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Woman with rheumatoid arthritis complains of left eye pain
A localized area of scleral injection was present temporally in the left eye.
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A 71-year-old woman at the New England Eye Center complained of 4 days of intermittent “stabbing” pain in her left eye, occurring one to two times per day and lasting 30 minutes to 90 minutes. The pain was severe, awakened her from sleep and worsened with eye movement. She described nausea and a dull frontal headache on the left side but denied a change in vision or photophobia. A complete review of systems was negative, including no recent fever, chills, weight loss, myalgias, arthralgias, scalp tenderness or jaw claudication.
The patient’s ocular history was remarkable for cataracts and suspicion of glaucoma based on a family history and elevated IOP. Previous testing showed no visual field loss or nerve fiber layer thinning on optical coherence tomography. Her medical problems included rheumatoid arthritis, hypothyroidism, hyperparathyroidism, hypertension and hyperlipidemia. Her medications were Levoxyl (levothyroxine, Pfizer), Lipitor (atorvastatin calcium, Pfizer), methotrexate and folic acid, and she had been on Plaquenil (hydroxychloroquine, Sanofi-Aventis) for 1 year. She did not smoke, drink or use illicit substances. She denied trauma.
Examination
On examination, uncorrected visual acuity was 20/25-2 in the right eye and 20/100+ in the left eye. The patient was corrected to 20/25-2 with a refraction of +1.50 + 0.75 × 015 in the left eye. This represented a hyperopic shift from 2 months prior, when the patient’s vision was 20/25 uncorrected in the left eye. Pupils were equal, round and reactive to light with no afferent pupillary defect. Extraocular movements were full. IOP was 22 mm Hg and 23 mm Hg in the right and left eyes, respectively. Visual fields were full to confrontation. The patient’s scalp was non-tender, and the temporal arteries were non-prominent with palpable pulses.
Anterior segment exam was remarkable for 3+ localized injection and dilated blood vessels of the temporal sclera in the left eye, which did not blanch with 2.5% phenylephrine. The anterior chamber was deep and quiet. There was 1+ nuclear sclerosis bilaterally. Dilated fundus exam was unremarkable.
Figure 1. B-scan shows scleral thickening (“T-sign”) typical of posterior scleritis.
Images: Bartolini CE, Mattox CG
Figure 2. B-scan after discontinuation of alendronate shows a decrease in scleral thickening and fluid.
What is your diagnosis?
Eye pain with localized injection
The differential diagnosis for an older woman with unilateral eye pain and localized injection included scleritis, episcleritis, myositis and nonspecific orbital inflammatory disease. The localized injection in the left eye did not blanch with phenylephrine, pointing toward scleritis as the most likely diagnosis. Moreover, the patient had a known history of rheumatoid arthritis, which can manifest with scleritis. The hyperopic shift and pain with eye movement suggested possible posterior involvement. Orbital inflammatory disease was considered less likely given there was no extraocular motility restriction or diplopia. A presumptive diagnosis of scleritis was made, and a B-scan was performed to confirm the clinical impression.
Follow-up
B-scan ultrasound of the left eye showed evidence of scleral thickening and fluid in Tenon’s space (Figure 1). The patient reported that her rheumatoid arthritis was well-controlled with methotrexate and hydroxychloroquine. Further questioning at this point revealed that she had started a new medication, alendronate, as a treatment for her hyperparathyroidism 2 days before the start of her eye pain.
The patient was told to discontinue the alendronate and start ibuprofen 600 mg three times daily. At a 1-week follow-up appointment, the patient’s symptoms had resolved. She reported that 1 to 2 days after discontinuing the alendronate, her eye pain had improved significantly. On examination, visual acuity was 20/30 in the left eye without correction, and the hyperopic shift and redness had resolved. B-scan showed decreased scleral thickening and fluid in Tenon’s space (Figure 2).
Discussion
Scleritis is a granulomatous, inflammatory condition centered in the sclera, but it may involve the adjacent cornea, uvea or episclera. It is a relatively uncommon disease, with a prevalence of six cases per 100,000 persons. However, it has been described in up to 6.3% of patients with rheumatoid arthritis. Most cases are unilateral, but 25% of patients have bilateral disease at presentation. The disease occurs between the ages of 30 and 50 years and is twice as likely to occur in women as in men. There is no racial or geographic predilection. The pathophysiology of scleritis is unknown, but there is evidence that T cells play a predominant role.
Scleritis can be anatomically divided into anterior and posterior types, depending on whether the inflammation is anterior or posterior to the insertion of the lateral and medial rectus muscles. Anterior scleritis is further subdivided into diffuse, nodular and necrotizing, with or without inflammation. Necrotizing without inflammation is also known as scleromalacia perforans.
