Mucous membrane pemphigoid L12.1

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 30.05.2022

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Synonym(s)

Benign mucosal pemphigoid; Benign mucous membrane pemphigoid; cicatricial pemphigoid; Cicatrising pemphigoid; Dermatite bulleuse mucosynéchiante; Dermatitis pemphigoides mucocutanea chronica; Desquamative gingivitis; muco-oculo-épithélial syndromes; mucosal pemphigoid scarring; mucosal pemphigus benigner; oculair pemphigus; Ocular MMP; Ocular mucosal epmphgoid; Ocular mucous membrane pemphigoid; ocular pemphigus; pemphigus conjunctivae; Pemphigus ocular; Scarring mucosal pemphigoid; scarring pemphigoid

History
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Lortat-Jakob, 1958; first mention by Wichmann, 1793

Definition
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Rare, chronic, blister-forming autoimmune disease of the mucous membranes of the conjunctiva, mouth, pharynx, esophagus, genitals and anus leading to scarring and loss of function. The disease shows immunohistologically identical findings with the bullous pemphigoid, is probably a variant.

Classification
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Immunohistologically 4 groups can be distinguished:

  • Anti-Epileprin Cicatrical Pemphigoid: Clinically this type cannot be distinguished from the others.
  • Ocular cicatrical pemphigoid: Patients with autoantibodies against β4-Integrin as well as α6β4-Integrin (see below integrins).
  • Patients with autoantibodies against BP 180 (corresponding to the bullous pemphigoid) and mucosal and skin lesions.
  • Anti-laminin 332 mucosal pemphigoid (about 20-30% of patients), which must be considered as paraneoplastic pemphigoid (35% of cases are associated with malignancies).
  • Heterogeneous group, mainly with mucosal involvement: pathogenesis regarding autoantibodies still unclear.

Occurrence/Epidemiology
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Rarely. No ethnic predilection. Incidence (Western Europe): 0.08-0.2/100,000. inhabitants/year.

Manifestation
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Occurs mainly in older people, especially in women between 60 and 80 years of age. Rarely starts in childhood.

Localization
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Frequency of infestation according to localisation:
  • Oral mucosa: 85%
  • subjunctives: 64%
  • Pharynx: 19%
  • external genitals: 17%
  • Nasal mucosa: 15%.
  • Larynx: 8%
  • Anal region 4%
  • Esophagus: 4%.

Clinical features
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Clinical manifestations begin with chronic, recurrent, painful and therapy-resistant erosive inflammation of the mucous membranes close to the skin. The predominant initial manifestation is therapy-resistant erosive stomatitis (DD pemphigus vulgaris). Very rarely, the initial manifestations affect the skin organ!

  • Oral mucosa (100% affected): Recurrent, erosive, painful stomatitis with rapidly bursting, scarred healing blisters (blisters often undetectable) on the palate, cheeks and gingiva. Depending on localization: restriction of tongue movement, mucosogenic lockjaw, tooth loss. After healing, possibly lichenoid leukoplakia.
  • Eyes (80% affected): Recurrent conjunctivitis. Symptoms usually start unilaterally, after 1-2 years there is usually bilateral involvement. There is a varied clinical presentation with the appearance of clear, rapidly bursting blisters, scarring shrinkage, entropion and trichiasis, synechiae between bulbar and palpebral conjunctiva, restriction of eye movements, obstruction of the lacrimal duct with xerophthalmia. Eyelid closure is often impossible.
  • Nasopharynx (30-40% affected), possibly also upper gastrointestinal tract: Crusted ulcerations, fibrous adhesions up to obstruction of breathing, dysphagia, life-threatening stenoses of the esophagus or trachea.
  • Genitoanal mucosa: blistering, synechiae, constricting scarring.
  • Integument (30-50% affected; face, umbilicus, mons pubis): bulging, in loco recurrent blisters on erythematous ground, formation of atrophic scars, possibly scarring alopecia.
  • Special forms: scarring pemphigoid type Brunsting-Perry and scarring disseminated pemphigoid.

Laboratory
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HLA-DQw7

Circulating anti-basement membrane antibodies are rarely detectable.

In contrast, IgA autoantibodies directed against BP 180 (BP230) are more frequently detectable.

Likewise, antibodies against the 168 kD antigen, which is only found in the buccal mucosa, can be found, and in patients with ocular infestation only, antibodies against the 45 kDa antigen can also be found.

Histology
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Subepidermal blistering with inflammatory infiltrates of neutrophil and eosinophilic granulocytes; in the upper dermis mostly weakly developed lymphocytic infiltrates; later dermal fibrosis.

