Pathogenesis, clinical manifestations, and diagnosis of pemphigus

INTRODUCTION — Pemphigus is defined as a group of life-threatening blistering disorders characterized by acantholysis (loss of keratinocyte to keratinocyte adhesion) that results in the formation of intraepithelial blisters in mucous membranes and skin [1]. The process of acantholysis is induced by the binding of circulating immunoglobulin G (IgG) autoantibodies to intercellular adhesion molecules [1-3]. Patients with pemphigus develop mucosal erosions and/or flaccid bullae, erosions, or pustules on skin.

The four major entities of the pemphigus group include pemphigus vulgaris, pemphigus foliaceus, immunoglobulin A (IgA) pemphigus, and paraneoplastic pemphigus. The different forms of pemphigus are distinguished by their clinical features, associated autoantigens, and laboratory findings [4,5].

The pathogenesis, clinical features, and diagnosis of pemphigus will be discussed here. The management of pemphigus and greater detail on paraneoplastic pemphigus are reviewed separately. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus" and "Management of refractory pemphigus vulgaris and pemphigus foliaceus" and "Paraneoplastic pemphigus".)

CLASSIFICATION — Common features of the major types of pemphigus are reviewed briefly below. A broader summary of the clinical and laboratory features of pemphigus is provided in the table (table 1).

●Pemphigus vulgaris

•Key features – Mucosal or mucosal and cutaneous involvement, suprabasal acantholytic blisters, IgG autoantibodies against desmoglein 3 or both desmoglein 1 and desmoglein 3

•Clinical variants – Pemphigus vegetans, pemphigus herpetiformis

●Pemphigus foliaceus

•Key features – Cutaneous involvement only, subcorneal acantholytic blisters, IgG autoantibodies against desmoglein 1

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

●IgA pemphigus

•Subtypes – Subcorneal pustular dermatosis-type IgA pemphigus (distinct from classic subcorneal pustular dermatosis [Sneddon-Wilkinson disease]), intraepidermal neutrophilic IgA dermatosis

•Key features – Grouped vesicles or pustules and erythematous plaques with crusts, subcorneal or intraepidermal acantholytic blisters, autoantibodies against desmocollin 1 in subcorneal pustular dermatosis-type IgA pemphigus [6]

●Paraneoplastic pemphigus

•Key features – Extensive, intractable stomatitis and variable cutaneous findings with multiform exanthems, associated neoplastic disease, suprabasal acantholytic blisters, autoantibodies against desmoplakins or other desmosomal antigens (see "Paraneoplastic pemphigus")

EPIDEMIOLOGY — Pemphigus vulgaris, which represents the most common form of pemphigus, is a rare disease. Although pemphigus vulgaris occurs worldwide, the frequency is influenced by geographic location and ethnicity. Incidence rates between 0.1 and 0.5 per 100,000 people per year have been reported most frequently; however, higher rates have been documented in certain populations [7]. Individuals with Jewish ancestry (particularly Ashkenazi Jews) and inhabitants of India, Southeast Europe, and the Middle East have the greatest risk for pemphigus vulgaris [8].

In most geographic locations, pemphigus vulgaris is more common than pemphigus foliaceus. However, in certain locations, such as North Africa and South America, the prevalence of pemphigus foliaceus exceeds pemphigus vulgaris [9]. Endemic pemphigus foliaceus (fogo selvagem) contributes to the higher rate of pemphigus foliaceus in some of these countries. In an endemic region in the state of Mato Grosso do Sul in Brazil, the prevalence of pemphigus foliaceus during the mid-1990s was around 3 percent [10]. An endemic form of pemphigus vulgaris also has been reported in a small number of patients residing in an endemic region of pemphigus foliaceus in Brazil [11].

Pemphigus usually occurs in adults, with an average age of onset of 40 to 60 years for pemphigus vulgaris and nonendemic pemphigus foliaceus [12,13]. Pemphigus is rare in children, with the exception of endemic pemphigus foliaceus, which frequently affects children and young adults in endemic areas [14]. 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. (See 'Neonatal pemphigus' below.)

Overall, the sex ratio for pemphigus vulgaris and pemphigus foliaceus appears to be equivalent or close to equivalent [15]. However, 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 [16] and a study that found a 19:1 ratio of males to females in an endemic location in Colombia [17].

