Mucous membrane pemphigoid

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Mucous membrane pemphigoid

Caroline P. Allen and Vanessa Venning

Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports

Mucous membrane pemphigoid (MMP) formerly known as cicatricial pemphigoid is a heterogeneous group of chronic acquired autoimmune sub-epidermal blistering diseases. It is characterized by blistering and erosions of one or more mucous membranes (eyes, oral mucosa, oesophagus, genitals) and to a lesser extent the skin. This may lead to permanent scarring of the affected area, particularly the conjunctiva.

Management strategy

MMP is a chronic disease and does not generally remit spontaneously; disease activity will fluctuate without treatment, and treatments are disease modifying rather than curative.

Optimal treatment for MMP is unclear as there is little evidence in the form of randomized control trials; international consensus guides treatment strategy, based on the site, severity, extent and rate of progression of disease. Patient co-morbidities must also be considered and a multidisciplinary approach is vital.

Interventions for mucous membrane pemphigoid and epidermolysis bullosa aquisitia.

Kirtshig G, Murrell D, Wojnarowska F, Khumalo N. Cochrane Database Syst Rev 2003;CD004056.

The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment and prognostic indicators.

Chan LS, Ahmed AR, Anhalt GJ, Bernauer W, Cooper KD, Elder MJ, et al. Arch Dermatol 2002; 138: 370–9.

Specific investigations

First-line therapies

Topical corticosteroids	C
Dapsone	C
Anti-inflammatory antibiotics	D
Systemic corticosteroids	C
Cyclophosphamide	C

Mild disease

The management of oral mucous membrane pemphigoid with dapsone and topical corticosteroid.

Arash A, Shirin L. J Oral Pathol Med 2008; 37: 341–4.

Five patients with mild MMP had a good response to triamcinolone in orabase.

Treatment of severe erosive gingival lesions by topical application of clobetasol propionate in custom trays.

Gonzales-Moles MA, Ruiz Avila I, Rodriguez-Archilla A, Morales-Garcia P, Mesa-Aguado F, Bascones-Martinez A, et al. Oral Surg Oral Med Oral Pathol Oral Radiol Endodont 2003; 95: 688–92.

Improvement in all 22 patients with oral MMP treated with topical clobetasol propionate with nystatin applied via a gingival tray.

Treatment-resistant or severe disease

Dapsone efficacy and adverse events in the management of mucous membrane pemphigoid.

Hegarty AM, Ormond M, Sweeney M, Hodgson T. Eur J Dermatol 2010; 20: 223–4.

Eight out of 20 patients improved with dapsone. One failed to respond and 11 developed side effects necessitating cessation.

The management of oral mucous membrane pemphigoid with dapsone and topical corticosteroid.

Arash A, Shirin L. J Oral Pathol Med 2008; 37: 341–4.

All 15 patients had a significant response to topical corticosteroids and dapsone 25–100 mg daily. Ten had complete resolution.

Dapsone therapy of cicatricial pemphigoid.

Rogers RS III, Mehregan DA. Semin Dermatol 1988; 7: 201–5.

Seventy-seven patients with oral, ocular or generalized MMP benefited from either 150 mg dapsone per day or 1500–3000 mg sulfapyridine per day for at least 12 weeks.

Treatment with dapsone 50–200 mg/day or sulfapyridine is effective in some patients.

Antiepiligrin cicatricial pemphigoid of the larynx successfully treated with a combination of tetracycline and niacinamide.

Sakamoto K, Mori K, Hashimoto T, Yancey KB, Nakashima T. Arch Otolaryngol Head Neck Surg 2002; 128: 1420–3.

Successful therapy with tetracycline and nicotinamide in cicatricial pemphigoid.

Kreyden OP, Borradori L, Trüeb RM, Burg G, Nestle FO. Hautarzt 2001; 52: 247–50.

Single case reports of effective treatment with tetracycline and nicotinamide (500–3000 mg/day).

Systemic minocycline as a therapeutic option in predominantly oral mucous membrane pemphigoid: a cautionary report.

Carrozzo M, Arduino P, Bertolusso G, Cozzani E, Parodi A. Int J Oral Maxillofac Surg 2009; 38: 1071–6.

