INTRODUCTION — Mucous membrane pemphigoid (MMP) is a rare, chronic, autoimmune, subepithelial blistering and erosive disease that affects the mucosal surfaces of the mouth (gingiva, movable mucosa, tongue, and palate), eyes, nose, nasopharynx, hypopharynx, larynx, esophagus, genitals, and/or anus (picture 1A-C) [1,2]. Limited cutaneous involvement (typically localized to the head, neck, or upper trunk) also may be present. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Clinical features of mucous membrane pemphigoid'.)
MMP may cause significant morbidity due to the tissue destruction and functional limitations that result from chronic mucosal inflammation, pain, and scarring. As examples, gingival inflammation and scarring may lead to gingival recession and loss of teeth, conjunctival scarring may contribute to blindness, and laryngeal scarring may result in airway loss.
The treatment of MMP, particularly MMP involving the oral cavity, will be reviewed here. The management of ocular MMP (ocular cicatricial pemphigoid) and the clinical manifestations and diagnosis of MMP are discussed separately. (See "Ocular cicatricial pemphigoid" and "Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid" and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid" and "Management and prognosis of bullous pemphigoid".)
APPROACH TO TREATMENT — The primary goals of the treatment of mucous membrane pemphigoid (MMP) are to halt the progression of the disease, improve symptoms, and prevent adverse sequelae of chronic tissue inflammation and scarring [3,4]. Few high-quality trials have evaluated interventions for MMP . Thus, treatment is largely guided by clinical experience and small uncontrolled studies. Consistent use of the recommended measures for disease activity and treatment outcomes published in 2014 may aid in the systematic interpretation of data from future studies .
The approach to therapy is influenced by the following clinical factors :
●Site(s) of involvement
●Severity of disease
●Rate of disease progression
While patients with limited disease of the oral mucosa may be successfully managed with local therapies, patients with even mild involvement of sites associated with a higher risk of serious morbidity (ocular, genital, nasopharyngeal, laryngeal, or esophageal MMP) require systemic agents as initial therapy. Patients with severe or rapidly progressive disease also benefit from early treatment with systemic agents. (See 'Extraoral disease' below and "Ocular cicatricial pemphigoid".)
After clinical remission is attained, treatment is slowly tapered. The pace of tapering should be slow (eg, over several months) to minimize the risk for disease flares. If discontinuation of all therapy is not possible due to relapses, patients are maintained on the lowest effective topical or systemic maintenance regimen.
In addition to pharmacologic interventions, proper management of MMP includes consideration of the need for multidisciplinary care. Based upon the sites of known or suspected involvement, comanagement between dermatologists, dentists, ophthalmologists, otolaryngologists, urologists, internists, gastroenterologists, or colorectal surgeons is often needed. Whenever feasible, patients should be managed by clinicians experienced in the treatment of MMP. (See 'Extraoral disease' below.)
ORAL DISEASE — The oral cavity is the most common site of mucous membrane pemphigoid (MMP) (picture 1A-C) . Our approach to the treatment of oral MMP varies based upon the severity of disease. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Clinical features of mucous membrane pemphigoid'.)
Mild disease — Patchy, localized involvement of the oral mucosa and skin can often be treated effectively with local therapy. Topical corticosteroids are the first-line local treatment due to extensive clinical experience with the use of these agents for MMP. Topical tacrolimus and intralesional corticosteroid injections are additional therapeutic options.
Topical corticosteroids — Topical corticosteroids, which may be used as monotherapy for patients with mild oral disease or as an adjunct to systemic treatment in patients with more extensive disease, are important components of the therapeutic arsenal. Randomized trials to evaluate the efficacy of topical corticosteroids have not been performed. As noted above, clinical experience supports the use of these agents .
Administration — Class I, super high-potency topical corticosteroids (eg, 0.05% clobetasol propionate) in an ointment or gel base are recommended by most experts for treatment of oral MMP (table 1). Gels and ointments can be easily applied to mucosal surfaces and lack the gritty texture of topical corticosteroids formulated in dental pastes that some patients find unpleasant.
