This study will investigate the safety and effectiveness of the drug Leflunomide to treat
uveitis-an inflammation of the eye caused by an immune system abnormality. Leflunomide
suppresses immune system activity and has been shown to control autoimmune diseases, such as
arthritis (joint inflammation), in animals. It has also improved symptoms in patients with
rheumatoid arthritis, and the Food and Drug Administration has approved it for treating
patients with this disease. Eye and joint inflammation may have similar causes, and
medicines for arthritis often help patients with eye inflammation. This study will examine
whether Leflunomide can help patients with uveitis.
Patients with uveitis who are not responding well to steroid treatment and patients who have
side effects from other medicines used to treat uveitis (such as cyclosporine,
cyclophosphamide, methotrexate or azathioprine) or have refused treatment because of
possible side effects of these medicines may be eligible for this study. Candidates will be
screened with a medical history, physical examination, blood test and eye examination. The
eye exam includes a check of vision and eye pressure, examination of the back of the eye
(retina) with an ophthalmoscope and the front of the eye with a microscope. They will also
undergo a procedure called fluorescein angiography to look at the blood vessels of the eye.
A dye called sodium fluorescein is injected into the bloodstream through a vein. After the
dye reaches the blood vessels of the eye, photographs are taken of the retina.
Study participants will be divided into two groups. One group will take 100 milligrams of
Leflunomide once a day for 3 days and then 20 milligrams once a day for 6 months. The other
group will take a placebo-a pill that looks like the Leflunomide pill but does not contain
the medicine. All patients in both groups will also take prednisone. Patients will have
follow-up examinations at weeks 1, 4, 8, 12, 16, and 24 (6 months) of the study. Each
follow-up visit will include a repeat of the screening exams and an evaluation of side
effects or discomfort from the medicine. Those who do well and want to continue their
assigned treatment after 6 months can continue that treatment for another 6 months and will
have follow-up exams at months 9 and 12.
Although corticosteroids remain the mainstay of therapy for intraocular inflammation, many
patients are intolerant or resistant to corticosteroid therapy. In these patients, other
immunosuppressive agents have been employed to control potentially sight-threatening
uveitis. Nevertheless, ideal therapy for these patients remains elusive, and there is a
need for new immunosuppressive agents with varying modes of action and side effect profiles.
Leflunomide, an isoxazole derivative, has profound immunosuppressive activity. Leflunomide
inhibits autoimmune disease in animal models and has been used to treat patients with
rheumatoid arthritis (RA). We propose a randomized masked pilot trial of leflunomide versus
placebo for the treatment of uveitis. Sixteen patients 16 years of age or older with active
intermediate, posterior, or panuveitis will be randomly assigned to receive prednisone and
leflunomide or prednisone and placebo. Patients will then have the prednisone tapered
according to a standardized schedule. The primary purpose of the study is to investigate
the safety and efficacy of leflunomide versus placebo. The primary safety endpoint is the
frequency of any of the following: abdominal pain, diarrhea, skin rash, hypertension, and
alopecia. In addition, weight loss distributions and change in liver function tests will be
described. The primary efficacy endpoint is any one or more of the following (1) a decrease
of 10 or more letters in visual acuity from the baseline score for any reason, or (2)
inability to taper prednisone to 10 mg qd by week 16 post randomization, or (3) inability to
maintain the prednisone taper through Month 6 or Month 12, or (4) the addition of systemic
therapy to treat ocular inflammatory disease. Secondary outcomes will include change in
vitreous haze and presence or absence of cystoid macular edema.
Diagnosis of current intermediate or posterior uveitis, or panuveitis.
Current evidence of active intraocular inflammation based on the presence of vitreous
haze, active retinal lesions, retinal vasculitis, or cystoid macular edema.
16 years of age or older.
Visual acuity of 73 letters or fewer (Snellen equivalent: 20/40 or worse) in at least one
The ability to understand and sign an informed consent form which must be obtained prior
The diagnosis of intermediate uveitis requires the presence of vitritis and either
peripheral retinal vascular disease, cellular debris in the inferior vitreous (vitreous
snowballs), exudate on the pars plana, or peripheral retinal infiltrates. The diagnosis
of posterior uveitis requires the presence of infiltrative retinal lesions involving the
posterior pole of the eye, usually with vitritis and often times with cystoid macular
edema. The amount of cystoid macular edema will be graded by a standard protocol using
Fluorescein Angiogram. The diagnosis of pan-uveitis requires the finding of active
anterior segment inflammation, vitritis, and infiltrative retinal lesions.
Ocular or systemic disease requiring greater than 1 mg/kg/day of prednisone or greater
than 80 mg qd if patients weigh more than 80 kg, or requiring other systemic
Periocular injections of corticosteroids within the previous 4 weeks.
Intolerance or contraindications to corticosteroids.
Female who is pregnant or lactating.
Patient refuses to use contraception during the study and 24 months after termination of
active study therapy or undergo a cholestyramine washout regimen or an activated charcoal
regimen under the care of a physician following termination of study therapy, if
child-bearing or fathering potential exists.
Patients with Behcet's disease.
Use of Latanoprost within 2 weeks prior to enrollment, or current or likely need for
Latanoprost during the course of the study.
Hypersensitivity to fluorescein dye.
Contraindications to use of steroids at dose and schedule.
SGOT (AST) or SGPT(ALT) greater than or equal to 2 times the upper limit of normal.
Allergic or hypersensitivity to leflunomide or any excipients.