BASICS
DESCRIPTION
- Cicatricial pemphigoid (CP) is an acquired autoimmune subepithelial blistering disorder that mainly affects mucous membranes.
- In descending order of involvement, CP affects the oral cavity (85%), conjunctivae (65%), skin (25 " ô30%), nasal cavity (20 " ô40%), anogenital region (20%), pharynx (20%), larynx (5 " ô10%), and esophagus (5 " ô15%).
- The clinical hallmark of CP is scarring; however, it may not be apparent, especially in the oral mucosa.
- Synonym(s): mucous membrane pemphigoid, oral pemphigoid, desquamative gingivitis, ocular CP, ocular pemphigus (incorrect nomenclature)
EPIDEMIOLOGY
- Mean onset at age 60 to 80 years
- Female to male ratio of 2 to 3:1
- No racial or geographic predilection
Incidence
1/1 million annually é á
ETIOLOGY AND PATHOPHYSIOLOGY
- Autoantibodies binding to specific epithelial basement membrane components:
- Type XVII collagen (bullous pemphigoid antigen 2), type VII collagen, laminin-5, laminin-6,α-6 and Ä ▓-4 integrin subunits, 120-kDa undefined epithelial antigen
- Exclusive ocular mucosal involvement: autoantibodies to Ä ▓-4 subunit of integrin
- Exclusive oral mucosal involvement: autoantibodies toα-6 subunit of integrin
- Association with internal malignancy: autoantibodies to antilaminin-5
- "Epitope spreading " Ł: previous inflammatory events may predispose epithelial basement membrane components to autoreactive T cells
- Several patients with Stevens-Johnson syndrome developed CP.
- Association with Sj â Âgren syndrome and ocular CP
- Mechanism linking the binding of the antibodies to the epithelial basement membrane zone and subsequent scarring process yet to be defined
Genetics
Association with HLA DQB1*0301 é á
GENERAL PREVENTION
None identified é á
COMMONLY ASSOCIATED CONDITIONS
Antilaminin-5 autoantibody " ôpositive patients have a higher risk of internal malignancy. é á
DIAGNOSIS
Diagnosis is based on direct immunofluorescence and clinical presentation. é á
HISTORY
- Oral: pain, sensitivity, bleeding, mucosal lesions
- Ocular: burning, dryness/tearing, itching, foreign body sensation, vision changes, photosensitivity
- Nasal: discharge, pain, congestion, epistaxis
- Larynx: hoarseness, sore throat, frequent throat clearing, loss of voice
- Esophagus: dysphagia, odynophagia, unintentional weight loss
- Anogenital: blisters, erosions, scarring, dyspareunia, hematuria
- Skin: tense vesicles and bullae, hair loss, pruritus
PHYSICAL EXAM
- Oral (especially on gingival and palatal mucosa, and less commonly on labial, buccal, and tongue mucosa): erythematous patches, blisters, erosions, reticulate scarring, and/or pseudomembrane-covered erosions, adhesions
- Patients with restricted oral involvement have mild to moderate disease process with less chance of scarring.
- Ocular: unilateral/bilateral involvement, conjunctival inflammation and erosions, malalignment of eyelashes or tarsal conjunctivitis may proceed to scar formation, causing symblepharon, trichiasis, neovascularization, and eventually blindness
- All patients should be seen by an ophthalmologist. Early disease detection requires slit-lamp examination and eversion of eyelids.
- Nasal: scarring, tissue loss, epistaxis, discharge; may resemble upper respiratory infections
- Larynx: erosions and edema leading to life-threatening airway obstruction requiring tracheostomy
- Esophagus: life-threatening stenosis
- Anogenital: blisters, erosions, scarring, urethral strictures, vaginal/anal stenosis, fusion of labial tissues
- Skin: tense vesicles/bullae, erosions generally on head, neck, and upper trunk; lesions heal with atrophic scars and milia
DIFFERENTIAL DIAGNOSIS
- Bullous pemphigoid
- Pemphigus vulgaris
- Linear IgA bullous dermatosis
- Paraneoplastic pemphigus
- Epidermolysis bullosa acquisita
- Stevens-Johnson syndrome
- Erythema multiforme major
- Drug-induced conjunctival cicatrization
- Ocular chemical/radiation trauma
- Lupus erythematosus
- Lichen planus
- Lichenoid drug eruptions
DIAGNOSTIC TESTS & INTERPRETATION
- Direct immunofluorescence (DIF)
- Linear deposition of IgG, IgA, and/or C3 along the epithelial basement membrane zone
- Biopsy for DIF are the following:
- Single mucous membrane involvement: Take biopsy from adjacent inflamed tissue.
- Multiple mucous membrane involvement: Take biopsy from adjacent nonocular inflamed tissue.
- Both mucous membrane and skin involvement: Take biopsy from adjacent inflamed skin lesion.
- Indirect immunofluorescence (low sensitivity)
- Serum samples tested with chemically separated normal human epithelial substrate split by 1 mol/L NaCl
- At low titers (1:10 to 1:40), contain anti " ödermal-epidermal junction antibodies
- Combined IgA and IgG reactivity is associated with more severe disease.
- Enzyme-linked immunosorbent assay (ELISA)
- More sensitive test for target antigen but limited access to the test
Test Interpretation
Histopathologic (hematoxylin-eosin [H+E]) é á
- Early lesions: subepidermal blisters with lymphohistiocytic infiltrates, granulocytes, and plasma cells
- Late lesions: subepidermal blisters with scant infiltrates, fibroblast proliferations, upper dermis lamellar fibrosis
- H+E is not a required criterion secondary to difficulty in biopsying a blister, especially in difficult areas such as ocular mucosae.
