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Pemphigus

Definition

Pemphigus is a group of organ specific autoimmune diseases characterized by the production of autoantibodies to desmogleins (a). They are mucocutaneous blistering diseases that demonstrate a loss of cohesion of the epidermal cells (acantholysis) which result in the formation of clefts in the epidermis. Autoantibodies directed against adhesion molecules cause epidermal keratinocytes to separate, resulting in intraepidermal bullae.

Types

There are two histological types of pemphigus: deep (e.g., pemphigus vulgaris) and superficial (e.g., pemphigus foliaceus). They differ in the epidermal layers that are affected, in the clinical manifestations of the diseases, and in the associated immunologic abnormalities (b).

Pemfigo volgare

Pemfigo volgare (PV) is the most common form of pemphigus (up to 80% of all pemphigus (c)). It is an acquired autoimmune disease in which IgG antibodies target desmosomal proteins to produce intraepithelial, mucocutaneous blistering. Desmoglein (Dsg) 3 is the major antigen but 50–60% of patients have additional antibodies to Dsg1, the antigen in pemphigus foliaceus.

The underlying antibody profile is a major determinant of the clinical phenotype. Studies have shown a lower mortality in patients with predominantly mucosal PV (1–17%) compared with those with mucocutaneous PV (34–42%) (d).

The mortality of PV was 75% on average before the introduction of corticosteroids in the early 1950s, which may be an underestimate.

Pemphigus Foliaceus

Pemphigus Foliaceus (PF) is the second most common form of pemphigus (b), (5:1 in the US, but more common in Finland, South Africa, Mali (e)), and is endemic in some areas of Brazil and Columbia, where an insect vector is suspected but none yet identified. The prognosis of untreated pemphigus foliaceus is more favorable than that of pemphigus vulgaris, as the lesions of pemphigus foliaceus are not as deep, and there is less chance for infection, fluid loss, and metabolic disturbance. Although pemphigus foliaceus is often less severe, the doses of medications required for control are similar to those used for pemphigus vulgaris (although some patients may be treated with drugs like dapsone, and may not require corticosteroids or immunosuppressives).

Clinical Variants

Pemphigus erythematosus (also known as Senear-Usher syndrome) has features of lupus erythematosus.

Fogo selvagem (Portuguese for “wild fire”; also known as endemic pemphigus and Brazilian pemphigus) which may be triggered by exposure to one or more environmental antigens (b).

Drug-Related Pemphigus

Both pemphigus vulgaris and pemphigus foliaceus can be either induced or triggered (i.e., latent disease unmasked) by certain drugs. (Pemphigus that continues after a patient stops using a drug is referred to as triggered, whereas lesions that clear soon after withdrawal are referred to as induced). Although drug-related pemphigus is uncommon, its possibility must be excluded in all patients with newly diagnosed disease. The clinical, histological and immunofluorescence abnormalities of drug-induced pemphigus are similar to those of the idiopathic variety. For a list of drugs please see following a table with known implicated agents.

There are several conditions with the name ‘pemphigus’ that are not the same condition as these discussed. These include:

Paraneoplastic Pemphigus

Paraneoplastic pemphigus (also known as Paraneoplastic autoimmune multi-organ syndrome) shares clinical features of both pemphigus and severe erythema multiforme, and shows cutaneous and systemic involvement (f). It is an autoimmune disease of the skin and oral mucosa that develops in patients with an underlying neoplasm, most typically non-Hodgkins lymphoma. It is characterized by erosions of the oral cavity, and large, tense bullae. Unfortunately, standard treatments for autoimmune blistering diseases fail in most paraneoplastic cases, but may resolve with treatment of underlying neoplasm.

Hailey-Hailey Disease

Familial benign chronic pemphigus, or Hailey-Hailey disease, is a different condition from Pemphigus, and is not an autoimmune condition and therefore the IPPF does not provide support for it. It is instead a hereditary, autosomal dominant disorder marked by multiple vesicles on inflammatory bases, and erosions in skin subject to friction or pressure, such as intertriginous areas. In addition to pharmacologic treatment, therapy includes keeping involved areas dry and free of friction is helpful. For more information and support resources please visit www.haileyhailey.com

