Clinical Variants of Pemphigus

Pemphigus Vulgaris

PV is a relatively rare disorder that primarily affects individuals in the 3rd to 5th decade without sex preference (Huilgol et al. 1995; Nousari and Anhalt 1999). PV is characterized by flaccid blisters/erosions of the mucous membranes and the skin. In the majority of patients, the oral mucosa is primarily affected but other mucous membranes may be involved as well. Initial blisters rapidly rupture leading to painful chronic lesions that may affect larynx and pharynx in addition to the oral mucosa. Once the disease progresses, skin lesions may occur at any site of the integument but there is a preferential involvement of the trunk. Due to extensive blistering of skin and mucosa, the prognosis of PV used to be fatal prior to introduction of glucocorticoids as the major therapeutic strategy. The natural course of the disease is progressive with death occuring within a few years of onset due to sepsis (Fig. 4; 5A-B).

Since IgG4 has the potential to pass the placenta, neonatal pemphigus may occur by the diaplacentar transfer of anti-Dsg3 IgG4 from mothers with PV to their unborn children. After birth, the newborn exhibit crusty erosions of the skin with the histopathological findings of PV. These skin lesions disappear after a few months once circulating auto-Ab are degraded.

Pemphigus Foliaceus

In PF, the areas of central face, scalp, chest and upper back are affected by painful crusted erosions with erythema. Mucosal lesions are virtually absent

Pemphigus Folicaceous Epidermis

Fig. 4. Key features of pemphigus. A. Clinical appearance with extensive erosions of the trunk (provided by Dr. John R. Stanley, Philadelphia, USA). B. histopathology with acantholysis. C. direct immunofluorescence with intercellular IgG deposits in the epidermis. D. electron-microscopic picture of a desmosome at the contact site of two epidermal keratinocytes

Fig. 4. Key features of pemphigus. A. Clinical appearance with extensive erosions of the trunk (provided by Dr. John R. Stanley, Philadelphia, USA). B. histopathology with acantholysis. C. direct immunofluorescence with intercellular IgG deposits in the epidermis. D. electron-microscopic picture of a desmosome at the contact site of two epidermal keratinocytes in contrast to PV (Huilgol et al. 1995) (Fig. 5). Fogo selvagem is a variant of PF which occurs endemically in distinct regions of Brazil. In contrast to PV, the acantholytic split occurs in the granular or subcorneal layers of the epidermis. PF has attracted considerable attention, despite its low incidence, because the associated auto-Ab are directly pathogenic, their target protein is known, and the presence of foci of endemic disease suggests an infectious cause in at least one variant of the disorder. Since the clinical hallmark of PF is the disruption of the superficial part of the epidermis, intact cutaneous blisters are rarely detectable. The endemic variant, known as fogo selvagem, is clinically indistinguishable from non-endemic PF, and the increase in its incidence in distinct location of South America is striking.

Ab against Dsg1 cause PF in adults, but transplacental passage of the Ab from affected mothers does not cause skin disease in their infants. The desmo-somes of subcorneal keratinocytes in newborn infants contain both Dsg1 and Dsg3, with each contributing to the strength of the intercellular desmosomal bridge (Iwatsushi et al. 1995; Wu et al. 2000). In contrast, subcorneal keratino-cytes in adults express only Dsg1. The absence of mucosal lesions in PF is

Pemphigus Vulgaris

Fig. 5. Clinical variability of pemphigus. A. Pemphigus vulgaris with flaccid cutaneous blisters. B. erosions of the oral cavity. C. Pemphigus foliaceus with crusty erosions of the skalp. D. Paraneoplastic pemphigus with extensive mucosal involvement. E. Pemphigus seborrhoicus with superficial crusty erosions

Fig. 5. Clinical variability of pemphigus. A. Pemphigus vulgaris with flaccid cutaneous blisters. B. erosions of the oral cavity. C. Pemphigus foliaceus with crusty erosions of the skalp. D. Paraneoplastic pemphigus with extensive mucosal involvement. E. Pemphigus seborrhoicus with superficial crusty erosions explained by the compensatory presence of Dsg3 at these sites. Recently, auto-Ab against constituents of the desmosomal plaque have been identified in PF sera; their significance is yet unclear (Kazerounian et al. 2000).

Paraneoplastic Pemphigus (PNP)