Seven of nine patients with oral disease responded to minocycline 200 mg/day; however, side effects limited treatment in five patients.

Combination therapy with nicotinamide and tetracyclines for cicatricial pemphigoid: further support for its efficacy.

Reiche L, Wojnarowska F, Mallon E. Clin Exp Dermatol 1998; 23: 254–7.

Minocycline 50–100 mg/day combined with 2.5–3 g nicotinamide per day was beneficial in five of eight patients.

Anti-inflammatory antibiotics can be of benefit. Side effects may limit treatment. Nicotinamide may confer additional protection.

Second-line therapies

Topical mitomycin	C
Mycophenolate mofetil	C
Azathioprine	D
Methotrexate	D
Cyclosporine	D

Intraoperative mitomycin C in the treatment of cicatricial obliterations of conjunctival fornices.

Secchi AG, Tognon MS. Am J Ophthalmol 1996; 122: 728–30.

Intraoperative topical mitomycin was useful in 4 of 4 patients.

Subconjunctival mitomycin C for the treatment of ocular cicatricial pemphigoid.

Donnenfeld ED, Perry HD, Wallerstein A, Caronia RM, Kanellopoulos AJ, Sforza PD, et al. Ophthalmology 1999; 106: 72–9.

No disease progression occurred in eight of nine patients whose eyes were treated with subconjunctival mitomycin C.

Ocular cicatricial pemphigoid review.

Foster CS, Sainz De La Maza M. Curr Opin Allergy Clin Immunol 2004; 4: 435–9.

Subconjunctival mitomycin did not prevent progression of scarring.

The benefit of mitomycin is uncertain.

Mycophenolate mofetil for ocular inflammation.

Daniel E, Thorne JE, Newcomb CW, Pujari SS, Kaçmaz RO, Levy-Clarke GA, et al. Am J Ophthalmol 2010; 149: 423–32.

Retrospective cohort study of 18 patients with ocular MMP treated with mycophenolate mofetil in combination with prednisolone. 41% achieved complete control at 6 months, increasing to 71% at 1 year; most relapsed on discontinuation of prednisolone but the authors report a steroid sparing effect.

Long-term results of therapy with mycophenolate mofetil in ocular mucous membrane pemphigoid.

Doycheva D, Deuter C, Blumenstock G, Stuebiger N, Zierhut M. Ocul Immunol Inflamm 2011; 19: 431–8.

Retrospective study of 10 patients (19 eyes) with ocular MMP treated with mycophenolate mofetil (1 g/day) with prednisolone (initially 1 mg/kg/day, tapered to 5 mg/day). Control of inflammation achieved in 58% (11 of 19 eyes). Progression was prevented in 47% (nine of 19 eyes).

Treatment of mucous membrane pemphigoid with the combination of mycophenolate mofetil, dapsone, and prednisolone: a case series.

Staines K, Hampton PJ. Oral Surg Oral Med Oral Pathol Oral Radiol 2012 ; 114: e49–56.

Six patients with skin and oral disease treated with mycophenolate mofetil (1–1.5 g/day) with dapsone 50 mg and prednisolone 0.5 mg/kg/day. At 18 months all had complete resolution of skin, oral, and pharyngeal disease.

Cicatricial pemphigoid: treatment with mycophenolate mofetil.

Ingen-Housz-Oro S, Prost-Squarcioni C, Pascal F, Doan S, Brette MD, Bachelez H, et al. Ann Dermatol Venereol 2005; 132: 13–16.

Mycophenolate mofetil helped to control the disease in 10 of 14 patients; most also received cyclophosphamide or dapsone.

Immunosuppressive therapy for ocular mucous membrane pemphigoid strategies and outcomes.

Saw VP, Dart JK, Rauz S, Ramsay A, Bunce C, Xing W, et al. Ophthalmology 2008; 115: 253–61.

In a retrospective non-comparative study of 115 patients, azathioprine was effective in 47%. Side effects limited treatment in 40%. Combination of sulphur/steroid/myelosuppressive may be superior to single therapy. Control of inflammation does not necessarily prevent progression.

Azathioprine for ocular inflammatory diseases.

Pasadhika S, Kempen JH, Newcomb CW, Liesegang TL, Pujari SS, Rosenbaum JT, et al. Am J Ophthalmol 2009; 148: 500–9.

