Presentation

A 42-year-old Korean male was seen at Wills Eye Institute for pain, severe photophobia and redness in both eyes which began four months prior to presentation. He was treated with a variety of topical steroids and antibiotics, but had minimal improvement in symptoms. Three months prior to presentation, a nasal pterygium excision of the left eye was performed with some relief, but symptoms had recurred. The patient developed a limbal epithelial defect with stromal thinning bilaterally and was referred to the Cornea Service at Wills Eye Institute. He had no history of other ocular surgery, trauma, infection, contact lens wear or herpes infection.

 


Medical History

Medical history was unremarkable. He reported no medications or drug allergy. Social history and family history were unrevealing. Review of symptoms was remarkable for a macular rash on the patient's extremities and fevers of unknown origin, but he denied joint pain and stiffness, weight loss, sinus disease, gastrointestinal or renal symptoms.


 


Examination

The patient's vision was 20/30 in the right eye and 20/40 in the left eye. There was no afferent pupillary defect. Extraocular movements were intact and visual fields were full to confrontational testing in both eyes. There was no proptosis or sign of an orbital process. Intraocular pressures were within normal limits. Slit-lamp examination of the right eye revealed a limbal epithelial defect with 15 percent thinning from 2 o'clock to 5 o'clock. The left eye also showed a large limbal epithelial defect with 60 to 70 percent thinning from 7 o'clock to 11 o'clock (See Figure 1). The central cornea was otherwise normal without keratic precipitates, infiltrates or pannus in both eyes. The anterior chamber in both eyes was deep and clear. Posterior exam was unremarkable with no vitritis, hemorrhages, cotton wool spots, vascular occlusion or vasculitis.

 


Diagnosis, Workup and Treatment

The differential diagnosis of a middle-aged male with bilateral peripheral ulcerative keratitis (PUK) is extensive and includes infectious, inflammatory and non-inflammatory etiologies.1,2 The infectious etiologies include: viral (herpes zoster, herpes simplex, hepatitis B and C); bacterial (staph marginal keratitis); fungal; acanthamoeba; lyme disease; syphilis; and tuberculosis. Inflammatory etiologies include: rheumatoid arthritis; Wegener's granulomatosis; polyarteritis nodosa; systemic lupus erythematosus; sarciodosis; cryoglobulinemia; Churg-Strauss vasculitis; ulcerative colitis, spondyloarthropathies; and relapsing polychondritis. Non-inflammatory conditions include: Terrien's marginal degeneration; pellucid marginal degeneration; senile furrows; poorly fitting contact lens; corneal exposure; trichiasis; keratoconjunctivitis sicca; and post-surgical changes.


Standard workup of a patient with scleritis/PUK should include: complete blood count; metabolic panel; urinalysis; antineutrophil antibody assay; antineutrophil cytoplasmic antibody; rheumatoid factor; rapid plasma reagin; flourescent treponemal antibody absorption assay; lyme titer; purified protein derivative; and chest X-ray. Additional testing should be directed by the patient's review of symptoms.
3


At the time of presentation, the patient was started on prednisone 80 mg PO daily, doxycycline 100 mg PO b.i.d., and bacitracin ointment OU q.i.d. He was referred to a rheumatologist for a systemic workup. The laboratory testing outlined above, in addition to complement studies, serum protein plasma electrophoresis, double-stranded DNA and perinuclear antineutrophil cytoplasmic antibody, were normal. At this time, a diagnosis of idiopathic PUK was made. Biopsy of the skin lesions revealed folliculosis.


Oral prednisone improved the patient's rash and pruritis, but not his ocular symptoms. Plaquenil was added, but the patient's corneal thinning progressed in the left eye. He was switched to methotrexate, but it was not tolerated due to systemic side effects.
Inflixamab was started next and the patient initially responded well. However, his corneal thinning progressed two months later and he was switched to cyclophosphamide and given bactrim prophylaxis. Despite these immunosuppressive treatments, the left eye developed a corneal perforation. He was then treated with a crescentic corneal patch graft at the limbus covered with amniotic membrane (See Figure 2). At this time, IV steroids and IV cyclophosphamide were also used, which appeared to stabilize the patient's clinical exam. As an outpatient, the steroids and cyclophosphamide were tapered over several months as tolerated. He was fitted with a rigid gas permeable contact lens and achieved 20/25 vision in the left eye.


