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. 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 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.
The four major types of 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 generally is 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.
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.
Types of pemphigus
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
- 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 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.
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. Mucous membranes at other sites are also often affected, including the conjunctiva, nose, esophagus, vulva, vagina, cervix, and anus. In women with cervical involvement, the histological findings of pemphigus vulgaris may be mistaken for cervical dysplasia in Papanicolaou (Pap) smears.
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.
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.
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
- 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.
Pemphigus foliaceus is a superficial variant of pemphigus that presents with cutaneous lesions. The mucous membranes are typically spared.
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. 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.
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
- 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.
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. The vesicles and pustules are usually, but not always, accompanied by erythematous plaques. A herpetiform, annular, or circinate pattern may be present.
The trunk and proximal extremities are common sites for involvement. The scalp, postauricular skin, and intertriginous areas are less common sites for lesion development. Pruritus may or may not be present. Mucous membranes are usually spared.
Key features: Extensive, intractable stomatitis and variable cutaneous findings; associated neoplastic disease; suprabasal acantholytic blisters; autoantibodies against desmoplakins or other desmosomal antigens
- Life-threatening pulmonary involvement consistent with bronchiolitis obliterans also may be seen.
- Paraneoplastic pemphigus is the rarest form of the pemphigus types.
Paraneoplastic pemphigus (also known as paraneoplastic autoimmune multiorgan syndrome) is an autoimmune multi-organ syndrome associated with neoplastic disease. 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.
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.
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. Pemphigus is rare in children, with the exception of endemic pemphigus foliaceus, which affects children and young adults in endemic areas. 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 and a study that found a 19:1 ratio of males to females in an endemic location in Columbia.
Epidemiological information on IgA pemphigus is sparse. The disorder may occur at any age and may be slightly more common in females. Paraneoplastic pemphigus is extremely rare and is more common in middle-aged adults, but may occur in children.
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. 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.
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.
Ultraviolet radiation has been proposed as an exacerbating factor for pemphigus foliaceus and pemphigus vulgaris, and pemphigus has been reported to develop following burns or cutaneous electrical injury. Viral infections, certain food compounds, ionizing radiation, and pesticides have been suggested as additional stimuli for this disease.
Pemphigoid is a group of subepidermal, blistering autoimmune diseases that primarily affect the skin, especially the lower abdomen, groin, and flexor surfaces of the extremities. Here, autoantibodies (anti-BPA-2 and anti-BPA-1) are directed against the basal layer of the epidermis and mucosa.
The condition tends to persist for months or years with periods of exacerbation and remission. Localized variants of the condition have been reported, most often limited to the lower extremities and usually affecting women.
There are two predominant types of pemphigoid: mucous membrane pemphigoid (MMP) also called cicatricial pemphigoid, and bullous pemphigoid (BP). Pathogenesis and management are quite different for these conditions. Scar formation in mucous membrane pemphigoid can lead to major disability.
Types of pemphigoid
Mucous membrane pemphigoid (MMP) is a chronic autoimmune disorder characterized by blistering lesions that primarily affect the various mucous membranes of the body, but also affects the skin (MMP is now the preferred term for lesions only involving the mucosa). It is also known as Cicatricial Pemphigoid (CP), as it is often scarring.
The mucous membranes of the mouth and eyes are most often affected, but those of the nose, throat, genitalia, and anus may also be affected. The symptoms of MMP vary among affected individuals depending upon the specific site(s) involved and the progression of the disease. Disease onset is usually between 40 and 70 years and oral lesions are seen as the initial manifestation of the disease in about two thirds of the cases. Blistering lesions eventually heal, sometimes with scarring. Progressive scarring may potentially lead to serious complications affecting the eyes and throat.
There is no racial or ethnic predilection although most studies have demonstrated a female to male ratio of approximately 2:1. The diagnosis of MMP is mainly based on history, clinical examination and biopsy of the lesions.
Bullous Pemphigoid (BP) is a subepidermal blistering autoimmune disease that primarily affects the skin, especially the lower abdomen, groin, and flexor surfaces of the extremities. Mucous membrane involvement is seen in 10%-40% of patients. The disease tends to persist for months or years with periods of exacerbation and remission.
The spectrum of presentations is extremely broad, but typically there is an itchy eruption with widespread blistering, and tense vesicles and bulla (blisters), with clear fluid (can be hemorrhagic) on apparently normal or slightly erythematous skin.
