This is a Phase 2, multicenter, randomized, double blind, double dummy, placebo and active-controlled, parallel group study to assess the efficacy and safety of PF 06650833 at Week 12 in subjects with moderate-severe, active, RA who have had an inadequate response to MTX. PF-06650833 or matching placebo tablets will be administered orally QD under fasting conditions, and tofacitinib or matching tofacitinib placebo tablets will be administered orally BID for 12 weeks in a blinded fashion.
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Inclusion Criteria: 1. Male and female (including WOCBP) subjects between the ages of 18 and 75 years, inclusive. 2. Diagnosis of RA and meeting the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA with a Total Score ≥6/10. 3. The subject has active disease at both Screening and Baseline, as defined by both: * 6 joints tender or painful on motion, AND * 6 joints swollen; and fulfills 1 of the following 2 criteria at Screening: * High sensitivity C reactive protein (hsCRP) \>7 mg/L at screening * Erythrocyte sedimentation rate (ESR) (Westergren method) \>28 mm/hr; 4. Meets Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA. 5. Subjects must be ACPA positive between screening and randomization. 6. Subjects must have been taking oral MTX for at least 3 months at an adequate dose to determine that the subject had an inadequate response to MTX 7. Up to 50 % of subjects may have received one (and only one) approved TNF-inhibiting biologic agent administered that was inadequately effective and/or not tolerated. The anti-TNF biologic could also have been discontinued due to lack of continued access. Exclusion Criteria: 1. Subjects with a known immunodeficiency disorder or a first degree relative with a hereditary immunodeficiency. 2. Subjects with any of the following infections or infections history: 1. Any infection requiring treatment within 2 weeks prior to screening (Visit 1). 2. Any infection requiring hospitalization, parenteral antimicrobial therapy within 60 days, or as otherwise judged to be an opportunistic infection or clinically significant by the investigator, within the past 6 months. 3. Infected joint prosthesis at any time with the prosthesis still in situ. 4. Recurrent (more than one episode) herpes zoster or disseminated (a single episode) herpes zoster or disseminated (a single episode) herpes simplex. 5. Subjects will be screened for HIV. Subjects who test positive for HIV will be excluded from the study. 6. Subjects will be screened for hepatitis B virus infection and will be excluded if positive for hepatitis B surface antigen (HBsAg). Subjects with HBsAg negative testing but who test positive for hepatitis B core antibody (HBcAb) must have further testing for hepatitis B surface antibody (HBsAb). If HBsAb is negative, the subject will be excluded from the study. 7. Subjects with clinically significant active hepatic disease or hepatic impairment by laboratory assessment. 8. Subjects will be screened for hepatitis C virus (HCV Ab). Subjects with positive HCV Ab tests will be reflex tested for HCV ribonucleic acid (HCV RNA). Only subjects with negative HCV Ab or HCV RNA will be allowed to enroll in the study. 3. Evidence of active or latent, untreated or inadequately treated infection with Mycobacterium tuberculosis (TB) 4. Pre-existing chronic autoimmune disease.