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Dermatology > BULLOUS DISEASES
Pemphigus, IgA
Article Last Updated: Aug 30, 2006
AUTHOR AND EDITOR INFORMATION
Section 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, Association of Professors of Dermatology, Chicago Dermatological Society, Dermatology Foundation, Illinois State Medical Society, and Society for Investigative Dermatology
Editors: Takeji Nishikawa, MD, Emeritus Professor, Department of Dermatology, Keio University School of Medicine; Director, Samoncho Dermatology Clinic; Managing Director, The Waksman Foundation of Japan Inc; David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic; Edward F Chan, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
intraepidermal neutrophilic IgA dermatosis, intercellular IgA vesiculopustular dermatosis, intercellular IgA dermatosis, intraepidermal IgA pustulosis, IgA pemphigus
Background
Immunoglobulin A (IgA) pemphigus is a group of newly characterized immune-mediated intraepidermal blistering skin diseases. Unlike typical immunoglobulin G (IgG)–mediated pemphigus, IgA pemphigus is characterized by tissue-bound and circulating IgA autoantibodies that target the desmosomal proteins of the epidermis.
Histopathologically, epidermal acantholysis and neutrophil infiltration predominate, hence the synonyms intraepidermal neutrophilic IgA dermatosis, intraepidermal IgA pustulosis, IgA herpetiform pemphigus, and intercellular IgA vesiculopustular dermatosis have been used to describe this group of diseases. No consensus has been reached concerning the nomenclature.
IgA pemphigus has not been described in animals. Although the term IgA pemphigus has not been established in the veterinary literature, IgA deposition around epidermal cells has been detected by direct immunofluorescence in animals affected with pemphigus foliaceus.
Pathophysiology
The exact pathomechanism of IgA pemphigus is not well defined. According to currently available data, IgA autoantibodies clearly bind to desmosomal components of the epidermis, desmogleins, or desmocollins. Since the IgA autoantibodies possess specific binding sites for the monocyte/granulocyte IgA-Fc receptor (CD89), hypothesis indicates that neutrophils accumulate intraepidermally, causing the blistering process to occur. The direct pathogenic effects of the IgA autoantibodies have not been established.
Frequency
United States
IgA pemphigus is a group of newly characterized diseases, and its frequency is unknown, although IgA pemphigus has been reported in the United States.
International
IgA pemphigus is a group of newly characterized diseases, and its frequency is not yet defined. IgA pemphigus has been reported in Asia (including Japan), South America, and Europe (including Scandinavian countries). A recent article surveying patients affected by autoimmune blistering diseases in Kuwait suggested that IgA pemphigus may be extremely rare in that part of the world.
Mortality/Morbidity
Mortality directly resulting from IgA pemphigus is not reported. In general, the clinical course of IgA pemphigus is less severe than that of IgG-mediated pemphigus, and no significant morbidity exists. In some patients with IgA pemphigus, pruritus is a significant symptom and may interfere with the patient's daily life.
Race
IgA pemphigus is a rare disease and is newly characterized; therefore, the race distribution is unknown. IgA pemphigus has been reported in American, European, South American, and Asian patients.
Sex
The sex distribution is unknown. A review of 28 cases reported from 1982-1997 revealed a male-to-female ratio of 1:1.33.
Age
IgA pemphigus has been reported to occur in persons aged 1 month to 85 years. A review of 28 cases reported from 1982-1997 determined the average age of onset to be 53 years.
History
Patients affected with IgA pemphigus usually have subacute onset of disease. In more than one half of reported patients, pruritus is present.
Physical
IgA pemphigus is a vesiculopustular skin disease. In general, lesions form within erythematous plaques but also can form in skin without plaques. The initial, clear, fluid-filled blisters fill with neutrophils and transform into pustules.
- In some patients, neutrophils settle at the lower part of the blister, forming a hypopyon pattern.
- In most patients, the trunk and proximal extremities primarily are involved.
- In some patients, scalp and postauricular areas are involved extensively.
- In some patients, intertriginous areas (axillary and inframammary areas) are involved.
- Mucous membranes, palms, and soles usually are spared.
- Lesions usually became flaccid after an initial tense appearance. Some lesions become crusted and form a herpetiform pattern.
Causes
The exact pathomechanism of IgA pemphigus is not well defined at the present time. Clearly, IgA autoantibodies are initiated to target desmosomal components, although the mechanism for such initiation is unknown. At least 3 desmosomal components, including desmoglein 3 (in intraepidermal neutrophilic–type [IEN-type] IgA pemphigus), desmoglein 1, and desmocollin 1 (in subcorneal pustular dermatosis–type [SPD-type] IgA pemphigus foliaceus), have been identified as target antigens in IgA pemphigus. Other unidentified target antigens also may be involved.
- Possible role of a specific cytokine: Interleukin 5, a TH2-secreted cytokine that preferentially induces B cells to produce IgA class antibodies, may be activated preferentially in patients with IgA pemphigus.