Epidemiologic information on IgA pemphigus is sparse. The disorder may occur at any age and may be slightly more common in females [6]. Paraneoplastic pemphigus is rare. The disorder is most commonly seen in middle-aged adults, but may also occur in children. (See "Paraneoplastic pemphigus", section on 'Epidemiology'.)

PATHOGENESIS

Overview — Intensive investigations to elucidate the pathogenesis of pemphigus have led to wide acceptance of the theory that acantholysis induced by the binding of autoantibodies to epithelial cell surface antigens leads to the clinical manifestations of pemphigus [2,18,19]. This theory is supported by the consistent detection of intercellular autoantibodies in perilesional tissue from patients with pemphigus (picture 1A-B) (see 'Diagnosis' below). Experimental findings that offer further support include the following:

●In vitro studies have demonstrated that IgG autoantibodies from patients with pemphigus vulgaris, pemphigus foliaceus, and IgA pemphigus are capable of inducing loss of epidermal cohesion [20-23].

●In vivo studies have shown that the passive transfer of IgG autoantibodies from patients with pemphigus vulgaris into neonatal mice induces blistering and erosions with histologic, ultrastructural, and immunofluorescence features consistent with pemphigus [24,25]. The blister-inducing potential of IgG autoantibodies in pemphigus foliaceus and paraneoplastic pemphigus has been demonstrated in similar in vivo mouse studies [26-28].

●Removal of serum autoantibodies from patients with pemphigus vulgaris or pemphigus foliaceus via antigen-specific immunoadsorption prior to injection into neonatal mice prevents blistering in injected neonatal mice [29,30].

The molecular mechanisms through which 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 [2,31,32]. 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 [33].

Target antigens — Autoantibodies against a variety of epithelial cell surface antigens, intracellular and transmembranous components of desmosomes, have been identified in patients with pemphigus.

Pemphigus vulgaris and pemphigus foliaceus — Desmogleins, which are transmembrane glycoproteins of the cadherin (calcium-dependent cell adhesion molecule) family, 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 (figure 1).

IgG autoantibodies to desmogleins are consistently detected via enzyme-linked immunosorbent assay (ELISA) in patients with pemphigus, and the expression of these autoantibodies often correlates with the type of disease [34,35]. IgG autoantibodies against desmoglein 3 are characteristic of mucosal pemphigus vulgaris, autoantibodies against desmoglein 1 have been linked to pemphigus foliaceus, and autoantibodies to desmoglein 1 and desmoglein 3 have been linked to mucocutaneous pemphigus vulgaris. The amino-terminal portions of desmogleins appear to be the important epitopes for pathogenicity as evidenced by studies that demonstrate that IgG directed against an amino-terminal recombinant fraction of desmoglein 3 (EC1-2) induces epithelial blistering when injected into neonatal mice or exposed to cultured human skin [36,37]. Findings demonstrate that IgG against the carboxy-terminal EC5 subdomain is also capable of inducing loss of cell-cell adhesion, presumably via mitogen-activated protein kinase (MAPK)-dependent signaling [38].

IgG autoantibodies considered to be pathogenic are of the immunoglobulin G4 (IgG4) subclass [25,37,39,40]. However, desmoglein-specific IgG autoantibodies may also belong to other isotypes. Emerging evidence suggests that other IgG subclasses, such as immunoglobulin G3 (IgG3), may have a pathogenic effect and that the diversity of the desmoglein 3-specific IgG subclasses impacts both disease activity and relapse risk [41].

In the 1990s, the desmoglein compensation theory was proposed as an explanation for the observed correlation between the clinical features and autoantibody profiles of pemphigus vulgaris and pemphigus foliaceus [42]. Although the theory is still widely cited, subsequent data has raised questions about whether this concept sufficiently explains the pathogenic mechanism of these diseases [43].

According to the desmoglein compensation theory, the correlation between clinical findings and ELISA results reflects innate differences in desmoglein expression in the skin and mucous membranes [42]. In the skin, desmoglein 1 is expressed most intensely in the upper portions of the epidermis, whereas desmoglein 3 is more strongly expressed in the basal and parabasal layers. In the mucous membranes, desmoglein 3 is present in abundance throughout the epithelium. In contrast, the expression of desmoglein 1 is much lower throughout the mucosal epithelium (figure 2).

The interpretation of this theory as it relates to the clinical findings in pemphigus is as follows:

●Patients with only autoantibodies against desmoglein 3 should have mucosal dominant pemphigus vulgaris because in skin, desmoglein 1 compensates for the loss of desmoglein 3. In the mucous membranes, the expression of desmoglein 1 is insufficient for compensation.

