IgA Pemphigus L10.9

Varigos, 1979; Wallach D, 1992;

Very rare, itchy or painful, blister- and pustule-forming autoimmune disease from the pemphigus group with infiltrated plaques, vesicles and blisters as well as pustules.

A distinction is made between 2 forms of IgA pemphigus:

• Intraepidermal neutrophilic IgA dermatosis (IEN)
• Subcorneal pustular dermatosis (SPD)

In a more recent classification, 5 different forms are distinguished:

• Subcorneal pustular dermatosis (SPD/ type IgA pemphigus)
• Intraepidermal neutrophilic IgA dermatosis (IEN/ type IgA pemphigus)
• IgA pemphigus vegetans (IgA-PVeg)
• IgA pemphigus vulgaris (IgA-PV)
• Unclassified IgA pemphigus (IGA-Puc)

Patients with vegetating lesions and a pemphigus vegetans-like histology are classified as IgA pemphigus vegetans (IgA-PVeg). Patients with desmoglein-1 or desmoglein-3 target antigens are diagnosed as IgA pemphigus foliaceus (IgA-PF) or IgA pemphigus vulgaris (IgA-PV). All other cases that do not fulfill these criteria are referred to as unclassified or atypical IgA dermatosis.

The aetiology of IgA pemphigus is not clearly understood. Based on previously investigated cases, IgA pemphigus has been associated with monoclonal IgA gammopathy and multiple myeloma. In a 1992 paper, Wallach et al. described six of 29 cases of IgA pemphigus in which monoclonal IgA gammopathy was detected. It is unclear whether the monoclonal gammopathy occurs before or after the onset of skin symptoms. However, most cases were detected at the time of presentation. There is evidence of dysfunction of desmosomal adhesion molecules due to circulating IgA autoantibodies:

• Intraepidermal neutrophilic IgA dermatosis (IEN): Pustules suprabasal or in the entire epidermis, rarely acantholysis, IgA deposition in the entire epidermis, 57% circulating IgA autoantibodies, target antigens desmoglein 1 and 3.
• Subcorneal pustular dermatosis (SPD): Changes only in the upper epidermis (subcorneal), 48% circulating IgA auto-AK, target antigen desmocollin 1. An association with monoclonal IgA gammopathy (see below paraproteinemia, skin changes) has been described in 20% of the SPD variant.

Associations with Crohn's disease, ulcerative colitis, Sjögren's syndrome, multiple myeloma of the IgA type, rheumatoid arthritis, B-cell lymphomas and HIV infections (Gimpel AK et al. 2022) have been reported. An association with COVID-19 vaccination has also been reported (Lansang RP et al. 2023).

The pathogenesis of IgA pemphigus is associated with IgA autoantibodies directed against desmosomal and non-desmosomal keratinocyte cell surface components. These components are cell-to-cell adherent molecules, including desmoglein-1, desmoglein-3 and desmocollin-1. Desmogleins and desmocollin are glycoproteins belonging to a superfamily of cadherin molecules.

The antigen of the subtype of subcorneal pustular dermatosis has been identified as desmocollin 1.

Both desmoglein 1 and desmocollin 3 were identified as antigens of the intraepidermal neutrophilic dermatosis subtype.

The binding of IgA antibodies to the Fc receptor CD89 on cell surfaces triggers a massive inflammatory reaction that leads to neutrophil infiltration of the epidermis, clinically manifested as blister and pustule formation. Although the points of attack of the IgA antibodies have been identified, the exact mechanism leading to the clinical picture of IgA pemphigus is not precisely known.

The connection between an IgA myeloma and IgA pemphigus, a constellation that has been reported several times, is equally unclear (see case report 2).

Mostly occurring in adults (in a review of 137 patients with IgA pemphigus, the average age was 51.5 ± 21.0 years). The disease is rare in children. Women are more frequently affected than men.

Initially, there is a subacute appearance of flaccid pustules on an erythematous base, which quickly break open and form ring-shaped crusts over the plaques, which are often surrounded by a collerette-like scaly border. Patients often describe the plaques as painful and pruritic. The lesions most commonly occur in the intertriginous areas such as the armpit and groin. However, it is not uncommon for the entire body and trunk to be affected. A key feature that distinguishes IgA pemphigus from other blistering diseases is the lack of mucosal involvement. The symptoms of patients are usually limited to skin symptoms. Systemic symptoms such as fever, malaise, headache, arthralgia and weight loss do not occur.

