OCULAR CICATRICIAL PEMPHIGOID

Signs and Symptoms

Mucous membrane pemphigoid is a heterogeneous group of autoimmune diseases.1-10 It affects primarily the mucous membranes of both the oral and ocular tissues. While disease affecting the oral mucosa tend to have a benign outcome, the ocular disease can demonstrate resistance to treatment with potential scarring and blindness.1-10 When the lesions are restricted to the conjunctiva, the term ocular cicatricial pemphigoid (OCP) is used.2

The risk of the development of ocular disease among patients who present at first with only oral mucous membrane pemphigoid is estimated at 15%-20% over five years.8

Signs include unilateral or bilateral recurrent conjunctival inflammation, chronic blepharitis, filamentary keratitis, non-healing corneal defects, raised intraocular pressure (IOP) with evidence of secondary open angle glaucoma, chronic subepithelial fibrosis of the eyelid which when left untreated may lead to fornix shortening, symblepharon formation, subsequent trichiasis and eventually entropion.1-15

Cicatrization of the plica is considered a pathognomonic sign early in the disease.2 Even in the absence of conjunctival inflammation, ankyloblepharon (adhesion of the ciliary margins of the upper and lower lids together) has been documented to form. The process can present differently with a varied course ranging from low-level chronic disease with a build up to more advanced stages with acute symptoms. Some cases are missed because they present with the nondescript signs of periodic conjunctival inflammation and minimal symptoms.10 The process is finally discovered when the more severe, chronic signs become visible. In cases exhibiting asymmetric presentation, the fellow eye typically begins to manifest signs within two years of the first.3,6

Patients with the condition often present with a variable list of ongoing symptoms ranging from ocular dryness and foreign body sensation to frank pain, photophobia, lacrimation, conjunctival blistering and vision loss.4 As the disease progresses, limbal stem cell deficiency, tear deficiency and lid malposition has the potential to produce total keratinization of the ocular surface.1-10 The condition is rare in children an has an estimated incidence of one in 12,000 to one in 60,000 in adults over the age of 65.3,6 Unfortunately, this grossly underestimates the scope because cases are typically not reported until the disease has entered its later stages.3,6 OCP has a preponderance for women at a rate of 3:1.3,6 There is no racial predilection.1-10

Pathophysiology

Ocular cicatricial pemphigoid is an autoimmune disease characterized by mucous membrane fibrosis and skin changes with resulting scarring.10 Its pathogenic mechanisms are not completely understood.10 Theories suggest that anti-basement membrane antibodies lead to subepithelial blistering and the formation of granulation tissue with inflammatory infiltrate depositing in the substantia propria layer at the dermal-epidermal junction of the affected region.10 Eosinophils and increased collagen type I and III along with human leukocyte antigens HLA-DR2, HLA-DR4 and DQw7 have been identified as conferring increased susceptibility.10

In the combination form (oral and ocular), lesions frequently develop in the oral cavity, followed by lesions in the conjunctiva, nasopharynx, the anogenital region, skin, larynx and esophagus.1,2

The Foster staging system has been used in the literature to define the advancement of the disease.

Foster Stage 1: OCP displays chronic conjunctivitis with a characteristic subepithelial fibrosis.

Foster Stage 2: In this stage, noted subepithelial fibrosis has progressed and contracts to create shortening of the inferior fornix; this stage of the disease can be further subdivided according to the percentage of forniceal shortening.

Foster Stage 3: Symblephara form in the inferior fornix inducing more fornix shortening.