●Patients with only autoantibodies against desmoglein 1 should have pemphigus foliaceus (superficial skin blistering and no mucous membrane involvement) because autoantibodies against desmoglein 1 result in separation of cells in the superficial epithelium, but not in the deeper epithelium, where desmoglein 3 compensates well for desmoglein 1 dysfunction. The mucous membranes are spared due to the high levels of desmoglein 3 and the relatively low levels of desmoglein 1 expressed in mucosa.

●Patients with both autoantibodies against desmoglein 1 and 3 should have mucocutaneous pemphigus vulgaris because dysfunction of both desmoglein 1 and 3 prevents the ability of these glycoproteins to compensate for one another, resulting in a loss of cell-cell adhesion in both skin and mucous membranes.

However, it is likely that the pathogenesis of pemphigus is more complex than this model predicts. Discordance between the clinical and serologic profiles (eg, patients with pemphigus foliaceus who have autoantibodies against desmoglein 3, patients with pure mucosal pemphigus vulgaris who have autoantibodies against desmoglein 1, and patients with pemphigus who have neither autoantibodies against desmoglein 1 nor autoantibodies against desmoglein 3) may occur in about one-third of cases [43,44]. This observation and the knowledge that the presence of IgG autoantibodies to both desmoglein 1 and desmoglein 3 does not result in complete dissolution of the epithelium suggest that additional factors contribute to the development of these diseases.

Autoantibodies against desmocollin 3 may contribute to pemphigus in some patients. Like desmogleins, desmocollins are transmembrane glycoproteins found within desmosomes (figure 1). Desmocollin 3-specific autoantibodies from patients with pemphigus have induced loss of keratinocyte adhesion ex vivo and in experimental animals [45,46]. Moreover, a subset of patients with clinical features most consistent with pemphigus herpetiformis or pemphigus vegetans and direct immunofluorescence findings consistent with pemphigus who have autoantibodies against desmocollin but no autoantibodies against desmoglein has been identified [47,48]. A study has shown that IgG against desmocollin-3 induces loss of cell-cell adhesion in vitro and in vivo. This process also involves MAPK-dependent signaling [38].

Additional autoantibodies detected in serum from patients with pemphigus include autoantibodies against desmoglein 4, the acetylcholine receptor, pemphaxin, and others [33,49-53]. Whether autoantibodies with any of these molecular specificities are pathogenic in pemphigus vulgaris or pemphigus foliaceus remains to be determined.

IgA pemphigus — Unlike the other forms of pemphigus, which are characterized by IgG autoantibodies targeting epithelial cell surface antigens, IgA pemphigus is characterized by antikeratinocyte cell surface autoantibodies of the IgA class [54]. The target antigen in the subcorneal pustular dermatosis type of IgA pemphigus is desmocollin 1, a transmembrane glycoprotein within desmosomes [55-57].

In contrast, the targeted antigens in the intraepidermal neutrophilic dermatosis variant of IgA pemphigus appear to be more heterogeneous. While autoantibodies against desmogleins 1 and 3 have been reported in several patients [56,58-60], immunoelectron microscopy studies suggest that IgA autoantibodies in these patients recognize an unidentified non-desmosomal transmembranous protein [61]. Thus, a common autoantigen remains elusive and the mechanism of blister formation in IgA pemphigus is not fully understood [23].

Paraneoplastic pemphigus — Multiple autoantibodies have been detected in patients with paraneoplastic pemphigus. The target antigens for this variant are reviewed separately. (See "Paraneoplastic pemphigus", section on 'Humoral immunity'.)

Contributing factors — 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 [9].

Genetics — Multiple studies have evaluated the relationship between pemphigus vulgaris and pemphigus foliaceus with human leukocyte antigen (HLA) class II alleles. Pemphigus vulgaris is associated with DR4 and DR14, though the susceptibility gene differs dependent upon ethnic origin. HLA-DRB1 0402 is associated with the disease in Ashkenazi Jews [62,63], and DRB1 1401/04 and DQB1 0503 have been associated with pemphigus vulgaris in some other populations [64-69]. Sporadic and endemic pemphigus foliaceus are also associated with DR4, DR14, and DR1 alleles [9].

