Chapter 055. Immunologically Mediated Skin Diseases (Part 6)

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Linear IgA Disease Linear IgA disease, once considered a variant form of dermatitis herpetiformis, is actually a separate and distinct entity. Clinically, these patients may resemble individuals with DH, BP, or other subepidermal blistering diseases. Lesions typically consist of papulovesicles, bullae, and/or urticarial plaques predominantly on central or flexural sites. Oral mucosal involvement occurs in some patients. Severe pruritus resembles that seen in patients with DH. Patients with linear IgA disease do not have an increased frequency of the HLA-B8/DRw3 haplotype or an associated enteropathy and hence are not candidates for treatment with a gluten-free diet. ...

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Chapter 055. Immunologically Mediated Skin Diseases (Part 6) Linear IgA Disease Linear IgA disease, once considered a variant form of dermatitis herpetiformis, is actually a separate and distinct entity. Clinically, these patients may resemble individuals with DH, BP, or other subepidermal blistering diseases. Lesions typically consist of papulovesicles, bullae, and/or urticarial plaques predominantly on central or flexural sites. Oral mucosal involvement occurs in some patients. Severe pruritus resembles that seen in patients with DH. Patients with linear IgA disease do not have an increased frequency of the HLA-B8/DRw3 haplotype or an associated enteropathy and hence are not candidates for treatment with a gluten-free diet.
The histologic alterations in early lesions may be virtually indistinguishable from those in DH. However, direct immunofluorescence microscopy of normal- appearing perilesional skin reveals linear deposits of IgA (and often C3) in the epidermal basement membrane zone. Most patients with linear IgA disease demonstrate circulating IgA anti-basement membrane autoantibodies directed against neoepitopes in the proteolytically processed extracellular domain of BPAG2. These patients generally respond to treatment with dapsone, 50–200 mg/d. Epidermolysis Bullosa Acquisita EBA is a rare, noninherited, polymorphic, chronic, subepidermal blistering disease. (The inherited form is discussed in Chap. 357.) Patients with classic or noninflammatory EBA have blisters on noninflamed skin, atrophic scars, milia, nail dystrophy, and oral lesions. Because lesions generally occur at sites exposed to minor trauma, classic EBA is considered to be a mechanobullous disease. Other patients with EBA have widespread inflammatory, scarring, and bullous lesions that resemble severe BP. Inflammatory EBA may evolve into the classic, noninflammatory form of this disease. Rare patients present with lesions that predominate on mucous membranes. The HLA-DR2 haplotype is found with increased frequency in EBA patients. Recent studies suggest that EBA is often associated with inflammatory bowel disease (especially Crohn's disease).
The histology of lesional skin varies depending on the character of the lesion being studied. Noninflammatory bullae show subepidermal blisters with a sparse leukocytic infiltrate and resemble those in patients with porphyria cutanea tarda. Inflammatory lesions consist of neutrophil-rich subepidermal blisters. EBA patients have continuous deposits of IgG (and frequently C3 as well as other complement components) in a linear pattern within the epidermal basement membrane zone. Ultrastructurally, these immunoreactants are found in the sublamina densa region in association with anchoring fibrils. Approximately 50% of EBA patients have demonstrable circulating IgG anti-basement membrane autoantibodies directed against type VII collagen—the collagen species that comprises anchoring fibrils. Such IgG autoantibodies bind the dermal side of 1 M NaCl split skin (in contrast to IgG autoantibodies in patients with BP). Recent studies have shown that passive transfer of experimental or patient IgG directed against type VII collagen can produce lesions in mice that clinically, histologically, and immunopathologically resemble those seen in patients with inflammatory EBA. Treatment of EBA is generally unsatisfactory. Some patients with inflammatory EBA may respond to systemic glucocorticoids, either alone or in combination with immunosuppressive agents. Other patients (especially those with neutrophil-rich inflammatory lesions) may respond to dapsone. The chronic, noninflammatory form of this disease is largely resistant to treatment, although
some patients may respond to cyclosporine, azathioprine, or IV immunoglobulin (IVIg). Cicatricial Pemphigoid Cicatricial pemphigoid (CP) is a rare, acquired, subepithelial immunobullous disease characterized by erosive lesions of mucous membranes and skin that result in scarring of at least some sites of involvement. Common sites of involvement include the oral mucosa (especially the gingiva) and conjunctiva; other sites that may be affected include the nasopharyngeal, laryngeal, esophageal, and anogenital mucosa. Skin lesions (present in about one-third of patients) tend to predominate on the scalp, face, and upper trunk and generally consist of a few scattered erosions or tense blisters on an erythematous or urticarial base. CP is typically a chronic and progressive disorder. Serious complications may arise as a consequence of ocular, laryngeal, esophageal, or anogenital lesions. Erosive conjunctivitis may result in shortened fornices, symblephara, ankyloblepharon, entropion, corneal opacities, and (in severe cases) blindness. Similarly, erosive lesions of the larynx may cause hoarseness, pain, and tissue loss that, if unrecognized and untreated, may eventuate in complete destruction of the airway. Esophageal lesions may result in stenosis and/or strictures that may place patients at risk for aspiration. Strictures may also complicate anogenital involvement.
Biopsies of lesional tissue generally demonstrate subepithelial vesiculobullae and a mononuclear leukocytic infiltrate. Neutrophils and eosinophils may be seen in biopsies of early lesions; older lesions may demonstrate a scant leukocytic infiltrate and fibrosis. Direct immunofluorescence microscopy of perilesional tissue typically demonstrates deposits of IgG, IgA, and/or C3 in the epidermal basement membrane of these patients. Because many of these patients show no evidence of circulating anti-basement membrane autoantibodies, testing of perilesional skin is important diagnostically. Although CP was once thought to be a single nosologic entity, it is now largely regarded as a disease phenotype that may develop as a consequence of an autoimmune reaction against a variety of different molecules in epidermal basement membrane (e.g., BPAG2, laminin 5, type VII collagen, and other antigens yet to be completely defined). Recent studies suggest that CP patients with anti-laminin 5 autoantibodies have an increased relative risk for cancer. Treatment of CP is largely dependent upon sites of involvement. Due to potentially severe complications, patients with ocular, laryngeal, esophageal, and/or anogenital involvement require aggressive systemic treatment with dapsone, prednisone, or the latter in combination with another immunosuppressive agent (e.g., azathioprine, mycophenolate mofetil, or cyclophosphamide) or IVIg. Less threatening forms of the disease may be managed with topical or intralesional glucocorticoids.