A 53 year old white male presents with a history of chronic conjunctivitis. Exam findings reveal symblepharon and conjunctival granulomas. Biopsies of the eyelid growths lead to a diagnosis of ocular cicatricial pemphigoid.
I. Case History
53 year old white male with a history of chronic conjunctivitis
Patient reports ocular irritation especially in the lateral canthus and a feeling of dryness bilaterally for eight months. The patient also complains of a “blister” like sensation underneath his eyelids. The eyes are also reported to be crusted shut every morning. The patient reports currently using artificial tears every ten minutes.
-Ocular and Medical history
(+) Allergic Rhinitis
(+) Bipolar Disorder
(+) Hepatitis C
(+) Cocaine Dependence
(+) Alcohol Dependence
(+) history of chronic conjunctivitis in both eyes (OU)
Posterior pole and Periphery: unremarkable
Patient reports negative skin or oral lesion/ulcerations during initial optometry examination. However the dermatology consult indicated that the patient reported previous episodes of developing blisters on his face, arms, back, legs, and buttocks. At the time of the exam, scars and post-inflammatory hyperpigmentation were found on areas of the body.
Upon subsequent visits, a biopsy of conjunctival tissue revealed deposits of immunoglobulin A (IgA), fibrin and weak complement 3 (C3) in focal areas of the basement membrane zone region, and deposits of IgA in the cystoid bodies in the epithelial layer. Results indicate linear IgA bullous dermatosis (LABD) a form of ocular mucous membrane pemphigoid (also known as cicatricial pemphigoid).
-Radiology Studies were not needed III. Differential diagnosis
Ocular cicatricial pemphigoid (OCP) is a systemic autoimmune inflammatory disease that is part of a range of disorders termed mucous membrane pemphigoid. This disease not only affects the conjunctiva of the eye, but also the skin, and mucous membrane linings of the mouth, esophagus, trachea, nose, vagina, and rectum (5). The most common site affected is the membrane linings of the mouth (3). Of the patients with oral involvement it is estimated that 15-20% will develop ocular involvement within five years of onset (4).
This is a rare condition generally found within the population of individuals aged between sixty and eighty; however a few cases have been reported in young children (3). The disease has been known to affect more women then men (5). No racial or geographic predilection has been found (5).
Patients with undiagnosed OCP will present with complaints of burning, redness, tearing, decreased vision, and foreign body sensation (7). These patients also generally have a history of chronic conjunctivitis (7). The disease is best described in four stages. Stage one is described as conjunctival injection and scarring. Stage two begins with the foreshortening of the inferior conjunctival cul-de-sac. This leads to the formation of a symblepharon which is described as stage three. Stage three also includes such signs as corneal neovascularization, keratopathy, trichiasis, entropion, dystichiasis and decreased tear production, which eventually lead to corneal damage. Stage four is considered the end stage of OCP and results in ankyloblepharon and ocular surface keratinization (7, 6). The clinical signs and symptoms of OCP are further confirmed with laboratory testing.
Once a patient is suspected of having OCP, a biopsy of the conjunctiva is ordered using the immunofluorescent or immunoperoxidase technique (7). For a definitive diagnosis of OCP a linear deposition of immunoreactants at the basement membrane of inflamed conjunctiva is necessary. A negative result does not exclude a diagnosis of OCP but a positive result confirms the clinical diagnosis (7). Immunofluorescent testing is both sensitive and specific for the diagnosis of mucous membrane pemphigoid and is considered the gold standard method of diagnosing the condition (4). The disease may take anywhere from ten to twenty years to progress through each stage. An untreated eye or even a treated eye can lead to blindness due to the severe corneal scarring and due to the likelihood of recurrences (6).
V. Treatment, management
-Treatment and response to treatment
The goal of treatment is to prevent inflammation and scarring, reduce recurrences, and decrease symptoms (7). Treatment today consists of oral and or intravenous medications. Topical and subconjunctival treatment with corticosteroids, mitomycin-C, cyclosporine, and retinoids have been shown to be in effective in controlling ocular inflammation (1). First line therapy commonly used today, consists of immunosuppressive medications with or without corticosteroids. However, studies have also shown the use of intravenous immunoglobulin therapies (IVIg) and anti-tumor necrosis factor agents (TNF-a) for treating OCP.
