บทความ
Management of mucous membrane pemphigoid
Abstract
Mucous membrane pemphigoid (MMP) is a chronic autoimmune subepithelial vesiculobullous disorder that predominantly affects the mucous membranes more frequently than the skin. Several target antigens in basement membrane zone have been identified in MMP. The disease severity and extension are highly variable. The patients may present with only mucosal or skin lesions or combined multiple sites. In the oral cavity, the most frequently affected site is the gingiva presented as desquamative gingivitis. The diagnosis of MMP is mainly based on clinical findings, histopathologic and immunofluorescence features. There is no gold standard therapy for MMP. The treatment should be individualized based on the sites of involvement, clinical severity and disease progression. Patients with mild disease can be treated effectively with topical therapy, such as topical corticosteroids or topical calcineurin inhibitors. In high-risk patients with multiple involving sites or rapid progression, systemic corticosteroids in combination with immunosuppressive drugs have been used. The significant complication is scarring of the oropharyngeal and ocular mucous membranes which can lead to strictures and blindness. Multidisciplinary approach is necessary for the diagnosis and management of MMP. This article reviews the management of MMP.
Keywords: Autoimmune, Mucous membrane pemphigoid, Corticosteroids, Immunosuppressants, Management
*DDS. College of Dental Medicine, Rangsit University, 52/347 Muang Ake, Phaholyothin Road, A. Muang, Pathum Thani 12000 Thailand, Phone: (66)2-9972000, email: nutchaporn.s@rsu.ac.th
**DDS., Ph.D., College of Dental Medicine, Rangsit University, 52/347 Muang Ake, Phaholyothin Road, A. Muang, Pathum Thani 12000 Thailand, Phone: (66)2-9972000, email: kraisorn.s@rsu.ac.th
MMP Management
Treatment of MMP is based on the involved sites, severity and disease progression. Additionally, it should be individualized depending on age, medical history and contraindications of any systemic medications (1). In low-risk patients with lesions affecting oral mucosa and/or
skin can be treated effectively with topical therapy, such as topical corticosteroids or topical calcineurin inhibitors. For more severe or recalcitrant lesions or during exacerbation of disease in low-risk patients, the treatment should be combined with systemic therapy. High-risk patients with rapid progression or multiple involving sites including ocular, genital, esophageal or nasopharyngeal mucosa require more aggressive systemic treatment, such as systemic corticosteroids combined with immunosuppressive drugs (1). A multidisciplinary approach including oral medicine experts, ophthalmologists, gastroenterologist, otolaryngologist, gynaecologist, and dermatologists is essential for the management of MMP and related to the treatment outcome (2).
Pharmacologic strategies
Topical agents
Topical corticosteroids
High potency topical corticosteroids are the first-line therapy for the localized lesions limiting only oral cavity or oral cavity and skin (3). Topical corticosteroids such as triamcinolone acetonide, betamethasone valerate, beclomethasone dipropionate, budesonide, fluocinonide, fluocinolone acetonide and clobetasol propionate have been used as the initial treatment of MMP (6). Triamcinolone acetonide 0.1-0.5% in an aqueous rinse or ointment is generally not adequate for controlling the disease. Fluocinonide 0.05%, fluocinolone acetonide 0.1%, clobetasol propionate 0.05% or betamethasone dipropionate 0.05% are commonly effective and can be applied 2-3 times/day (4). After application, the patients should be advised not to drink or eat for 30 minutes. When the lesions are improved, the frequency of application is tapered gradually. In patients presenting with gingival lesions in the form of desquamative gingivitis, topical corticosteroids are generally more effective when used in custom tray that cover the involved gingiva (5). The common adverse effect associated with topical steroid therapy is secondary infection with candida which can be treated with antifungal agents, such as nystatin oral suspension, miconazole gel or clotrimazole troche. For frequent recurrence of oral candidiasis, antifungal prophylaxis may be necessary (6).
Intralesional corticosteroid injection with triamcinolone acetonide 10mg/ml 0.1 cc/cm2, every 2-4 weeks can be used in the treatment of recalcitrant MMP or as an adjunctive therapy for topical steroid. Multiple site injection should be performed to distribute the drug throughout the lesion (1).