Scleritis is usually suspected from the clinical history and confirmed by characteristic clinical signs. Patients typically complain of severe, constant “boring” eye pain that is often worse in the morning, awakens the patient from sleep and is aggravated by eye movement. Decreased vision may suggest the presence of posterior scleritis, which can induce a hyperopic shift. In 20% of cases, patients may have little or no eye pain, and this is typically true in cases with milder disease or when the patient has already been on immunosuppressive medications. Scleromalacia perforans also presents without pain.
The examination findings can vary depending on the location and type of disease. In general, anterior scleritis presents with dilation of the superficial and deep scleral vessels that persists after the application of phenylephrine. In nodular scleritis, there is a firm, immobile, red nodule usually close to the limbus. Necrotizing scleritis has the added feature of yellow to white areas of edematous, necrotic sclera. Posterior scleritis may occur with anterior scleritis or in isolation. If it occurs in isolation, the exam may be normal or show optic disc swelling, exudative retinal detachment, macular edema, retinal striae or choroidal folds. B-scan may be confirmatory by showing thickening of the sclera and fluid in Tenon’s space.
Scleritis can be confused with episcleritis, but it is important to differentiate the two because the management, prognosis and complications are very different. Episcleritis is a benign, self-limiting condition that is rarely associated with underlying systemic disease and does not require aggressive treatment. Clinically, patients typically have less pain with episcleritis. In addition, the involved episcleral vessels are superficial and blanch with phenylephrine.
In contrast, scleritis is a serious eye condition that is associated with an underlying systemic disease in 50% of cases, requires aggressive treatment and can result in significant eye morbidity. The most common diseases associated with scleritis include rheumatoid arthritis, Wegener’s granulomatosis, seronegative spondyloarthropathy, relapsing polychondritis, systemic lupus erythematosus and inflammatory bowel disease. To rule out an underlying systemic disease, several laboratory studies should be ordered, including a CBC, complete metabolic panel, urinalysis with microscopic analysis, ESR, CRP, RPR, FTA-ABS, rheumatoid factor, anti-citrullinated peptide antibodies, ANA, ACE, lysozyme and chest radiograph. If clinical suspicion warrants, a tuberculin skin test, sacroiliac joint radiograph, CT scan of the sinuses or gastrointestinal evaluation can be obtained. Rarer causes of scleritis include infection, most commonly herpes zoster, trauma, surgery or medications such as bisphosphonates, as in our patient.
Visual loss can result from several complications of scleritis, such as cataracts, uveitis, corneal melts, glaucoma, posterior segment disease and, rarely, scleral thinning leading to globe perforation. The rate of complications is highest in patients with necrotizing scleritis.
A step ladder approach is used in the treatment of scleritis. Initial treatment consists of high-dose oral NSAIDs. If a patient is unresponsive to NSAIDs or has necrotizing scleritis, oral prednisone is started. The starting dose of prednisone is typically 1 mg/kg/day, followed by a tapering schedule based on clinical response. If the patient does not respond within 1 month to oral prednisone or if more than 10 mg/day of prednisone is required to control the disease, immunomodulatory therapy must be used. For patients with non-necrotizing scleritis, methotrexate is first-line treatment, followed by azathioprine or mycophenolate mofetil. By comparison, cyclophosphamide is the drug of choice for patients with necrotizing scleritis or Wegener’s-associated scleritis. In the case of medication-induced scleritis, the offending agent should be discontinued immediately.
Interestingly, our patient had two risk factors, rheumatoid arthritis and bisphosphonate use, that predisposed her to scleritis. The likely cause of her scleritis was use of bisphosphonate, as supported by the proximity between the first administration of the drug and the onset of her symptoms. In addition, her symptoms resolved rapidly when the drug was withdrawn. It is also possible that her underlying inflammatory condition, rheumatoid arthritis, played a synergistic role.
It is estimated that by 2020, 50% of Americans older than 50 years will be at risk for osteoporosis. Bisphosphonates are the most frequently used medication in the treatment of osteoporosis but are also used to treat Paget’s disease, hypercalcemia of malignancy and hyperparathyroidism. Several case reports have linked scleritis to the use of non-nitrogen-containing bisphosphonates, including alendronate and pamidronate. A relative risk of 1.5 has been reported. The evidence linking scleritis with bisphosphonate therapy is further supported by the onset of ocular findings occurring within 72 hours of drug use, rapid resolution of symptoms with drug withdrawal and positive rechallenge tests. Bisphosphonates inhibit bone resorption through stimulation of a distinct group of gamma and delta T cells, which then release pro-inflammatory cytokines. It is believed that these same cytokines may contribute to the immunologic reaction seen in patients with scleritis.
Conclusion
In summary, a 71-year-old woman presented with pain and localized redness in the left eye and was presumed to have scleritis based on the clinical appearance and persistence of erythema with phenylephrine. This diagnosis was confirmed with a B-scan that showed posterior involvement. The cause of the scleritis was confounded by the history of rheumatoid arthritis. However, a careful history revealed that the more likely etiology was the use of alendronate, which had been started 2 days before the onset of her symptoms. This was further supported by resolution of the patient’s symptoms upon discontinuation of the drug.