In contrast to pemphigus vulgaris, the association with HLA alleles in pemphigus foliaceus is less restricted. DRB1 0402, 0403, 0404, 0406, 1401, 1402, 1406, and 0102 subtypes have been detected at increased frequency in patients with pemphigus foliaceus, while DRB1 0301, 0701, 0801, 1101, 1104, and 1402 are negatively associated with this disease [70-73].

The involvement of genetic factors in susceptibility to pemphigus is further strengthened by detection of low titers of desmoglein 3-specific autoantibodies in asymptomatic relatives of patients with both pemphigus vulgaris and foliaceus [11,74]. In addition, a case-control study found that compared with relatives of healthy controls, first-degree family members of patients with pemphigus had an increased prevalence of autoimmune diseases [62]. The findings of one study suggest that pemphigus vulgaris clusters with autoimmune thyroid disease, rheumatoid arthritis, and type 1 diabetes in patients and their families [75].

Environment — While most cases of pemphigus foliaceus are idiopathic, environmental factors appear to contribute in the development of endemic pemphigus foliaceus (fogo selvagem) [49,76]. A black fly (Simulium nigrimanum) or other insects may serve as a vector for the endemic form of this disease [77].

Ultraviolet radiation has been proposed as an exacerbating factor for pemphigus foliaceus and pemphigus vulgaris [78-81], and pemphigus has been reported to develop following burns or cutaneous electrical injury [82]. Viral infections, certain food compounds, ionizing radiation, and pesticides have been suggested as additional stimuli for this disease [83-88].

Drug exposure — Pemphigus vulgaris and pemphigus foliaceus may be precipitated by drugs. Thiol drugs, including penicillamine and captopril, are the most common inciting agents [89]. In one series of 104 patients treated with penicillamine for at least six months, 7 percent developed pemphigus foliaceus [90]. Examples of additional drugs that have been associated with pemphigus vulgaris or pemphigus foliaceus include penicillins, cephalosporins, enalapril, rifampin, and nonsteroidal anti-inflammatory agents (table 2) [89,91,92].

Drug-induced biochemical and/or immunologic reactions may contribute to the development of acantholysis in drug-induced pemphigus. Potential mechanisms include effects on enzymes that mediate keratinocyte aggregation, direct interference through binding to molecules involved in cell adhesion, and stimulation of neoantigen formation [91].

Direct immunofluorescence (DIF) and indirect immunofluorescence (IIF) studies are negative in some patients with drug-induced pemphigus. In a series of six patients with this disorder, DIF was negative in one patient and IIF was negative in two patients [92]. ELISA was positive for desmoglein 1 or desmoglein 3 in all patients in this series.

The introduction of immune checkpoint inhibitors in the treatment of various solid tumors has revealed novel, immune-related adverse events, including loss of self-tolerance and the development of autoimmunity. In addition to the induction of lichenoid dermatitis, bullous pemphigoid, and granulomatous/sarcoid-like reactions, there are several cases of pemphigus vulgaris, pemphigus foliaceus, or paraneoplastic pemphigus that developed de novo or found to be aggravated upon introduction of the immune checkpoint inhibitor [93].

Diet — Dietary factors including garlic, leek, onion, black pepper, red chili pepper, red wine, and tea have been implicated as inducers of pemphigus vulgaris and pemphigus foliaceus based on concise case reports. However, the existing evidence does not support a strong link between diet as an environmental factor and pemphigus [87].

CLINICAL FEATURES

Pemphigus vulgaris — 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 [94]. Mucous membranes at other sites are also often affected, including the conjunctiva, nose, esophagus, vulva, vagina, cervix, and anus [95-97]. In women with cervical involvement, the histologic findings of pemphigus vulgaris may be mistaken for cervical dysplasia in Papanicolaou (Pap) smears [98].

Since mucosal blisters erode quickly, erosions are often the only clinical findings (picture 2A-C). The buccal mucosa and palatine mucosa are the most common sites for lesion development in the oral cavity [99].

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.

Most patients also develop cutaneous involvement manifesting as flaccid blisters on normal-appearing or erythematous skin (picture 3A-B). The blisters rupture easily, resulting in painful erosions that bleed easily (picture 3B-D). 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 [100]. (See "Approach to the patient with cutaneous blisters", section on 'Nikolsky sign'.)

Rarely, mucous membrane involvement is not observed despite the presence of circulating autoantibodies to both desmoglein 1 and desmoglein 3 [101-103]. The term "cutaneous-type pemphigus vulgaris" is used to refer to this presentation of the disease. (See 'Target antigens' above.)