Direct Immunofluorescence
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Linear IgG (less frequently IgA or IgM) and complement (C3) deposits. In the salt split technique (see below Salt split examination) the antibodies are detected at the epidermal as well as the dermal basement membrane. The IgG deposits are predominantly IgG4 and IgG1 subclasses. Remark: It could be shown that examinations of non-lesional skin give better results than the examination of inflammatory bulbar or tarsal conjunctiva!

Immunoelectron microscopy shows immunoglobulin deposits in the lower lamina lucida and above the lamina densa, but also on the hemidesmosomes.

Indirect immunofluorescence
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Circulating anti-basement membrane antibodies are rarely detectable.

In contrast, IgA autoantibodies directed against BP 180 (BP230) are more frequently detectable. Similarly, antibodies against the 168 kD antigen, which is only present in the buccal mucosa, are also found. In patients with exclusive eye infestation, antibodies against the 45 kDa antigen are also found.

Differential diagnosis
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In case of eye infestation: Secondary scarring changes after membranous conjunctivitis, after trauma or epidermolysis bullosa or IgA linear dermatosis. S.a.u. blistering dermatoses.

General therapy
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The therapy is difficult because the disease is extremely chronic. It requires eminent patience on the part of both the patient and the doctor.

External therapy
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  • Topical therapy with glucocorticoids is the first choice therapy for the localized type of scarring pemphigoid.
  • In mild cases, local glucocorticoid applications such as dexamethasone or hydrocortisone-containing eye ointments (e.g. Jenapharm dexamethasone eye ointment, Ficortril eye ointment) may be sufficient. alternating with corticoid-free indifferent eye drops (e.g. zinc sulphate eye drops R297 R022 ) or vasoconstrictive ophthalmics such as 0.05% naphazolin eye drops (e.g. proculin) in combination with eye rinses.
  • In the case of moderate to severe conjunctival infestation, the local application of 1-2% Ciclosporin A eye drops is recommended. If there is evidence of bacterial superinfection, antibiotic-containing eye drops should be used.
  • Analogous procedure for stomatological symptoms with predominantly buccal erosions or ulcerations localised in the area of the tooth closure line, which are often painful and extensive.
    • Therapy of the 1st choice is a local therapy with glucocorticoids, which are applied as adhesive mouth gels, e.g. betamethasone valerate mouth adhesive paste R032. Alternatively, non-alcoholic O/W emulsion (e.g. Topisolon Lotio) or Betamethasone solution(e.g. Celestamine N 0.5 liquidum) can be used.
    • In therapy-resistant cases, Ciclosporin A-containing adhesive paste ( Ciclosporin A adhesive paste 2.5%) is also suitable.
    • Alternatively: 0,1% Tacrolimus ointment (e.g. Protopic); application 2 times/day, leave for 15 minutes, then rinse.
    • Furthermore, the application of mild mucosal therapeutics such as Dexpanthenol solution R066 or of astringents such as Tormentillae solution R255 is recommended.

Internal therapy
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Combined immunosuppression with glucocorticoids and azathioprine (in case of ocular involvement), see also pemphigoid, bullous. Initial daily doses should be 2.0 mg/kg bw p.o. for prednisone (e.g. Decortin) and 2.0 mg/kg bw p.o. for azathioprine (e.g. Imurek). Observe contraindications! Laboratory controls!

Alternatives to azathioprine include cyclophosphamide (Endoxan), ciclosporin A (2.5-3.5mg/kg bw p.o.) and mycophenolate mofetil (2.0g/day p.o.), see below. Pemphigoid, bullous.

Own experiences with DADPS (e.g. dapsone fatol) are disappointing and therefore not very recommendable.

In studies successful: therapy trial with etanercept.

In case reports positive results are reported by infusion therapy with the monoclonal antibody Rituximab (dosage: 375mg/kgKOF i.v.).

Increasingly, combinations of DADPS + glucocorticoids (e.g. prednisolone (20-10mg/day p.o.) + immunosuppressants (e.g. mycophenolate mofetil (2.0g/day p.o.) are used in cases of therapy resistance.

Notice. Scarring mucous membrane pemphigoid is often resistant to therapy and requires consistent, long-term and high-dose immunosuppression!

Operative therapie
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The local medication must be supplemented by careful (symptom-oriented) surgical measures. These include in particular the eyes:
  • Loosening of adhesions between bulbar and tarsal conjunctiva ( symblepharon).
  • Elimination of scarring shrinkage of the eyelids, especially the loosening of entropies, in order to prevent secondary injuries of the cornea by trichiasis.
  • In case of a particularly persistent entropial condition complete extirpation of the cilia.
  • Dilatation or surgery of oesophageal structures.

