IgA Pemphigus 

Updated: Jun 18, 2021
Author: Jose A Plaza, MD; Chief Editor: Dirk M Elston, MD 

Overview

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.[1, 2, 3, 4, 5]

Histopathologically, epidermal acantholysis and neutrophil infiltration predominate, hence the synonyms intraepidermal neutrophilic (IEN) IgA dermatosis, intraepidermal IgA pustulosis, IgA herpetiform pemphigus, and intercellular IgA vesiculopustular dermatosis have been used to describe this group of diseases. However, no consensus has been reached concerning the nomenclature.

Two subtypes of IgA pemphigus have been identified: subcorneal pustular dermatosis (SPD)–type IgA pemphigus and IEN-type IgA dermatosis. Although clinical presentation is similar, these variants have distinct autoantibody target proteins. Several studies have also suggested the possibility that IgG/IgA pemphigus represents an additional subtype of IgA pemphigus; however, a consensus is not yet determined.[6, 7, 8, 9] Nonetheless, in a systematic review, Kridin et al showed that if IgG/IgA pemphigus was a unique subtype of IgA pemphigus it would be the third most common subtype behind SPD and IEN types.[7]

Hashimoto et al described an alternative classification for IgA pemphigus, terming the disease “intracellular IgA dermatosis”.[10] In addition to the SPD and IEN types, four disease subtypes have been described. Patients with vegetating lesions and pemphigus vegetans–like histology are classified as IgA pemphigus vegetans (IgA-PVeg). Those with desmoglein-1 or desmoglein-3 target antigens are diagnosed with having IgA pemphigus foliaceus (IgA-PF) or IgA pemphigus vulgaris (IgA-PV), respectively. All other cases not meeting these criteria are diagnosed as unclassified or atypical IgA dermatosis.

Exact classification of IgA pemphigus is not always straightforward, with cases often showing multiple overlapping immunological profiles with regard to IgA reactivity against autoantigens of the epidermis or basement membrane zone. Geller et al conducted a literature review of multiple cases of atypical IgA pemphigus, wherein each case showed a heterogeneous immunological profile, such that they did not fit into the conventional classification schemes based on their autoantibodies against various adhesion molecules.[11, 12] After this review, Geller et al suggested the reclassification of these atypical variants of IgA pemphigus under the general term “IgA pemphigus spectrum” in an effort to combat the limitations of the current classification scheme.

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.

Medscape articles on other variants of pemphigus include Pemphigus Erythematosus, Pemphigus Foliaceus, Pemphigus Herpetiformis, Pemphigus Vulgaris, Drug-Induced Pemphigus, and Paraneoplastic Pemphigus.

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. The SPD-type variant exhibits IgA autoantibodies targeting the transmembrane glycoprotein desmocollin 1 present within keratinocyte desmosomes. In contrast, heterogenous target antigens are seen in the IEN IgA dermatosis subtype. IgA autoantibodies in these patients have been shown to bind to desmogleins 1 and 3 in addition to an unspecified nondesmosomal transmembrane protein.[13] The hallmark finding in IgA pemphigus is autoantibodies binding to sites containing the monocyte/granulocyte IgA-Fc receptor (CD89), causing intraepidermal neutrophilic pustules.[14, 15, 16] The direct pathogenic effects of the IgA autoantibodies and exact mechanism of blister formation have not been established.

In a systematic review of 137 cases, Kridin et al found that only 20.5% of cases diagnosed as a specific subtype of IgA pemphigus (either IEN or SPD) had supporting data regarding immunoreactivity. The available data in the review support the currently accepted association of SPD type with desmocollin 1, as well as the association of heterogenous antigens with regard to IEN-type.[7]

Etiology

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 initiating mechanism is unknown. At least three desmosomal components, including desmoglein 3 (in IEN-type IgA pemphigus), desmoglein 1, and desmocollin 1 (in SPD-type IgA pemphigus foliaceus), have been identified as target antigens in IgA pemphigus.[17, 18, 19, 20, 13, 21, 22] Other unidentified target antigens also may be involved.

