Introduction

Canine uveitis can be classified according to etiology into infectious, neoplastic, metabolic, immune-mediated, traumatic, or reflex. Immune-mediated uveitis is diagnosed by excluding other possible causes of uveitis, and most cases of idiopathic uveitis are immune-mediated.¹

For the treatment of anterior uveitis, topical anti-inflammatory therapy should be promptly initiated. If anterior uveitis is not controlled early in the disease process, it may cause adverse sequelae, including synechiae, secondary glaucoma, cataracts, endophthalmitis, and phthisis bulbi. Topical therapy alone may control mild anterior uveitis, but it is not sufficient for the treatment of severe uveitis, posterior uveitis, and uveitis secondary to systemic disease.² Systemic corticosteroids have been conventionally used as first-line treatment and for severe inflammation of the uvea in cats and dogs, and some other systemic medications may be administered to canine patients deemed immune-mediated or unresponsive to first-line therapy. However, the use of these immunosuppressive agents can evoke undesired complications including gastrointestinal upset and myelosuppression.³ Leflunomide is well tolerated by dogs below a certain dose and has recently been found to be an option for the successful treatment of immune-mediated inflammatory diseases in dogs.^4–8 This report presents a case in which leflunomide was administered as a systemic monotherapy for treating bilateral recurrent uveitis.

Case Description

A 5 yr old castrated male bichon frise presented with persistent bilateral ocular redness and intermittent blinking of both eyes. The patient’s history included an episode of severe pancreatitis at 1 yr old and allergic reaction to duck and lamb meat; subsequently, occasional vomiting was noted after stressful events. The patient had no history of travel, trauma, or infection. In a previous clinic, complete ophthalmic examination and ocular ultrasonography resulted in a diagnosis of bilateral cataracts and uveitis with posterior synechiae. Treatment was commenced with systemic prednisolone (2 mg/kg q 12 hr) and topical agents administered bilaterally: 0.2% cyclosporine ointment (q 12 hr), 1% prednisolone acetate (q 6 hr), 0.03% flurbiprofen sodium (q 6 hr), ofloxacin (q 6 hr), and 1% atropine sulphate (q 48 hr). After 4 mo, the uveitis had improved, and oral prednisolone was tapered over 2 mo to a final dose of 0.5 mg/kg q 12 hr, and azathioprine was added to the treatment (2 mg/kg q 24 hr). Two months later, the azathioprine was discontinued because of the recurrence of uveitis. At this point, after 6 mo of treatment with oral prednisolone, the patient had gained 30% of his original body weight, was unable to sleep due to polyuria/polydipsia, and was exhibiting continuous panting; these were considered to be side effects of the systemic prednisolone over 6 mo, which was the therapeutic period of bilateral uveitis. The current treatments consisted of oral prednisolone (0.5 mg/kg) and the same bilateral topical agents as at initiation of treatment.

On examination, the patient’s body condition score was 7/9, and there were no abnormalities such as lymph node enlargement or skin lesions. At initial neuro-ophthalmic examination, menace response and dazzle reflex were observed in both eyes, but the bilateral pupillary light reflex was incomplete because of posterior synechiae of the iris. Ophthalmic examination using a slit lamp biomicroscope revealed bilateral moderate conjunctival hyperemia with mild episcleral vessel congestion, incipient anterior subcapsular cataract, and extensive posterior synechiae. Mild, central, subepithelial opacity suspected to be corneal lipidosis was observed bilaterally. Mild and moderate aqueous flare were present in the right and left anterior chambers, respectively. Neither pupil would pharmacologically dilate after topical application of 1% tropicamide (Figure 1A), and the equatorial regions of the lenses could not be evaluated. The Schirmer tear test showed a flow of 19 mm/min in both eyes, and the intraocular pressure (IOP) was 11 and 6 mm Hg in the right and left eyes, respectively. The fundus could not be completely examined because of the limited visibility due to the synechiae and cataracts. Primary intraocular neoplasm, which was not identified on the previous ultrasonographic findings, was ruled out. The complete blood count and serum chemistry results were normal except for the mildly elevated neutrophil count (14,080/uL, reference interval 2950–11,640/uL). The increased body condition score and neutrophil count were thought to be due to long-term steroid use. Regarding the clinical treatment history and examinations, the dog was diagnosed with idiopathic anterior uveitis and tentatively diagnosed with immune-mediated anterior uveitis.

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To treat the uveitis while avoiding systemic side effects, the dose of oral prednisolone was tapered over 1 wk, and oral cyclosporine^a (5 mg/kg q 12 hr) was prescribed for the following 2 wk. Bilaterally, 1% prednisolone acetate ophthalmic suspension and a combined mydriatic^b (0.5% phenylephrine and 0.5% tropicamide) were topically administered four times a day, and 0.2% cyclosporine ophthalmic ointment was applied twice a day. The patient was followed up weekly, and the aqueous flare was not observed in both eyes at the second recheck after the oral cyclosporine administration. IOP was 7 and 6 mmHg in the right and left eyes, respectively. Therefore, the dose of oral cyclosporine was reduced to 5 mg/kg q 24 hr. The patient experienced severe vomiting after 2 wk of dose reduction. The vomiting persisted even after changing the type of cyclosporine to liquid^c (5 mg/kg q 24 hr), and oral esomeprazole magnesium^d (0.7 mg/kg q 24 hr) was added. The abdominal ultrasonography revealed no abnormality, except the generalized thickening of the gastric wall.

