Pemphigus

Pemphigus is a group of rare, autoimmune blistering disorders that are characterised by intraepidermal blisters and erosions on the skin and/or mucosa. It occurs due to Ig-G mediated attack against desmogleins.

There are multiple subtypes of pemphigus which we will discuss in this condition:

• Pemphigus vulgaris (PV) - this is the most commmon subtype, accounting for 70%-80% of cases.
• Pemphigus foliaceus (PF) - it accounts for 10% of cases. The lesions occur on the skin only (not on mucosal surfaces). It is associated with antibodies to desmoglein 1.
• Paraneoplastic pemphigus - linked to underlying malignancies (it may be a marker for unknown malignancies).
• Pemphigus herpetiformis - shares clinical features of dermatitis herpetiformis and immunological features of pemphigus.
• IgA pemphigus or IgG/IgA pemphigus -  IgG/IgA pemphigus is described as an overlap of PV or PF with IgA pemphigus (pemphigus mediated by IgA as opposed to IgG).

Pathophysiology

Desmogleins are a form of desmosome proteins. Desmosomes are specialised structures that facilitate cell-to-cell adhesion in epithelial tissues. They are vital for maintaining the structural integrity of the epidermis. The main ones to be concerned with, especially in the context of pemphigus, includes desmoglein 1 (DSG1) and desmoglein 3 (DSG3). DSG1 is predominantly found in the superficial layers of the epidermis while DSG3 is predominantly in the deeper layers above the stratum basale.

The aetiology of pemphigus involves immunological, environmental and genetic factors.

Genetic predisposition is seen in individuals with:

• HLA-DR4 - especially in Askenazi Jews, it predisposes to PV.
• HLA-DQ1 - predisposes to PV.

Environmental triggers include:

• Drugs - such as penicillamine, penicillin, ACE inhibitors, nifedipine, rifampicin.
• Infections

Now let’s take a look at the different subtypes in more detail:

• Pemphigus vulgaris

Primarily caused by autoantibodies to DSG3 and sometimes both DSG1 and DSG3. It disrupts the adhesive function of desmogleins and results in acantholysis (loss of cohesion between keratinocytes). This leads to intraepidermal blisters. It involves both the skin and mucous membranes (mouth, nose, throat and genitalia).

• Pemphigus foliaceus

Primarily caused by antibodies to DSG1 which is mainly located in the superficial layers of the epidermis. This results in crusted, scaly lesions similar to eczema or seborrheic dermatitis. It does not involve the mucous membranes (typically).

• Paraneoplastic pemphigus

Associated with underlying malignancies (most commonly lymphproliferative disorders such as Non-Hodgkin lymphoma, chronic lymphocytic leukemia and Castleman’s disease). The pathogenesis not only involves antibodies to desmogleins but also to other desmosomal proteins such as envoplakin and periplakin. It involves both the mucous membranes and skin. It has a high morbidity and mortality rate due to malignancy association and potential respiratory involvement.

• Pemphigus herpetiformis

A rare variant with features of pemphigus and dermatitis herpetiformis. Once again antibodies are formed against DSG1 and DSG3 but it presents with erythematous plaques and vesicles in a herpetiform pattern.

• IgA pemphigus

Another rare form that is characterised by IgA autoantibodies against desmosomal proteins which distinguishes it from other types of pemphigus (which primarily involve IgG antibodies).

⚠️ Risk factors

• Increasing age - most patients who develop PV are >40 years old.
• HLA-DR3, HLA-DQ1 - increase risk of PV.
• Malignancy - especially lymphoproliferative disorders.
• Drugs - such as penicillamine, penicillin, ACE inhibitors, nifedipine, rifampicin.
• Burns
• Stress
• Pregnancy
• UV light

😷 Presentation

Pemphigus vulgaris

This is the most common variant.

1. It often begins with oral mucosal lesions (in the buccal and/or gingival regions) that are painful and persisting.
2. Skin involvement presents with flaccid blisters (blisters which are not firm and rupture easily) that contain clear fluid. They then form postbullous erosions.
3. The lesions may be localised or generalised. They predominate on the chest, face, scalp and back (interscapular region).
4. Presence of autoantibodies to DSG3 as well as DSG1 (although to a lesser extent).

Pemphigus foliaceus

This variant has no mucosal involvement.

1. It presents with flaccid blisters that begin on the trunk. Postbullous erosions form subsequently.
2. Lesions are often scaly, crusty and have a red, inflamed base.
3. The lesions first form on the trunk and they are mainly found on the abdomen, back, face and scalp.
4. Presence of autoantibodies to DSG1.

Paraneoplastic pemphigus

This is a form of pemphigus that presents with concomitant malignancy. The malignancies are often lymphoproliferative disorders. It may also be an indicator of an undiagnosed underlying malignancy.

It does include mucosal involvment. This may include oral, ocular, genital, pharyngeal and respiratory involvement.

🚨 Pulmonary involvement is a life-threatening complication.

Pemphigus herpetiformis

It combines clinical features of dermatitis herpetiformis and immunopathologic features of pemphigus.

🔍 Investigations

• 🏆 Skin biopsy the biopsy should include both blistered/eroded skin as well as adjacent, intact epidermis.
• Skin biopsy with haemotoxylin and eosin stain - shows structural details and identifies acantholysis and the level of blister formation.
• Pemphigus vulgaris - basal cells lose adhesions to superior, adjoining keratinocytes (suprabasal acantholysis) while maintaining adhesion to the basement membrane (giving a tombstone appearance).
• Pemphigus foliaceus - intraepidermal blistering with acantholysis in the upper eidermis (primarily in the stratum granulosum).
• Paraneoplastic pemphigus - suprabasal and subepidermal acantholysis and necrosis.
• Pemphigus herpetiformis - eosinophilic spongiosis (presence of eosinophils in the intercellular spaces of the epidermis accompanied by oedema (spongiosis)) and mild acantholysis with vesicular formation.
• IgA pemphigus - intraepidermal blistering with acantholysis (mainly differentiated on immunofluorescence).
• ⭐️ Skin biopsy with direct immunofluorescence - detects specific autoantibodies in the skin and helps distinguish between subtypes.
• Pemphigus vulgaris - IgG and C3 deposits in characteristic fishnet pattern (reticular pattern) in the suprabasal regions.
• Pemphigus foliaceus - IgG and C3 deposits in the upper epidermis (primarily in the stratum granulosum) in the same fishnet pattern.
• Paraneoplastic pemphigus - IgG and C3 deposits in characteristic fishnet pattern (reticular pattern) in the suprabasal regions as well as antibodies against plakin proteins.
• Pemphigus herpetiformis - IgG deposition similar to other pemphigus variants.
• IgA pemphigus - IgA deposits in intercellular spaces of the epidermis.

🧰 Management