Methotrexate and Mycophenolate Mofetil for UVEITIS

This is a randomized comparative effectiveness trial to determine which treatment,
methotrexate or mycophenolate mofetil, is more effective as first-line corticosteroid-sparing
treatment for patients with non-infectious intermediate, posterior and panuveitis requiring
corticosteroid-sparing therapy. The primary outcome is treatment success assessed at the 6
month visit (Phase 1, 0-6 months). If patients are a treatment success, they continue on the
medication for another 6 months (Phase 1, 6-12 months). Patients who are a treatment failure
can crossover to the other medication (Phase 2, 0-6 months).

Inclusion Criteria:

- All the following criteria must be met at enrollment:

Historical non-infectious intermediate, anterior and intermediate, posterior or panuveitis
in at least one eye

Active inflammation within the last 180 days, defined by the presence of any of the
following (in at least one eye) according to SUN criteria:

- ≥ 2+ anterior chamber cells

- ≥ 2+ vitreous haze

- active retinal or choroidal lesions

Active inflammation at enrollment, defined by the presence of any of the following (in at
least one eye) according to SUN criteria:

- ≥1+ anterior chamber cells and/or

- ≥1+ vitreous haze and/or

- active retinal/choroidal lesions

At least one of the following criteria must be met before or at enrollment:

- Active inflammation after 4 weeks of high-dose (1mg/kg prednisone equivalent)
corticosteroid treatment or 4 weeks following a regional corticosteroid injection

- Treatment with oral corticosteroids resulting in a reduction of inflammation, followed
by an increase in inflammation (of at least 1 grade in anterior chamber cells or
vitreous haze or a change of non-active to active lesions) when corticosteroid is
tapered, in the 180 weeks prior to enrollment

- Active inflammation after long-acting corticosteroid injection 4 weeks to 180 days
prior to enrollment

- Active inflammation after treatment with >10mg/day oral prednisone for at least the
past 90 days prior to enrollment

- Known chronic condition necessitating corticosteroid-sparing immunosuppressive
treatment: Behcet's disease with posterior segment involvement, multifocal choroiditis
with panuveitis, serpiginous choroidopathy, birdshot retinochoroidopathy, diffuse
retinal vasculitis, Vogt-Koyanagi-Harada with bullous serous retinal detachments
and/or choroidal detachments, sympathetic ophthalmia. No prior therapy required for
these patients

Willingness to start corticosteroid treatment at 1mg/kg or 60mg a day of prednisone,
whichever is less

Willingness to limit alcohol consumption

Willingness to use an acceptable method of contraception during the study period (i.e.
pharmacologics, devices, barrier methods) or abstinence.

- Exclusion Criteria: Any of the following

Any infectious cause of uveitis

Prior immunosuppressive therapy other than corticosteroids in the past 12 months

Prior intolerability or safety issues with methotrexate or mycophenolate mofetil

Prior failure to control ocular or other inflammation using methotrexate or mycophenolate
mofetil

Prior biologic therapy at any time

Media opacity (such as cataract and/or corneal scar) and/or extensive posterior synechiae
such that examination of the posterior segment is not possible in both eyes

Chronic hypotony (IOP < 5 mm Hg for > 3 months) in both eyes

Periocular or intravitreal corticosteroid injection in the past 4 weeks

Fluocinolone acetonide implant in either eye in < 3 years

Intraocular surgery in < 30 days, or planning on getting surgery within the next 6 months

Best spectacle-corrected visual acuity (BSCVA) of hand motions or worse in better eye

< 16 years of age at enrollment

Planning to conceive during the study period, pregnant or breast-feeding (blood or urine
pregnancy test for all females, excluding those who are post-menopausal is mandatory)*

Any history of cancer (If a patient has a history of non-melanoma skin cancer they can
still be considered for inclusion in this study, provided it is not currently active).

Systemic autoimmune disease anticipated to dictate treatment course

Abnormal Complete blood count (≤ 2,500 white blood cells and/or ≤ 75,000 platelets and/or
≤9 hemoglobin) within 4 weeks prior to enrollment*

Abnormal alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥ 2 times
the upper limit of normal for the lab and/or creatinine ≥ 1.5 within 4 weeks prior to
enrollment*

Evidence of active tuberculosis, HIV infection, syphilis, or hepatitis B or C (patients
must have a tuberculin skin test, or interferon-gamma release assay, a chest radiograph,
RPR/VDRL, FTA-ABS, or other treponemal tests, Hepatitis B surface antigen, Hepatitis C
antibody tests, and HIV test within 90 days prior to enrollment)**

*Testing required within 4 weeks prior to enrollment; **Testing required within 90 days
prior to enrollment.