Other uncommon clinical presentations of pemphigus vulgaris include:

●Pemphigus vegetans – Patients with pemphigus vegetans present with vegetating plaques composed of excessive granulation tissue and crusting (picture 4). The intertriginous areas, scalp, and face are the most common sites for these lesions. Two clinical presentations of pemphigus vegetans have been described [104]. In pemphigus vegetans of Neumann, vegetating plaques evolve from typical pemphigus vulgaris lesions. Pemphigus vegetans of Hallopeau is a milder form of pemphigus vegetans in which the vegetating plaques are not preceded by bullae. Lesions of pemphigus vegetans of Hallopeau usually are found in intertriginous areas.

●Pemphigus herpetiformis – Pemphigus herpetiformis (also known as herpetiform pemphigus) is a term that describes pemphigus vulgaris or pemphigus foliaceus that manifests with urticarial plaques and cutaneous vesicles arranged in a herpetiform or annular pattern (picture 5) [1,105-108]. Pruritus is frequently present. Mucosal involvement is uncommon.

The clinical features of drug-induced pemphigus vulgaris are similar to idiopathic disease.

Pemphigus foliaceus — 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 (picture 6A-C). The Nikolsky sign often is present [13]. 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 [12].

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

Clinical variants of pemphigus foliaceus include:

●Endemic pemphigus foliaceus (fogo selvagem) – Endemic pemphigus foliaceus presents with clinical features that are similar to the idiopathic form of the disease [13]. An environmental trigger is believed to account for this variant of the disease. (See 'Epidemiology' above.)

●Pemphigus erythematosus (Senear-Usher syndrome) – This term pemphigus erythematosus is used to describe pemphigus foliaceus localized to the malar region of the face (picture 7) [12]. Historically, the term was used to refer to patients who exhibited immunofluorescence findings consistent with pemphigus as well as laboratory features of systemic lupus erythematosus. However, the term is no longer used in this manner.

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

IgA pemphigus — 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 [6]. The vesicles and pustules are usually, but not always, accompanied by erythematous plaques. A herpetiform, annular, or circinate pattern may be present [6,57,99].

The trunk and proximal extremities are common sites for involvement. The scalp, postauricular skin, and intertriginous areas are less common sites for lesion development [6,57,109]. 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. (See "Neutrophilic dermatoses", section on 'Subcorneal pustular dermatosis' and 'IgA pemphigus' below.)

Paraneoplastic pemphigus — Paraneoplastic pemphigus (also known as paraneoplastic autoimmune multiorgan syndrome) is an autoimmune multi-organ syndrome associated with neoplastic disease [27]. Typically, patients suffer from severe and acute mucosal involvement with extensive, intractable stomatitis (picture 8A-C). 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 (picture 9A-B). Life-threatening pulmonary involvement consistent with bronchiolitis obliterans also may be seen [110]. (See "Paraneoplastic pemphigus", section on 'Clinical manifestations'.)

Neonatal pemphigus — Neonatal pemphigus is a rare transient condition in which neonates develop blisters due to placental transmission of autoantibodies from a mother with pemphigus. Neonatal pemphigus vulgaris occurs more frequently than neonatal pemphigus foliaceus [111,112]. The clinical, histologic, and direct immunofluorescence findings of neonatal pemphigus are consistent with pemphigus. Indirect immunofluorescence has been positive in the majority of reported cases [111]. The disease manifestations usually resolve within three weeks.

COMORBIDITIES — Cross-sectional studies have found increased prevalence rates for other disorders in patients with pemphigus, including hematologic malignancies, solid malignancies (esophageal and laryngeal cancer), other autoimmune diseases (Sjögren's disease, systemic lupus erythematosus, and alopecia areata), psoriasis, and neurologic diseases (dementia, Parkinson disease, and epilepsy) [113-116]. Further studies are necessary to firmly establish the clinical relevance of these findings.

Although an increased prevalence of malignancy in patients with pemphigus has been reported, malignancy is uncommon overall [113,117]. A cross-sectional study of 1985 patients with pemphigus vulgaris or pemphigus foliaceus and 9874 matched controls found modest increases in the prevalence rates of chronic leukemia (0.9 versus 0.4 percent, odds ratio [OR] 2.1, 95% CI 1.2-3.6), multiple myeloma (0.8 versus 0.4 percent, OR 2.2, 95% CI 1.2-3.9), and non-Hodgkin lymphoma (1.8 versus 1.2 percent, OR 1.5, 95% CI 1.0-2.2) among pemphigus patients [117]. Paraneoplastic pemphigus, a very rare obligate paraneoplastic disease, is a distinct subtype of pemphigus that occurs only in association with malignancy and is reviewed separately. (See "Paraneoplastic pemphigus".)

