Chapter 055. Immunologically Mediated Skin Diseases (Part 3)

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Pemphigus Foliaceus Pemphigus foliaceus (PF) is distinguished from PV by several features. In PF, acantholytic blisters are located high within the epidermis, usually just beneath the stratum corneum. Hence PF is a more superficial blistering disease than PV. The distribution of lesions in the two disorders is much the same, except that in PF mucous membranes are almost always spared. Patients with PF rarely demonstrate intact blisters but rather exhibit shallow erosions associated with erythema, scale, and crust formation. Mild cases of PF resemble severe seborrheic dermatitis; severe PF may cause extensive exfoliation. Sun exposure (ultraviolet irradiation) may be...

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Chapter 055. Immunologically Mediated Skin Diseases (Part 3) Pemphigus Foliaceus Pemphigus foliaceus (PF) is distinguished from PV by several features. In PF, acantholytic blisters are located high within the epidermis, usually just beneath the stratum corneum. Hence PF is a more superficial blistering disease than PV. The distribution of lesions in the two disorders is much the same, except that in PF mucous membranes are almost always spared. Patients with PF rarely demonstrate intact blisters but rather exhibit shallow erosions associated with erythema, scale, and crust formation. Mild cases of PF resemble severe seborrheic dermatitis; severe PF may cause extensive exfoliation. Sun exposure (ultraviolet irradiation) may be an aggravating factor. Fogo selvagem (FS), an endemic form of PF
thought to develop as a consequence of environmental stimuli (e.g., insect bites), is found in south central rural Brazil as well as selected sites in Latin America and Tunisia. Patients with PF have immunopathologic features in common with PV. Specifically, direct immunofluorescence microscopy of perilesional skin demonstrates IgG on the surface of keratinocytes. Similarly, patients with PF have circulating IgG autoantibodies directed against the surface of keratinocytes. Guinea pig esophagus is the optimal substrate for indirect immunofluorescence microscopy studies of sera from patients with PF. In PF, autoantibodies are directed against Dsg1, a 160-kDa desmosomal cadherin. As noted for PV, the autoantibody profile in patients with PF (i.e., anti-Dsg1 IgG) and the tissue distribution of this autoantigen (i.e., expression in oral mucosa that is compensated by coexpression of Dsg3) is thought to account for the distribution of lesions in this disease. Although pemphigus has been associated with several autoimmune diseases, its association with thymoma and/or myasthenia gravis is particularly notable. To date, >30 cases of thymoma and/or myasthenia gravis have been reported in association with pemphigus, usually with PF. Patients may also develop pemphigus as a consequence of drug exposure; drug-induced pemphigus usually resembles PF rather than PV. Drugs containing a thiol group in their chemical structure (e.g., penicillamine, captopril, enalapril) are most commonly
associated with drug-induced pemphigus. Nonthiol drugs linked to pemphigus include penicillins, cephalosporins, and piroxicam. It has been suggested that thiol- and nonthiol-containing drugs induce pemphigus via biochemical and immunologic mechanisms, respectively. Hence, the better prognosis upon drug withdrawal in cases of pemphigus induced by thiol-containing medications. Some cases of drug-induced pemphigus are durable and require treatment with systemic glucocorticoids and/or immunosuppressive agents. PF is generally a less severe disease than PV and carries a better prognosis. Localized disease can sometimes be treated with topical or intralesional glucocorticoids; more active cases can usually be controlled with systemic glucocorticoids. Patients with severe, treatment-resistant disease may require more aggressive interventions as described above for patients with severe PV. Paraneoplastic Pemphigus Paraneoplastic pemphigus (PNP) is an autoimmune acantholytic mucocutaneous disease associated with an occult or confirmed neoplasm. Patients with PNP typically show painful mucosal erosive lesions in association with papulosquamous and/or lichenoid eruptions that often progress to blisters. Palm and sole involvement is common in these patients and raises the possibility that prior reports of neoplasia-associated erythema multiforme actually may have represented unrecognized cases of PNP. Biopsies of lesional skin from these
patients show varying combinations of acantholysis, keratinocyte necrosis, and vacuolar-interface dermatitis. Direct immunofluorescence microscopy of patient skin shows deposits of IgG and complement on the surface of keratinocytes and (variably) similar immunoreactants in the epidermal basement membrane zone. Patients with PNP have IgG autoantibodies against cytoplasmic proteins that are members of the plakin family (e.g., desmoplakins I and II, bullous pemphigoid antigen 1, envoplakin, periplakin, and plectin) and cell-surface proteins that are members of the cadherin family (e.g., Dsg3 and Dsg1). Passive transfer studies have shown that autoantibodies from patients with PNP are pathogenic. The predominant neoplasms associated with PNP are non-Hodgkin's lymphoma, chronic lymphocytic leukemia, thymoma, spindle cell tumors, Waldenström's macroglobulinemia, and Castleman's disease; the latter is particularly common among children with PNP. In addition to severe skin lesions, many patients with PNP develop life-threatening bronchiolitis obliterans. PNP is generally resistant to conventional therapies (i.e., those used to treat PV); rare patients may improve (or even remit) following ablation or removal of underlying neoplasms.