In a review study of 137 patients, most patients showed 80.8 % vesicles, 75.0 % pustules and 63.6 % circular plaques. Itching occurred in 65.6 % of patients.

The histology of IgA pemphigus is important in order to detect the characteristic feature of the disease, intraepidermal neutrophil infiltration. In blistering, signs of acantholysis are completely absent or only present to a small extent. Depending on the subtype of IgA pemphigus, neutrophil infiltration is localized either in the upper epidermis, the middle epidermis or the lower epidermis. In the upper dermis, a perivascular and interstitial infiltrate of lymphocytes, neutrophils and eosinophils is visible.

Direct immunofluorescence is considered an early screening tool for the diagnosis of IgA pemphigus. Direct immunofluorescence can be used to detect the absence or presence of IgA autoantibodies on epidermal cell surfaces. In addition, direct immunofluorescence can be used to differentiate IgA pemphigus from classical pemphigus by detecting minimal or no acantholysis.
Both subtypes differ in the amount of IgA deposits. In intraepidermal neutrophilic IgA dermatosis (IEN type), IgA deposits are detectable throughout the epidermis. In the SPD type, IgA deposits are only detectable in the upper epithelial layers.

Indirect immunofluorescence is a useful tool for detecting circulating IgA autoantibodies in a patient's serum.

Pustulosis, subcorneal (Sneddon-Wilkinson): The classic subcorneal pustular dermatosis shows a similar clinical morphology. Similar to the subcorneal pustular subtype of IgA pemphigus, the pustular lesions in Sneddon-Wilkinson disease form ring-shaped patterns. The pustules also burst easily and form encrusted plaques. The two diseases even have the same area of distribution, with the groin, trunk and armpits being favored. The mucous membranes remain free. Histological examination of Sneddon-Wilkinson disease shows perivascular infiltration of neutrophils and mild spongiosis. However, in contrast to IgA pemphigus, direct immunofluorescence of Sneddon-Wilkinson syndrome is negative for IgA deposits against adhesion molecules such as desmocollin-1, which are crucial for the diagnosis of the SPD subtype of IgA pemphigus.

Pemphigus foliaceus: Pemphigus foliaceus is a disease characterized by flaccid blisters that usually appear on the trunk and eventually crust over similar to the lesions in IgA pemphigus. Clinical differentiation between IgA pemphigus and pemphigus foliaceus is almost impossible. Therefore, immunofluorescence is the key to diagnosis. Direct immunofluorescence of pemphigus foliaceus shows IgG autoantibodies against desmoglein-1 in contrast to the IgA deposits against desmocollin-1 that occur in IgA pemphigus. Therefore, a correct diagnosis by histology and immunofluorescence is crucial to differentiate between the two diseases.

Dermatitis herpetiformis: formation of small, grouped, very itchy vesicles. Immunohsitology is conclusive.

Dermatosis, IgA-linear: blistering, no pustules. Mostly infestation of the face (especially perioral and ears) and/or the capillitium. On the trunk, here without particular predilection sites, possibly with emphasis on the sacral region, the groin and anogenital region. This (classic large-bubble form) cannot be distinguished from a bullous pemphigoid by its distribution pattern.

Erythema anulare centrifugum-like psoriasis: Rare, mild special form of pustular generalized psoriasis (Zumbusch type) with the formation of characteristic, anular and confluent garland-shaped (circulatory) skin patterns. In erythema anulare centrifugum-like psoriasis (EACP), the immunofluorescence phenomena are absent.

Impetigo contagiosa: Mostly children, usually beginning after minor trauma with red 0.5-3.0 cm itchy red patches. Later on, flaccid but also tense vesicles and blisters with clear contents. Subsequently rapid transformation into thin-walled, smaller and larger, also confluent pustules. After the pustules burst, there is a strong exudation of purulent serous tissue fluid, which finally dries up with the formation of typical honey-yellow to brownish barky crusts

Due to the inflammatory nature of the disease, the main agents used to treat IgA pemphigus are oral and topical corticosteroids with a recommended daily dose of 0.5 to 1 mg/kg. However, in contrast to IgG pemphigus, IgA pemphigus often cannot be controlled with steroids alone.

Many studies have shown that the additional administration of dapsone is superior to the administration of steroids alone. The main effect of dapsone in the treatment of IgA pemphigus is thought to be related to the suppression of neutrophil infiltration that occurs in this disease. During long-term treatment with dapsone, attention should be paid to possible adverse effects, including hemolysis and methemoglobinemia.

