Mechanistic Study of GSK3196165 Plus Methotrexate (MTX) in Subjects With Active Rheumatoid Arthritis

Inclusion Criteria:

- Age >=18 years at the time of signing informed consent.

- Meets American College of Rheumatology (ACR)/European League Against Rheumatism
(EULAR) 2010 RA Classification Criteria AND subject not diagnosed before age of 16
years.

- Functional class I, II or III defined by the 1992 ACR Classification of Functional
Status in RA.

- Active disease as defined by:

- Swollen joint count of >=4 (66-joint count) and tender joint count of >=4
(68-joint count) at screening and Day 1.

AND • Disease activity score for 28 different joints with C-reactive protein (CRP) value
(DAS28[CRP]) >=3.2 at screening.

AND

• CRP >=3.0 milligrams (mg)/liter (L).

- Signs of inflammation such as synovitis in the MRI scan of the most-affected hand.

- Must be currently taking MTX (15-25 mg weekly) (oral/injected) for at least 12 weeks
before screening, with no change in route of administration, with a stable and
tolerated dose for >=4 weeks prior to Day 1. A stable dose of MTX >=7.5 mg/week is
acceptable, if the MTX dose has been reduced for reasons of documented intolerance to
MTX, example (e.g.) hepatic or hematologic toxicity, or per local requirement.

- Body weight >=45 kilograms (kg).

- Male or female subjects are eligible to participate so long as they meet and agree to
abide by the contraceptive criteria.

- Capable of giving signed informed consent as described in protocol which includes
compliance with the requirements and restrictions listed in the consent form and in
the protocol.

- Willing to continue or initiate treatment with oral folic acid (at least 5 mg/week) or
equivalent and be treated during the entire study (mandatory co-medication for MTX
treatment).

- Diffusing capacity of the lung for carbon monoxide (DLCO) >=60% predicted; forced
expiratory volume in 1 second (FEV1) >=70% predicted.

- No evidence of active or latent infection with Mycobacterium tuberculosis (TB).

Exclusion Criteria:

- Pregnant or lactating, or women planning to become pregnant or initiating
breastfeeding.

- History of other inflammatory rheumatologic or autoimmune disorders, other than
Sjögren's syndrome secondary to RA.

- History of any respiratory disease which (in the opinion of the investigator) would
compromise subject safety or the ability of the subject to complete the study (e.g.
significant interstitial lung disease, such as pulmonary fibrosis, chronic obstructive
pulmonary disease (COPD), moderate-severe asthma, bronchiectasis, previous pulmonary
alveolar proteinosis [PAP]).

- Clinically-significant (in the opinion of the investigator) persistent cough or
clinically significant or unstable dyspnea that is unexplained.

- Significant unstable or uncontrolled acute or chronic disease which, in the opinion of
the investigator, could confound the results of the study or put the subject at undue
risk.

- A history of malignancy.

- Contraindication to MRI scanning.

- Current/previous Hepatitis B virus (HBV), Hepatitis C virus (HCV) or human
immunodeficiency virus (HIV) 1 or 2 infection.