Benign mucosal pemphigoid= الفقاعاني المخاطي الحميد |
Cicatricial pemphigoid
Cicatricial pemphigoid (CP) refers to a group of rare chronic autoimmune blistering diseases that predominately affects the mucous membranes, including the conjunctiva, and occasionally the skin. Patients with cutaneous involvement present with tense blisters and erosions, often on the head and the neck or at sites of trauma. Scarring of the mucous membranes is common, hence the designation cicatricial, which can lead to decreased vision, blindness, and supraglottic stenosis with hoarseness or airway obstruction. The first international consensus on mucous membrane pemphigoid was published in 2002.1
The classification of cicatricial pemphigoid patients has been difficult because some patients with other autoimmune blistering diseases, including bullous pemphigoid (BP) and epidermolysis bullosa acquisita (EBA), may have mucosal involvement. Also, clinical heterogeneity exists in the clinical manifestations of this disease, with some patients presenting with ocular involvement and others with oropharyngeal involvement. The heterogeneity in clinical manifestations does not appear to be linked to the heterogeneity of the target antigens alone. PathophysiologyAs in other autoimmune diseases, environmental factors combined with genetic susceptibility lead to development of autoantibodies. By direct immunofluorescence (DIF) study, antibodies bound in a linear band at the epidermal-dermal junction have been found in patients with cicatricial pemphigoid, as depicted below. By immunoelectron microscopy, these antibodies are found in the lamina lucida. In some patients, autoantibodies extend to the lamina densa. When detectable, circulating autoantibodies are present in a low titer. Different epithelial membrane zone components have been recognized by antibodies in patients with cicatricial pemphigoid, including bullous pemphigoid antigen 1 and 2 (BPAG1 and BPAG2), laminin 5, laminin 6, type VII collagen, b4 integrin subunit, and antigens with unknown identities (a 45-kd protein, uncein, a 168-kd epithelial protein, and a 120-kd epithelial protein). While circulating autoantibodies in a given patient tend to target a single antigen, sera of patients with same clinical features may target different autoantigens
History
Physical
Causes
Laboratory StudiesImaging StudiesOther TestsHistologic FindingsBiopsy of the edge of an early blister typically reveals a noninflammatory, subepidermal blister. When present, the inflammatory infiltrate localizes to the dermal-epidermal junction and the perivascular areas. This histologic feature can also be seen in other autoimmune subepidermal blistering diseases, including cell-poor BP, EBA, and linear IgA bullous dermatosis. The histologic features of porphyria cutanea tarda and variegate porphyria may also resemble cicatricial pemphigoid.
Medical CareThe goal of treatment is to suppress extensive blister formation, to promote healing, and to prevent scarring. The lowest dose of medication to suppress disease activity and to minimize the risk for the patient should be used. This disorder is extremely difficult to treat. Even with optimum control, blisters may continue to develop in some patients. The risks and the benefits of therapy must always be evaluated for each patient. Wound care of erosions includes daily gentle cleaning or compresses, topical agents to promote wound healing, and biologic dressings. The goals of wound care are to minimize trauma to the surrounding skin, to promote healing, and to diminish scarring. Increased risk of malignancies has been documented in patients with antiepiligrin cicatricial pemphigoid, especially in the first year of disease; hence, appropriate screening is warranted. Surgical CareSurgical intervention may be required to improve functioning or to prevent further morbidity. Such intervention is directed at the sequelae of chronic blistering. ConsultationsThe management of cicatricial pemphigoid requires a coordinated team approach. Specific consultations are dictated by the phenotype of the disease and the target organ or organs that are involved. DietActivityPatients are encouraged to lead as normal a life as possible; however, cutaneous and mucosal blisters may be induced by trauma. Contact lenses, dental plates, or bridges may precipitate or exacerbate mucosal disease. Patients may benefit by minimizing activities, such as contact sports, that traumatize the skin and precipitate blistering. Nontraumatic exercises, such as swimming or aquatic exercises, may be beneficial. MedicationPatients with mild localized disease may benefit from topical steroids (eg, triamcinolone [Kenalog in Orabase]) in gel-based topical agents for oral disease or in ointment-based topical steroids for cutaneous disease. Intralesional steroids can be administered as triamcinolone acetonide (Kenalog susp) 10 mg/mL injected weekly or biweekly for oral and cutaneous lesions. Patients with more extensive disease and progressive scarring require systemic therapy with prednisone and/or steroid-sparing agents, such as cyclophosphamide, azathioprine, cyclosporin, mycophenolate mofetil. Evidence from 2 small randomized controlled trials indicates that ocular cicatricial pemphigoid responds best to cyclophosphamide, while mild-to-moderate disease seems effectively suppressed by treatment with dapsone. High-dose intravenous immune globulin has been used successfully in the treatment of cicatricial pemphigoid in patients who were refractory to other therapies. Immunosuppressive agents should be prescribed and monitored by physicians familiar with these medications. The 2002 consensus statement on cicatricial pemphigoid1 reports expert panel opinion on the management of the disease. Anti-inflammatory AgentsThese agents decrease the inflammatory response. Triamcinolone topical (Kenalog, Kenalog in Orabase)Agent for mild disease or used as an adjuvant in patients receiving concurrent systemic therapy. