Overview

Have you heard of rare skin diseases that form bubbles on the skin?

The word pemphigus is derived from the Greek word “pemphix” meaning ‘bubble or blister’.¹ Pemphigus describes a group of chronic blistering skin diseases. The skin has three main layers: the epidermis, dermis, and subcutaneous tissue.  Each layer has a unique structure and function to protect the underlying body structures. Specifically, the epidermis (or topmost layer of skin) is responsible for the protection, sensation, and regulation of one’s body temperature and water loss through the skin.² Pemphigus occurs when the immune system mistakenly attacks healthy epidermal cells. This occurs when normal antibodies attack the cellular structures (glue) that hold the epidermis together.¹

Types of pemphigus

Pemphigus is a potentially lethal condition, and understanding this rare skin disease is critical to ensure that prompt medical care is received in cases of potential or confirmed diagnosis.¹ There are four types of pemphigus including: 

• Pemphigus foliaceus
• Pemphigus vulgaris
• Paraneoplastic pemphigus
• IgA pemphigus

Pemphigus foliaceus and pemphigus vulgaris

Pemphigus foliaceus and pemphigus vulgaris are the most common forms of pemphigus and can be differentiated by their lesions which appear in different body locations. It is important to differentiate pemphigus foliaceus from pemphigus vulgaris because there is a significant difference in their prognosis and treatment. Pemphigus foliaceus responds better to treatment and requires a shorter treatment length.²

Pemphigus foliaceus

This variant is found on the superficial layer of skin and is usually present on the scalp, face, or upper body. Oral lesions are rare and this type of pemphigus includes the uncommon variant known as pemphigus erythematosus.^4,5 

Pemphigus vulgaris

It is the most common pemphigus variant and can be more severe than pemphigus foliaceus This specific type of pemphigus is seen as many blisters and erosions, especially in the mouth. This type of pemphigus includes the uncommon variant pemphigus vegetans.⁴

Pemphigus: who's most at risk?

Pemphigus foliaceus affects people assigned male at birth and people assigned female at birth equally, and the average age at onset is usually 50 to 60 years. However, Pemphigus foliaceus has also been reported in children.⁵ On the other hand, Pemphigus vulgaris is more prevalent among people AFAB and while it can occur at any age, it is usually seen between 40 and 60. It is also more likely to occur in children and the elderly.⁴

The underlying cause of pemphigus foliaceus and vulgaris pemphigus is an autoimmune response. Antibodies mistakenly attack the “glue”, called desmogleins, that holds cells together leading to the formation of blisters. These blisters occur in the outermost layer of skin, called the epidermis. Desmogleins are classified as types 1 and 3 and hold the keratinocytes (skin cells) together. Desmoglein 1 is found in the skin while desmoglein 3 is found in the mucosa of the mouth.⁶

Pemphigus foliaceus occurs in the topmost layer of the epidermis and causes skin blistering. The antibodies attack Desmoglein 1 in pemphigus foliaceus.⁵ Pemphigus vulgaris attacks the cells present in the mouth leading to oral lesions. The antibodies attack Desmoglein 3 in pemphigus vulgaris.⁴ 

It is not clear what causes the autoantibody production. However, there do seem to be some potential factors including:¹

• Genetics
• Environment: ultraviolet radiation, burns, electrical injury, or contact allergens
• Diet
• Viral infections
• Drug-induced

Certain drugs can affect the immune balance and symptoms usually improve once the medication is stopped. Pemphigus foliaceus is seen more commonly in patients receiving penicillamine drugs.

Signs and symptoms

Pemphigus foliaceus

Blisters or erosions

Blisters or erosions are often present and may appear scaly or crusty. Lesions appear most commonly on the trunk, face, and scalp. In mild cases, individuals may only report individual, small, crusted lesions on the face. Erythematous (red) patches are common, and on the scalp, cracked and crusty lesions are seen.⁷

Pain or burning sensation

The crusted lesions may be itchy, painful, or have a burning sensation.⁷

No history of oral or other mucosal lesions⁷

Positive nikolsky’s test as an indicator

Nikolsky's Test is highly specific in diagnosing pemphigus. This is performed by applying lateral pressure to the affected skin. If the topmost layer separates from the lower layers this is a positive sign of pemphigus foliaceus.^5,7 In the variant pemphigus erythematosus, lesions are most likely to appear in areas that have received heavy sun exposure including the face, scalp, upper chest and back. This is similar to lesions seen in lupus erythematosus.⁷

Pemphigus vulgaris

Pemphigus vulgaris is usually identified by the involvement of the oral cavity (mucosa). Mucosal lesions are seen with or without cutaneous (skin) involvement.⁴

Painful mucosal ulceration beginning with ulcers in the mouth

These ulcers are persistent, with individual ulcers that may come and go while new lesions continue to appear. Oral lesions develop first in most cases, and blisters may not be noticed initially because they are fragile and break easily. Painful erosions develop and can be seen in oral mucosa. Erosions appear mostly in the cheek and palatine mucosa, lips, and gums. Gum erosion can eventually lead to more serious dental concerns.

Other mucous membranes of the conjunctiva (mucous membranes of the eye), pharynx, larynx, esophagus, vagina, penis, and anus may be involved.⁴

Cutaneous involvement

Loose blisters form on the skin which break easily and create painful bleeding erosions. These are usually found in the trunk, groin, armpits, scalp, and face. Because these lesions become crusted over, they usually do not heal.⁴ Typically, the scalp lesions crust over and lead to alopecia (hair loss).

