Part A: 30 patients suffering from active rheumatoid arthritis despite continued treatment with methotrexate will receive once daily two capsules containing either GLPG0259 (25 mg/capsule) or matching placebo, for 12 weeks. In the course of the study the patients will be examined for severity of disease, as well as for any adverse effects that may occur. If needed, dosing may be split to one capsule twice daily, or reduced to one capsule of 25 mg.

Part B: If results of Part A suggest test medication to have a therapeutic advantage over placebo and to be well-tolerated, more patients will be recruited for Part B, where various dosages will be assessed. These dosages will be established based on results from Part A.

Inclusion Criteria:

• Must have active RA (≥5 tender or painful joints on motion and ≥5 joints swollen AND a C-reactive protein (CRP) concentration ≥1.5 mg/dL).
• Must have been on methotrexate for ≥6 months at a stable dose of 7.5-25 mg/week for ≥12 weeks, to be continued throughout study;
• If on oral steroids, these should be at a dose ≤10 mg/day of prednisone eq and stable for ≥4 weeks prior to screening;
• If on NSAIDs, these must be at a stable dose for ≥2 weeks prior to screening;
• Women must have negative pregnancy test unless surgically sterile or post-menopausal for ≥1 year;
• Women of childbearing potential must use a medically acceptable means of birth control and agree to continue its use during the study and for ≥12 weeks after the last dose of study drug.
• Informed consent

Exclusion Criteria:

• Must not have received treatment with DMARDs, other than background methotrexate;
• Must not be receiving or have received RA treatment with a biological agent, except if administered in a clinical study ≥six months prior to screening (12 months for rituximab or other B cell depleting agents);
• Must not have received any treatment with a cytotoxic agent, other than methotrexate, before screening (e.g. chlorambucil, cyclophosphamide, nitrogen mustard, or other alkylating agents);
• Must not have received intra-articular or parenteral corticosteroid injection within four weeks prior to screening;
• Must not regularly be using aspirin or any other anti-coagulant medication;
• Must not have a known hypersensitivity to study drug ingredients or a significant allergic reaction to any drug as determined by the Investigator, such as anaphylaxis, requiring hospitalization;
• Must not have positive serology for human immunodeficiency virus (HIV)1 or 2 or hepatitis B or C, or any history of HIV or hepatitis from any cause with the exception of hepatitis A;
• Must not have a history of any inflammatory rheumatological disorders other than RA;
• Must not have undergone (or planned) surgical treatments for RA;
• Must not have symptoms of clinically significant illness other than RA (including but not limited to cardiopulmonary, renal, metabolic, hematologic, or psychiatric disorders) within three months prior to screening;
• Must not have a history of active infections requiring intravenous antibiotics within the past four weeks;
• Must not have a history of malignancy within the past five years (except for basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been treated with no evidence of recurrence);
• Must not have a history of tuberculosis (TB) infection as determined by a positive diagnostic TB test result (defined as a positive QuantiFERON TB Gold test), AND a recent chest radiograph (both posterior-anterior and lateral views), read by a qualified radiologist, with evidence of current active TB or old inactive TB.
• Must not have been administered a live vaccine within four weeks prior to screening;
• Must not have participated in any investigational drug/device clinical study within four weeks prior to screening, in biological agents clinical studies within six months prior to screening, and B cell-depleting agent clinical studies within 12 months prior to screening;
• Must not have a history within the previous two years or current evidence of drug or alcohol abuse;
• Must not have any condition or circumstances which in the opinion of the Investigator may make a subject unlikely or unable to complete the study or comply with study procedures and requirements, or may pose a risk to the patient's safety.