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability. AdultApply topically to gingiva and oral blisters tid PediatricApply as in adults None reported Documented hypersensitivity; fungal, viral, and bacterial skin infections; not indicated in extensive mucosal involvement PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus PrecautionsDo not use in decreased skin circulation; prolonged use, applying over large areas, and using potent steroids and occlusive dressings may result in systemic absorption; systemic absorption may cause Cushing syndrome, reversible HPA-axis suppression, hyperglycemia, and glycosuria Dapsone (Avlosulfon)DOC for ocular cicatricial pemphigoid and often beneficial in patients with oral mucosal disease. Bactericidal and bacteriostatic against mycobacteria. Mechanism of action is similar to that of sulfonamides where competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth. Adult50 mg PO qd initial; increase to 100 mg/d as tolerated Pediatric>1 month: 1 mg/kg/d PO; not to exceed 100 mg May inhibit anti-inflammatory effects of clofazimine; hematologic reactions may increase with folic acid antagonists, eg, pyrimethamine (monitor for agranulocytosis during second and third months of therapy); probenecid increases toxicity; trimethoprim with dapsone may increase toxicity of both drugs; because of increased renal clearance, levels may significantly decrease when administered concurrently with rifampin; concomitant administration of zidovudine may increase risk of hematologic toxicity; amprenavir and saquinavir may inhibit cytochrome P4503A (CYP3A), the hepatic isoenzyme group with major activity related to dapsone metabolism, thereby leading to increased dapsone serum concentrations and potential toxicity Documented hypersensitivity; known G-6-PD deficiency (assay for G-6-PD activity prior to initiation of therapy) PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus PrecautionsAssociated with a variety of systemic toxicities, including agranulocytosis, anemia, methemoglobinemia, hepatitis, and neuropathy; patients may experience headache and/or GI distress on initiation of therapy; perform weekly blood counts (first mo), then monthly WBC counts (6 mo), then semiannual WBC counts; discontinue if a significant reduction in platelets, leukocytes, or hematopoiesis occurs; caution in methemoglobin reductase deficiency, G-6-PD deficiency, or hemoglobin M because of high risk for hemolysis and Heinz body formation; caution in patients exposed to other agents or conditions (eg, infection, diabetic ketosis) capable of producing hemolysis; peripheral neuropathy can occur (rare); phototoxicity may occur when exposed to UV light; pancreatitis may occur; various forms of renal complications including acute renal failure, acute tubular necrosis, and oliguria have occurred with dapsone use Prednisone (Deltasone, Orasone, Sterapred)May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Adult20-40 mg/kg/d PO qam or in divided doses initially; if no response, dose is typically increased by 50% q3-5d Pediatric1-2 mg/kg PO qd or divided bid/qid; taper over 2 wk as symptoms resolve Coadministration with estrogens may decrease clearance; when used with digoxin, digitalis toxicity secondary to hypokalemia may increase; phenobarbital, phenytoin, and rifampin may increase the metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics; coadministration with ritonavir may significantly increase serum concentrations of prednisone; concomitant therapy with montelukast may result in severe peripheral edema; clarithromycin may increase risk of psychotic symptoms Documented hypersensitivity; viral, fungal, tubercular skin, or connective tissue infections; peptic ulcer disease; hepatic dysfunction PregnancyB - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals PrecautionsMay unmask hypertension or diabetes or exacerbate peptic ulcer disease and tuberculosis; long-term sequelae associated with long-term steroid use include osteoporosis, cataracts, and pituitary-hypothalamic axis suppression; with high doses, patients may develop a steroid psychosis and are at increased risk of infections, particularly when oral steroids are used in conjunction with other immunosuppressants; frequently monitor patient's blood sugar level, blood pressure, and weight; monitor for Cushing syndrome ImmunosuppressantsThese agents inhibit immune reactions resulting from diverse stimuli. Azathioprine (Imuran)Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity. Adult1 mg/kg/d PO for 6-8 wk; increase by 0.5 mg/kg q4wk until response or dose reaches 2.5 mg/kg/d PediatricAdminister as in adults Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine; coadministration with mycophenolate may increase toxicity; alfalfa, black Cohosh, and echinacea may reduce immunosuppressive drug effectiveness Documented hypersensitivity; deficiency of thiopurine methyltransferase (can result in severe myelosuppression and leukopenia); history of treatment with alkylating agents PregnancyD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus PrecautionsIncreases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; hepatotoxicity and pancreatitis reported Cyclosporine (Sandimmune, Neoral)Demonstrated to be helpful in a variety of skin disorders. Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions, such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease for a variety of organs. For children and adults, base dosing on ideal body weight. Adult3-9 mg/kg/d PO PediatricAdminister as in adults Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UV-B radiation in patients with psoriasis because it may increase risk of cancer PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus PrecautionsEvaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzyme levels and blood pressure; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO; adverse effects include nephrotoxicity, hypertension, hepatotoxicity, gingival enlargement, hyperkalemia, hypomagnesemia, pancreatitis, and paresthesia; factors that may increase risk for neurotoxicity from cyclosporine include hypomagnesemia, hypocholesterolemia, fever, infection, hypertension, intravenous administration, and rapidly increasing cyclosporine blood levels; caution with medications metabolized by cytochrome P450 3A4 Cyclophosphamide (Cytoxan, Neosar)Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. Adult1-5 mg/kg/d IV; alternatively 2.5-3 mg/kg/d PO divided qid PediatricAdminister as in adults Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity; concurrent use of NSAIDs has resulted in increases in cyclosporine levels, nephrotoxicity, and increased plasma creatinine concentrations Documented hypersensitivity; severely depressed bone marrow function PregnancyD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus PrecautionsRegularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; adverse effects include oligospermia or azoospermia, cardiomyopathy, infectious disease, interstitial pneumonia, increase risk of malignancy, possibility of increased toxicity in adrenalectomized patients Mycophenolate (CellCept)Inhibits purine synthesis and proliferation of human lymphocytes. Adult1-1.5 g PO bid Pediatric<3 months: Not established . |