Epidemiology

  • PV shows has an approximately equal prevalence among men and women.
  • Peak incidence 30-60 years of age (i)
  • Mean onset of age is 50 to 60 years (ranges on subtype and can affect persons at all ages)
  • Ethnicity: The disorder tends to affect persons of Mediterranean ancestry but can occur in persons of any ethnicity. Geographic variation is wide, with no special variation within the United States. High prevalence of subtype pemphigus foliaceus in Brazilian rain forest and Columbia.
  • Genetics:
    • The occurrence of the disease in first-degree relatives, although rare, suggests an inherited susceptibility transferred as a dominant trait.
    • Pemphigus is more common in persons with certain HLA allotypes
      • HLA DR4 and DR14 (DRB1*0402 and DRB1*0401 more specifically) crucial in susceptibility
      • HLA-DRB1*0402 is associated with the disease in Ashkenazi Jews and DRB1*1401/04 and DQB1*0503 in non-Jewish patients of European or Asian descent.
  • Socioeconomic features: none known as a risk factor or predictor
  • Incidence of 1-10 new cases per 1 million people worldwide, with variations in different regions and among different ethnic groups. Incidence is increased in patients of Ashkenazi Jewish descent and those of Mediterranean origin (ccc) (as high as 16 to 32 cases per million people)
  • Estimated prevalence of 30,000 40,000 cases in the U.S.
  • Pediatric Profile: Pediatric pemphigus is rare, but identical to adult in presentation

Histology

The basic abnormality in all forms of pemphigus is the separation of keratinocytes (acantholysis). This process leads to the formation of a cleft within the epidermis, which then enlarges into a bulla, which then breakdown into coalescing ulcers. All forms of pemphigus are associated with the presence of circulating and fixed autoantibodies—referred to as intercellular antibodies—against keratinocyte cell-surface antigens.

  • Circulating intercellular antibodies are present in about 80-90% of patients with active disease.
  • Tissue fixed intercellular antibodies are present in lesions and adjacent healthy skin in about 90% of patients.

Clinical Features

Pemphigus Vulgaris

The oral mucosa is often the first site of involvement. Typically patients will have had multiple oral ulcers (broken blisters) that persist for weeks to months.

PV affects the oral mucosa in nearly all cases (>80%) and affects the oral mucosa first in the majority of cases (c), and may in fact be the only site in patients.

A minority will present only with cutaneous erosions. Skin involved is typically the upper chest, back, scalp, and face, but lesions can occur on any part of the body. Note that the skin dominant form manifests the Dsg1 autoantibody profile (as in pemphigus foliaceus), whereas the mucosally dominant form manifests the Dsg3 autoantibody profile. A mixed pattern of skin and mucosa manifests a mixed Dsg1 and Dsg3 autoantibody profile. The condition progresses over weeks to months.

Sites often overlooked include around the nails (manifest as painful, red, and swollen), the pharynx and larynx (pain on swallowing and hoarseness), and the nasal cavity (nasal congestion and a bloody mucous discharge, particularly noticeable upon blowing the nose in the morning). As many as 49% of patients were shown to have laryngeal and nasal involvement (a).

Vesciche può essere accompagnata da dolore severo, prurito, masterizzazione, e pungente. If extensive, vesciche può portare alla perdita di liquidi letali, infezione, e deturpazione. PV può anche causare gravi danni alla pelle, tra cui la perdita del chiodo e l'alterazione della pigmentazione, rendendo la tempestività di intervento e trattamento essenziale per la prevenzione della disabilità.

If left untreated, the erosions and bullae of pemphigus vulgaris gradually spread, involving an increasing surface area, and can become complicated by severe infections and metabolic disturbances.

Before the advent of corticosteroids, pemphigus had a high fatality rate, with approximately 70+% of patients dying within a year (q, p).

With treatment, lesions can heal normally without scarring and the hyperpigmentation associated with pemphigus often resolves after several months (r). Most patients treated for pemphigus will enter a partial remission within 2 to 5 years. (In a longitudinal study of outcome in 40 patients with pemphigus vulgaris, 45% entered a complete and long-term remission after 5 years and 71% after 10 years (b).

Pemfigo volgare (or foliaceus) may present or worsen during pregnancy, especially in the first and second trimesters, and is associated with an increased risk of premature birth and fetal death (o).

Pemphigus Foliaceus

Pemphigus foliaceus usually begins with small (approximately 1 cm), pruritic, crusted lesions resembling corn flakes on the upper torso and face. The crusts are easily removed, leaving chronic, superficial erosions.

Over weeks to months, the condition progresses, with an increasing number of lesions appearing on the upper torso, face, and scalp. In extensive cases, lesions develop over the entire body, become confluent, and can progress to an ‘exfoliative erythroderma’.

In contrast to pemphigus vulgaris, oral involvement in pemphigus foliaceus does not occur.

(Note: 2 clinical variants: pemphigus erythematosus and fogo selvagem)