Lesions normally appear on the torso and flexures, particularly on the inner thighs. Blisters can range in size from a few millimeters to several centimeters, and although pruritic, typically heal without scarring.
Sometimes erosions and crusting is seen. Also itchy bumps (papules) and crusts (plaques) can be seen with an annular or figurate pattern. A characteristic feature is that multiple bullae usually arise from large (palm-sized or larger), irregular, urticarial plaques. Mucosal (oral, ocular, genital) involvement is also sometimes present, but ocular involvement, is rare. BP can be difficult to diagnose in its ‘non-blistering’ stage, when just itchy, red, elevated patches are visible. Erosions are much less common than in pemphigus, and the Nikolsky sign is negative.
BP is characterized by spontaneous remissions followed by flares in disease activity that can persist for years. Even without therapy, BP is often self-limited, resolving after a period of many months to years, but may become very extensive.
Localized variants of the disease have been reported, most often limited to the lower extremities and usually affecting women. One such variant, localized vulvar pemphigoid, reported in girls aged 6 months to 8 years, presents with recurrent vulvar vesicles and ulcerations that do not result in scarring.
Bullous pemphigoid is distinguished from other blistering skin diseases, such as linear IgA dermatosis, epidermolysis bullosa acquisita, and MMP/cicatricial pemphigoid, by the following clinical items (it can also be distinguished by biopsy and certain immunological tests):
- Absence of atrophic scars;
- Absence of head and neck involvement;
- Relative absence of mucosal involvement.
Pemphigoid gestationis (PG) is a rare autoimmune bullous dermatosis of pregnancy. The disease was originally named herpes gestationis on the basis of the morphological herpetiform feature of the blisters, but this term is a misnomer because PG is not related to or associated with any active or prior herpes virus infection. PG typically manifests during late pregnancy, with an abrupt onset of extremely pruritic urticarial papules and blisters on the abdomen and trunk, but lesions may appear any time during pregnancy, and dramatic flares can occur at or immediately after delivery. PG usually resolves spontaneously within weeks to months after delivery.
- BP is the most frequent blistering disease of the skin (and mucosa) affecting typically the elderly (>65 years), but can occur at any age and in any race.
- Overall incidence: ± 7-10 new cases per million inhabitants per year.
- After the age of 70 incidence significantly increases.
- Relative risk for patients > 90 y have a 300-fold higher than those < 60.
- Women and men equally afflicted.
- Precipitating factors include trauma, burns, ionizing radiation, ultraviolet light, and certain drugs such as neuroleptics and diuretics, particularly lasix (furosemide), thiazides, and aldosterone antagonists.
- Correlations between BP flare activity and recurrence of underlying cancer suggest such an association in some patients.
- Even without therapy, BP can be self-limited, resolving after a period of many months to years, but is still a serious condition especially in the elderly.
- 1-y survival probability may be as high as 88.96% (standard error 5.21%), with a 95% confidence interval (75.6%, 94.2%) but other analyses have documented 1 year mortalities of as much as 25-30% in moderate to severe pemphigus even on therapy.
Genetics: Genetic predisposition, but not hereditary
- Is a condition of pregnancy (childbearing age women).
- In the United States, PG has an estimated prevalence of 1 case in 50,000-60,000 pregnancies.
- No increase in fetal or maternal mortality has been demonstrated, although a greater prevalence of premature and small-for-gestational-age (SGA) babies is associated with PG.
- Patients with PG have a higher relative prevalence of other autoimmune diseases, including Hashimoto thyroiditis, Graves disease, and pernicious anemia.
The earliest lesion of BP is a blister arising in the lamina lucida, between the basal membrane of keratinocytes and the lamina densa. This is associated with loss of anchoring filaments and hemidesmosomes. Histologically, there is a superficial inflammatory cell infiltrate and a subepidermal blister without necrotic keratinocytes. The infiltrate consists of lymphocytes and histiocytes and is particularly rich in eosinophils. There is no scarring.
Approximately 70% to 80% of patients with active BP have circulating antibodies to one or more basement membrane zone antigens.
- Autoantibodies to BP180 (and BP230).
- BP180 and BP230 are two components of hemidesmosomes, junctional adhesion complexes.
- T cell autoreactive response to BP180 and BP230 regulate autoantibody production.
- On direct immunofluorescence, the antibodies are deposited in a thin linear pattern; and on immune electron microscopy, they are present in the lamina lucida. (By contrast, the antibodies to basement membrane zone antigens that are present in cutaneous lupus erythematosus are deposited in a granular pattern).