IgG/IgA-PemphigusL10.0

Since the first descriptions by Wallach et al. in 1982, the spectrum of IgA pemphigus has continued to expand. The classic IgG pemphigus types, pemphigus vulgaris (PV) and pemphigus foliaceus (PF) react autoimmunologically with desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1) respectively. This spectrum has been extended by cases with IgA anti-CS antibodies, which are referred to as IgA pemphigus (Nishikawa T et al. 1987). An alternative diagnosis is intercellular IgA dermatosis (IAD) (Nishikawa T et al. 1987; Hashimoto T et al. 2017).

IgG/IgA pemphigus is an extremely rare (<50 casuistic reports are available) blister- or pustule-forming autoimmune disease with <50 cases reported to date. It is characterized by in vivo bound and/or circulating anti-keratinocyte CS antibodies of both the IgG and IgA class (Hashimoto T et al. 2016). Due to the rarity of the disease, no systematic studies are available to date. The disease entity of this disease has also not yet been clarified.

In a larger cross-sectional study (n= 36 cases of IgG/IgA pemphigus/Hashimoto T et al. 2018), 18 Japanese, 6 Europeans, 3 US-Americans, 2 Indians and 1 Australian were represented. m:w=1:1;

The following molecular mechanisms are being discussed: the simultaneous production of IgG and IgA class autoantibodies against various keratinocyte antigens. Furthermore, a "class switch recombination/ CSR" is conceivable. This occurs through a genomic rearrangement within the locus of the constant region of the immunoglobulin heavy chain, where the gene segments of all immunoglobulin classes are arranged in tandem downstream of the locus of the variable VDJ region (Stavnezer J et al. 2008; Hashimoto T et al. 2018). The high rates of simultaneous detection of IgG and IgA anti-Dsg3 antibodies in the same sera could indicate that IgG-producing B cells convert to IgA-producing B cells. It is conceivable that the predominance of the IgG1 class in human serum indicates that the autoantibody switches from IgG1 to IgA1.

It is still unclear whether IgG/IgA pemphigus is an intermediate form of pemphigus, a characteristic pemphigus variant caused by inflammation-induced epitope spreading, or a new entity resulting from an antibody class change in an altered immunological milieu.

The average age is 55.6 years. The time between the onset of the disease and the consultation is between 2 weeks and 10 years (average 18 months).

The trunk and extremities are preferentially affected, less frequently the intertriginous areas, capillitium and face. Lesions of the oral mucosa are found in around 50% of cases. Lesions of the ocular conjunctiva can occur rarely, as can lesions of the genital, nasal and oesophageal mucosa.

Clinically, the majority of cases present with erythema, sometimes also anularly configured with vesicles, bulging blisters and, more rarely, flaccid blisters. Around 30% of patients show pustular formations, another 30% erosions. Further clinical manifestations are crusting and pigmentation.

Intraepidermal blistering in the upper or middle epidermis is usually detectable, and in around 50% of cases intraepidermal pustules in the upper, middle or lower epidermis. Spongiosis and acantholysis are occasionally observed. The infiltrates consist of neutrophils, eosinophils and lymphocytes.

Intraepithelial IgG, IgA and C3 deposits on keratinocytes are detectable. IgG deposits can be found in the upper epidermis, but also in the lower epidermis or in the entire epidermis. IgA deposits are found in the upper epidermis, but also in the lower epidermis and in the entire epidermis. IgG, IgA and C3 deposits are occasionally observed in the epidermal BMZ.

In the indirect IF of normal human skin, IgG and IgA antibodies against keratinocytes can regularly be detected. Occasionally, IgG and IgA anti-basement membrane antibodies are also detected. In the case of IgG antibodies, reactivity with Dsg1 and Dsg3 can be detected less frequently with Dsc. Reactivity with Desmoplakin I, BP230 and Envoplakin is occasionally detectable. Reactivities against Dsg3 and desmocollin are found with IgA antibodies.