A possible role for a specific cytokine has been postulated in IgA pemphigus. 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.

A possible role for specific T-cell receptors has also been suggested in IgA pemphigus. Gamma/delta T-cell receptor–containing T cells, which have been found to be important in influencing mucosal IgA production, may be involved in the IgA pemphigus process.[23]

Additionally, a possible role for the binding site for monocyte/granulocyte IgA-Fc receptor (CD89) in human IgA1 has been suggested for IgA pemphigus. 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.[16]

Postembedding immunoelectron microscopy has localized the target antigen of SPD-type IgA pemphigus to the extracellular domain of desmocollin, whereas the target antigen of 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.

An association of IgA pemphigus and IgA gammopathy and lung cancer has been reported.[24] Additionally, an association of peripheral T-cell lymphoma complicated by IgA pemphigus has been reported.[25]

Historically, numerous studies have hypothesized various disease correlations with IgA pemphigus, including IgA gammopathy, multiple myeloma, and ulcerative colitis. In their systemic review, Kridin et al found that IgA pemphigus was associated with IgA gammopathy in 9.5% of cases and ulcerative colitis in 6.6% of cases.[7] Only two of the 137 patients examined presented with IgA-type multiple myeloma in conjunction with the IgA pemphigus. Other possible hematologic associations include peripheral T-cell lymphoma, chronic myeloid leukemia, and diffuse large B-cell lymphoma.[7] Ultimately, given the possible correlations with IgA pemphigus, screening for associated comorbidities is recommended at the time of presentation.

The 2005 report of cases of pemphigus characterized by the presence of both IgA and IgG classes of autoantibodies raises the question of whether this IgA/IgG pemphigus is a subset of IgA pemphigus or a novel disease entity.[26] There is currently no consensus regarding the validation of IgA/IgG pemphigus as a unique subtype of IgA pemphigus.

In some cases of IgA pemphigus, IgA autoantibodies from a single patient were detected against all three desmocollin proteins (desmocollins 1, 2, and 3),[27] and, in some patients, IgA autoantibodies from an individual patient were found to recognize both desmocollin and desmoglein proteins.[28] These cases of multiple target antigens identified by patient IgA autoantibodies support the occurrence of epitope spreading, an interesting autoimmune phenomenon in which the inflammatory event "releases" a new target antigen (or antigens) to be recognized by the immune system, leading to a subsequent autoimmunity to the new target antigen (or antigens).[29]

Epidemiology

Frequency

IgA pemphigus is a group of newly characterized diseases, and its frequency is unknown. It has been reported in the United States. IgA pemphigus also has been reported in Asia (including Japan and India[30] ), South America (including Brazil[31] ), and Europe (including Scandinavian countries[32] ). A 2004 article surveying patients affected by autoimmune blistering diseases in Kuwait suggested that IgA pemphigus may be extremely rare in that part of the world.[33] A systematic review by Kridin et al shows that IgA pemphigus has been reported in 26 different countries as of 2019.[7]

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 of IgA pemphigus is unknown. Kridin et al performed a systematic review of IgA pemphigus in 2019.[7] They looked at 119 studies spanning 137 patients with IgA pemphigus and found a slight female to male preponderance of 1.1 : 1.

Age

The systematic review by Kridin et al shows that IgA pemphigus has been reported in persons ranging in age from 1 month to 94 years in a review of 137 cases reported from 1983-2019.[7] This review determined the average to be 51.5 years.

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 pruritic superficial blistering disease and usually heals without scarring if treated properly.

Mortality directly resulting from IgA pemphigus has not been 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. Some authors have suggested that the most severe symptoms of the disease actually arise from the adverse effects of the immunosuppressive treatments, including corticosteroids.[34, 35]

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. Patients may be inclined to scratch lesions as pruritus may be a prominent symptom. Scratching may cause excoriations, increasing the risk of secondary infection.