Several months after discontinuing systemic immunosuppresion, he developed recurrent inflammation and thinning in the left eye (See Figure 3). Recently, cyclophosphamide and prednisone was restarted.


 


Discussion

PUK is a rare form of ocular inflammation and is most frequently associated with systemic conditions, such as rheumatoid arthritis and Wegener's granulomatosis. The most common infectious association is herpes zoster. A British study estimated the incidence to be three cases per 1 million people per year.4 Women and men are affected equally and one study found that it occurs bilaterally in up to 40 percent of cases. It is associated with scleritis in 36 percent of cases.5,6


The goals of therapy in treating PUK are to: 1) lubricate; 2) promote re-epithelialization; 3) suppress systemic-mediated inflammation.5 The severity of ocular and extraocular disease determines the treatment of non-infectious PUK. The first-line therapy is oral steroids, started at a dose of 1 mg/kg/day (max. 60 mg/day) and slowly tapered depending on the clinical response. If vision loss is imminent, IV pulsed methylprednisolone is used (1 g/day for three days) followed by an oral taper. Steroid sparing agents are also utilized if the initial course of high dose steroids fails to control inflammation, or if more than 10 mg/day of steroids are needed for chronic control.6,7 In patients with systemic vasculitis and/or imminent risk of corneal perforation, the addition of alkylating agents (i.e. methotrexate) is usually the next step in treatment. Temporizing measures such as cyanoacrylate glue and bandage contact lenses are often helpful.


Several steroid sparing agents have been successfully used to treat PUK, including methotrexate, azathioprine, mycophenolate mofetil, cyclophosphamide, and infliximab. First line steroid sparing therapy is usually methotrexate, azathioprine or mycophenolate mofetil. Second line options include cyclosporine, infliximab  or rituximab. In patients with a systemic vasculitis, such as Wegener's, cyclophosphamide is the first-line drug of choice.6 Of note, if a patient has had prior therapy with etanercept, cyclophosphamide is relatively contraindicated due to a significantly higher risk of developing solid tumors relative to those receiving cyclophosphamide alone.8,9 All of these immunosuppressive medications have potential side effects and a risk of morbidity and mortality, especially when used in conjunction with high-dose steroids. Frequent clinic visits and blood work are necessary. Pneumocystis carinii pneumonia (PCP) prophylaxis (i.e., bactrim) is essential when using steroids and other immunosuppressants.
6


Ultimately, it is important to recognize PUK as a vision-threatening condition that is associated with many systemic diseases. A systemic workup is crucial in its diagnosis and treatment. Topical lubrication along with systemic immunosuppressive therapy is often necessary to effectively treat the ocular inflammation. Adjunctive immunosuppressants are frequently used to reduce the systemic side effects of chronic steroid use. A slow taper over several months is critical to minimize recurrences.

 

The author would like to acknowledge Kristen Hammersmith, MD, of the Cornea Service at Wills Eye Institute for her assistance with this manuscript.

 

1. Akpek EK, et al. Evaluation of patients with scleritis for systemic disease. Ophthalmology 2004;111(3):501-6.

2. Sutphin J. External disease and cornea. In: 2008-2009 Basic and Clinical Science Course. American Academy of Ophthalmology 2008-2009:229-232.

3. Galor A, et al. Scleritis and peripheral ulcerative keratitis. Rheum Dis Clin N Am 2007;33:835-854.

4. McKibbin M, et al. Incidence of corneal melting in association with systemic disease in the Yorkshire region, 1995-7. Br J Ophthalmol 1999;83(8):941-3.

5. Tauber J, et al. An analysis of theraperutic decision making regarding immunosuppressive chemotherapy for peripheral ulcerative keratitis. Cornea 1990;9:66-73.

6. Sainz de la Maza M, et al.Ocular characteristics and disease associations in scleritis-associated peripheral keratopathy. Arch Ophthalmol 2002;120:15-9.

7. Jabs DA, et al. Standarization of uveitis nomenclature for reporting clinical data: Results of the first international workshop. Am J Ophthalmol 2005;140:509-16.

8. Wegener's Granulomatosis Etanercept Trial (WGET) Research Group: Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med 2005;352:351-361.

9. Michalova, K et al. Biologic agents in the management of inflammatory eye diseases. Current Allergy and Asthma Reports 2008;8(4):339-47.