Leflunomide (Arava®)-induced cystoid macular oedema
A. Barak1,2,
L. S. Morse1 and
I. Schwab1
1Department of Ophthalmology, UC Davis, Sacramento, CA, USA and 2Tel Aviv Medical Center, Tel Aviv, Israel.
Correspondence to: A. Barak. The Tel Aviv Medical Center, 6 Waitzmann Street, Tel Aviv, 64239, Israel. E-mail: adielbarak{at}yahoo.com
SIR, Leflunomide (Arava®), an immunomodulatory agent, was the first oral agent for active rheumatoid arthritis labelled for slowing the progression of the disease, slowing structural damage to joints and relieving arthritis symptoms [1]. While it has potent immunosuppressive and anti-inflammatory activity, its use has not been studied in uveitis, yet it clearly is a potential anti-uveitic agent [2]. We report a case of bilateral cystoid macular oedema which developed recently after initiation of leflunomide treatment.
RS is a 57-yr-old white male who started on leflunomide owing to severe rheumatoid arthritis. His current medical problems included rheumatoid arthritis, which was diagnosed 7 yr ago, and his medications included 5 mg of prednisone (taken for 2 yr, with no change in steroid regimen during the last 6 months), Arthroteck (voltarin + cytotec to protect the gastrointestinal tract) and leflunomide. He was taking no ocular medications, had no previous eye problems and had no previous ocular surgery or any fundoscopic examination that he recalled. Two weeks after initiation of leflunomide treatment he developed blurring of the vision in both eyes. On examination he was 20/20 in the right eye and 20/25 in the left eye with refraction. His skin was within normal limits. His conjunctiva was quiet. His anterior segment examination was completely normal and the intraocular pressures were 12 and 14 mmHg. His funduscopic examination showed mild cystoid macular oedema on the right and mild but more prominent cystoid macular oedema on the left. No vitreitis or any other signs of scleritis were found. His angiogram, taken at the UC Davis medical centre 2 weeks after initiation of ocular symptoms, confirmed the diagnosis of cystoid macular oedema in both eyes, more in the left eye than in the right eye, with disk hyperfluorescence and no perivascular leakage (Fig. 1). He was diagnosed as having cystoid macular oedema, and was advised to stop the leflunomide. Four weeks after cessation of the leflunomide treatment, subjective visual improvement was noted, but his vision continues to be somewhat blurred. Three months later, visual acuity was 20/20 VA in both eyes, with no further symptoms. On clinical examination no cystoid macular oedema was seen. No additional angiograms were taken.

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FIG. 1 Fluorescein angiography image of the right (A) and left eye (B). The angiogram was taken 4 weeks after initiation of leflunomide treatment and 2 weeks after complaining of ocular blurring. Late venous phase images showing diffuse optic nerve head fluorescein leakage, and perifoveal fluorescein leakage in a patelloid pattern representing cystoid macular oedema. No perivascular leakage is identified.
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Leflunomide, an isoxazole derivative, inhibits T- and B-cell proliferation, suppresses immunoglobulin production and interferes with cell adhesion. The leflunomide active metabolite, A77 1726 inhibits the enzymatic activity of protein tyrosine kinase as well as the mitochondrial dihydro-orotate dehydrogenase. This results in diminished interleukin-2 receptor signal transduction and inhibition of pyrimidine nucleotide synthesis [3]. Administration of the drug requires a loading dose of 100 mg for the first 3 days, followed by 20 mg/day thereafter. Adverse effects include diarrhoea, weight loss, skin rash, alopecia and changes in liver function tests [3]. The drug is excreted via the biliary and renal systems with a half-life of 1416 days, and its use is contraindicated during pregnancy and in lactating mothers [3]. We present a case in which bilateral cystoid macular oedema and disc hyperfluorescence developed shortly after initiation of leflunomide treatment in a rheumatoid arthritis patient. Although rheumatoid arthritis is known to cause scleritis and vitreitis, the temporal relationship of the symptoms as well as the resolution of the symptoms after discontinuation of the drug support the suspicion that the administration of leflunomide was the direct cause of the cystoid macular oedema. Other drugs have been shown to cause cystoid macular oedema, including ocular hypotensive lipids [4] and Latanoprost [5], which was shown to cause cystoid macular oedema in pseudophakic patients. The mechanism for the cystoid macular oedema in these drugs is presumed to be triggering of the biosynthesis of endogenous prostaglandins by the drug, thus causing disruption of the bloodaqueous barrier and the creation of cystoid macular oedema [6]. We have no evidence of such action in leflunomide, but we can speculate that a similar mechanism is probably causing cystoid macular oedema. Currently, no such eye condition has been associated with second-line drugs for treatment of rheumatoid arthritis [7]. In the absence of pre-treatment examination and fluorescein angiography, and rechallenges with the suspected drug, a casual relationship cannot be established. However, the case raises the possibility of such a complication. Until definite studies are carried out that prove or disprove the association between ocular complications and leflunomide, it would be prudent to exercise caution in the use of the drug in patients with high-risk eyes, especially owing to its potential use in the treatment of uveitis.
Informed patient consent was obtained.
We received an unrestricted grant from Research to Prevent Blindness, New York City, NY.
The authors have declared no conflicts of interest.
References
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Accepted 14 May 2003