Treatment is applied two to four times per day immediately after the affected areas are dried with soft disposable tissue paper. Drying the mucosa prior to application may enhance the adherence of the medication to the treatment area. Patients should avoid eating or drinking for at least 30 minutes after application.
We encourage patients to do one of their daily applications immediately before bed since oral secretions are lessened during sleep. This may allow the medication to stay in place for a longer period.
An alternative mode of topical corticosteroid administration for patients who find the direct application of topical corticosteroids difficult is the use of 5 mL of dexamethasone (0.1 mg/mL) as a swish and spit mouth rinse two to three times per day. Patients treated in this manner should be instructed to avoid swallowing the medication.
Drug delivery via gingival trays is an additional method of drug administration that can be useful for patients with gingival involvement. The trays aid in the application of topical corticosteroids to lesional sites under occlusion [8,9]. The gingival tray should be fashioned in soft vinyl and fitted to cover the patient's gingiva (ie, not the patient's teeth). Trays containing topical corticosteroids are left in place for 10 to 20 minutes per treatment.
Beneficial effects of topical corticosteroid therapy are usually evident within several weeks. If topical corticosteroid therapy is successful, treatment can be tapered slowly (over several months) by reducing the frequency of application and using lower-potency agents. In our experience, patients who experience disease flares during topical corticosteroid tapering may benefit from a maintenance regimen in which treatment with a topical corticosteroid is alternated with topical tacrolimus (eg, topical tacrolimus applied Monday to Friday and a topical corticosteroid applied on weekends). Intermittent use of topical corticosteroids may help to reduce the risk for corticosteroid side effects.
Side effects — Examples of potential adverse effects of topical corticosteroid therapy include mucosal atrophy, oropharyngeal candidiasis, and dyspepsia. Topical or systemic antifungal therapy is effective for secondary candidiasis. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)
Topical tacrolimus — Topical tacrolimus, a calcineurin inhibitor, appears to be effective for some patients. Case reports document marked improvement in oral MMP with topical tacrolimus, including some patients who failed to respond well to topical corticosteroids [10-12].
Topical tacrolimus 0.1% ointment initially is applied two to three times per day and is tapered as tolerated. The method of administration mirrors that for topical corticosteroid treatment (see 'Administration' above). The higher cost of tacrolimus relative to many topical corticosteroids prohibits use of this therapy for some patients.
A transient burning sensation may occur following the application of topical tacrolimus. In addition, concern has been raised regarding a relationship between the use of topical calcineurin inhibitors and cancer, resulting in the issuing of a public health advisory by the US Food and Drug Administration . However, a causative relationship has not been proven. (See "Treatment of atopic dermatitis (eczema)", section on 'Topical calcineurin inhibitors'.)
Intralesional corticosteroids — Intralesional corticosteroid therapy is an option for disease in the anterior aspects of the mouth that does not respond sufficiently to other local measures. Support for the efficacy of this treatment is limited to clinical experience .
Injections should be placed into the superficial submucosa beneath erosions; deeper injections may increase the risk for mucosal atrophy. We inject 0.1 to 0.5 mL of triamcinolone acetonide (10 mg/mL) per injection site. We limit the total dose of triamcinolone acetonide administered during a single treatment session to 20 mg. (See "Intralesional corticosteroid injection", section on 'Adverse effects and pitfalls'.)
Moderate to severe disease — Patients with oral MMP that fails to respond adequately to local therapy or who present with widespread oral disease may benefit from systemic agents. Systemic glucocorticoids and dapsone are frequently used to manage these patients . The local therapies used for mild oral MMP are often prescribed as adjunctive agents. (See 'Mild disease' above.)
Systemic glucocorticoids — Systemic glucocorticoids are frequently used for oral MMP . However, data to support the efficacy of systemic glucocorticoids are limited. Our treatment regimen for systemic glucocorticoids is based upon clinical experience.