ELISAs: In a larger study (n=30), commercially available IgG ELISAs for Dsg1 and Dsg3 showed IgG reactivity with Dsg1 in 63.6 %, IgG reactivity with Dsg3 in 46.7 %, IgA reactivity with Dsg1 in 63.3 % and IgA reactivity with Dsg3 in 43.3 %. The association between the detection of IgG and IgA antibodies against the same Dsgs is very high. Around 95% of cases with IgG antibodies against Dsg1 also showed IgA antibodies against Dsg1 at the same time. Around 80% of cases with IgG anti-Dsg3 antibodies also had IgA anti-Dsg3 antibodies at the same time. In contrast, the coexistence of IgG and IgA antibodies against Dsc1-Dsc3 is only around 50% (Hashimoto T et al. 2018).

The most important differential diagnoses include bullous impetigo, subcorneal pustular dermatosis, pemphigus foliaceus, linear IgA bullous dermatosis and paraneoplastic pemphigus.

Oral steroids, dapsone (DDS), minocycline and combinations of these drugs

Cheng HF et al. (2022): A 36-year-old Chinese woman with a history of atopic dermatitis reported the appearance of skin blisters and crusty changes on the scalp for 3 months. They had appeared 1 and 2 months after taking herbal medicines. There were pustular eruptions with perivesicular erythema and pustules on the trunk and in the proximal area of the limbs. The scalp showed pityriasis amiantacea-like lesions. Serology was negative for antiepithelial AK. Histologically, there was subcorneal clefting with marked acantholysis. The inflammatory infiltrates consisted predominantly of neutrophils and scattered eosinophils. DIF: negative. The disease was treated as subcorneal pustular dermatosis, the main differential diagnosis being a pustular drug eruption. Discontinuation of the herbal medicine and administration of dapsone 50 mg once daily resulted in remission. Dapsone was successfully discontinued months later. Two months after discontinuation of dapsone, the vesicles and pustules reappeared. A repeat skin biopsy revealed similar histopathological findings. The DIF showed granular, intercellular positivity of IgA and IgG in perivesicular skin. The features corresponded to those of IgA pemphigus with an additional IgG immune reaction. Dapsone was resumed at a dose of 25 mg daily. All blisters subsequently regressed.

1. Cetkovska P et al. (2014) Management of a pemphigus with IgA and IgG antibodies and coexistent lung cancer. Dermatol Ther 27:236-239.
2. Cheng HF et al. (2022) IgG/IgA pemphigus with differing regional presentations. JAAD Case Rep 28:119-122.
3. Hashimoto T et al. (2018) Clinical and Immunological Study of 30 Cases With Both IgG and IgA Anti-Keratinocyte Cell Surface Autoantibodies Toward the Definition of Intercellular IgG/IgA Dermatosis. Front Immunol 9:994.
4. Hashimoto T et al. (2017) Clinical and immunological studies of 49 cases of various types of intercellular IgA dermatosis and 13 cases of classical subcorneal pustular dermatosis examined at Kurume University. Br J Dermatol 176:168-175.
5. Hashimoto T et al. (2016) Summary of results of serological tests and diagnoses for 4774 cases of various autoimmune bullous diseases consulted to Kurume University. Br J Dermatol 175:953-965.
6. Hashimoto T et al. (1997) Human desmocollin 1 (Dsc1) is an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus. J Invest Dermatol 109:127-131.
7. Inoue-Nishimoto T et al. (2016) IgG/IgA pemphigus representing pemphigus vegetans caused by low titres of IgG and IgA antibodies to desmoglein 3 and IgA antibodies to desmocollin 3. J Eur Acad Dermatol Venereol 30:1229-1231.
8. Kanwar AJ et al. (2014) IgG/IgA pemphigus reactive with desmoglein 1 with additional undetermined reactivity with epidermal basement membrane zone. Indian J Dermatol Venereol Leprol 80:46-50.
9. Nie Z et al. (1999) IgA antibodies of cicatricial pemphigoid sera specifically react with C-terminus of BP180. J Invest Dermatol 112:254-255.
10. Nishikawa T et al. (1987) Role of IgA intercellular antibodies: report of clinically and immunopathologically atypical cases. Proc XVII World Congr Dermatol:383-384.
11. Stavnezer J et al. (2008) Mechanism and regulation of class switch recombination. Annu Rev Immunol 26:261-92.
12. Uchiyama R et al. (2014) IgA/IgG pemphigus with infiltration of neutrophils and eosinophils in an ulcerative colitis patient. Acta Derm Venereol 94:737-738.