Optimal MTX Dose With Folic Acid Randomized Case-control Trial

Inclusion Criteria: 1. According to the revised 1987 American Academy of Rheumatology (ACR) RA classification criteria, subjects must be diagnosed as rheumatoid arthritis ≥6 months. 2. MTX was given 10 mg/week（not the maximum dose of MTX (calculated as 0.3 mg/kg)) for ≥3 months before admission. 3. At the screening and baseline phases, the number of swollen joints (SJC) should be ≥1 (counting 66 joints), and the number of tender joints (TJC) should be ≥ 1 (counting 66 joints); the ESR should be ≥20 mm/h, and/or the CRP should be ≥ 10 mg/l; 4. The age of the subjects ranged from 18 to 70 years. 5. The following RA drugs can be used in combination within 3 months before admission; oral glucocorticoid (prednisone ≤10 mg/d or its equivalent), non-steroidal anti-inflammatory drugs (≤ the maximum recommended dose), leflunomide, hydroxychloroquine, sulfasalazine, total paeoniflorin, Tripterygium glycoside, azathioprine, and MTX. The stable dose of DMARDs should be at least 4 weeks before baseline, and the combined dose of DMARDs beside MTX could not reach the full dose. 6. Women of childbearing age should agree to take effective contraceptive measures during the trial period; 7. The urinary pregnancy test of women of childbearing age was negative at screening time. 8. Understand the steps and contents of the experiment and sign the informed consent to participate in the experiment. Exclusion Criteria: 1. Those who underwent major surgery (including joint surgery) within 8 weeks before screening or who planned major surgery within 6 months after random selection; 2. Patients with autoimmune diseases except RA include SLE, MCTD, scleroderma and polymyositis. But subjects with RA and secondary Sjogren syndrome were allowed to participate in the trial. 3. Inflammatory arthritis (such as gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) . 4. Intra-articular injection or other injection of corticosteroids within 4 weeks before baseline; 5. Those who had been vaccinated with live/inactivated vaccine within 4 weeks before baseline; 6. Three months before admission, the following drugs were used: cyclophosphamide, biological agents and folic acid. 7. DMARDs dose reached maximum dosage in 3 months before admission， or DMARDs≥3 were used in 3 months before admission 8. Subjects with severe uncontrolled diseases including cardiovascular disease, nervous system disease, pulmonary disease (including obstructive pulmonary disease and interstitial lung disease), nephropathy, liver disease, endocrine disease (including uncontrolled diabetes mellitus) and gastrointestinal diseases; 9. known history of active or recurrent bacterial, viral, fungal, Mycobacterium or other infections (including, but not limited to, tuberculosis and atypical mycobacterium diseases, chest X-rays showing granulomatous diseases, hepatitis B and C, HIV infection, herpes zoster, but excluding Onychomycosis) ，any infection requiring hospitalization and intravenous antibiotic therapy within 4 weeks before screening ，or oral antibiotic therapy within 2 weeks before screening; active hepatitis B refers to HBsAg-positive patients without antiviral drugs and HBV-DNA \> 10\^4; active hepatitis C refers to anti-HCV-positive patients without antiviral drugs and HCV-RNA \> 10\^4; 10. Subjects with a history of malignant tumors, including solid tumors and hematological malignancies (except excised or cured skin basal cell carcinomas); 11. Pregnant or lactating women (breastfeeding); 12. Subjects with neuropathy and other painful diseases may interfere with pain assessment. 13. Serum creatinine \> 1.5 mg/dl (equivalent to 133 umol/L); 14. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2 times of the upper limit of normal value (if ALT or AST is greater than 2 times of the upper limit of normal value for the first time, it should be sampled again during the screening period), or total bilirubin is greater than the upper limit of normal value (if total bilirubin is greater than the upper limit of normal value for the first time at the screening, sampling should be done again during the selection period). 15. Platelet count \< 100 x 10\^9/L, or white blood cells \< 3 x 10\^9/L;