We typically treat patients with 0.25 to 0.5 mg/kg of prednisone per day given as a single morning dose. Since long-term treatment with systemic glucocorticoids is unfavorable due to drug-related side effects, we taper and discontinue prednisone within six months, if possible. Topical therapy or a systemic drug (eg, dapsone, azathioprine, mycophenolate mofetil) is used as a glucocorticoid-sparing agent to maintain clinical improvement during and after prednisone tapering. Patients who respond insufficiently to 0.25 to 0.5 mg/kg of prednisone may require higher doses of prednisone or alternative therapies. (See 'Severe and refractory disease' below.)
Systemic glucocorticoid therapy may lead to endocrinologic, musculoskeletal, cardiovascular, and other system abnormalities. The adverse effects of systemic glucocorticoids are reviewed separately. (See "Major adverse effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Dapsone — Dapsone in doses of 50 to 200 mg per day may be used for oral MMP that cannot be adequately managed with local therapy . Data on the efficacy of dapsone for oral manifestations of MMP are limited to a few uncontrolled studies and case series in which some patients improved after the initiation of dapsone therapy [15-21]. As an example, dapsone appeared to be effective in a retrospective study that included 11 patients with MMP localized to the gingiva. Treatment with dapsone (up to 150 mg per day) for at least 12 weeks was associated with major or complete improvement in 10 patients (91 percent) . Additional support for the use of dapsone comes from studies performed in patients with ocular MMP [22,23]. (See "Ocular cicatricial pemphigoid", section on 'Mild to moderate disease'.)
Dapsone is initiated at a low dose (eg, 25 to 50 mg per day) and is titrated upward as tolerated (eg, 25 to 50 mg per week depending on patient age and tolerance). The slow dose escalation is accompanied by close laboratory monitoring for adverse effects.
Hemolysis and methemoglobinemia are pharmacologic side effects of dapsone that occur in virtually all treated patients. Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency have an increased risk for adverse consequences due to these pharmacologic effects of dapsone. We assess for G6PD deficiency prior to initiating treatment. Other potentially severe (and usually rare) adverse effects of dapsone include leukopenia, agranulocytosis, aplastic anemia, hypersensitivity reactions, and neuropathy (usually motor, though a sensory component may coexist). More common adverse effects include headache, nausea, weakness, dizziness, and fatigue. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)
Due to the potential for serious hematologic side effects, laboratory monitoring is necessary for patients receiving dapsone therapy. We typically obtain a complete blood count (CBC) with differential, liver function tests, and renal function tests prior to the start of therapy and repeat the CBC with differential every week during the first month of therapy and twice monthly for the subsequent two months. Thereafter, monitoring of the CBC, liver function tests, and renal function tests can be performed every three to four months . The more frequent monitoring schedule is repeated following dose increases.
Severe and refractory disease — Aggressive immunosuppressive regimens and biologic therapies may lead to improvement in patients with severe MMP that cannot be managed with the interventions described above. The potential for serious adverse effects and/or high cost of these agents limit their use as first-line therapy.
Immunosuppressants — Immunosuppressants, such as azathioprine, mycophenolate mofetil, and cyclophosphamide, are typically used in combination with systemic glucocorticoids for patients with severe, refractory oral MMP . Support for the use of these agents primarily stems from uncontrolled studies of patients with ocular involvement and clinical experience with patients with oral disease [1,22,26-32]. (See "Ocular cicatricial pemphigoid", section on 'Treatment'.)