Retrospective cohort of 33 patients with ocular disease treated with azathioprine and oral prednisolone. 44% achieved control by 6 months with 12% off prednisolone treatment. This increased to 67% controlled by 1 year with 17% off prednisolone.

Methotrexate for ocular inflammatory diseases.

Gangaputra S, Newcomb CW, Liesegang TL, Kaçmaz RO, Jabs DA, Levy-Clarke GA, et al. Ophthalmology 2009; 116: 2188–98.

Retrospective cohort study of 58 patients with ocular MMP. 39.5% achieved complete control of inflammation at 6 months, increasing to 65.0% at 1 year with 26.8% off prednisolone at 1 year.

Methotrexate therapy for ocular cicatricial pemphigoid.

McCluskey P, Chang JH, Singh R, Wakefield D. Ophthalmology 2004; 111: 796–801.

In 12 of 17 patients with mainly ocular MMP oral methotrexate (and topical treatment) prevented progression of scarring.

Cyclosporine for ocular inflammatory diseases.

Kaçmaz RO, Kempen JH, Newcomb C, Daniel E, Gangaputra S, Nussenblatt RB, et al. Ophthalmology 2010; 117: 576–84.

Cyclosporine was minimally effective. All patients remained on corticosteroids.

Ocular autoimmune pemphigoid and cyclosporine.

Alonso A, Bignone ML, Brunzini M, Brunzini R. Allergol Immunopathol (Madr) 2006; 34: 113–15.

Treatment-resistant ocular pemphigoid in 82 patients was treated with cyclosporine 100 mg/day, with an attendant reduction in the dose of steroids.

There is evidence that the immunosuppressive agents are effective. Mycophenolate mofetil 0.5–1 g twice daily and azathioprine 1–3 mg/kg/day are used most freqeuently. Methotrexate 5–25 mg/week and cyclosporine 2–4 mg/kg/day are less widely used.

Third-line therapies

Intravenous immunoglobulin	C
Plasmapheresis	E
Rituximab	D
Etanercept	E
Infliximab	E
Pentoxifylline	C
Topical tacrolimus	E
Colchine	E
Low level laser	E

Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases.

Ahmed AR, Dahl MV. Arch Dermatol 2003; 139: 1051–9.

Good review on uses and regimes.

Treatment of epidermolysis bullosa acquisita with intravenous immunoglobulin in patients non-responsive to conventional therapy: clinical outcome and post-treatment long-term follow-up.

Ahmed AR, Gürcan HM. J Eur Acad Dermatol Venereol 2012; 26: 1074–83.

Retrospective case series of 10 patients with EBA, seven of whom had mucosal disease. IVIG was used as monotherapy with 2 g/kg/cycle given over 3 days initially monthly then tapered. Complete clinical response occurred in all with prolonged remission.

Intravenous immunoglobulins and mucous membrane pemphigoid.

Mignogna MD, Leuci S, Piscopo R, Bonovolontà G. Ophthalmology 2008; 115: 752.

IVIG treatment was beneficial in six patients with generalized MMP also affecting the eyes.

Intravenous immunoglobulin at doses 0.5–2 g/day (over 3 to 5 days) initially once monthly is justified in rapidly progressive or recalcitrant disease either in combination with other treatments or as monotherapy.

Combination of rituximab and intravenous immunoglobulin for recalcitrant ocular cicatricial pemphigoid: a preliminary report.

Foster CS, Chang PY, Ahmed AR. Ophthalmology 2010; 117: 861–9.

Six patients were treated with combination of IVIG and rituximab. Disease progression was arrested in all six patients.

Rituximab for treatment-refractory pemphigus and pemphigoid: a case series of 17 patients.

Kasperkiewicz M, Shimanovich I, Ludwig RJ, Rose C, Zillikens D, Schmidt E. J Am Acad Dermatol 2011; 65: 552–8.

Five patients with refractory MMP were treated with rituximab. Complete remission occurred in three patients, partial remission in the other two patients. No serious side effects were noted.

Rituximab for patients with refractory mucous membrane pemphigoid.

Le Roux-Villet C, Prost-Squarcioni C, Alexandre M, Caux F, Pascal F, Doan S, Caux, et al. Arch Dermatol 2011; 147: 843–9.

