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Pemphigoid, Cicatricial

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Pemphigoid, Cicatricial

BASICS

DESCRIPTION

1/1 million annually Г© ГЎ

Association with HLA DQB1*0301 Г© ГЎ

None identified Г© ГЎ

Antilaminin-5 autoantibody " Гґpositive patients have a higher risk of internal malignancy. Г© ГЎ

Diagnosis is based on direct immunofluorescence and clinical presentation. Г© ГЎ

Histopathologic (hematoxylin-eosin [H+E]) Г© ГЎ

For patients receiving long-term prednisone and immunosuppressive treatment, add anti-Candida medication to prevent osteoporosis. Г© ГЎ

Surgery for patients with ocular involvement: entropion surgery, tarsorrhaphy, mucous membrane grafting, amniotic membrane transplantation, tectonic keratoplasty, keratoprosthesis. Г© ГЎ

11 Kirtschig Г© ГЎG, Murrell Г© ГЎD, Wojnarowska Г© ГЎF, et al. Interventions for mucous membrane pemphigoid and epidermolysis bullosa acquisita. Cochrane Database Syst Rev. 2003;(1):CD004056.22 Culton Г© ГЎDA, Diaz Г© ГЎLA. Treatment of subepidermal immunobullous diseases. Clin Dermatol. 2012;30(1):95 " Гґ102.

  • 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 " Гґ30%), nasal cavity (20 " Гґ40%), anogenital region (20%), pharynx (20%), larynx (5 " Гґ10%), and esophagus (5 " Гґ15%).
  • 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

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 Г„ в–“-4 integrin subunits, 120-kDa undefined epithelial antigenExclusive ocular mucosal involvement: autoantibodies to Г„ в–“-4 subunit of integrinExclusive oral mucosal involvement: autoantibodies toα-6 subunit of integrinAssociation with internal malignancy: autoantibodies to antilaminin-5
  • "Epitope spreading " ЕЃ: previous inflammatory events may predispose epithelial basement membrane components to autoreactive T cellsSeveral patients with Stevens-Johnson syndrome developed CP.Association with Sj Гў Г‚gren 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
  • Type XVII collagen (bullous pemphigoid antigen 2), type VII collagen, laminin-5, laminin-6,α-6 and Г„ в–“-4 integrin subunits, 120-kDa undefined epithelial antigenExclusive ocular mucosal involvement: autoantibodies to Г„ в–“-4 subunit of integrinExclusive oral mucosal involvement: autoantibodies toα-6 subunit of integrinAssociation with internal malignancy: autoantibodies to antilaminin-5
  • Exclusive ocular mucosal involvement: autoantibodies to Г„ в–“-4 subunit of integrin
  • Exclusive oral mucosal involvement: autoantibodies toα-6 subunit of integrin
  • Association with internal malignancy: autoantibodies to antilaminin-5
  • Several patients with Stevens-Johnson syndrome developed CP.
  • Association with Sj Гў Г‚gren syndrome and ocular CP

GENERAL PREVENTION

COMMONLY ASSOCIATED CONDITIONS

DIAGNOSIS

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, adhesionsPatients 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 blindnessAll 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
  • Patients with restricted oral involvement have mild to moderate disease process with less chance of scarring.
  • All patients should be seen by an ophthalmologist. Early disease detection requires slit-lamp examination and eversion of eyelids.

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 zoneBiopsy 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 NaClAt low titers (1:10 to 1:40), contain anti " Г¶dermal-epidermal junction antibodiesCombined 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
  • Linear deposition of IgG, IgA, and/or C3 along the epithelial basement membrane zoneBiopsy 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.
  • 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.
  • 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.
  • 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 " Г¶dermal-epidermal junction antibodies
  • Combined IgA and IgG reactivity is associated with more severe disease.
  • More sensitive test for target antigen but limited access to the test
  • 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.
  • Ocular biopsy may worsen inflammation.

TREATMENT

  • Low-risk patients (oral mucosa Г© в–’ skin involvement)Topical corticosteroids (moderate to high potency) (1)[A],(2): can use an oral insertable prosthetic deviceTetracycline hydrochloride (1 to 2 g/day)Nicotinamide (2 to 2.5 g/day)Nonresponsive diseasePrednisone (0.5 mg/kg/day) + dapsoneSerious 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/dayIncrease 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 cyclophosphamidePreliminary reports show rituximab Г© в–’ 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 " Г¶appropriate monitoring required the following:Azathioprine and mycophenolate mofetil: severe liver toxicity, bone marrow suppressionCyclophosphamide: hemorrhagic cystitis, bone marrow suppression
  • 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 diseasePrednisone (0.5 mg/kg/day) + dapsoneSerious 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/dayIncrease 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)
  • Prednisone (0.5 mg/kg/day) + dapsoneSerious 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)
  • 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
  • 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 Г© в–’ 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.
  • Blepharitis may be treated with tetracycline and lid hygiene.Patients should see the appropriate specialists for systems involved.
  • Patients should see the appropriate specialists for systems involved.
  • Azathioprine and mycophenolate mofetil: severe liver toxicity, bone marrow suppression
  • Cyclophosphamide: hemorrhagic cystitis, bone marrow suppression

ADDITIONAL THERAPIES

SURGERY/OTHER PROCEDURES

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 Г© в–’ skin involvementPoorer prognosis, high likelihood for loss of function and scarring: ocular, genital, nasopharyngeal, esophageal, laryngealOcular scarring and blindnessGenital and urinary scarringScarring can only be prevented, not reversed (2).Airway obstructionEsophageal strictures
  • Better prognosis and better response to treatment: oral Г© в–’ skin involvement
  • Poorer prognosis, high likelihood for loss of function and scarring: ocular, genital, nasopharyngeal, esophageal, laryngealOcular scarring and blindnessGenital and urinary scarringScarring can only be prevented, not reversed (2).Airway obstructionEsophageal strictures
  • Ocular scarring and blindness
  • Genital and urinary scarring
  • Scarring can only be prevented, not reversed (2).
  • Airway obstruction
  • Esophageal strictures

REFERENCES

ADDITIONAL READING

  • Allen Г© ГЎCP, Venning Г© ГЎV. Mucous membrane pemphigoid. In: Lebwohl Г© ГЎMG, Heymann Г© ГЎWR, Berth-Jones Г© ГЎJ, et al, eds. Treatment of Skin Disease: Comprehensive Therapeutic Strategies. 4th ed. Philadelphia, PA: Saunders; 2013:469 " Гґ472.
  • Chan Г© ГЎLS. Ocular and oral mucous membrane pemphigoid (cicatricial pemphigoid). Clin Dermatol. 2012;30(1):34 " Гґ37.
  • Chan Г© ГЎLS, Ahmed Г© ГЎAR, Anhalt Г© ГЎGJ, 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 " Гґ379.
  • Kourosh Г© ГЎAS, Yancey Г© ГЎKB. Pathogenesis of mucous membrane pemphigoid. Dermatol Clin. 2011;29(3):479 " Гґ484.
  • Schiavo Г© ГЎAL, Puca Г© ГЎRV, Ruocco Г© ГЎV, et al. Adjuvant drugs in autoimmune bullous diseases, efficacy versus safety: facts and controversies. Clin Dermatol. 2010;28(3):337 " Гґ343.
  • Schmidt Г© ГЎE, Zillikens Г© ГЎD. Pemphigoid diseases. Lancet. 2013;381(9863):320 " Гґ332.

CODES

ICD10

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.