- Possible role of specific T-cell receptors (TCRs): Gamma/delta TCR-containing T cells, which have been found to be important in influencing mucosal IgA production, may be involved in the IgA pemphigus process.
- Possible role of the binding site for monocyte/granulocyte IgA-Fc receptor (CD89) in human IgA subclass 1 (IgA1): Human IgA1 antibody has a binding site for the monocyte/granulocyte IgA-Fc receptor (CD89) that is located distally to the hinge region, thus providing a stronger resistance to protease digestion. The protease-resistant property of IgA1 may provide efficient binding of neutrophils, thus allowing the intraepidermal neutrophil infiltration that may contribute to the blistering process.
- Postembedding immunoelectron microscopy has localized the target antigen of the SPD-type IgA pemphigus to the extracellular domain of desmocollin, whereas the target antigen of the IEN-type IgA pemphigus was found to be in an intercellular space outside the desmosomal areas. These findings suggest that the pathomechanism of IgA pemphigus involves the weakening of extracellular components of cell-to-cell adhesion molecules.
Dermatitis Herpetiformis
Eosinophilic Pustular Folliculitis
Pemphigus Foliaceus
Subcorneal Pustular Dermatosis
Lab Studies
Other Tests
- Perform other tests, if available, to document the diagnosis of IgA pemphigus, including immunoblotting, enzyme-linked immunosorbent assay (ELISA), and special immunofluorescence studies.
- Immunoblotting
- Immunoblotting documents the specific skin antigen recognized by the patient's IgA autoantibodies.
- Immunoblotting has documented IgA autoantibodies (from 1 patient with IEN-type IgA pemphigus) that target desmosomal component desmoglein 3, which is located at the lower part of epidermis. However, other investigators were unable to detect IgA immunoreactivity to this protein in patient sera; therefore, the significance of the antigen remains unknown.
- Enzyme-linked immunosorbent assay
- In theory, ELISA should be a good methodology for documenting the specific desmosomal antigen(s) recognized by patient IgA autoantibodies, since it uses native protein and increases detection sensitivity.
- Recently, ELISA has detected IgA autoantibodies recognizing desmoglein 3 and desmoglein 1 in a small percent of patients with IgA pemphigus.
- Special immunofluorescence tests
- Special immunofluorescence tests using cultured cells that express recombinant desmosomal component (desmocollin 1) document the presence of circulating IgA autoantibodies that recognize desmosomal component.
- Special immunofluorescence tests have documented IgA autoantibodies from patients with SPD-type IgA pemphigus. The tests detected desmosomal component desmocollin 1; however, this test is not generally available.
Procedures
- Skin biopsy is performed and specimens analyzed to establish the diagnosis using histopathology and direct and indirect immunofluorescence.
- Histopathology is performed on specimens of blistered skin.
- Histopathology demonstrates an intraepidermal blister, which may be located subcorneally (SPD-type IgA pemphigus), suprabasally, or at mid epidermis (IEN-type IgA pemphigus).
- Histopathology demonstrates acantholysis, but it is not characteristic as is acantholysis observed in classic pemphigus. The intraepidermal neutrophil infiltration tends to form neutrophilic microabscess, which is the hallmark of IgA pemphigus (see Media File 1).
- Direct immunofluorescence is performed on perilesional skin sections.
- Direct immunofluorescence documents the immune-mediated disease process.
- Direct immunofluorescence predominantly detects IgA and sometimes, to a lesser extent, IgG and complement component C3 deposited at the cell surfaces of the epidermis.
- Indirect immunofluorescence is performed using patient serum on monkey esophagus or other epithelial substrates.
- Indirect immunofluorescence documents the presence of IgA circulating autoantibodies in patient serum that recognize skin epidermal cell surface components (see Media File 2).
- Indirect immunofluorescence usually detects IgA circulating autoantibodies in serum that bind to epithelial cell surfaces in approximately 50% of patients. Titers of IgA pemphigus autoantibodies are much lower than the titers of IgG autoantibodies observed in IgG-mediated pemphigus.
Medical Care
Medical therapy should be directed towards reducing inflammation, since IgA pemphigus represents a group of autoimmune blistering skin diseases manifested clinically as chronic inflammation. Since IgA pemphigus is uncommon, therapy is based on the mechanism of disease and anecdotal reports.
- Generally, corticosteroids are the mainstay of treatment.
- Dapsone also may be helpful because of its antineutrophilic effects.
- Rapid response to treatment with adalimumab and mycophenolate mofetil was reported in 2005.
Activity
Usually, no restrictions are placed on patient activities; however, advise patients to avoid contact sports during the active disease state.
In general, corticosteroids are the mainstay of treatment. Dapsone, a medication with antineutrophilic effects, also may be helpful.