DIAGNOSIS — The diagnosis of pemphigus is made through the assessment of clinical, histologic, immunopathologic, and serologic findings (table 1). Even in cases in which the clinical findings strongly suggest pemphigus, laboratory investigations to confirm the diagnosis are indicated since other disorders may present with similar clinical findings. (See 'Differential diagnosis' below.)

Pemphigus vulgaris and pemphigus foliaceus — In addition to a complete examination of cutaneous and mucosal surfaces, the clinical assessment should include a review of the patient's medications since clinical and laboratory studies cannot reliably distinguish between idiopathic pemphigus and drug-induced pemphigus. In addition, patients who may have pemphigus vulgaris should be questioned about ocular symptoms, hoarseness, dysphagia, dysuria, and dyspareunia to evaluate for symptoms suggestive of extraoral mucus membrane involvement. (See 'Drug exposure' above and 'Clinical features' above.)

Our standard laboratory work-up for patients with clinical findings suggestive of pemphigus vulgaris or foliaceus includes:

●A lesional skin or mucosal biopsy for routine hematoxylin and eosin (H&E) staining

●A perilesional skin or mucosal biopsy for direct immunofluorescence (DIF)

●Serum collection for enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence (IIF)

Histopathology — The biopsy for routine histologic examination should be taken from an early lesion. The biopsy should be placed at the edge of a blister or erosion. A 4 mm punch biopsy is usually sufficient. (See "Approach to the patient with cutaneous blisters", section on 'Skin biopsy'.)

The characteristic findings in pemphigus vulgaris include (picture 10):

●Intraepithelial cleavage with acantholysis (detached keratinocytes) primarily localized to the suprabasal region

●Retention of basal keratinocytes along the basement membrane zone, resulting in an appearance that resembles a "row of tombstones"

●Sparse inflammatory infiltrate in the dermis with eosinophils

In the pemphigus vegetans variant of pemphigus vulgaris, the suprabasal cleavage is accompanied by hyperkeratosis, papillomatosis, and prominent acanthosis with downward proliferation of the rete ridges [118]. Eosinophils may be present within the areas of cleavage.

The characteristic findings of pemphigus foliaceus include (picture 11) [118]:

●Intraepithelial cleavage with acantholysis beneath the stratum corneum or within the granular layer; neutrophils within the blister cavity are occasionally seen

●Mixed inflammatory infiltrate in the superficial dermis with eosinophils and neutrophils; eosinophils may be more prevalent in drug-induced pemphigus foliaceus

Direct immunofluorescence — Unlike the biopsy for routine histologic examination, the biopsy for DIF should be taken from normal-appearing perilesional skin or mucosa. The biopsy should not be placed in formalin. (See "Approach to the patient with cutaneous blisters", section on 'Direct immunofluorescence'.)

Both pemphigus vulgaris and pemphigus foliaceus demonstrate intercellular deposition of IgG on DIF (picture 1A-B). Although some cases of pemphigus foliaceus demonstrate deposition of IgG that is primarily distributed in upper levels of the epidermis (picture 1B), DIF cannot be used to reliably distinguish between these diseases.

Essentially all patients with idiopathic pemphigus vulgaris or pemphigus foliaceus have positive DIF results. Thus, if DIF is negative, the diagnosis should be questioned. In contrast, negative DIF studies may occur in patients with drug-induced pemphigus (see 'Drug exposure' above) [89,92]. Occasionally, intercellular deposition of antibodies occurs in other diseases (eg, spongiotic dermatitis, burns, toxic epidermal necrolysis, systemic lupus erythematosus, or lichen planus) [99].

Serology — IIF and ELISA are serologic studies that can detect circulating autoantibodies that bind epithelial cell surface antigens. In patients with positive DIF results, these tests are used to further support the diagnosis of pemphigus.