Foster Stage 4: Labeled end-stage OCP demonstrates debilitating ocular surface keratinization with complete absence of any inferior fornix and the initiation of processes that will result in corneal vascularization. While the inferior fornix is affected earlier in the disease than the superior, ultimately no aspect of the conjunctival surface is spared.3,6

The pathophysiology related to the secondary open-angle glaucoma seen in patients with OCT may have multiple mechanisms.3,6,11-15 Patients with the combination of OCP and glaucoma typically present with a long history of raised intraocular pressure as well as a difficult battle with disease stabilization.3,6,11-15

The elevated IOP condition is theorized to develop from, among other things, response to the systemic anti-inflammatory therapy (steroids), impaired outflow of aqueous humor created by chronic high-grade conjunctival inflammation and the anterior chamber congestion that accompanies it, a genetic susceptibility to glaucoma, and conjunctival cicatrization inducing alterations in aqueous outflow.12

The diagnosis of OCP requires direct immunofluorescence microscopy to demonstrate a linear deposition of immunoglobulin (Ig)G or IgA or complement component 3 (C3) at the epithelial basement membrane junction of a conjunctival biopsy.3 Although the target antigens vary, subsets of patients affected exclusively by oral and ocular mucosal diseases have autoantibodies that target -6 and -4 integrins, respectively.1 Other useful diagnostic findings include the presence of tumor necrosis factor-, autoantibodies against type XVII and VII collagen, laminin 5 and 6, alpha 6 beta 4 integrin.1-4,16

Management

Since OCP primarily destroys the support systems for the ocular surface, the priority must be lid, tear film and conjunctival preservation and protection. As the disease is a manifestation of autoimmune disease, concurrent systemic anti-inflammatory and immunomodulatory management with the internist and rhematologist is mandatory.1-11,14,16-24

Ocular management consists of copious artificial lubrication in combination with topical anti-inflammatory agents.21-24 Cyclosporine BID in concert with topical steroids (prednisolone acetate or prednisolone sodium phosphate, difluprednate) QID can be used to decrease symptoms and surface inflammation, slowing or arresting scar development.21-23

Topical non-steroidal anti-inflammatory medications BID-QID can also be used. Recently, other topically applied calcineurin inhibitors, namely tacrolimus and pimecrolimus have shown benefit.22 Punctal plugs can be installed to increase the lacrimal lake.23 Filamentary keratopathy can be managed by removing the corneal filaments with a forceps or by bandaging them with a soft hydrogel contact lens.25

Corneal defects can be prophylaxed with topical antibiotics until they heal. Persistent corneal defects can be managed with rigid gas permeable, soft hydrogel or scleral contact lenses.26-29 Scleral lenses are often underused because of inexperience.

The benefits of these larger-diameter devices include the creation of a substantial precorneal tear reservoir improving and maintaining corneal hydration while simultaneously providing complete coverage and protection of the corneal surface from external environmental stress and the iatrogenic effects of the lid margins and lashes.28,29 Contact lenses relieve pain, prevent exposure and enhance the surface chemistry improving epithelial healing.26-29

Systemic immunomodulatory therapy is the treatment of choice for controlling disease activity and limiting progression, given the systemic nature of the disease and the poor efficacy of current local or topical therapies.1-22,30-32 The management should be accomplished using a multidisciplinary approach.17 Systemic cyclophosphamide with short-term adjunctive high-dose prednisone is the preferred treatment for severe and/or rapidly progressing OCP.17,30 Data suggests that cyclophosphamide provides an effective bridge to lowering the dose of systemic corticosteroids (10mg prednisone or less).30 Oral low-dose weekly methotrexate is another useful first-line treatment for mild-to-moderate OCP.17 In many instances, disease remission can be induced with well-tolerated therapy.17,18,24 This aspect of therapy is best directed by a rheumatologist.