The vomiting stopped immediately after oral cyclosporine was discontinued, and the bilateral uveitis relapsed 1 wk later. Therefore, oral leflunomide^e (2 mg/kg q 12 hr) was prescribed. Topical medications were administered as before. The follow-up interval was every fortnight, and the clinical signs of uveitis gradually improved. Two months after initiation of leflunomide therapy, aqueous flare was not observed, and the hyperemia had resolved (Figure 1B). The posterior synechiae were no more extensive compared to the appearance at the initiation of leflunomide therapy, and very mild episcleral vessel congestion was observed bilaterally. The intraocular pressure was 15 mm Hg in the right eye and 10 mmHg in the left eye, and the menace response and dazzle reflex were present bilaterally. As the symptoms of uveitis resolved, the oral leflunomide dose was gradually tapered with periodic monitoring over 13 mo, following which it was maintained at 0.5 mg/kg q 12 hr. For the tapering periods, 1% prednisolone acetate ophthalmic suspension was administered q 6 hr as the only topical medication.

Fifteen months after leflunomide initiation, the patient experienced anorexia, hematemesis, and diarrhea several times. Despite the discontinuation of leflunomide, the gastrointestinal disturbance was not alleviated, and the patient was hospitalized in a local animal hospital for 3 wk. The topical medication was same as before. According to the reports from the local animal hospital, platelet and liver enzyme values were within normal ranges, and abdominal ultrasonographic impressions suggested acute gastroenteritis and pancreatitis as diagnoses.

On the ophthalmic examination after the 3 wk systemic leflunomide discontinuation, the IOPs were 12 and 9 mm Hg in the right and left eyes, respectively, and aqueous flare was not observed in either eye. Menace response and dazzle reflex of both eyes were present, and the posterior synechiae and cataracts were static compared to the last examination. Systemic immune suppression using leflunomide was not resumed as per the owner’s request, despite being notified that uveitis might recur if the systemic medication would be continuously discontinued. The patient did not return for follow up for 7 mo and received only topical 1% prednisolone acetate ophthalmic suspension q 12 hr during that period.

The patient was evaluated again 8 mo after discontinuing leflunomide with clinical signs of relapsed uveitis. For the treatment of the relapsed uveitis, oral leflunomide (2 mg/kg) and famotidine (0.5 mg/kg) were administered twice a day, and 1% prednisolone acetate ophthalmic suspension (q 6 hr) was prescribed as a topical medication. During the following 8 mo, repeated clinical signs of uveitis, including aqueous flare and episcleral vessel congestion, occurred when <2 mg/kg q 12 hr of oral leflunomide was administered despite the intermittent addition of low dose oral prednisolone (0.5 mg/kg q 12 hr). Getting tired of the repeated oral medication for several years, the owner adjusted the administration of oral leflunomide arbitrarily according to hyperemia. The patient was observed to have lost vision bilaterally 10 mo after secondary leflunomide initiation.

The patient revisited 8 mo after the loss of vision in the glaucomatous right eye (IOP 37 mm Hg). Ocular sonography revealed decreased lens size, irregular posterior lens capsule continuity, and increased echogenicity in vitreous chamber with retinal detachment. Enucleation was strongly recommended, but the owner declined in favour of evisceration and intrascleral prosthesis; however, the surgery was delayed for 2 mo at the owner’s request. At the time of evisceration, the uveal tissue was fragile because of inflammation, and fibrin strands were observed in the posterior segment of the right eye along with the ruptured lens capsule.

Histologic examination of the eviscerated material comprised hemorrhage, fibrin, and collagen with retinal and uveal tissue and several short segments of linear basement membrane-like material with some associated mineral, presumed to be lens capsule. The uveal tissues were infiltrated by lymphocytes and plasma cells and also contained melanin-laden macrophages (Figure 2). The retinal tissues were atrophied. A histopathologic diagnosis of moderate lymphoplasmacytic and granulomatous uveitis with melanin-laden macrophages was made, which was suggestive of immune-mediated uveitis. Based on the clinical history and histopathologic results, the patient was diagnosed with immune-mediated uveitis. After evisceration, the inflammatory signs, including hyperemia and episcleral congestion, resolved. At the request of the owner, the left eye was treated with only with topical 1% prednisolone acetate ophthalmic suspension (q 12 hr), and the eye progressed to phthisis bulbi due to chronic mild inflammation.