Positive nikolsky’s test as an indicator⁴

Malnutrition

Oral lesions can cause pain and make eating difficult. This can lead to malnutrition and dehydration (loss of body fluids). Pemphigus vulgaris can lead to an increased risk for infection because of the loss of barrier function in an extensive area of skin. A lack of proper treatment can lead to death.⁴

Secondary infections

The most common complication of pemphigus vulgaris is a secondary bacterial infection which can progress to septic shock.⁴

Rare manifestations

In severe cases, the nails may also become abnormally thickened and develop crusting or small blood clots under the nail plate. Ulcers may develop on the feet. The tongue may become enlarged and blisters may develop on the palms, soles, fingers, and toes (dyshidrotic eczema).⁴

Differential diagnosis

Pemphigus foliaceus 

These lesions can be easily misdiagnosed as eczema, seborrhoeic dermatitis, actinic keratosis, or psoriasis. If the blisters are broken or there is the presence of a peripheral rim or epidermal peeling, this can denote pemphigus foliaceus.⁵

Other forms of pemphigus include:⁴ IgA pemphigus, drug eruption, subcorneal pustular dermatosis, subacute cutaneous lupus erythematosus, and bullous impetigo. 

Pemphigus vulgaris 

In pemphigus vulgaris, oral erosions may mimic several diseases including:⁴

• aphthous stomatitis (canker sores)
• mouth sores due to infection with herpes 
• systemic lupus erythematosus, 
• pemphigus caused by an underlying cancer 
• allergic skin responses to medication including the more severe Stevens-Johnson syndrome
• lichen planus (an inflammatory condition of the skin and mucous membranes)
• mucous membrane pemphigoid (a rare autoimmune disease causing blistering of numerous mucous membranes)

Cutaneous pemphigus vulgaris can be easily misidentified as the following ⁴: 

• Pemphigus foliaceus
• IgA pemphigus
• bullous pemphigoid (a rare blistering autoimmune disease with blisters between the dermis and epidermis)
• bullous erythema multiforme
• skin lesions caused by Celiac disease or gluten intolerance (dermatitis herpetiformis)
• linear IgA bullous dermatosis (a rare blistering autoimmune disease caused by IgA antibodies being deposited between the dermis and epidermis)

Evaluation

A thorough evaluation is required to exclude other causes of the blistering skin rash. These should include:

• A medication review to determine if the rash is from drug-induced pemphigus foliaceus
• A skin biopsy of a fresh lesion to determine the location of blister formation when compared to the skin structures
• Tests for the presence of autoantibodies such as direct immunofluorescence (in the tissue), indirect immunofluorescence (in the blood), and enzyme-linked immunosorbent assay (ELISA) (in the blood)⁵
• Other serological tests including immunoblotting and immunoprecipitation⁴
• Trichoscopy is a useful tool to evaluate scalp pemphigus⁵

Treatment

Treatment should be initiated as early as possible. It is usually a long process and can even last many years. Overall, the goal is to heal the skin, prevent any lasting complications, improve the quality of life, and minimize the use of long-term immunosuppressive drugs.⁸

Treatment is usually given in a specific sequence and includes both steroids and other non-steroid immunosuppressant medications.

Corticosteroids 

Given as one of the first lines of treatment, systemic corticosteroids are the gold standard for pemphigus vulgaris treatment, as they have potent immunosuppressive and anti-inflammatory actions. Prednisone is the most commonly used oral corticosteroid.⁸

Noncorticosteroids

Rituximab may be given if corticosteroids are not the best option for the individual or if prednisone has been used before and now requires a different treatment. This monoclonal antibody has also been shown to be more effective in severe cases or when other treatments have failed. 

In addition to corticosteroids or rituximab, there are two other first-line medications that can be used. These two medications, azathioprine, and mycophenolate mofetil are used as the first choices in steroid-sparing treatment. 

There are other available medications but they are not used as frequently because treatment is more intense and they have significant side effects. These medications include cyclophosphamide, dapsone, methotrexate, cyclosporine, intravenous human immunoglobulin (IVIG), and anti-tumour necrosis factor alpha drugs.^4,5,8 

Other treatments

There are two other treatments that can be used to reduce the symptoms of pemphigus. Specifically for pemphigus vulgaris, plasmapheresis is used to remove autoantibodies from the bloodstream to reduce their attack on normal, healthy tissues.⁴ However, when the autoantibodies are removed, the body produces even more so this treatment is best combined with steroids or other immunosuppressive medications.

Topical creams can be applied to reduce and prevent skin infections. These are always given with other steroids or immunosuppressive medications. They include:

• Tacrolimus
• Triamcinolone acetonide
• Potassium permanganate
• Chlorhexidine^4,8

Supportive treatment

Supportive treatment can help reduce the physical side effects of treatment, in addition to the physical symptoms of pemphigus. These treatments can include good dental hygiene, special attention to skincare (including antiseptic baths), covering lesions to facilitate better healing, and using topical treatments for pain management of the lesions.⁸ In the case of pemphigus vulgaris with oral sores, nutritionists can help form a nutrition plan to ensure comfort while eating and still provide excellent nutrition for healing.⁸

Pemphigus requires a lengthy treatment course and can affect an individual’s perception of themself and their overall quality of life. Depression and suicidal thoughts are a potential concern. To help alleviate, or even prevent, serious mental health concerns, those with pemphigus should have adequate support from a general practitioner or even one who specialises in psychiatry.⁹

Summary

To summarise, pemphigus vulgaris and pemphigus foliaceus are two potentially fatal chronic blistering skin diseases. Pemphigus occurs when the immune system mistakenly attacks healthy cells though the exact cause for this autoimmune response is unknown. Pemphigus foliaceus is typically seen on the skin whereas pemphigus vulgaris is usually identified in the mouth as oral blisters.  To obtain the best results, treatment should be started as early as possible and individuals should be supported both physically and mentally through the lengthy treatment.