Other drugs that have been shown to be successful in the treatment of IgA pemphigus include colchicine, mycophenolate mofetil and adalimumab. Isotretinoin has been used successfully in IgA pemphigus of the subcorneal pustular dermatosis (SPD) type (Gruss C et al. 2000).

DADPS, possibly in combination with systemic glucocorticoids.

Alternative: Systemic administration of colchicine or sulfapyridine can be used for both pemphigus variants.

Alternative: Mycophenolate mofetil (Cell Cept) at a dose of 2.0 g/day p.o., possibly in combination with prednisolone (initial 100 mg/day i.v.; maintenance dose < 10 mg/day).

Alternatively: adalimumab. Adalimumab, a recombinant human immunoglobulin antibody, is considered therapeutically effective due to its inhibition of tumor necrosis factor (TNF-alpha). TNF-alpha is involved in the activation of neutrophil infiltration of the epidermis, so it is assumed that its inhibition prevents the further progression of IgA pemphigus.

Individual reports on the use of cyclophosphamide and plasmapheresis in SPD type (with monoclonal gammopathy) are available.

In contrast to classic pemphigus, IgA pemphigus has a milder and more limited course. With appropriate treatment and aftercare, IgA pemphigus usually heals without scarring. Studies have shown that if oral prednisone is stopped abruptly, the lesions recur, so a gradual reduction of the dose and discontinuation is recommended. If IgA pemphigus is associated with other diagnoses (malignancies, monoclonal gammopathy), the prognosis depends on the progression of these associated diseases.

Associated diseases include human immunodeficiency virus (HIV) infection, Sjögren's syndrome, rheumatoid arthritis and Crohn's disease. Although the direct relationship between the various diseases and IgA pemphigus is still unclear, a thorough examination of the hematologic and infectious diseases is recommended in patients with IgA pemphigus.

Case1) Casustic (Neethu KC et al. 2016): a 6-year-old girl with a three-year history had multiple annular to circinate lesions all over the body with central crusting and pus accumulation at the edges. Some pustules and discrete flaccid vesicles with hypopyon formation were also seen on the trunk. The vesicles, which initially contained a clear fluid, filled with pus within 2 days and then expanded in a ring shape before healing with hyperpigmentation after about 10 days. The oral cavity was normal. A Tzanck smear of one vesicle showed polymorphonuclear leukocytes; a bacterial culture of the pus showed no growth after 48 hours. Skin biopsy of a vesicle revealed a subcorneal pustule with neutrophil granulocytes. Direct immunofluorescence microscopy of peri-lesional skin showed intercellular IgA depletion in the upper epidermis; indirect immunofluorescence microscopy using the patient's serum and normal human skin as substrate revealed circulating IgA antibodies at a titer of 1:10 with an intercellular epidermal staining pattern. Enzyme immunoassays for anti-desmoglein-1 and 3 immunoglobulin G were negative. Diagnosis: subcorneal pustular dermatosis of the IgA pemphigus type. In view of the extensive skin lesions, our patient was put on a stepwise administration of oral steroids (prednisolone 30 mg/day) together with dapsone (25 mg/day), which resulted in a good improvement.

Case 2) Koga H et al. (2023) In a 35-year-old Japanese woman with a 3-year history of pruritic papulovesicles on the lower legs and trunk, histopathologic examination revealed acantholytic blistering. Direct and indirect immunofluorescence were negative. Approximately 7 years after her first visit, the patient underwent another histopathologic examination due to an exacerbation of the disease. The findings now showed subcorneal blistering with acantholysis and heavy neutrophil infiltration. Indirect immunofluorescence was positive for IgA in the upper epidermal cell layers. Furthermore, both the desmoglein (Dsg) 1/3 and the (Dsc) desmocollin 1-3 enzyme-linked immunosorbent assay (ELISA) for IgA were positive. The histologic findings and the positive Dsc1-IgA ELISA led to the diagnosis of subcorneal pustular dermatosis (SPD) of the IgA pemphigus type.

Further examinations revealed hyper-IgA globulinemia, elevated IgA-κ protein in the serum and increased plasma cells in the bone marrow with a diagnosis of IgA-type multiple myeloma. Treatment with daratumumab, lenalidomide and dexamethasone (DLd) was effective for both MM and skin lesions. The Dsg1/3 and Dsc1-3 IgA ELISAs were negative.

Note: The association between IgA pemphigus and IgA-type multiple myeloma remains unclear, and only seven cases including the present case have been reported to date.

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