When treating patients with severe, refractory oral MMP, we typically utilize a higher dose of prednisone than the dose we use as initial therapy for patients with moderate to severe oral MMP. We prescribe 1 mg/kg per day of prednisone in addition to one of the following immunosuppressive agents :
●Azathioprine (2 to 2.5 mg/kg per day; dose adjustments may be indicated based upon thiopurine methyltransferase [TPMT] activity)
●Mycophenolate mofetil (1 to 2.5 g per day)
●Cyclophosphamide (1 to 2 mg/kg per day)
We continue treatment with both drugs until disease control is achieved and has remained stable for at least four to six months. We then attempt to taper prednisone gradually (eg, over another four to six months) while maintaining the dose of the nonsteroidal immunosuppressant. Once disease control is maintained without prednisone for four to six months, we attempt a slow taper to treatment discontinuation. However, because MMP is a chronic disease, most patients require continuation of some level of therapy. Whenever feasible, we attempt to maintain improvement with local rather than systemic therapy. (See 'Mild disease' above.)
Other regimens may be beneficial. Based upon the findings of a retrospective study of six patients with MMP, combination therapy with prednisone, dapsone, and mycophenolate mofetil may be another useful treatment regimen for oral MMP . In another retrospective study, 9 of 13 patients given oral cyclophosphamide without systemic glucocorticoids responded to this treatment .
Potential adverse effects of immunosuppressive therapies include bone marrow suppression and increased risk for infection or malignancy. The adverse effects of azathioprine, mycophenolate mofetil, and cyclophosphamide are reviewed in greater detail separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects' and "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Adverse effects' and "General principles of the use of cyclophosphamide in rheumatic diseases".)
Intravenous immune globulin — IVIG (1 to 2 g/kg body weight administered over two to three days every two to six weeks for four to six months) is an often well-tolerated therapy that may be beneficial for patients with severe, refractory MMP, although the response to treatment is variable [35-42]. The use of IVIG for oral MMP is supported by a retrospective study of 20 patients with severe oral MMP in which 12 patients were treated with conventional immunosuppressive therapy and 8 patients, in whom conventional therapy was contraindicated, were treated with IVIG (1 to 2 g/kg per three-day cycle, initially repeated every four weeks). The mean follow-up period was four years. Patients treated with IVIG had better outcomes than those treated with conventional therapy; IVIG-treated patients had significantly shorter durations of treatment, fewer relapses, higher remission rates, fewer adverse effects, and better quality-of-life assessments . The mean time to disease control was six months for patients who received IVIG compared with approximately nine months for patients who received conventional therapy.
IVIG (1 to 2 g/kg per three-day cycle, initially repeated every four weeks) also appeared to be effective in an uncontrolled study of 15 patients with severe MMP involving multiple mucosal surfaces that was poorly responsive to conventional immunosuppressive therapies . All patients responded to therapy and were eventually able to discontinue concurrent systemic treatments. Treatment efficacy was evident within a mean of five months.
The frequency of IVIG infusions is slowly tapered once disease control is attained, often by progressively increasing the period between treatments by two weeks and discontinuing treatment after a 16-week, disease-free interval occurs [40,41]. Potentially severe adverse effects of IVIG include anaphylaxis (especially in patients with immunoglobulin A [IgA] deficiency), aseptic meningitis, acute renal failure, hypertension, thrombotic events, and fluid overload. Other adverse effects of IVIG include headache, back pain, chills, fever, flushing, myalgias, hypertension, nausea, vomiting, and phlebitis at the site of infusion. The adverse effects of IVIG are discussed in greater detail separately. (See "Intravenous immune globulin: Adverse effects".)
Achievement of long-term remission in MMP with IVIG has been reported. In a retrospective study of six patients with MMP (including ocular involvement) who failed to respond to conventional therapy or who could not tolerate long-term systemic glucocorticoid therapy, all maintained remission of ocular disease for up to nine years . The initial frequency of IVIG cycles was every two to four weeks. Intervals between treatments were gradually lengthened to 16 weeks following achievement of disease control. Systemic glucocorticoids and other immunosuppressive therapies were gradually tapered during IVIG therapy.