Drug Category: Anti-inflammatory agents
IgA pemphigus is characterized histologically by inflammatory cell (neutrophil) infiltration in the upper epidermis. Anti-inflammatory agents theoretically block the inflammatory process and improve the disease conditions.
| Drug Name | Prednisone (Deltasone) |
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| Description | Effective treatment for IgA pemphigus. Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. Consult the pediatrician before prescribing medication in children. |
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| Adult Dose | 0.5-2 mg/kg/d PO; taper as condition improves; single morning dose is safer for long-term use but divided doses have more anti-inflammatory effect |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI tract disease |
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| Interactions | Coadministration with estrogens may decrease prednisone clearance; when used with digoxin, digitalis toxicity secondary to hypokalemia may increase; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics |
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| Pregnancy | B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
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| Precautions | Abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur |
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| Drug Name | Dapsone (Avlosulfon) |
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| Description | Bactericidal and bacteriostatic against mycobacteria; mechanism of action is similar to sulfonamides in which competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth. Used alone or in conjunction with other anti-inflammatory medications for treating IgA pemphigus. Consult the pediatrician before prescribing medication in children. |
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| Adult Dose | 75-100 mg/d PO
Alternatively, 50-300 mg PO qd |
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| Pediatric Dose | 25-50 mg/d PO |
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| Contraindications | Documented hypersensitivity; G-6-PD deficiency |
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| Interactions | May inhibit anti-inflammatory effects of clofazimine; hematologic reactions may increase with folic acid antagonists, eg, pyrimethamine (monitor for agranulocytosis during second and third months of therapy); probenecid increases dapsone toxicity; trimethoprim with dapsone may increase toxicity of both drugs; because of increased renal clearance, dapsone levels may significantly decrease when administered concurrently with rifampin |
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| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
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| Precautions | Perform weekly blood counts (first month), then perform WBC counts monthly (6 mo), then semiannually; discontinue if significant reduction in platelets, leukocytes, or hematopoiesis is seen; caution in methemoglobin reductase deficiency, G-6-PD deficiency, or hemoglobin M because of high risk for hemolysis and Heinz body formation; caution in 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 |
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| Drug Name | Acitretin (Soriatane) |
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| Description | Retinoic acid analog. Mechanism of action is unknown. Used effectively in several reported cases of IgA pemphigus. |
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| Adult Dose | 25-50 mg/d PO |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity; pregnancy; women of childbearing age |
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| Interactions | Toxicity may occur with beta carotene coadministration; absorption increased with milk; increases toxicity of methotrexate (avoid concomitant use); interferes with effects of microdosed progestin minipill |
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| Pregnancy | X - Contraindicated; benefit does not outweigh risk
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| Precautions | Do not use in patients with severe obesity; women of childbearing age must be capable of complying with effective contraceptive measures; perform AST, ALT and LDH tests prior to initiation of therapy and at 1- to 2-wk intervals until stable and thereafter at intervals as clinically indicated; perform retinal ophthalmoscopic examination because acitretin-associated maculopathy has been reported |
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Complications
- Infection may occur secondary to open wounds from the blistering process or secondary to medications.
- Malignancies may occur secondary to the chronic inflammatory process or secondary to medications.
- Growth retardation is possible secondary to medications used during childhood.
- Adrenal insufficiency may result secondary to chronic prednisone treatment.
- Osteoporosis is a complication secondary to chronic prednisone treatment.
Prognosis
- Unlike IgG-mediated pemphigus, as a group of diseases, IgA pemphigus usually exhibits a milder clinical phenotype. The prognosis usually is good according to the limited clinical data available.
- IgA pemphigus is a superficial blistering disease and usually heals without scarring if treated properly.
Patient Education
- Instruct patients with IgA pemphigus regarding the potential adverse effects of immunosuppressive treatment (eg, prednisone use). Adverse effects may include infection, malignancies, adrenal insufficiency, and osteoporosis.
- Teach patients to recognize the symptoms and signs of adverse effects and to report them to the physician if noted.
Medical/Legal Pitfalls
- Failure to monitor severe adverse effects of systemic corticosteroids may result in bone fracture, adrenal suppression, development of diabetes, and other serious sequelae.
| Media file 1:
Histopathologic examination of a blister lesion obtained from a patient with immunoglobulin A pemphigus shows a suprabasal blistering process, acantholysis, and an inflammatory cell infiltrate containing numerous neutrophils (hematoxylin and eosin, original magnification X50). |
 |  View Full Size Image | |
Media type: Photo
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| Media file 2:
Indirect immunofluorescence microscopy performed on monkey esophagus substrate (with serum from a patient with immunoglobulin A pemphigus) detects the immunoglobulin A1 subclass of circulating autoantibodies that label the epithelial cell surfaces of the substrate. |
 | View Full Size Image | |
Media type: Photo
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Pemphigus, IgA excerpt Article Last Updated: Aug 30, 2006
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