Pemphigus: causes, symptoms, diagnosis and treatment

By Cristiano Antonino On Aug 17, 2023

Pemphigus is an autoimmune bullous dermatosis of the skin and mucous membranes characterised by disruption of the cell adhesion mechanisms of the epidermis, particularly the desmosomes

It appears following an autoimmune reaction mainly involving a particular group of antibodies called IgG4 and IgA in some rarer forms.

The disease has a chronic course and can be potentially fatal if not treated properly.

What is pemphigus?

The term pemphigus comes from the Greek and literally means ‘pustule’ and identifies a group of bullous dermatoses.

This rare skin disease is characterised by acantholysis, i.e. the loss of intracellular adhesion resulting in the appearance of painful lesions (vesicles) on the skin and mucous membranes.

The onset of the disease generally occurs in individuals between 50 and 60 years of age or in the elderly, although cases of onset have also been reported in children.

The onset of the disease is characterised by the appearance of flaccid boils that have a tendency to rupture easily and cause painful lesions and erosions.

In most cases the blisters initially appear in the mucous membranes, but may also affect the face, scalp, chest, axillary cavities, groin, oesophagus, rectum, nose and/or eyelids.

The distinctive clinical findings of pemphigus, reflecting the lack of epidermal cohesion, are

Nikolsky’s sign: by pressing or rubbing the healthy skin near a blister with a finger, a characteristic dislocation of the epidermis occurs.
The Asboe-Hansen sign: through gentle pressure on intact blisters, the fluid extends under the adjacent skin.

It appears that the disease predominantly affects patients belonging to the Mediterranean ethnic group, particularly Ashkenazi Jews.

Causes

Pemphigus is mainly due to altered cell adhesion mechanisms in the epidermis. Specifically, the disease is triggered by the presence of specific autoantibodies (IgG or IgA) that attack a component of the desmosomes, damaging these structures that are responsible for the binding of adjacent epidermal cells.

These abnormal antibodies react with particular glycoproteins present on the desmosomes: the desmogleins.

By attacking these components, the autoantibodies induce the release of plasminogen, which consequently destroys the intercellular bridges and lyses the cells of the epidermal layer, triggering the phenomenon called acantholysis.

As a result of this process, osmotic diffusion of the transudative fluid is attracted, thus forming the characteristic swelling beneath the outer skin layer, i.e. the blister.

Types of pemphigus

Several clinical forms of this disease have been identified, varying in severity, the location of the vesicles in the different layers of the epidermis, and the type of desmoglein affected by the antibodies.

The main forms of pemphigus are:

Pemphigus vulgaris
Pemphigus vegetans
Pemphigus foliaceus

There are also some particular forms of pemphigus, recently clinically framed

IgA pemphigus
Paraneoplastic pemphigus
Drug-induced pemphigus
Pemphigus herpetiformis
Pemphigus vulgaris
Pemphigus vulgaris is among the most common clinical forms of this disease.

In this case the autoantibody acting on desmoglein causes acantholysis at a low level of the epidermis, resulting in the formation of blisters on mucous membranes and skin.

The onset of the disease initially involves the mucous membranes of the oral cavity and surrounding regions, with the appearance of blisters that are often mistaken for simple aphthae.

As time passes, the disease tends to worsen, with the appearance of lesions on the skin as well, which can be similar to those that appear following second-degree burns.

The boils tend to rupture and heal with difficulty, making the patient susceptible to infection.

The lesions appear

Flaccid and extremely fragile
Varying in size from one to several centimetres
Cold
With clear contents

Timely and correct diagnosis and subsequent treatment are very important as the course of the disease is subacute and chronic, which can have fatal consequences.

Pemphigus vegetans

Pemphigus vegetans is a hypertrophic variant of pemphigus vulgaris, of which it represents an evolution.

Although presenting with a similar clinical picture to pemphigus vulgaris, pemphigus vegetans has a better prognosis.

Lesions initially present as

Soft to the touch
Red in colour
Secreting liquid with a foul odour (moist vegetations)

Later, rupture of these vesicles causes erosive plaques to form.