 

Presentation

History

Patients affected with IgA pemphigus usually have subacute onset of disease. In more than one half of reported patients, pruritus is present. The systematic review by Kridin showed that the most common presenting symptoms are vesicles (80.8%), pustules (75%), circinate plaques (63.6%), and pruritus (65.6%).[7] Further, the trunk was the most common area of involvement (83.5%), followed by the extremities (80.2%). Intertriginous involvement was noted in 39.3% of cases, head/neck involvement in 29.8%, and mucosal involvement in 13.2% of cases.

Physical Examination

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 associated with IgA pemphigus fill with neutrophils and transform into pustules.

In some IgA pemphigus patients, neutrophils settle at the lower part of the blister, forming a hypopyon pattern. Lesions usually became flaccid after an initial tense appearance. Some lesions become crusted and form a herpetiform pattern.[36]

In most IgA pemphigus patients, the trunk and proximal extremities primarily are involved. In some IgA pemphigus patients, scalp and postauricular areas are involved extensively. In some IgA pemphigus patients, intertriginous areas (axillary and inframammary areas) are involved. Mucous membranes, palms, and soles usually are spared. In one patient with IgA pemphigus, involvement of perianal skin and oral mucosa was observed.[37]

 

DDx

Diagnostic Considerations

Disorders presenting with grouped pustules or vesicular lesions may resemble IgA pemphigus. These include bullous impetigo, pustular psoriasis, linear IgA bullous dermatosis, and dermatitis herpetiformis. Classic subcorneal pustular dermatosis (SPD) (Sneddon-Wilkinson disease) may present clinically and histologically identical to IgA pemphigus, but direct immunofluorescence yields a negative result. Although there is much clinical overlap owing to the diverse presentation of IgA pemphigus, pemphigus foliaceus tends to form fragile vesicles or bullae concentrating mostly on the face, scalp, and trunk on the chest and upper back. Additional differential diagnoses to consider are listed below.

Differential Diagnoses

 

Workup

Laboratory Studies

Skin biopsy is performed in IgA pemphigus (see Procedures).

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 in IgA pemphigus

Immunoblotting documents the specific skin antigen recognized by the patient's IgA autoantibodies. Immunoblotting has documented IgA autoantibodies (from one patient with intraepidermal neutrophilic (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. Immunoblotting has shown a low sensitivity rate for showing IgA reactivity to any autoantigen (40%).[7]

Enzyme-linked immunosorbent assay in IgA pemphigus

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. In 2001, ELISA detected IgA autoantibodies recognizing desmoglein 3 and desmoglein 1 in a small percentage of patients with IgA pemphigus.[10] In many patients, no antigens are detected, suggesting the presence of alternative unidentified target proteins. ELISAs have shown a low sensitivity rate for showing IgA reactivity to any autoantigen (55%).[7]

Special immunofluorescence tests in IgA pemphigus

Special immunofluorescence tests using cultured cells that express recombinant desmosomal component (desmocollin 1) document the presence of circulating IgA autoantibodies that recognize a desmosomal component. Special immunofluorescence tests have documented IgA autoantibodies from patients with subcorneal pustular dermatosis (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. In contrast to classic IgG-mediated pemphigus, acantholysis may be minimal or absent in IgA pemphigus. In the case of patients presenting with extensive pustular eruptions, some authors recommend direct immunofluorescence of perilesional skin as an early screening test, owing to its high detection rate of IgA deposition in the epidermis.[38, 39] Direct immunofluorescence of the perilesional biopsy has shown intercellular deposition of IgA in 97% of cases.[7]

Histopathology is performed on specimens of blistered skin. The SPD-type IgA pemphigus shows a subcorneal blister with neutrophils and some rare acantholytic cells. The IEN-type IgA pemphigus shows an acantholytic cleft and blister in the lower and middle epidermis with increase number of neutrophils. In some cases, eosinophils can be seen.[7]

See the images below.