The immunosuppressive medications that are routinely used are Dapsone (Jacobus, diamino-diphenyl sulfone), methotrexate, mycophenolate mofetil, azathioprine, cyclophophamide, and systemic prednisone. High doses of corticosteroids alone were found to control scarring, but did not fully control the disease. Patients generally have to remain on the medication for a long period of time and due to the long term complications of steroid use, it may be an undesirable treatment option. Patients were also found to have recurrences during the tapering period of the steroid (1). Ahmed et al., reported that of the immunosuppressive medications, Dapsone was most commonly used, followed by methotrexate, axathioprine, and cyclophophamide, and prednisone was commonly used as adjunctive treatment (1). The medications were found to control ocular inflammation in 90% of the sixty-one patients studied even when medications were discontinued, but 46% needed to remain on a maintenance dose to prevent recurrences, and 10% progressed regardless of different drugs used. It was also reported, that some patients in this study were required to take more then one drug to control ocular inflammation. Some patients needed anywhere from two to six different medications to control the disease. Common side effects of the medications included hematologic, gastrointestinal, cardiovascular, and urinary complications. Dapsone was found to cause the greatest number of side effects while methotrexate was found to cause the least number of side effects.
Letko, E. et al compared the clinical outcome of ocular involvement in patients with OCP between conventional immunosuppressive and intravenous immunoglobulin therapies. Sixteen people were divided into two groups of eight. One group received IVIg therapy and the other group received immunosuppressive therapy. In the end it was found that patients treated with IVIg had a more rapid control of ocular inflammation and did not progress to advanced stages of OCP, where as patients treated with immunosuppressive therapy had multiple recurrences. Side effects were also non significant when compared to the side effects of immunosuppressive drugs.
Canizanes et al. described three cases of patients with mucous membrane phemphigoid who were treated with the anti-tumor necrosis factor agent, Etanercept (Enbrel). Of the three patients, all of them had oral involvement and one had ocular involvement. All three patients were initially treated with some form of steroid, immunosuppressive, or intravenous immunoglobulin therapies with little success in suppressing the disease. The patients were then treated with 25 mg of Etanercept twice weekly. In all three patients the oral mucosal disease improved and the patient with the ocular involvement had stabilization of progression. This study shows some indication that TNF-a may play a role in the pathogenesis of the disease, and therefore could be a promising treatment modality in the future.
Thus, our patient was treated on initial presentation with artificial tears, punctal plugs, Restasis (Allergan) four times a day OU, cromolyn four times a day OU, ketotifen four times a day OU, and tobredex ointment at bedtime OU. Once diagnosed with OCP the patient was treated with 60 mg prednisone orally per day and upon follow-up, mycophenolate moteil 1000 mg BID orally may be added to his treatment plan.
-Bibliography, literature review encouraged
1. Ahmed, A.R. et al.“The effect of Treatment and it’s Related Side Effects in
Patients with Severe Ocular Cicatricial Pemphigoid.” Ophthalmology 2002; 109, 111-118.
2. Ahmed, M. et al., “Ocular cicatricial pemphigoid: pathogenesis, diagnosis and
treatment.” Progress in Retinal and Eye Research. 2004; 23, 579-592
3. Canizares MJ, Smith Dl, Conners MS, et al. “Successful treatment of mucous
membrane pemphigoid with Etanercept in 3 patients.” Archives of Dermatology.
4. Danier, E., and Thorne, J.E. “Recent advances in mucous membrane Pemphigoid.”
Current Opinion in Ophthalmology. 2008, 19; 292-297.
5. Foster, C. S. “Ocular Cicatricial Pemphigoid.” American Uveitis Society. 2003.
6. Friedman, N. and Kaiser, P. The Massachusetts Eye and Ear Infirmary Illustrated
Manual of Ophthalmology. Pennsylvania: Elsevier, Inc, 2004. pp 132-134.
7. Letko, E. et al., “A nonrandomized comparison of the clinical outcome of ocular
Involvement in patients with mucous membrane (cicatricial) pemphigoid between
conventional immunosuppressive and intravenous immunoglobulin therapies.”
Clinical Immunology. 2004; 111, 303-310.
-Clinical pearls, take away points if indicated Ocular cicatricial pemphigoid is a rare disease but one that optometrists should be aware of. Due to the difficulty of distinguishing the early signs and symptoms of conjunctival conditions, OCP is often diagnosed in stages three or four. As a result, aggressive treatment is sometimes necessary. As discussed in this report, different modes of therapy are available. However due to the lack of well controlled clinical trials, a gold standard for treatment has yet to be developed. Choice of treatment is made based on clinical experience, recent case reports, trial and error, and cost of the treatment plan. When treating OCP it is also important to co-manage the disease with other health care providers such as dermatologists, primary care providers, and dentists due to the possibility of systemic involvement. Even with the development of new therapies recurrences are still possible; therefore frequent follow up are important. In the end, the best thing you can do for your patient is to treat their symptoms.