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Discussion

Most idiopathic uveitis is immune-mediated uveitis and can be diagnosed by excluding all other known causes of uveitis.¹ Histopathologic evaluation through biopsy could be the most accurate diagnostic method for immune mediated disease, but it is not commonly applied to intraocular tissues. The therapeutic response could be employed to diagnose immune-mediated disease if extensive diagnostic testing was not feasible.⁹

The patient in this case had already been treated with immunosuppressives for uveitis, and primary neoplasia or metabolic diseases were excluded through hematology, blood chemistry, and ocular ultrasonography. Although the limitation was that serologic tests were not performed to determine the cause of infection, the clinical symptoms of uveitis in this patient were notably improved after several months of immunosuppressive treatment without systemic side effects related to infection. After long-term oral prednisolone administration, complete blood count analysis showed no findings suggestive of infection, and the patient had not visited any known endemic areas where uveitis could develop as the result of infection with leptospirosis, which was prevalent in rural areas of the Republic of Korea. According to these clinical histories, the patient was tentatively diagnosed with immune-mediated uveitis, and immunosuppressive treatment was continuously being considered.

Leflunomide has been used to treat immune-mediated diseases in dogs, including immune-mediated polyarthritis, refractory inflammatory colorectal polyps, and immune-mediated thrombocytopenia.^4–6 Experimental studies have shown that leflunomide can cause disease inhibition in an S-antigen-induced autoimmune uveitis rat model.¹⁰ In humans, the use of oral leflunomide in combination with other medications, such as cyclosporine or methotrexate, can reportedly control severe uveitis successfully.¹¹ A recent study investigated the use of leflunomide in dogs for several immune-mediated disorders included a single case of uveitis but did not provide detail descriptions of the therapeutic dose and prognosis of the uveitis case.⁷

Our patient experienced side effects of weight gain, polyuria/polydipsia, and severe gastrointestinal disturbance, which were presumed to be the result of long-term use of systemic prednisolone and cyclosporine. Mycophenolate mofetil (MMF) can also be used to treat immune-mediated uveitis, such as uveodermatologic syndrome.¹² However, MMF was not employed to treat this patient after consulting with our internal medicine veterinarian because of the high risk of gastrointestinal adverse effects. In a more recent study compared to our case, gastrointestinal adverse effects were most common among the adverse effects in the dogs administered MMF.¹³ Although cyclophosphamide and chlorambucil could have been used for the treatment of uveitis, they were not considered because they are conventionally used for chemotherapy and often lead to gastrointestinal side effects.^3,8,14

Leflunomide reportedly causes decreased appetite, lethargy, lymphopenia, thrombocytopenia, hepatotoxicity, and vomiting but appears to be well tolerated by dogs, particularly at doses of <4 mg/kg per day.⁸ In a retrospective study of efficacy and safety of leflunomide on 92 dogs, acute diarrhea, lethargy, and unexplained hemorrhage were reported as adverse events, although these typically resolved within 1 wk after discontinuation except one case of euthanasia. It was also reported that acute diarrhea and lethargy began within 1 wk after leflunomide was first administered.⁷ Because our patient did not show significant adverse effects for the first 15 mo after starting leflunomide therapy and occasionally vomited prior to leflunomide administration, it could not be concluded that the gastroenteritis and pancreatitis were induced by the leflunomide. Leflunomide therapy was relatively well tolerated in this patient, vision was maintained, and uveitis was controlled during the first continuous-treatment period.

The efficacy and toxicity of leflunomide was known to be monitored using the serum concentrations of teriflunomide in humans. However, it was not considered in this case because measuring serum teriflunomide concentration of dog was impossible in our country. Furthermore, the specific cut-off for the serum concentration of teriflunomide has not been established, and the pharmacokinetics of leflunomide differ between dogs and humans.¹⁵ A recent study found significant dose differences between groups with and without adverse effects in dogs using leflunomide.⁷ The suggested starting dosage of leflunomide in canine patient was 2 mg/kg/day, which was lower than that used in our case. Our patient started treatment with leflunomide prior to that publication, and the dosage at the time of discontinuation due to gastrointestinal disorders was 1 mg/kg/day, which was lower than median dosage of the group without adverse events in Sato’s study.

The histopathologic result of our patient led us to consider canine uveodermatologic syndrome, a common cause of bilateral immune-mediated uveitis, as a differential diagnosis. However, the patient did not present with the characteristic clinical signs of uveodermatologic syndrome such as dermatitis or skin problems including vitiligo. Furthermore, the progression of uveitis in both eyes indicated a chronic course, and there were no neoplastic changes and microorganisms in the eviscerated uvea. Considering both the histopathologic findings and clinical signs, a final diagnosis of idiopathic immune-mediated uveitis was made.

Conclusion

Although the patient lost vision due to oral leflunomide discontinuation, oral leflunomide therapy alone was effective in controlling relatively early stage immune-mediated uveitis without side effects for over a year in this patient, who experienced side effects when using other immunosuppressants. Therefore, it appears that leflunomide can be a viable treatment option for canine idiopathic immune-mediated uveitis.