Histopathologic examination of a blister lesion ob Histopathologic examination of a blister lesion obtained from a punch biopsy shows prominent subcorneal and intraepidermal pustule formation with numerous neutrophils (hematoxylin and eosin, X40).
Histopathologic examination of a blister lesion ob Histopathologic examination of a blister lesion obtained from a punch biopsy shows prominent subcorneal and intraepidermal pustule formation with numerous neutrophils (hematoxylin and eosin, X40).
Histopathologic examination of a blister lesion ob 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).

Direct immunofluorescence performed on perilesional skin sections is considered the criterion standard test. Direct immunofluorescence documents the immune-mediated disease process. In both types of IgA pemphigus, direct immunofluorescence predominantly detects IgA and, sometimes, to a lesser extent, IgG and complement component C3 deposited at the cell surfaces of the epidermis. Since acantholysis in IgA pemphigus is minimal and sometimes even absent, it can be argued that immunofluorescence should be used as an early screening test for the diagnosis of patients with widespread pustular eruptions.

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 the image below). Indirect immunofluorescence with monkey esophagus usually detects IgA circulating autoantibodies in serum that bind to epithelial cell surfaces in approximately half the patients. Intercellular antibody deposition is detected more frequently using human skin for indirect immunofluorescence. Using this method, studies have found intercellular antibody deposition in up to 65% of patients with IgA pemphigus. Titers of IgA pemphigus autoantibodies are much lower than the titers of IgG autoantibodies observed in IgG-mediated pemphigus.

Indirect immunofluorescence microscopy performed o 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.
 

Treatment

Medical Care

Medical therapy for IgA pemphigus should be directed towards reducing inflammation, because IgA pemphigus represents a group of autoimmune blistering skin diseases manifested clinically as chronic inflammation. Because IgA pemphigus is uncommon, therapy is based on the mechanism of disease and anecdotal reports.

Generally, corticosteroids are the mainstay of treatment for IgA pemphigus. To minimize adverse effects, slow tapering of corticosteroids is advised in order to identify the lowest efficacious dose. Dapsone also may be helpful in IgA pemphigus because of its antineutrophilic effects. Rapid response to treatment with adalimumab and mycophenolate mofetil was reported in 2005.[40] One case report described lesion regression after the addition of azithromycin to a local steroid and keratolytic agent, while another case report described rapid response in subcorneal pustular dermatosis (SPD)–type IgA pemphigus with oral isotretinoin treatment.[41, 42]

Activity

Usually, no restrictions are placed on patient activities; however, advise IgA pemphigus patients to avoid contact sports during the active disease state.

Complications

Infection may occur secondary to open wounds from the blistering process of IgA pemphigus or secondary to medications used to treat IgA pemphigus.

Malignancies may occur secondary to the chronic inflammatory process or secondary to medications.

Growth restriction is possible secondary to medications used to treat IgA pemphigus during childhood.

Adrenal insufficiency may result secondary to long-term prednisone treatment. Osteoporosis is a complication secondary to long-term prednisone treatment.

Other complications due to long-term therapy, specifically with corticosteroids, include anemia, hypertension, diabetes, and weight gain. Infections with oral candidal organisms and herpes simplex virus may occur.

 

Medication

Medication Summary

In general, corticosteroids are the mainstay of treatment for IgA pemphigus. Dapsone, a medication with antineutrophilic effects, also may be helpful. Anti-inflammatory agents theoretically block the inflammatory process and improve the disease conditions.[41, 43]

Anti-inflammatory agents

Class Summary

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.

Prednisone (Deltasone)

Prednisone is an effective treatment for IgA pemphigus. It is an immunosuppressant 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. Consult a pediatrician before prescribing this medication in children.

Dapsone (Avlosulfon)

Dapsone is bactericidal and bacteriostatic against mycobacteria; its mechanism of action is similar to sulfonamides, in which competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth. Dapsone is used alone or in conjunction with other anti-inflammatory medications for treating IgA pemphigus. Consult a pediatrician before prescribing medication in children.

Acitretin (Soriatane)

Acitretin is a retinoic acid analog. Its mechanism of action is unknown. Acitretin has been used effectively in several reported cases of IgA pemphigus.