Pathogenesis of Mucous Membrane Pemphigoid

Mucous membrane pemphigoid (MMP) is the clinical phenotype of a group of autoimmune blistering diseases characterized by autoantibodies directed against different structural proteins in epidermal basement membranes. The clinical course and prognosis of MMP are affected by the specific autoantigen targeted, the titer and bioactivity profile of corresponding autoantibodies, and the specific mucosal sites of disease activity. Irreversible scarring and loss of function must be prevented by early diagnosis and appropriate interventions.

Mucous membrane pemphigoid (MMP) is the designation for a class of rare autoimmune blistering disorders in which autoantibodies directed against structural proteins of the epidermal basement membrane cause erosive lesions followed by scarring of the skin and mucous membranes. It is for their shared cicatrizing clinical phenotype that disorders of immunologic heterogeneity and of predilection for different sites of the body have been classified together using the designation MMP.

As an orphan disease with an approximate incidence of 1 person per million annually, and with early presenting symptoms that can be subtle and nonspecific, the signs of MMP often go unrecognized until the resulting erosions and scarring are established. As a chronic and progressive disorder with sequelae that are irreversible and often debilitating, early diagnosis is critical because the limited therapeutic options available have the greatest potential to affect the course of the disease before scarring develops. Thus, the challenge for clinicians lies in recognizing an uncommon disorder underlying seemingly common complaints, and to establish timely diagnosis and appropriate interventions.

Clinical features

MMP was first differentiated from other bullous disorders based on its predominance on mucous membranes, tendency for scarring, and resistance to treatment. Multiple mucosal sites may be simultaneously affected, and occasionally the skin, particularly on the head and upper body. Although scarring is its clinical hallmark, this may not always be obvious, particularly in sites such as the oral mucosa. Clinical manifestations and the form and gravity of possible complications, such as blindness and life-threatening airway obstruction, depend on the sites involved.

MMP is generally a disease of later life, with mean age of onset between 60 and 80 years. Women seem to be more often affected than men by a factor of 1.5 to 2. No geographic or racial predilection has been found; however, associations with certain human leukocyte antigen (HLA) haplotypes (HLA-DQB1*0301) have been described.

Although the onset of lesions may begin or occur at any mucosal site, the oral mucosa seems to be most commonly affected, followed by the ocular, then the nasal, nasopharyngeal, anogenital, skin, laryngeal, and the esophageal mucosa ( Table 1 ).

Table 1

Manifestations and diagnosis by mucosal site

Site	Symptoms/Signs	History/Examination	Possible Complications
Mouth	Painful, erosive/blistering lesions: More common: gingival, buccal mucosa, and palate Less common: tongue, lips, alveolar ridge Desquamative gingivitis Tense blisters on oral mucosa Mucosal erosions Delicate white pattern of reticulated scarring	Question regarding: Pain/sensitivity on eating or brushing teeth Gum, dental pain Bleeding, mucosal lesions On Examination ^a: Erythema or erosions of the gingiva Delicate pattern of reticulate scarring	Adhesions between tongue and floor of mouth and around uvula and tonsils Dental complications: Caries Periodontal ligament damage Loss of bone mass Loss of teeth
Eye	Conjunctivitis slowly progressing to scarring Subtle and nonspecific symptoms, usually first in one eye, then both: Foreign body sensation Photophobia Tearing Itching Dryness Blurry vision, decreased visual acuity	Question regarding chronic symptoms such as: Burning, dryness, itching, tearing Photophobia or photosensitivity Persistent foreign body sensation Blurry vision, decreased visual acuity Unilateral or bilateral symptoms On examination ^a: Red/pink eyes, resembling conjunctivitis Malalignment of eyelashes Inward turning eyelashes Tarsal conjunctivitis	Painful, erosive conjunctivitis Conjunctival scarring Shortened fornices Loss of goblet cells Decrease in tear mucus content Unstable tear film Symblepharon Ankyloblepharon Ectropion Trichiasis Corneal irritation Superficial punctate keratinopathy Corneal neovascularization Corneal ulcers Scarring, occlusion, secondary infection of the tear ducts Blindness
Nose	Discharge Epistaxis Excessive crust formation Impaired air flow Chronic sinusitis	Question regarding: Chronic sinus symptoms Discharge Epistaxis Pain Congestion	Scarring Tissue loss Loss of air passages
Larynx	Hoarseness Chronic sore throat Loss of phonation Frequent throat clearing	Question regarding: Hoarseness, loss of voice, or sore throat Frequent throat clearing Symptoms last more than a few week Exacerbation by GERD	Chronic erosions, edema, scarring leading to: Stenosis of hypopharyngeal region\aspiration Airway compromise
Esophagus	Dysphagia Odynophagia Reflux symptoms/GERD Weight loss	Questions regarding: Difficulty eating/swallowing Pain with swallowing Rapid and/or unintentional weight loss	Esophageal dysfunction and reflux causing: Exacerbation of laryngeal disease Bronchospasm Stricture formation Weight loss Aspiration
Anogenital region	Dysuria Constipation Pain on voiding Rectal bleeding Dyspareunia	Question regarding: Pain, difficulty and/or bleeding on voiding Pain during intercourse	Urethral strictures Vaginal and/or anal stenosis Secondary infection