses, monitoring for pancytopenia, then increasing the dose is an alternative; if clinical response is not good, patient may be a homozygote for high activity and may need increased dose; Wolverton does not recommend using this assay (Wolverton, Comprehensive Dermatologic Drug Therapy); some references recommend checking before treatment in all patients TPMT <5 U: No treatment with azathioprine TPMT 5-13.7 U: Not to exceed 0.5 mg/kg TPMT 13.7-19 U: Not to exceed 1.5 mg/kg TPMT >19 U: Not to exceed 2.5 mg/kg |
| Pediatric Dose | Safety and efficacy not established |
| Contraindications | Absolute: Documented hypersensitivity, pregnancy or attempting pregnancy, clinically significant active infection Relative: Concurrent use of allopurinol; prior treatment with alkylating agents (eg, cyclophosphamide, chlorambucil, melphalan, others [high risk of neoplasia]) |
| Interactions | Allopurinol increases risk of pancytopenia; captopril/ACE inhibitors may increase risk of anemia and leukopenia; warfarin dose may need to be increased; pancuronium dose may need to be increased for adequate paralysis; live virus vaccines and cotrimoxazole increase risk of hematologic toxicity; rifampicin may cause transplants to possibly be rejected; clozapine may increase risk of agranulocytosis |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Increased risk of neoplasia; caution in liver disease and renal impairment; hematologic toxicities may occur; rarely, patients may develop fever without associated infections; measure thiopurine methyltransferase level prior to treatment; periodically monitor CBC count and liver function |
| Media file 1: Histopathologic examination of a blister lesion obtained from a patient with pemphigus herpetiformis shows a subcorneal blistering process, acantholysis, and neutrophilic infiltrate. | |
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| Media file 2: 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. | |
 | View Full Size Image | Media type: Photo |
Pemphigus Herpetiformis excerpt
Article Last Updated: Sep 8, 2006
