Pemphigus is rare.

Pemphigus vulgaris is the most common form of pemphigus. However, in certain areas, particularly in locations where an endemic form of pemphigus foliaceus occurs, pemphigus foliaceus is more prevalent.

Research is needed.

The intraepidermal blistering observed in pemphigus occurs due to an immune response that results in the deposition of autoantibodies against epidermal cell surface antigens within the epithelium of mucous membranes or skin. The mechanism through which acantholysis occurs is not fully understood.

Similar but different.

Pemphigus vulgaris generally is a more severe than pemphigus foliaceus. Pemphigus vulgaris usually presents with widespread mucocutaneous blisters and erosions. Cutaneous blistering in pemphigus foliaceus tends to occur in a seborrheic distribution. Blistering in pemphigus foliaceus is more superficial compared with pemphigus vulgaris.

Easy to misdiagnose.

The diagnosis of pemphigus is based upon the recognition of consistent clinical, histological, and direct immunofluorescence findings, as well as the detection of circulating autoantibodies against cell surface antigens in serum. Laboratory studies are useful for distinguishing pemphigus from other blistering and erosive diseases.

Pemphigus is defined as a group of life-threatening blistering disorders characterized by acantholysis resulting in the formation of intraepithelial blisters in mucous membranes and skin [1]. Acantholysis is the loss of keratinocyte to keratinocyte adhesion, or the skin cells no longer being held together. Patients with pemphigus develop mucosal erosions and/or flaccid bullae (blisters), erosions, or pustules on skin (small bumps that fill with pus or fluid).

The four major types of the pemphigus include pemphigus vulgaris, pemphigus foliaceus, IgA pemphigus, and paraneoplastic pemphigus. The different forms of pemphigus are distinguished by their clinical features, associated autoantigens, and laboratory findings.

Pemphigus vulgaris

Key features: Mucosal or mucosal and cutaneous involvement, blisters on the upper skin layer, autoantibodies attack desmoglein 3 or both desmoglein 1 and desmoglein 3

Clinical variants: Pemphigus vegetans, pemphigus herpetiformis

Pemphigus foliaceus

Key features: Cutaneous (skin) involvement only, subcorneal acantholytic blisters, autoantibodies against desmoglein 1

Clinical variants: Endemic pemphigus foliaceus (fogo selvagem), pemphigus erythematosus (Senear-Usher syndrome), pemphigus herpetiformis

IgA pemphigus

Key features: Grouped vesicles or pustules and erythematous plaques with crusts, subcorneal or intraepidermal blisters, autoantibodies against desmocollin 1

Subtypes: Subcorneal pustular dermatosis-type IgA pemphigus (Sneddon-Wilkinson disease), intraepidermal neutrophilic IgA dermatosis

Paraneoplastic pemphigus

Key features: Extensive, intractable stomatitis and variable cutaneous findings; associated neoplastic disease; suprabasal acantholytic blisters; autoantibodies against desmoplakins or other desmosomal antigens

EPIDEMIOLOGY

Pemphigus vulgaris (the most common form of pemphigus) occurs worldwide and the frequency is influenced by geographic location and ethnicity. Incidence rates are between 0.1 and 2.7 per 100,000 people per year. The higher rates have been documented in certain populations. People of Jewish ancestry, particularly Ashkenazi Jews, and inhabitants of India, Southeast Europe, and the Middle East have the greatest risk for pemphigus vulgaris.

In certain locations, such as North Africa, Turkey, and South America, the prevalence of pemphigus foliaceus exceeds pemphigus vulgaris [2]. 

Pemphigus usually occurs in adults, with an average age of onset between 40 to 60 years of age for pemphigus vulgaris and nonendemic pemphigus foliaceus [3,4]. Pemphigus is rare in children, with the exception of endemic pemphigus foliaceus, which affects children and young adults in endemic areas [5]. Neonatal pemphigus is a rare transient form of pemphigus that occurs as a consequence of placental transmission of autoantibodies to the fetus from a mother with the disease.

A few studies have found large imbalances in the sex distribution, such as a study that found a 4:1 ratio of females to males with pemphigus foliaceus in Tunisia [6] and a study that found a 19:1 ratio of males to females in an endemic location in Columbia [7].

Epidemiological information on IgA pemphigus is sparse. The disorder may occur at any age and may be slightly more common in females [8]. Paraneoplastic pemphigus is extremely rare and is more common in middle-aged adults, but may occur in children.

