Pemphigus

Pemphigus refers to a group of rare, potentially lethal acantholytic autoimmune diseases affecting skin and mucous membranes. Loss of cell-to-cell adhesion and acantholysis causes bullae and erosions. Since the discovery of the autoantibodies of pemphigus, the advancements in the understanding of distinct clinical features and pathophysiology of this disease have aided in identifying multiple subtypes including pemphigus vulgaris (PV), pemphigus foliaceus (PF), IgA pemphigus, and paraneoplastic pemphigus (PNP). Due to the significant morbidity and mortality associated with this group of autoimmune blistering diseases, an accurate diagnostic work-up is imperative for management.

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Diagnostic Role of Direct Immunofluorescence and Serology

Pathophysiology

  • Intraepithelial blister formation in pemphigus is caused by loss of adhesions between the keratinocytes due to autoantibodies to desmoglein 1 (Dsg1) and desmoglein 3 (Dsg3), the transmembrane glycoproteins associated with desmosomes. 

Clinical Features

  • Pemphigus vulgaris

    • PV is characterized by flaccid blisters and erosions, predominantly in oropharyngeal mucous membranes. Other sites, such as eyes, nose, esophagus, and genital area can be involved. More than 90% patients with PV present with mucous membrane involvement. Skin lesions are seen in muco-cutaneous form of PV. Cutaneous lesions typically include flaccid blisters and crusted erosions on an erythematous base. The lesions are often Nikolsky sign positive. The lesions are excruciatingly painful and can affect any surface. Palms and soles are typically spared in PV.

  • Pemphigus foliaceus

    • Unlike pemphigus vulgaris, pemphigus foliaceus typically does not affect mucosal sites. Patients usually present with multiple pruritic, scaly, and crusted erosions with flaky circumscribed patches. 

Diagnosis

  • Light microscopy

    • This may give the first clue to implicate pemphigus.Confirmatory DIF and serology studies are indicated. Histologic studies reveal intraepidermal or intraepithelial, acantholytic bullae. Particularly in cases that are negative by direct IF, histology may yield key findings. Since acantholysis may also appear in other bullous diseases including Hailey, Darier’s and Grover’s disease (or transient acantholytic dermatosis), serum studies for pemphigus antibodies are indicated for confirmation.

  • Direct immunofluorescence

    • Biopsy studies of perilesional skin or mucosa by direct IF are considered a gold standard for the diagnosis of pemphigus. The sensitivity of DIF for pemphigus ranges from 90%-100% and the specificity and the positive predictive value of this test for pemphigus is 100%. Perilesional biopsies of skin or mucous membranes of pemphigus patients usually reveal IgG, strong IgG4 and frequently focal complement component C3 in the intercellular areas. Selection of sites of biopsies play a key role in detecting the in vivo bound antibodies. Skin biopsies need to include normal skin and a small edge of a lesion, a fresh one if possible. Mucosal biopsies should include only normal areas ~ 5-10 mm (about 0.39 in) from a lesion. Lesional areas often yield negative direct IF reactions since the bound antibodies are degraded primarily in mucosal areas and in old pemphigus skin lesions; the in vivo bound pemphigus antibodies appear only transiently. 

  • Serology

    • Circulating antibodies in pemphigus vulgaris can be detected by two serum tests:

      • Indirect immunofluorescence (IIF) tests (#013, #025) for IgG and IgG4 intercellular antibodies/cell surface antibodies. IIF tests can be done on substrates such as monkey esophagus, guinea pig esophagus epithelium or normal human skin (NHS) (100% sensitive for PF, 75% for PV). Each substrates contains variable quantitates of Dsg1 and Dsg3. ME is more sensitive for PV (100%, PF is 67%) and GP is more sensitive for PF. Sensitivity can be enhanced by using multiple substrates. Overall, the sensitivity of IIF ranges from 70%-95% for the diagnosis of pemphigus. At Beutner Labs, only ME is used for IIF but additional tests can be used for IgG4 antibodies, and Dsg1 and Dsg3 ELISA are used for differentiation between PV and PF.

      • ELISA for Dsg1 and Dsg3 antibodies (test#015, #025) Sensitivity of Dsg1 ELISA for pemphigus foliaceus is reported to be 96.0% and specificity 98.6%.  Sensitivity of Dsg3 ELISA for pemphigus vulgaris is 100% and specificity 99.2%. 

 

Other Forms of Pemphigus

  • Pemphigus vulgaris may also present clinically as pemphigus vegitans. Similarly, pemphigus foliaceus may also present clinically as pemphigus erythematosus or herpetiform pemphigus. Other forms can be distinguished by diagnostic laboratory studies. 

  • IgA pemphigus cases have intercellular IgA deposits as seen in direct IF studies (sensitivity 86%-100%). 10% of cases show concomitant IgA and IgG deposition (Test#001). IgA pemphigus can be differentiated into 2 subtypes based on clinical presentation and immunoreactivity: subcorneal pustular dermatosis (SPD) and intraepidermal neutrophilic dermatosis (IEN). Clinically, IgA pemphigus more closely resembles pemphigus foliaceus (PF) than pemphigus vulgaris (PV). Serum studies are usually negative for IgG Dsg1 and Dsg3 antibodies but IgA autoantibodies to Desmocollin 1-3 can be found in 30-65% cases, mostly in the SPD type.

  • Paraneoplastic pemphigus (PNP) shares some clinical, histologic, direct IF and serologic features of pemphigus vulgaris and has some distinct features; it is characterized by the presence of plakin antibodies. 

Pemphigus Tests:

Selected References

  • Beutner EH, Lever WF, Witebsky E, Jordon RE, Chertock B. Autoantibodies in pemphigus vulgaris. Responses to an intercellular substance of epidermis. J Am Med Assoc 1965;192:682-8.

  • Beutner EH, Jordon RE, Chorzelski TP. The immunopathology of pemphigus and bullous pemphigoid. J Invest Dermatol 1968;51:63-80.

  • Bhol K, Mohomen A, Ahmed R. Correlation of subclasses of IgG with disease activity in pemphigus vulgaris. Dermatol 1994;189:85-89.

  • Kasperkiewicz M, Ellebrecht CT, Takahashi H, Yamagami J, Zillikens D, Payne AS, Amagai M. Pemphigus. Nat Rev Dis Primers. 2017;3:17026. 

  • Harrell J, Rubio XB, Nielson C, Hsu S, Motaparthi K. Advances in the diagnosis of autoimmune bullous dermatoses. Clin Dermatol. 2019;37(6):692-712.

  • Kridin K, Patel PM, Jones VA, Cordova A, Amber KT. IgA pemphigus: A systematic review. J Am Acad Dermatol. 2020;82(6):1386-1392. 

  • Malik AM, Tupchong S, Huang S, Are A, Hsu S, Motaparthi K. An Updated Review of Pemphigus Diseases. Medicina (Kaunas). 2021;57(10):1080.