Rituximab — Rituximab, a chimeric, murine/human immunoglobulin G1 (IgG1) kappa monoclonal antibody directed against CD20 on pre-B and B lymphocytes, has been used successfully for the treatment of severe MMP [42,44-51]. The drug usually is given in combination with a systemic glucocorticoid, with or without other immunosuppressive agents:
●In a series of 25 patients with severe, refractory MMP involving the eyes, pharynx, larynx, or esophagus (including five patients classified as having mucous membrane predominant epidermolysis bullosa acquisita), one cycle of rituximab (375 mg/m2 given weekly for four weeks) was associated with complete responses in 17 patients (68 percent) . All patients were simultaneously treated with dapsone, sulfasalazine, and/or immunosuppressants.
The median time to remission after one cycle of rituximab was 12 weeks, and five additional patients responded completely after a second cycle. Relapses were common after treatment; 10 patients who achieved complete responses after one cycle of rituximab relapsed (mean time to relapse = four months after a complete response). However, seven of eight of the relapsed patients regained complete responses after a second cycle of rituximab. Two patients who were simultaneously treated with conventional immunosuppressants and high-dose systemic glucocorticoids died due to serious infections.
●In a retrospective study including a total of 49 patients with moderate to severe MMP treated with conventional immunosuppressive therapy, 24 patients who had failed therapy with immunosuppressants were concurrently treated with rituximab (four weekly infusions of 375 mg/m2 or two infusions of 1000 mg given 15 days apart) . Eleven patients received a single course of rituximab, whereas 13 required 2 to 16 additional infusions.
All 24 patients treated with rituximab achieved disease control an average of 10 months after the first dose of rituximab; of the 25 patients treated with conventional therapy alone, 10 achieved disease control an average of 38 months after starting immunosuppressive therapy. Relapse occurred in 10 of the 24 patients treated with rituximab 3 to 19 months after complete response and was controlled with additional rituximab therapy in five patients. Three of the 10 patients who achieved disease control with conventional therapy relapsed after one to three months and required increased immunosuppressive therapy to regain control.
Additional data on rituximab in patients with ocular MMP are reviewed separately. (See "Ocular cicatricial pemphigoid", section on 'Rituximab'.)
Adverse effects of rituximab include dizziness, nausea, itching, fever, chills, sneezing, myalgias, weakness, and/or dyspnea. Severe adverse effects of rituximab include severe infusion reactions, tumor lysis syndrome, acute renal failure, severe mucocutaneous reactions, cardiac arrhythmias, angina, and progressive multifocal leukoencephalopathy. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)
Other therapies — Examples of additional agents that have been reported to be effective in small numbers of patients include tetracyclines with nicotinamide , minocycline [53,54], sulfapyridine , thalidomide , bortezomib , baricitinib , etanercept [58-60], infliximab , and tofacitinib .
Adjunctive measures — Patients with oral involvement should follow a strict regimen of oral hygiene to avert the accumulation of plaque, the loss of gingiva, and acceleration of tooth decay. This includes brushing of the teeth two to three times each day along with daily flossing and obtaining regular dental cleanings every three to four months. Use of a pediatric toothbrush with soft bristles, toothpaste that lacks sodium lauryl sulfate, and mouthwashes free of alcohol facilitate patient compliance with oral hygiene measures by minimizing pain.
Topical anesthetics (eg, viscous lidocaine, topical dyclonine) may be used to reduce pain. Patients may apply topical anesthetics before meals, toothbrushing, dental procedures, or other occasions in which pain control is required. The anesthetic should be manually applied directly to painful erosions, rather than used as a mouth rinse. Care should be taken to avoid spread of the anesthetic to pharyngeal, hypopharyngeal, or laryngeal areas to diminish the likelihood of aspiration.
EXTRAORAL DISEASE — Patients with extraoral mucous membrane pemphigoid (MMP; ocular, nasal, laryngeal, esophageal, or anogenital MMP) are considered to be at high risk for developing serious functional limitations as a consequence of mucosal inflammation and scarring. Thus, the approach to the treatment of patients with these manifestations of MMP differs from the approach to patients with only oral disease. Overall, pharmacologic therapy is more aggressive; systemic agents are often utilized initially regardless of the severity of disease . In addition, early involvement of ophthalmologists, otolaryngologists, and gastroenterologists are indicated for patients with ocular, laryngeal, or esophageal symptoms, respectively. Consultation with an urologist or colorectal surgeon may be useful for patients with anogenital disease.