Paraneoplastic pemphigus (PNP) is usually characterized by painful lesions of the mucosal surfaces and erythema multiforme-like lesions of palms and soles (Anhalt et al. 1990) (Fig. 5D). This relatively rare disease is mainly associated with B cell lymphoma and other hematological disorders and may precede the clinical manifestation of these disorders (Huilgol et al. 1995; Anhalt et al. 1990). PNP may be also associated with benign tumors, i.e. thymoma and Castleman's tumor. In contrast to the other pemphigus variants, PNP may involve lung epithelium. Progressive respiratory failure due to pulmonary involvement constitutes the terminal complication in up to 30% of the patients (Nousari and Anhalt 1999). Endobronchial biopsy reveals the typical pattern of intraepithelial acantholysis of the bronchial epithelium. Direct immunofluorescence of lesional skin shows that IgG is deposited both in the intercellular space and along the basal membrane zone, and circulating auto-Ab against the intercellular space and the dermoepidermal basement membrane are present in almost all cases (Anhalt et al. 1990). PNP is primarily associated with anti-Dsg3 and anti-Dsg1 auto-Ab (Hashimoto et al. 1995b; Nousari and Anhalt 1999). A number of additional target antigens has been identified, including desmoplakins I and II (Oursler et al. 1992), bullous pemphigoid antigen 1 (BP230) (Anhalt et al. 1990) and as yet unidentified antigens of lower molecular weight (Joly et al. 1993). The reactivity of PNP sera seems to be heterogeneous, and the antigen(s) that ultimately play(s) a pathogenic role have not yet been identified. The Ab directed against these epidermal proteins represent useful markers for the diagnosis of PNP but may not play a critical role in the pathogenesis of PNP (Hashimoto et al. 1995b). Intracellular constituents of the desmosomal plaque such as envoplakin, periplakin (Kim et al. 1997; Mahoney et al. 1998; Kazerounian et al. 2000) and HD1/plektin (Proby et al. 1999) have been recently identified as additional target antigens of PNP sera (Table 1).

Drug-Induced Pemphigus

The drugs that cause pemphigus most commonly contain thiol or sulfur groups that may be converted to thiols, such as D-penicillamine, captopril, propan-olol, indomethacin, phenylbutazone, pyritinol, piroxicam, and tuberculosta-tic agents (Huilgol et al. 1995; Brenner et al. 1997). The clinical picture most commonly mimics PF but may also resemble PV, pemphigus erythematosus, or herpetiform pemphigus. Oral lesions are uncommon. Direct and indirect immunofluorescence are usually positive with a pemphigus pattern. Auto-Ab against the basal membrane zone may be also present (Huilgol et al. 1995). Several target antigens have been identified in drug-induced pemphigus. Korman et al. (1991b) reported about three patients who had circulating auto-Ab to both Dsg3 and Dsg1, a pattern which is generally found in patients with PV. Brenner et al. (1997) detected serum reactivity to Dsg3 and/or Dsg1 in the sera of ten patients with drug-induced pemphigus supporting the observation of Korman et al. that the auto-Ab response was similar in both spontaneous and drug-induced pemphigus. In addition, longterm interferon-a therapy has been shown to induce auto-Ab against epidermal antigens (Fleischmann et al. 1996). Recently, several reports have described the induction of PV or PF upon treatment with interferon-y or interleukin-2 of hepatitis C (Niizeki et al. 1994), Kaposi sarcoma (Parodi et al. 1993) or lymphoma (Ramseur et al. 1989; Kirsner et al. 1995).

IgA Pemphigus

Typically, this pemphigus variant is characterized clinically by pustules with a tendency to confluence forming annular and circinate patterns (Huilgol et al. 1995). Mucosal involvement is rare. There is an association with benign and malignant monoclonal IgA gammopathies and gastrointestinal disease. IgA is deposited in the epidermal intercellular space in all patients and usually represents the only tissue-bound Ig class. Circulating IgA auto-Ab are present in about 50% of cases. Several desmosomal target antigens have been identified including desmocollins I and II (Huigol et al. 1995). Hashimoto et al. (1997) identified human desmocollin I as an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus (Table 1). The intraepidermal neutrophilic dermatosis subtype is associated with IgA against Dsg1 and Dsg3 (Wallach 1992). While in the majority of cases IgA targets Dsg1 (Karpati et al. 2000), two independent recent studies have also identified Dsg3 as a target antigen of circulating IgA (Prost et al. 1995; Wang et al. 1997). IgA seems to possess acantholytic properties at least in vitro (Supapannachart and Mutasim 1993). It thus remains to be clarified whether anti-Dsg IgA also induces acantholysis in vivo.

Rare Pemphigus Variants

Pemphigus herpetiformis is characterized by skin lesions resembling those of dermatitis herpetiformis, eosinophilic spongiosis without apparent acantholysis as well as by the presence of circulating and tissue-bound Ab against the kera-tinocyte surface (Jablonska et al. 1975; Santi et al. 1996). Pemphigus herpetiformis sera have been shown to contain IgG reactive with the Dsg3 antigen of PV (Kubo et al. 1997). Using two recently established ELISA with baculovirus-derived Dsg3 and Dsg1 proteins (ECD), Ishii et al. (1998) demonstrated that sera of patients with herpetiform pemphigus contain Ab against Dsg1 and Dsg3 suggesting that herpetiform pemphigus is a clinical variant of PF and PV.

Pemphigus erythematosus (Senear Usher) can be considered as a variant of PF which is characterized by sharply demarcated erythematous plaques with scaling. The lesions are primarily localized on the face and the upper trunk (Senear and Usher 1926). A characteristic immunoserological feature is the presence of IgG and C3 deposits along the dermoepidermal membrane similar to lupus erythematosus. About 80% of these patients have serum antinuclear Ab. The precise nature of this disorder and the role that anti-Dsg1 auto-Ab play remains to be elucidated.

Pemphigus vegetans is a clinical variant of PV characterized by cutaneous blisters and pustules that tend to transform into verruciform and papillo-matous vegetations. These lesions typically present in the intertriginous areas, such as the axillae and groins. In addition, oral lesions identical to those of PV are fairly common. The type Neumann is characterized by a more

How To Deal With Rosacea and Eczema

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