Ocular cicatricial pemphigoid can also be treated with cytoxan (a synthetic antineoplastic agent), dapsone (a sulfa antibacterial), minocycline, etanercept and azathioprine (an immunosuppressive agent).32 Etanercept is a recombinant human dimeric fusion protein that acts as a competitive inhibitor of TNF-alpha. Pentoxifylline added to doses of pulsed steroid and cyclophosphamide therapy is an alternative, effective and economical method of controlling OCP through reduction of TNF- levels.16,32

Mycophenolate mofetil (MMF) is a potent immunomodulatory drug that inhibits the function of T- and B-lymphocytes.20 MMF can be used alone or in combination with other immunomodulatory drugs for moderate to severe cases of uveitis, scleritis and ocular cicatricial pemphigoid.20

Recent developments on mucous membrane pemphigoid medical therapy include the additions of daclizumab (monoclonal antibody agent), intravenous immunoglobulin therapy and methotrexate (antimetabolite/antifolate agent).10,33

Surgical therapies include keratolimbal allografts and amniotic membrane transplantation with or without penetrating keratoplasty.4,34 Amniotic membrane transplantation, in the setting of pre- and post-immunosuppressive therapy is very useful for reconstruction of the conjunctival fornices.4,34 Keratoprosthesis can be used in cases where the ocular surface is beyond repair or reconstruction.35

Finally, ophthalmic plastic surgery is essential for the management of lid malposition and corneal exposure. Corneal and ocular surface reconstructive surgery may be required in the most advanced stages. All surgery must be integrated with ocular surface treatment and immunosuppressive treatment to avoid disease exacerbations.

Clinical Pearls

Patients with OCP and disrupted lid/globe relationships become susceptible to microbial colonization from normal eyelid flora. Combination anti-infective and anti-inflammatory therapies are necessity for success.

Severe dry eye is a late finding in ocular cicatricial pemphigoid. The disease induces conjunctival scarring that obstructs the meibomian gland ducts and lacrimal gland ducts, creating deficiencies in both the lipid and aqueous components of tears.

Goblet cell loss reduces the mucus component of the tear film, retarding the tears’ ability to maintain surface contact. Without appropriate mitigation of all issues, the ocular surface will become permanently disfigured and functionally compromised.

Other processes have the ability to produce cicatricial conjunctival changes, including mechanical trauma, chemical injury, ligneous conjunctivitis, adnoviral conjunctivitis, Steven’s-Johnson syndrome, Wegener’s granulomatosis, chlamydia infection, sarcoidosis, Sjögren’s syndrome, systemic lupus erythematosus, conjunctival cancers and drug-induced exposure to epinephrine and pilocarpine. Each of these conditions must be considered in the differential diagnosis.

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19. Tauber J. Ocular cicatricial pemphigoid. Ophthalmology. 2008;115(9):1639-40.

20. Klisovic DD. Mycophenolate mofetil use in the treatment of noninfectious uveitis. Dev Ophthalmol. 2012;51(1):57-62.

21. Kaçmaz RO, Kempen JH, Newcomb C, et al. Cyclosporine for ocular inflammatory diseases. Ophthalmology. 2010;117(3):576-84.

22. Fistarol SK, Itin PH. Anti-inflammatory treatment. Curr Probl Dermatol. 2011;40(1):58-70.

23. Kiire CA, Srinivasan S, Inglis A. Peripheral ulcerative keratitis after cataract surgery in a patient with ocular cicatricial pemphigoid. Cornea. 2011;30(10):1176-8.

24. Saw VP, Dart JK. Ocular mucous membrane pemphigoid: diagnosis and management strategies. Ocul Surf. 2008;6(3):128-42.

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31. Ford RM, Khalifa YM. Improvement in ocular cicatricial pemphigoid following treatment for porphyria cutanea tarda. Clin Ophthalmol. 2012;10(6):1709-12.

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34. Liu J, Sheha H, Fu Y, Giegengack M, Tseng SC. Oral mucosal graft with amniotic membrane transplantation for total limbal stem cell deficiency. Am J Ophthalmol. 2011;152(5):739-47.

35. Ciralsky J, Papaliodis GN, Foster CS, ET AL. Keratoprosthesis in autoimmune disease. Ocul Immunol Inflamm. 2010;18(4):275-80.

36. Fania L, Giannico MI, Fasciani R, et al. Ocular mucous membrane pemphigoid after Lyell syndrome: occasional finding or predisposing event? Ophthalmology. 2012;119(4):688-93.