Data are limited on the management of patients with nonocular extraoral MMP. In general, the approach to drug therapy of nasal, laryngeal, esophageal, and anogenital MMP mirrors the approach to ocular involvement [1,25]. The treatment of ocular MMP (ocular cicatricial pemphigoid) is reviewed in detail separately. (See "Ocular cicatricial pemphigoid", section on 'Treatment'.)
In addition to systemic pharmacologic therapy, other interventions may be useful for managing the extraoral manifestations of MMP:
•Twice-daily irrigation of nasal passages with saline or tap water via a bulb syringe, a piston syringe, a neti pot, or a nasal irrigation device helps to gently remove crusts.
•Topical corticosteroid nasal sprays or drops.
•Interventions to diminish gastroesophageal reflex and/or gastric acidity
•Esophageal dilation of strictures
•Topical corticosteroids or topical calcineurin inhibitors
Adjunctive measures for ocular MMP (eg, lubrication, lid hygiene, and management of trichiasis) are reviewed separately. (See "Ocular cicatricial pemphigoid", section on 'Ocular care'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mucous membrane pemphigoid".)
SUMMARY AND RECOMMENDATIONS
●Disease overview – Mucous membrane pemphigoid (MMP) is a rare, autoimmune blistering and erosive disorder that may affect multiple mucous membranes. The oral cavity is the most common site of involvement (picture 1A-C). (See 'Introduction' above and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Clinical features of mucous membrane pemphigoid'.)
●Approach to treatment – The approach to the treatment of MMP is influenced by the site(s) of mucosal involvement and the severity of disease. Multidisciplinary management is often needed to minimize risk for adverse sequelae of this disease. (See 'Approach to treatment' above.)
●Mild disease – Patients with mild oral MMP (patchy, localized involvement of the oral mucosa) may respond well to local therapy. For patients with mild oral MMP, we suggest a high-potency topical corticosteroid as initial therapy (Grade 2C). Topical tacrolimus and intralesional corticosteroid injections are additional options for local therapy. (See 'Mild disease' above.)
Gingival trays may facilitate treatment of patients with significant gingival involvement by allowing application of topical corticosteroids to lesional sites under occlusion. Patients who have difficulty applying topical corticosteroids directly to affected sites may benefit from treatment with a corticosteroid mouth rinse. (See 'Administration' above.)
●Moderate to severe disease or disease resistant to local therapy – Patients with extensive oral involvement or who fail to improve adequately with local therapy are candidates for systemic treatment. We suggest treating these patients with prednisone or dapsone (Grade 2C). We use prednisone more frequently based upon personal experience of better results with this drug. However, the side effect profile of prednisone is a limiting factor for therapy. (See 'Moderate to severe disease' above and "Major adverse effects of systemic glucocorticoids".)
Since long-term treatment with prednisone therapy is not desired, topical or systemic glucocorticoid-sparing agents (eg, dapsone, azathioprine, mycophenolate mofetil) are used to maintain improvement during and after prednisone tapering. (See 'Systemic glucocorticoids' above.)
●Severe, refractory disease – Patients with severe, refractory MMP may benefit from more aggressive therapy. High-dose prednisone given in combination with immunosuppressants, intravenous immune globulin (IVIG), and rituximab are options for therapy. (See 'Severe and refractory disease' above.)
●Extraoral disease – Pharmacologic therapy for the nonoral forms of MMP is similar to the approach used for ocular MMP (ocular cicatricial pemphigoid). Nonpharmacologic interventions are also useful for the management of these patients. (See 'Extraoral disease' above and "Ocular cicatricial pemphigoid", section on 'Treatment'.)
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