PATHOGENESIS

The molecular mechanisms where the binding of autoantibodies to epithelial cells leads to acantholysis are still intensively debated. Several mechanisms for antibody-mediated acantholysis have been proposed, including the induction of signal transduction events that trigger cell separation and the inhibition of adhesive molecule function through steric hindrance [9,10,11]. In particular, the theory of apoptolysis suggests that acantholysis results from autoantibody-mediated induction of cellular signals that trigger enzymatic cascades that lead to structural collapse of cells and cellular shrinkage [12].

Autoantibodies against a variety of epithelial cell surface antigens have been identified in patients with pemphigus.

Desmogleins are the antigens that have been most extensively studied in pemphigus vulgaris and pemphigus foliaceus. Desmogleins are components of desmosomes, integral structures for cell-to-cell adhesion.

As with many other autoimmune diseases, the precipitating factors of pemphigus diseases are poorly understood. Both genetic and environmental factors may influence the development of pemphigus [2].

Ultraviolet radiation has been proposed as an exacerbating factor for pemphigus foliaceus and pemphigus vulgaris [14-16], and pemphigus has been reported to develop following burns or cutaneous electrical injury [17]. Viral infections, certain food compounds, ionizing radiation, and pesticides have been suggested as additional stimuli for this disease [18-23].

Almost all patients with pemphigus vulgaris develop mucosal involvement. The oral cavity is the most common site of mucosal lesions and often represents the initial site of disease [30]. Mucous membranes at other sites are also often affected, including the conjunctiva, nose, esophagus, vulva, vagina, cervix, and anus [31,32]. In women with cervical involvement, the histological findings of pemphigus vulgaris may be mistaken for cervical dysplasia in Papanicolaou (Pap) smears [33].

Since mucosal blisters erode quickly, erosions are often the only clinical findings. The buccal mucosa and palatine mucosa are the most common sites for lesion development in the oral cavity [34].

Most patients also develop cutaneous involvement manifesting as flaccid blisters on normal-appearing or erythematous skin. The blisters rupture easily, resulting in painful erosions that bleed easily. Pruritus usually is absent. Although any cutaneous site may be affected, the palms and soles are usually spared. The Nikolsky sign (induction of blistering via mechanical pressure at the edge of a blister or on normal skin) often can be elicited [12].

The pain associated with mucosal involvement of pemphigus vulgaris can be severe.

Oral pain is often augmented by chewing and swallowing, which may result in poor alimentation, weight loss, and malnutrition.

Pemphigus foliaceus is a superficial variant of pemphigus that presents with cutaneous lesions. The mucous membranes are typically spared [1].

Pemphigus foliaceus usually develops in a seborrheic distribution. The scalp, face, and trunk are common sites of involvement. The skin lesions usually consist of small, scattered superficial blisters that rapidly evolve into scaly, crusted erosions. The Nikolsky sign often is present [5]. The skin lesions may remain localized or may coalesce to cover large areas of skin. Occasionally, pemphigus foliaceus progresses to involve the entire skin surface as an exfoliative erythroderma [4].

Pain or burning sensations frequently accompany the cutaneous lesions. Systemic symptoms are usually absent.

The clinical manifestations of drug-induced pemphigus foliaceus are similar to idiopathic disease.

Both the subcorneal pustular dermatosis and intraepidermal neutrophilic IgA dermatosis types of IgA pemphigus are characterized by the subacute development of vesicles that evolve into pustules [8]. The vesicles and pustules are usually, but not always, accompanied by erythematous plaques. A herpetiform, annular, or circinate pattern may be present [8,29].

The trunk and proximal extremities are common sites for involvement. The scalp, postauricular skin, and intertriginous areas are less common sites for lesion development [8,35]. Pruritus may or may not be present. Mucous membranes are usually spared.

The subcorneal pustular dermatosis type of IgA pemphigus is clinically similar to classic subcorneal pustular dermatosis (Sneddon-Wilkinson disease).

Immunofluorescence studies are necessary to distinguish these diseases.

Paraneoplastic pemphigus (also known as paraneoplastic autoimmune multiorgan syndrome) is an autoimmune multi-organ syndrome associated with neoplastic disease [36]. Typically, patients suffer from severe and acute mucosal involvement with extensive, intractable stomatitis. The cutaneous manifestations are variable, and include blisters, erosions, and lichenoid lesions that may resemble other autoimmune blistering diseases, erythema multiforme, graft versus host disease, or lichen planus

Life-threatening pulmonary involvement consistent with bronchiolitis obliterans also may be seen [100].

Paraneoplastic pemphigus is the rarest form of the pemphigus types.

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