This form of pemphigus is almost always localised in the large folds such as the axillary or groin area and is characterised by the presence of superinfections, very often fungal.

The course of the disease is longer than that of the vulgar version but also more benign as it localises in limited skin regions.

Pemphigus foliaceus

Pemphigus foliaceus does not affect the mucous membranes, but presents cutaneous damage to the more superficial layers of the epidermis.

The disease is characterised by flaccid bullae that generally form on the scalp and gradually spread to the chest, back and face.

If left untreated, these bullae tend to spread all over the body, rupture very easily and give rise to erosive lesions and thin scaly crusts.

Unlike pemphigus vulgaris, in pemphigus foliaceus most lesions are itchy.

In addition, the bullae continue to scab and reform, giving the skin an exfoliative appearance that may be misleading.

In fact, the disease is often misdiagnosed and confused with dermatitis or eczema.

IgA pemphigus

IgA pemphigus is among the less harmful forms of pemphigus and is also among the rarer forms.

Again, the disease is characterised by flaccid intraepidermal bullae with an arciform arrangement, generally located on the trunk and near the limbs.

The course of the disease is fairly benign, although it tends to recur.

IgA pemphigus is further subdivided into subcorneal pustular dermatosis and neutrophilic intraepidermal dermatosis, which, although clinically similar, have different antigenic targets.

Paraneoplastic pemphigus

Disease associated with the presence of a neoplasm, often malignant in form.

It is therefore a complication of certain forms of cancer, especially carcinomas, lymphomas and sarcomas.

It may result from the tumour’s production of particular antigens and general depression of the immune system.

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The disease manifests itself with large areas of discolouration of the skin and mucous membranes.

It often results in severe ulcers in the mouth and lip area, often severely involving the lungs.

The conditions associated with paraneoplastic pemphigus may improve following treatment aimed at curing the tumour lesion, but the associated damage to the lungs is generally irreversible.

Drug-induced pemphigus

Pemphigus may sometimes develop as a side effect of the use of certain drugs such as ACE inhibitors or substances such as penicillin.

Clinically, this form of pemphigus resembles autoimmune pemphigus. However, the disease tends to resolve spontaneously and without any treatment following the causative factor, i.e. after discontinuation of the drug that induces the disease.

Pemphigus herpetiformis

This type of pemphigus is characterised by the appearance of lesions intermediate between vesicles and bullae that tend to develop in peripheral areas with centrifugal extension.

The course of the disease tends to be benign, but it is not excluded that it may evolve into more severe forms such as pemphigus vulgaris or foliaceus.

Diagnosis

As pemphigus is a rare disease, it is not always immediate to diagnose, as the presence of lesions is not sufficient to define the disease with certainty.

In order to correctly diagnose pemphigus, an objective test to demonstrate the two signs mentioned above – the Nikolsky sign and the Asboe-Hansen sign – plays an important role.

However, today’s diagnosis is based on skin biopsy of areas of injured skin and surrounding (perilesional) skin.

In addition, immunofluorescence techniques on patients’ serum or skin are used in the diagnosis, which serve to highlight the presence of autoantibodies directed against the desmogleins of keratinocyte membranes.

It is also not uncommon for the doctor to prescribe further in-depth analyses such as blood tests.

Treatment

As already mentioned, pemphigus is generally associated with a fairly severe prognosis, being a type of disease that reacts unpredictably to treatment.

If treated promptly and correctly, the condition allows survival and, in some cases, cure.

The aim of treatment is to reduce the clinical signs and symptoms of the disease and prevent complications.

Treatments include local measures, drugs and, in severe cases, hospitalisation and protective isolation as open wounds make the patient vulnerable to infection that could prove fatal.

Medications used for treatment include:

Oral corticosteroids
Immunosuppressants
Antibiotics, antivirals and antifungal drugs

The doctor, in more persistent cases of pemphigus, may propose some alternative treatments such as:

Periodic plasmapheresis, which consists of removing the IgG characteristic of the disease from the plasma through specific separation techniques.
Biological therapy with Rituximab, which involves the administration of a monoclonal antibody recently introduced in the treatment of pemphigus.
IVIg, i.e. the introduction of immunoglobulins intravenously.

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