Efficacy, Safety and Costs of Methotrexate, Adalimumab, or Their Combination in Non-infectious Non-anterior Uveitis

Inclusion Criteria:

1. Subjects diagnosed with non-infectious intermediate-, posterior-, or pan-uveitis in atleast one eye;
2. Adult patients (≥18 years);
3. Subjects with at least one flare of active eye inflammation in the previous 180 daysbefore Baseline visit, defined by the presence of at least 1 of the followingparameters in either eye:
4. Active chorioretinal or retinal vascular lesion, AND/OR
5. Presence of macular edema by optical coherence tomography (OCT:thickness >350 μmAND cysts or intraretinal fluid), AND/OR
6. ≥ 2+ anterior chamber cells (ACC; SUN criteria4) , AND/OR
7. ≥ 2+ vitreous haze (National Eye Institute [NEI]113/SUN criteria4).
8. Subjects with active eye inflammation at Baseline visit, defined by the presence of atleast 1 of the following parameters in either eye:
9. Active chorioretinal or retinal vascular lesion, AND/OR
10. Presence of macular edema by OCT (thickness >350 μm AND cysts or intraretinalfluid), AND/OR
11. ≥ 1+ ACC, AND/OR
12. ≥ 1+ vitreous haze.
13. Subjects meeting at least ONE of the following criteria:
14. Subjects with known chronic condition necessitating GCs-sparing immunosuppressivetreatment: Behçet's disease with posterior segment involvement, multifocalchoroiditis with panuveitis, serpiginous choroidopathy, birdshotretinochoroidopathy, diffuse retinal vasculitis, Vogt-Koyanagi-Harada withbullous serous retinal and/or choroidal detachments, sympathetic ophthalmia. Noprior therapy is required for these patients. AND/OR
15. Subjects with registered local/systemic corticosteroid refractory uveitis in theprevious 180 months before Baseline visit, defined as:

• Presence of active inflammation after 4 weeks of high-dose (1mg/kgprednisone equivalent) corticosteroid treatment, resulting in an incompleteresponse (there was an amelioration, but there is still inflammation);AND/OR, Presence of active inflammation 4 weeks after a regionalcorticosteroid injection; AND/OR,
• Treatment with oral corticosteroids resulting in a reduction ofinflammation, followed by relapse [increase in ≥1 grade in ACC or vitreoushaze or a change of non-active to active lesions (including chorioretinal orretinal vascular lesion and/or macular edema)] when GCs was tapered; AND/OR,
• Presence of active inflammation after a long-acting corticosteroidintramuscular injection administered between 4 weeks to 180 days before theBaseline visit); AND/OR, Active inflammation after treatment with >10mg/dayoral prednisone for at least the past 90 days before Baseline.

6. If female, subject is:
7. Not of childbearing potential: at least 1 year or more since the final menstrualperiod or surgically sterile (bilateral tubal ligation, bilateral oophorectomy orhysterectomy);
8. Of childbearing potential and willing to use an acceptable method ofcontraception during the study period (i.e. pharmacologics, devices, barriermethods) or abstinence, and for 150 days after the last dose of study drugs;
9. Not pregnant or breastfeeding
10. Subject has a negative tuberculosis skin test (PPD test or equivalent) andnonpathological Chest X-ray (CXR; Posterior-anterior and lateral view) at Screening orin the previous 90 days before Baseline visit. If the subject has a positive PPD test (or equivalent), has had a past ulcerative reaction to PPD placement and/or a CXRconsistent with prior tuberculosis (TB) exposure, the subject must initiate, becurrently receiving or have documented completion of a course of prophylactic anti-TBtherapy
11. Subjects able and willing to provide written informed consent and to comply with thestudy protocol.
12. Do not participate in another clinical trial.

Exclusion Criteria:

1. Subjects with confirmed or suspected infectious uveitis, including ocularhistoplasmosis syndrome
2. Subjects with previous intolerability, safety issues according to investigatorcriteria, AND/OR previous failure to control ocular or other inflammation with MTX
3. Subjects with previous exposure to any biological therapy at any time (excludingintravitreal anti-vascular endothelial growth factor [anti-VEGF] therapy anddenosumab), including those with that have a potential or known association withprogressive multifocal leukoencephalopathy (i.e. natalizumab, rituximab orefalizumab);
4. Subjects with previous exposure to synthetic immunosuppressive therapy (such asmycophenolate or cyclosporine) other than corticosteroids in the past 6 months beforeBaseline;
5. Subjects with chronic structural eye damage considered by the Site's Investigator to: a. Interfere with the measurement of any of the study outcomes, AND/OR b. Cause eye damageregardless of the inflammatory process, AND/OR c. Prevent the normalization of the eyestructures; 6. Chronic hypotony (IOP < 5 mm Hg for in the last 3 months and/or in thebaseline visit) in both eyes; 7. Subjects receiving local GCs 8. Subjects receivingintravitreal anti-VEGF therapy 9. Subjects with a history of prior intraocular surgerywithin 30 days prior to the Baseline visit, AND/OR any planned eye surgery within the next 52 weeks from Baseline Visit 10. Subjects with best spectacle-corrected visual acuity (BCVA) worse than 20/400 (ETDRS logMAR > 1.34) in the better eye during the screening or atBaseline visit 11. Subjects with active malignancy considered by the Site's Investigator,including lymphoma, leukemia, non-melanoma skin cancer, and confirmed or suspected ocularmasquerade syndromes 12. Subjects with systemic autoimmune disease or ocular condition (besides uveitis) anticipated to dictate treatment course, as considered by the Site'sInvestigator 14. Subjects with systemic active or chronic recurring infections, such asactive TB, syphilis, or hepatitis B or C, at Screening visit or in the previous 90 daysbefore Baseline visit; AND/OR a history of invasive infection (e.g., listeriosisandhistoplasmosis); 15. Subjects with history of moderate to severe congestive heart failure (NYHA class III or IV), recent cerebrovascular accident (6 months) and any other conditionwhich, in the opinion of the Site's Investigator, would put the subject at risk byparticipation in the study 16. Subjects with clinically significant abnormal screeninglaboratory results as evaluated by the Site's Investigator (at screening/baseline or in theprevious4 weeks).
6. Central nervous system demyelinating disease