A Case of Mucous Membrane Pemphigoid: Treatment Resistance

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The diagnosis of mucous membrane pemphigoid (MMP), also known as cicatricial pemphigoid, encompasses a variety of autoimmune diseases characterized by subepithelial blisters or erosions primarily occurring on mucous membranes and frequently presenting with scarring. This condition manifests most commonly on the oral mucosa and conjunctiva, as well as the nasal mucosa, genitalia, esophagus, and laryngopharyngeal mucosa with less prevalence. If occurring in the latter, subsequent scarring can lead to complications, such as blindness, dysphagia, ulcerations, and genitourinary stenosis.¹ 

Case Presentation 

A 71-year-old woman presented with recurrent blisters and exudate on the lips for a period of 3 years (Figure 1). Immunoserology was positive for cell-surface IgG, but diagnosis of foliaceus and vulgaris was made less likely by negative titers for DSG1 and DSG3.^2,3 Indirect immunofluorescence (IIF) showed negative serum IgG and IgA basement membrane zone (BMZ) and cell surface antibodies, type VII collagen antibodies, and BP180 and BP 320 antibodies as part of the immunobullous disease panel. These results indicate less likelihood of other diseases commonly mistaken for MMP, such as bullous pemphigoid, epidermolysis bullosa, linear IgA disease, pemphigus vulgaris, pemphigus foliaceus, and IgA pemphigus. It is important to note that IIF only detects serum autoantibodies in about 17% to 53% of patients with MMP and thus may not be a sensitive marker for diagnosis of this disease.⁴ The patient also tested negative for HSV 1 and 2. 

A diagnosis of MMP was confirmed via direct immunofluorescence (DIF) of a lower lip punch biopsy, which revealed continuous linear staining of C3 in the basement membrane, along with focal linear staining of IgG in the basement membrane away from the subepidermal vesicle (Figure 2). The patient also experienced recurrent bacterial infections by Streptococcus aureus and Pseudomonas aeruginosa as a complication of the blisters. Due to the lack of involvement of systems besides the oral mucosa, the patient would be classified as low risk. 

Prednisone (20 mg) was prescribed. It improved symptoms for a week, but relapse occurred afterward. The patient’s additional medication history encompassed the following: mycophenolate mofetil, dapsone, minocycline, dupilumab, fluconazole, iprofloxacin (for suspected fungal infection), and valacyclovir. Previous topical medications included metronidazole, tacrolimus, ketoconazole, mupirocin, fluticasone propionate, hydrocortisone, and gentamicin. Although some of these medications improved symptoms initially, relapse occurred within a week or so. 

Although medications such as dapsone⁵ and mycophenolate mofetil⁶ have demonstrated efficacy in treating moderate to severe MMP, they were ineffective in mitigating the recurrence of the blisters in our patient. Rituximab infusions were also attempted. They provided relief for a week, but the patient relapsed and was placed on low-dose oral prednisone (4 mg) once more. Symptoms are currently improving. The patient also utilizes topical fluocinonide for acute exacerbations, which is perceived to be effective. 

Discussion 

The true incidence of MMP in the United States remains to be investigated, but previous studies have found an incidence of 1.3 to 2.0 per million people per year in France.⁷ Subtypes of MMP can be classified by target antigens of structural proteins in the epidermal BMZ, such as BP180, BP230, a6ß4 integrin, laminin 332, and type VII collagen.⁸ Diagnosis of this disease requires the presentation of blisters, erosions, or erythematous patches primarily affecting mucous membranes, as well as continuous, linear deposition of IgG, C3, and/or IgA along the BMZ shown by DIF on a perilesional mucosa or skin biopsy¹ (see The Journey to Diagnosis). 

Unlike other classical cases of MMP,⁹ our patient seems to be unresponsive to standard courses of therapy used when there are no manifestations in body systems except for the oral mucosa, such as dapsone and prednisone. Rituximab has been previously used to treat MMP. The lymphoma protocol (4 weekly infusions of 375 mg/m2) was documented to achieve a higher rate of complete remission¹⁰ when compared to the rheumatoid arthritis protocol (1000 mg on day 1 and day 14), although the validity of these results is uncertain. Although the patient has no ocular, nasal mucosal, genitourinary, laryngeal, or pharyngeal involvement of the disease, treatments standardized for high-risk patients may have to be administered to mitigate symptoms. 

Conclusion 

MMP can lead to severe sequelae if not properly diagnosed and managed. Although this patient has oral lesions that would normally be classified as low risk, she demonstrated resistance to treatment and faced complications such as recurrent bacterial infections. Thus, it is crucial to monitor disease status once treatment regimens are initiated or altered and implement new strategies if the previous ones fail to mitigate symptoms or progression.
 

References 

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2. Lepe K, Yarrarapu SNS, Zito PM. Pemphigus foliaceus. In: Stat Pearls [Internet]. Stat Pearls Publishing; 2023. 

3. Porro AM, Seque CA, Ferreira MCC, Enokihara MMSES. Pemphigus vulgaris. An Bras Dermatol. 2019;94(3):264-278. doi:10.1590/abd1806-4841.20199011 

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7. Bernard P, Vaillant L, Labeille B, et al. Incidence and distribution of subepidermal autoimmune bullous skin diseases in three French regions. Bullous Diseases French Study Group. Arch Dermatol. 1995;131(1):48-52. 

8. Xu HH, Werth VP, Parisi E, Sollecito TP. Mucous membrane pemphigoid. Dent Clin North Am. 2013;57(4):611-630. doi:10.1016/j.cden.2013.07.003 

9. Neff AG, Turner M, Mutasim DF. Treatment strategies in mucous membrane pemphigoid. Ther Clin Risk Manag. 2008;4(3):617-626. doi:10.2147/tcrm.s1140 

10. Farooq MM, Miloslavsky EM, Konikov N, Ahmed AR. Use of rituximab in the treatment of mucous membrane pemphigoid: an analytic review. Autoimmun Rev. 2022;21(8):103119. doi:10.1016/j.autrev.2022.103119