- Ocular biopsy may worsen inflammation.
TREATMENT
- Low-risk patients (oral mucosa é ▒ skin involvement)
- Topical corticosteroids (moderate to high potency) (1)[A],(2): can use an oral insertable prosthetic device
- Tetracycline hydrochloride (1 to 2 g/day)
- Nicotinamide (2 to 2.5 g/day)
- Nonresponsive disease
- Prednisone (0.5 mg/kg/day) + dapsone
- Serious adverse effects of dapsone are rare; check for G6PD deficiency prior to initiation; CBC weekly during first month then monthly for 6 months, then periodically thereafter; LFTs should also be followed.
- Starting dose: 25 mg/day
- Increase by 25 to 50 mg/day every 1 to 4 weeks as tolerated up to 150 to 200 mg/day; if no response with prednisone + dapsone, add azathioprine (100 to 150 mg/day) or mycophenolate mofetil (1 g/day)
- High-risk patients (involvement of any of the following mucosae: ocular, genital, nasopharyngeal, esophageal, laryngeal):
- Slow moderate progression of disease: dapsone + corticosteroids (1 mg/kg/day) + azathioprine (2 to 2.5 mg/kg/day) or mycophenolate mofetil (1 to 1.5 g/day)
- Patients with rapid progression of disease (especially ocular, esophageal, or laryngeal involvement): prednisone (1 to 1.5 mg/kg/day) + cyclophosphamide (1 to 2 mg/kg/day)
- After control of disease, taper prednisone and continue cyclophosphamide
- Preliminary reports show rituximab é ▒ IV immunoglobulin is effective for treatment-resistant ocular disease.
- Ocular involvement requires lubricant without preservative:
- Blepharitis may be treated with tetracycline and lid hygiene.
- Patients should see the appropriate specialists for systems involved.
- Extensive side effect profiles, condensed to most important ones " öappropriate monitoring required the following:
- Azathioprine and mycophenolate mofetil: severe liver toxicity, bone marrow suppression
- Cyclophosphamide: hemorrhagic cystitis, bone marrow suppression
ADDITIONAL THERAPIES
For patients receiving long-term prednisone and immunosuppressive treatment, add anti-Candida medication to prevent osteoporosis. é á
SURGERY/OTHER PROCEDURES
Surgery for patients with ocular involvement: entropion surgery, tarsorrhaphy, mucous membrane grafting, amniotic membrane transplantation, tectonic keratoplasty, keratoprosthesis. é á
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
- Cancer screening for patients with antilaminin-5 autoantibodies
- All patients should be seen by an ophthalmologist. Early detection of disease is key
- Long-term follow up with appropriate specialists.
PROGNOSIS
- IgG and IgA antibasement membrane autoantibodies are associated with more severe disease.
- Prognosis mostly depends on site involved:
- Better prognosis and better response to treatment: oral é ▒ skin involvement
- Poorer prognosis, high likelihood for loss of function and scarring: ocular, genital, nasopharyngeal, esophageal, laryngeal
- Ocular scarring and blindness
- Genital and urinary scarring
- Scarring can only be prevented, not reversed (2).
- Airway obstruction
- Esophageal strictures
REFERENCES
11 Kirtschig é áG, Murrell é áD, Wojnarowska é áF, et al. Interventions for mucous membrane pemphigoid and epidermolysis bullosa acquisita. Cochrane Database Syst Rev. 2003;(1):CD004056.22 Culton é áDA, Diaz é áLA. Treatment of subepidermal immunobullous diseases. Clin Dermatol. 2012;30(1):95 " ô102.
ADDITIONAL READING
- Allen é áCP, Venning é áV. Mucous membrane pemphigoid. In: Lebwohl é áMG, Heymann é áWR, Berth-Jones é áJ, et al, eds. Treatment of Skin Disease: Comprehensive Therapeutic Strategies. 4th ed. Philadelphia, PA: Saunders; 2013:469 " ô472.
- Chan é áLS. Ocular and oral mucous membrane pemphigoid (cicatricial pemphigoid). Clin Dermatol. 2012;30(1):34 " ô37.
- Chan é áLS, Ahmed é áAR, Anhalt é áGJ, et al. The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators. Arch Dermatol. 2002;138(3):370 " ô379.
- Kourosh é áAS, Yancey é áKB. Pathogenesis of mucous membrane pemphigoid. Dermatol Clin. 2011;29(3):479 " ô484.
- Schiavo é áAL, Puca é áRV, Ruocco é áV, et al. Adjuvant drugs in autoimmune bullous diseases, efficacy versus safety: facts and controversies. Clin Dermatol. 2010;28(3):337 " ô343.
- Schmidt é áE, Zillikens é áD. Pemphigoid diseases. Lancet. 2013;381(9863):320 " ô332.
CODES
ICD10
L12.1 Cicatricial pemphigoid é á
ICD9
- 694.60 Benign mucous membrane pemphigoid without mention of ocular involvement
- 694.61 Benign mucous membrane pemphigoid with ocular involvement
SNOMED
- Benign mucous membrane pemphigoid (disorder)
- Benign mucous membrane pemphigoid with ocular involvement
- Oral involvement by mucous membrane pemphigoid
- Oral cicatricial pemphigoid (disorder)
CLINICAL PEARLS
- Patients diagnosed with CP require thorough mucous membrane and skin examinations.
- Scarring is the clinical hallmark of disease, although it is not always evident.
- Treatments are disease-modifying rather than curative.
- Prognosis depends on site involved; oral and/or skin involvement has a better prognosis and better response to treatment. Ocular, genital, nasopharyngeal, esophageal, and laryngeal mucosal involvement are more likely to scar and can lead to life-threatening emergencies such as blindness and airway obstruction.