Aminopterin Dose Finding Treatment for Methotrexate-Naïve Rheumatoid Arthritis

Inclusion Criteria:

1. > 18 years of age.

2. A diagnosis of RA established by the ACR/EULAR 2010 criteria applied to patients who:

1. have >1 joint with definite clinical synovitis (swelling); 2) with the synovitisnot better explained by another disease. Add scores of categories A-D; a score >6/10 is required for study entry. A. Joint involvement:

1 large joint=0; 2-10 large joints=1; 1-3 small joints (with or without involvement oflarge joints=2; 4-10 small joints (with or without involvement of large joints)=3; >10joints (at least 1 small joint)=5. B. Serology (at least 1 test result is needed for classification): Negative RF and negative ACPA=0; Low-positive RF or low-positive ACPA=2; High-positive RFor high-positive ACPA=3. C. Acute-phase reactants (at least 1 test result is needed for classification): Normal CRP and normal ESR=0; Abnormal CRP or abnormal ESR=1. D. Duration of symptoms: less than 6 weeks=0; 6 weeks or greater=1.

3. Class I, II or III functional according to the ACR 1992 revised criteria for theclassification of global functional status in RA.

4. RA is active, defined as ≥ 6 swollen joints and ≥ 6 tender joints.

5. Ability to understand and sign written informed consent.

6. For sexually active men and for women of childbearing potential, an adequate form ofcontraception.

7. For pre-menopausal women, a negative pregnancy test, obtained within 1 week prior tofirst study drug dose.

8. Negative serology for hepatitis B and hepatitis C.

9. The following screening laboratory blood tests must have the following values, or notclinically significant as determined by the PI and Medical Monitor: WBC WNL; absoluteneutrophil count > lower limit of normal; platelet count WNL; hemoglobin >10.0 g/dL; ASTWNL.

10. Adequate renal function: GFR estimated by Cockcroft-Gault formula >60 ml/min

Exclusion Criteria:

1. Known history of hepatitis, HIV infection, interstitial lung disease.

2. Alcohol consumption on a regular basis and unwilling, or unable, to discontinue thisconsumption during the study period.

3. Prior methotrexate or aminopterin therapy.

4. Prior biologic drug therapy (e.g., etanercept, adalimumab, infliximab).

5. Within 2 weeks prior to Study Day 0, or on Study Day 0, or at any time during thestudy, use of any of the following medications that may result in drug/druginteractions with AMT: trimethoprim with or without sulfamethoxazole; sulfonamides;sulfonylureas; pyrimethamine; triamethamine; dipyridamole; colchicine; probenecid;aminoglycosides; theophylline; phenytoin; and folinic acid (i.e., leucovorin).

6. At Study Day 0 use of DMARDs and biologics (except antimalarials) including oral orinjectable gold, azathioprine, penicillamine, sulfasalazine or cyclosporine. Subjectspreviously treated with any of these medications are eligible provided a 28 daywash-out is completed prior to Study Day 0. Antimalarial can be continued at the samedose if they have been administered at the same dose for 8 weeks before Study Day 0,and they will be administered at the same dose throughout the study. NSAIDs orcorticosteroid (≤ 10 mg prednisone or equivalent/day) may be continued at the samedose if they have been used at a stable dose for two weeks prior to Study Day 0, andwill be continued at the same doses throughout the study.

7. Use of corticosteroids in excess of 10 mg prednisone or equivalent/day.

8. Known concurrent malignancy except basal or squamous cell skin carcinoma, or cervicalcarcinoma in situ.

9. Concurrent participation in another clinical trial involving experimental treatmentwithin 30 days of Study Day 0.

10. Current and uncontrolled infection, cardiovascular, renal, pulmonary, hepatic or GIconditions that will interfere with the conduct of the trial or pose a morbid risk.

11. Investigator's opinion that a concurrent disease or condition impairs the subject'sability to complete the trial: includes psychological, familial, sociological,geographical or medical conditions.