Twenty-five patients with severe refractory MMP received one or two cycles of rituximab; complete response occurred in 22 patients and partial response in one patient. Two patients died from infectious complications; these patients also received high-dose immunosuppression for laryngeal and tracheal edema.

Bullous and mucous membrane pemphigoid show a mixed response to rituximab: experience in seven patients.

Lourari S, Herve C, Doffoel-Hantz V, Meyer N, Bulai_Livideanu C, Viraben R, et al. J Eur Acad Dermatol Venereol 2011; 25: 1238–40.

Two patients with MMP were treated with rituximab leading to complete remission in one and partial remission in the other.

Case series suggest some benefit of rituximab but reports are mixed; further evidence is needed.

Therapeutic effect of etanercept in anti-laminin 5 (laminin 332) mucous membrane pemphigoid.

Schulz S, Deuster D, Schmidt E, Bonsmann G, Beissert S. Int J Dermatol 2011; 50: 1129–31.

Recalcitrant cicatricial pemphigoid treated with the anti-TNF-alpha agent etanercept.

Kennedy JS, Devillez RL, Henning JS. J Drugs Dermatol 2010; 9: 68–70.

Treatment of ocular cicatricial pemphigoid with the tumour necrosis factor alpha antagonist etanercept.

Prey S, Robert PY, Drouet M, Sparsa A, Roux C, Bonnetblanc JM, et al. Acta Derm Venereol 2007; 87: 74–5.

Case reports describe patients who responded to etanercept, including five with ocular disease. Two patients maintained remission after cessation of the drug, another relapsed.

Successful treatment of mucous membrane pemphigoid with infliximab.

Heffernan MP, Bentley DD. Arch Dermatol 2006; 142: 1268–70.

Mucous membrane pemphigoid in a series of 7 children and a review of the literature with particular reference to prognostic features and treatment.

Veysey EC, McHenry P, Powell J, et al. Eur J Pediatr Dermatol 2007; 17: 218–26.

Two cases with MMP benefited from infliximab; disease was ocular and oral in both and esophageal in one.

The biologics, particularly the anti-TNF agent etanercept, may have a role, but evidence is limited.

Pentoxifylline (anti-tumor necrosis facter drug): effective adjunctive therapy in the control of ocular cicatricial pemphigoid.

El Darouti MA, Fakhry Khattab MA, Hegazy RA, Hafez DA, Gawdat HI. Eur J Ophthalmol 2011; 21: 529–37.

Randomized blinded study of 30 patients with ocular MMP treated with intravenous methylprednisolone and cyclophosphamide either with or without adjuvant pentoxifylline (intravenous then oral). Inflammation and progression of scarring was reduced in patients receiving pentoxifylline.

Adjuvant pentoxifylline appears beneficial in control of ocular disease; further evidence is needed.

Oral mucous membrane pemphigoid: complete response to topical tacrolimus.

Lee HY, Blazek C, Beltraminelli H, Borradori L. Acta Derm Venereol 2011; 91: 604–5.

Single case of a complete response to oral suspension of tacrolimus 0.03% in aqueous solution.

Successful treatment of mucous membrane pemphigoid with tacrolimus.

Suresh L, Martinex Caixto LE, Radfar L. Spec Care Dentist 2006; 26: 66–70.

Case report: patient treated with tacrolimus ointment.

Single case reports suggest topical tacrolimus may be of benefit.

Low-level laser therapy for oral mucous membrane pemphigoid.

Cafaro A, Broccoletti R, Arduino PG. Lasers Med Sci 2012; 27: 1247–50.

Laser light may improve the symptoms of oral lesions of cicatricial pemphigoid: a case report.

Oliveira PC, Reis Junior JA, Lacerda JA, Silveira NT, Santos JM, Vitale MC, et al. Photomed Laser Surg 2009; 27: 825–8.

Low-level laser therapy in the treatment of mucous membrane pemphigoid: a promising procedure.

Yilmaz HG, Kusakci-Seker B, Bayindir H, Tözüm TF. J Periodontol 2010; 81: 1226–30.

Five patients with oral disease received treatment with low-level laser either as an adjunct or alone, with benefit reported.

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