Indirect immunofluorescence — More than 80 percent of patients with pemphigus vulgaris or pemphigus foliaceus have circulating antibodies detectable by IIF [104]. The substrate used influences the test sensitivity [104]. Monkey esophagus is the preferred substrate for the diagnosis of pemphigus vulgaris. In contrast, normal human skin and guinea pig esophagus are the most sensitive substrates for the diagnosis of pemphigus foliaceus. In both disorders, IgG deposits are found intercellularly (picture 12). IIF cannot be used to distinguish between these diseases. (See "Approach to the patient with cutaneous blisters", section on 'Indirect immunofluorescence'.)

Enzyme-linked immunosorbent assay — ELISA for IgG antibodies to desmoglein 1 and desmoglein 3 is commercially available. ELISA is more sensitive and specific than IIF for the diagnosis of pemphigus vulgaris and pemphigus foliaceus [104]. The sensitivity of ELISA exceeds 90 percent [12].

In addition, since desmoglein antibody levels often fall in the setting of clinical improvement, ELISA may aid with monitoring disease activity and the response to treatment [119-121]. In a retrospective study that assessed the predictive values of pemphigus autoantibodies in patients with pemphigus vulgaris and pemphigus foliaceus, desmoglein 1 autoantibodies were more closely correlated with the disease course than desmoglein 3 autoantibodies [120]. Desmoglein 3 antibody levels remained high during disease remissions in some patients with mucosal pemphigus vulgaris. In patients with pemphigus vulgaris, levels of IgE antibodies to desmoglein 3 may also correlate with disease activity [122]. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus" and "Management of refractory pemphigus vulgaris and pemphigus foliaceus".)

Other — Additional serologic tests that may be used for the diagnosis of pemphigus vulgaris and pemphigus foliaceus include immunoblotting and immunoprecipitation. However, these tests are more difficult to perform than IIF and ELISA. Thus, they are infrequently used in the clinical setting.

Aside from the detection of pemphigus antibodies in serum, pemphigus is not associated with specific laboratory abnormalities. Other laboratory abnormalities may occur related to complications of the disease or its treatment.

IgA pemphigus — Similar to other forms of pemphigus, the diagnosis of IgA pemphigus is based upon the combined assessment of clinical and laboratory findings. The standard laboratory workup consists of histologic examination, DIF, and IIF.

Typical histologic findings of IgA pemphigus include [6,118]:

●Intraepidermal clefts and pustules located in a subcorneal location (subcorneal pustular dermatosis-type IgA pemphigus) or in the entire or mid-epidermis (intraepithelial neutrophilic dermatosis)

●Slight or absent acantholysis

●Mixed inflammatory infiltrate in the dermis

DIF microscopy of perilesional skin reveals intercellular IgA deposition within the epidermis that is occasionally more pronounced in the upper epidermis. Weaker intercellular deposits of IgG and/or C3 may also be present [6,57]. IIF on monkey esophagus demonstrating intercellular deposits of IgA offers further support for the diagnosis. However, IIF on monkey esophagus is positive in less than or equal to 50 percent of patients [6,57]. IIF on human skin may demonstrate intercellular antibody deposition more frequently; in one series of patients with IgA pemphigus, IIF of normal human skin showed intercellular deposition of IgA in 31 of 48 patients (65 percent) [57].

Other studies that have been utilized to identify circulating IgA pemphigus desmocollin autoantibodies include immunoblotting [123], ELISA using recombinant desmocollin [57,109], and immunofluorescence molecular assay using desmocollin-transfected COS-7 cells [55,57]. The availability of these studies is limited to specialized centers and research settings.

Although autoantibodies against desmocollin 1 appear to be strongly associated with the subcorneal pustular dermatosis type of IgA pemphigus, autoantibodies to desmogleins may be present in other patients with IgA pemphigus [56,57]. In one series of 22 patients with IgA pemphigus, ELISA tests for IgA autoantibodies against desmoglein 1 or desmoglein 3 were positive in three patients and one patient, respectively [56]. The patients with desmoglein autoantibodies had either the intraepidermal neutrophilic type of IgA pemphigus or a presentation that had clinical and pathologic features of pemphigus foliaceus. None of the 10 patients with subcorneal pustular dermatosis-type IgA pemphigus had autoantibodies against these desmogleins, but all 10 had serum samples that reacted with desmocollin 1 expressing COS-7 cells.

Paraneoplastic pemphigus — Similar to other forms of pemphigus, the diagnosis of paraneoplastic pemphigus involves review of clinical, histologic, immunopathologic, and serologic findings. The diagnosis of paraneoplastic pemphigus vulgaris is reviewed separately. (See "Paraneoplastic pemphigus", section on 'Diagnosis'.)