Topical calcineurin inhibitors
Topical calcineurin inhibitors including tacrolimus, pimecrolimus and cyclosporine are effective in patients not response to topical corticosteroids (7). Topical tacrolimus has been effectively used in the treatment of recalcitrant MMP affecting oral mucosa, skin and conjunctiva by down-regulating effect on local T-cells (6). Daily use of topical tacrolimus 0.1% may be combined with prednisolone (40 mg/day) to control the lesions and allowed tapering of the prednisolone dose (8). Additionally, application of topical tacrolimus alone resulted in complete healing of erosive lesions after 3 months and can prevent disease progression .
Systemic corticosteroids
Systemic corticosteroids have efficacy in patients with severe and multiple oral lesions or rapid progression (1). They have a rapid action since the treatment is initiated (3). Prednisolone 0.75-1 mg/kg/day is usually an initial dose, and this dose is continued until the therapeutic response has been achieved (no new lesions developed and all lesions are healed). After that, the dose should be reduced gradually by 5-10 mg/week. If the disease exacerbates while steroid tapering, the dose using before the disease flaring is represcribed and should be maintained that dose for about 4 weeks. Several corticosteroid-sparing agents such as azathioprine, cyclophosphamide or mycophenolate mofetil have been used as an adjuvant therapy to decrease the dose of systemic corticosteroids and minimize many adverse effects of long-term corticosteroid treatment (1).
Long-term systemic corticosteroid therapy can cause several adverse effects, including hypertension, weight gain, hyperglycemia, hyperlipidemia, water retention, peptic ulcers, secondary infection, cataract, osteoporosis, myopathy, adrenal suppression, difficulty sleeping, and nervousness, so it should be used at the lowest effective dose and for the shortest time, possible.
Azathioprine
Azathioprine is effective for management of autoimmune blistering diseases, including MMP (9). Because it has a long onset of action (up to 8 weeks), so It is typically use as an adjuvant medication to corticosteroids. The dose ranges from 1 to 2 mg/kg per day. However, the dosage should be individualized depended on the patient’s thiopurine methyltransferase level (5).
Cyclophosphamide
Cyclophosphamide combined with systemic corticosteroid is the first-line therapy for high-risk patients to prevent severe complications including esophageal stenosis, asphyxiation and blindness (10). In addition, for patients with severe refractory MMP, cyclophosphamide with or without corticosteroids achieve efficacy in controlling disease rapidly (1). The dose ranges between 1-2 mg/kg/day or 50-200mg/day. However, the dosage should be determined according to the progression of the disease and the adverse effects (10).
Mycophenolate mofetil
Mycophenolate mofetil is an immunosuppressant which inhibits inosine monophosphate dehydrogenase, an important enzyme in the de novo purine synthesis. This results in inhibition the proliferation of T and B lymphocytes and the production of antibodies (1).
Methotrexate
Methotrexate is an antimetabolite that inhibits to dihydrofolate reductase, an enzyme that catalyses the conversion of dihydrofolate to the tetrahydrofolate. Tetrahydrofolate is a cofactor necessary for the synthesis of nucleotides required for DNA and RNA synthesis. Methotrexate for the immunosuppression is that it inhibits proliferation of the lymphocytes and other cells responsible for inflammation (1).
Dapsone
Some studies have reported the effectiveness of dapsone in management of MMP . Additionally, dapsone can be used as first-line treatment in localized MMP or extensive MMP without rapid progression. It can be used alone or combined with systemic corticosteroid (1) .
Cyclosporine
The combination therapy of cyclosporine and corticosteroids was reported an effective therapy in controlling disease (11). However, Foster et al. reported cyclosporine was ineffective in the treatment of MMP (11). More studies are needed to determine the ability of cyclosporine in treatment of MMP.
Tetracyclines
The mechanisms of anti-inflammatory and immunomodulatory actions are related to the inhibition of neutrophil and eosinophil chemotaxis, decrease antibody production and prostaglandin synthesis. Tetracyclines have also reduced various tissue enzymes, including collagenase, lipase, and metalloproteinases 2 and 9, resulting in reducing extracellular matrix breakdown (12).
Biologics
More recently, biologic agents have been found to be effective for management of mucocutaneous diseases including MMP (13). In serum and blister fluid of patients with autoimmune blistering disorders have shown increasing of tumor necrosis factor alpha (TNF-α), so anti-TNFα agents such as etanercept, infliximab and thalidomide are considered as an alternative treatment for these conditions (14).