Progression/forecast
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Wavy, year-long course, blindness in 20% of cases. The risk of malignancy in scarring pemphigoid is controversial. According to studies, there is an increased risk of malignoma with anti-laminin-5 pemphigoid.

Diet/life habits
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Accompanying low acid and spice diet (in acute phases happened diet). Sufficient and balanced diet (vitamins and minerals), if necessary diet plan.

Remember! Painfulness in the mouth area leads to restricted food intake!

Case report(s)
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In a 66-year-old patient inflammatory changes of the oral mucosa for 10 years. First diagnosis 5 years ago: Lichen planus mucosae. Intercurrent topical (Volon A adhesive ointment) and systemic therapy with glucocorticoids. Occasionally also therapies with chloroquine, cyclosporine A and acitretin.
  • Findings: Painful redness and extensive erosions of the upper and lower gingiva. Both buccal cheeks are reddened over the whole surface and described erosionally.
  • Diagnosis (discontinuation of any immunosuppressive therapy for 14 days!)
  • Histology (buccal mucosa): Eroded and partially ulcerated epithelium. In the dermis partly diffuse, band-like, partly flekc-shaped infiltrate of lymphocytes, eosinophilic and neutrophilic leukocytes.
  • DIF: Linear deposits of IgG along the basement membrane and on the bladder roof.
  • Indirect IF: Negative; no IgA autoantibodies detectable.
  • Dg.: Oral scarring mucosal pemphigoid.
  • Therapy: 2 times/day local monotherapeutic local therapy with 1% tacrolimus ointment(protopic). Leave for 15-20 minutes, then rinse (0,9% saline solution). Under this therapy (without systemic therapy) satisfactory local findings for 1/2 year.

Literature
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  1. Bhol KC et al (2000) The autoantibodies to a6ß4 integrin of patients affected by ocular cicatricial pemphigoid recognize predominantly epitopes within the large cytoplasmic domain of ß4 J Immunol 165: 2824-2829
  2. Egan CA, Yancey KB (2000) The clinical and immunopathological manifestations of antipiligrin cicatrical pemphigoid, a recently defined subepoidethelial autoimmune blistering disease. Eur J Dermatol 10: 585-590
  3. Egan CA et al (2001) Anti-epiligrin cicatricial pemphigoid and relative risk for cancer. Lancet 357: 1850-1851
  4. Fleming TE et al (2000) Cicatricial pemphigoid. J Am Acad Dermatol 43: 571-591
  5. Kaune KM et al (2015) Anti-p200/anti-laminin γ1 pemphigoid and BP180 NC16A/4575- positive mucous membrane pemphigoid: late diagnosis in a patient with disease-related loss of vision and multiple previous surgical interventions. Dermatologist 66:60-64
  6. Lee JB, Liu Y et al (2003) Cicatricial pemphigoid sera specifically react with the most C-terminal portion of BP180. J Dermatol Sci 32: 59-64
  7. Leverkus M et al (2001) Cicatricial pemphigoid with circulating autoantibodies to beta4 integrin, bullous pemphigoid 180 and bullous pemphigoid 230 Br J Dermatol 145: 998-1004
  8. Mehra T et al. (2015) The diagnostic relevance of direct immunofluofescence in ocular mucosal pemphigoid. JDDG 13: 1268-1275
  9. Murrell DFet al. (2015)Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international panel of experts. J Am Acad Dermatol 72:168-174
  10. Sacher C et al (2002) Treatment of recalcitrant cicatricial pemphigoid with the tumor necrosis factor alpha antagonist etanercept. J Am Acad Dermatol 46: 113-115
  11. Schempf U et al (2014) Scarring mucous membrane pemphigoid presenting as double stenosis of the larynx and esophagus: precautions during therapy can avoid complications. Endoscopy 46 Suppl 1 UCTN: E617-618
  12. Schmidt E et al (2009) Research in practice: diagnosis of subepidermal autoimmune bullous disorders. J Dtsch Dermatol Ges 7: 296-300
  13. Vodegel RM et al (2003) Anti-epiligrin cicatricial pemphigoid and epidermolysis bullosa acquisita: differentiation by use of indirect immunofluorescence microscopy. J Am Acad Dermatol 48: 542-547
  14. Wichmann JE (1793) Pemphigus. In: Wichmann JE (ed.) Ideen zur Diagnostik, Volume 1, Verlag der Helwing'schen Hof-Buchhandlung, Hannover, p. 89

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Last updated on: 30.05.2022