DIFFERENTIAL DIAGNOSIS — Multiple mucocutaneous blistering diseases share clinical features with the different forms of pemphigus (table 3). In all forms of pemphigus, laboratory investigations, particularly immunopathologic tests, usually easily distinguish pemphigus from other diseases:

●Pemphigus vulgaris – Cutaneous involvement in pemphigus vulgaris must be distinguished from other autoimmune blistering diseases. The morphology of cutaneous blisters in pemphigus vulgaris can be helpful for narrowing the differential diagnosis. The flaccid blisters often seen in pemphigus vulgaris contrast with the tense blisters that are frequently seen in association with subepithelial blistering diseases, such as bullous pemphigoid, linear IgA bullous dermatosis, and epidermolysis bullosa acquisita (picture 13A-C and algorithm 1). (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid" and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Clinical features of bullous pemphigoid' and "Linear IgA bullous dermatosis", section on 'Clinical manifestations' and "Epidermolysis bullosa acquisita", section on 'Clinical manifestations'.)

Mucosal lesions pemphigus vulgaris can resemble other blistering or erosive disorders of the mucous membranes. As examples, the possibility of other pemphigus variants, mucous membrane pemphigoid, mucosal linear IgA bullous dermatosis or epidermolysis bullosa acquisita, erythema multiforme, and Stevens-Johnson syndrome should be considered. (See "Approach to the patient with cutaneous blisters", section on 'Mucous membrane involvement'.)

●Pemphigus foliaceus – The lesions of pemphigus foliaceus may resemble other inflammatory disorders, such as seborrheic dermatitis (picture 14), impetigo, subacute cutaneous lupus erythematosus (picture 15A-B), IgA pemphigus, and the non-IgA pemphigus form of subcorneal pustular dermatosis (picture 16A-B). (See "Neutrophilic dermatoses", section on 'Subcorneal pustular dermatosis'.)

●IgA pemphigus – The differential diagnosis of IgA pemphigus overlaps with pemphigus foliaceus. In addition, disorders that may present with grouped vesicular lesions or pustules, such as dermatitis herpetiformis (picture 17), bullous impetigo, linear IgA bullous dermatosis (picture 13B), and pustular psoriasis (picture 18A-B) should be considered.

●Paraneoplastic pemphigus – The differential diagnosis of paraneoplastic pemphigus is reviewed separately. (See "Paraneoplastic pemphigus", section on 'Differential diagnosis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pemphigus".)

SUMMARY AND RECOMMENDATIONS

●Overview – Pemphigus comprises a group of autoimmune blistering diseases that are characterized by histologic acantholysis (loss of cell-to-cell adhesion) and mucosal and/or cutaneous blistering. The four major types of pemphigus are pemphigus vulgaris, pemphigus foliaceus, IgA pemphigus, and paraneoplastic pemphigus (table 1). (See 'Classification' above.)

●Epidemiology – 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. (See 'Epidemiology' above.)

●Pathogenesis – 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 (figure 2). The mechanism through which acantholysis occurs is not fully understood. (See 'Pathogenesis' above.)

●Clinical features – Pemphigus vulgaris generally is a more severe disease than pemphigus foliaceus. Patients with pemphigus vulgaris usually present with widespread mucocutaneous blisters and erosions (picture 2A-B, 3A-D). Cutaneous blistering in pemphigus foliaceus tends to occur in a seborrheic distribution (picture 6A-C). Compared with pemphigus vulgaris, blistering in pemphigus foliaceus is more superficial. (See 'Clinical features' above.)

Vesicles, pustules, and crusts on skin are common features of IgA pemphigus. The skin lesions may appear in an annular, circinate, or herpetiform distribution. (See 'IgA pemphigus' above.)

●Diagnosis – The diagnosis of pemphigus is based upon the recognition of consistent clinical, histologic, and direct immunofluorescence (DIF) findings, as well as the detection of circulating IgG and IgA autoantibodies against cell surface antigens in serum (table 1). Laboratory studies are useful for distinguishing pemphigus from other blistering and erosive diseases. Our standard laboratory work-up for patients with clinical findings suggestive of pemphigus vulgaris or foliaceus includes (see 'Diagnosis' above):

•A lesional skin or mucosal biopsy for routine hematoxylin and eosin (H&E) staining

•A perilesional skin or mucosal biopsy for DIF

•Serum collection for detection of autoantibodies by enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence (IIF)