The principal aim of this study is to fill a clear knowledge gap and provide guidance for rheumatologists and reassurance to the patient group on a management challenge faced daily in rheumatology practice. Specifically, it aims to provide robust evidence on the optimal management of patients with established RA that have failed an anti-TNF therapy (the first of the biological therapies to be introduced); in particular, the investigators wish to address whether the currently licensed but non NICE-approved treatment options, TNF-blocking drug or abatacept, are equivalent to the NICE-approved treatment, rituximab. If so, the intention is to broaden treatment options and target these specific therapies to disease sub-groups.

Inclusion Criteria

1. Male and female subjects aged ≥18 years at the time of signing the Informed Consent Form.

2. Patients with a diagnosis of rheumatoid arthritis as per the ACR/EULAR 2010 classification criteria (Appendix 7) confirmed at least 24 weeks prior to the screening visit.

3. Patients who have failed conventional DMARD therapy as per NICE/BSR Guidelines (49) i.e. failure of at least 2 DMARDS including MTX.

4. Patients with persistent RA disease activity despite having been treated with a current initial TNFi agent for at least 12 weeks. Active RA defined as*:

   1. Primary non-response: failing to improve DAS28 by > 1.2 (Appendix 6) or failing to achieve DAS28 ≤ 3.2 within the first 12 to 24 weeks of starting the initial TNFi.

      • This may include patients that have shown a reduction in DAS28 of > 1.2 but still demonstrate unacceptably high disease activity in the physician's judgement with evidence of an overall DAS28 of ≥ 3.2 OR

   2. Secondary non-response: defined as inefficacy to first TNFi (having demonstrated prior satisfactory response) as per clinician judgement; with intolerance not the reason for cessation of first TNFi.

5. MTX dose stable for 4 weeks prior to the screening visit and to be continued for the duration of the study.

6. Patients on NSAIDs and / or corticosteroids (oral prednisolone not exceeding 10mg daily) who have been on an unchanged regimen for at least 4 weeks prior to the screening visit and are expected to remain on a stable dose until the baseline assessments have been completed.

7. Provided written informed consent prior to any trial-specific procedures.

Exclusion Criteria

1. Major surgery (including joint surgery) within 8 weeks prior to the screening visit or planned major surgery within 52 weeks following randomization.

2. Patients with inflammatory joint disease of different origin, mixed connective tissue disease, Reiter's syndrome, psoriatic arthritis, systemic lupus erythematosus, or any arthritis with onset prior to 16 years of age.

3. Patients receiving doses of prednisolone > 10mg/day within the 4 weeks prior to the screening visit.

4. Patients receiving intra-articular or intra-muscular steroid injections within 4 weeks prior to the screening visit.

5. Patients who have previously received more than 1 TNFi drug OR any other biological therapy for the treatment of RA.

6. Patients unable or unwilling to stop treatment with a prohibited DMARD (i.e synthetic DMARD aside from MTX e.g. oral or injectable gold, chloroquine, hydroxychloroquine, cyclosporine, azathioprine, leflunomide, sulphasalazine) prior to the start of protocol treatment.

7. Treatment with any investigational drug in the last 12 weeks prior the start of protocol treatment.

8. Patients with other co-morbidity including acute, severe infections, uncontrolled diabetes, uncontrolled hypertension, unstable ischaemic heart disease, moderate/severe heart failure (Class III/IV of the New York Heart Association (NYHA) functional classification system (79)), active bowel disease, active peptic ulcer disease, recent stroke (within 12 weeks before the screening visit), or any other condition which, in the opinion of the investigator, would put the patient at risk to participate in the study or would make implementation of the protocol difficult.

9. Patients with any major episode of infection requiring hospitalisation or treatment with IV antibiotics within 12 weeks of start of treatment protocol or oral antibiotics within 4 weeks of start of protocol treatment.

10. Patients at significant risk of infection, which in the opinion of the investigator would put the patient at risk to participate in the study (e.g. leg ulceration, indwelling urinary catheter, septic joint within 52 weeks (or ever if prosthetic joint still in situ)).

11. Patients with known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections including herpes zoster (for tuberculosis and Hepatitis B and C see below), but excluding fungal infections of nail beds as per clinical judgment.

12. Patients with untreated active current or latent tuberculosis (TB). Patients should have been screened for latent TB (as per BSR guidelines) within 24 weeks prior to the screening visit and, if positive, treated following local practice guidelines prior to the start of protocol treatment.

13. Patients with active current hepatitis B and/or C infection. Patients should have been screened for hepatitis B and C within 24 weeks prior to the screening visit and if positive, excluded from the study.

14. Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation.

15. Pregnancy, lactation or women of child-bearing potential (WCBP) unwilling to use an effective birth control measure (Appendix 2) whilst receiving treatment and after the last dose of protocol treatment as indicated in the relevant SmPC/IB.

16. Men whose partners are of child-bearing potential but who are unwilling to use an effective birth control measure (Appendix 2) whilst receiving treatment and after the last dose of protocol treatment as indicated in the relevant SmPC/IB.

17. Patients with known significantly impaired bone marrow function as for example significant anaemia, leukopaenia, neutropaenia or thrombocytopaenia as shown by the following laboratory values at the time of the screening visit:

    • Haemoglobin < 8.5 g/dl
    • Platelet count < 100 x 109 / L
    • White blood cell count < 2.0 x 109 / L
    • Neutrophil count < 1 x 109 / L

18. Patients with known severe hypoproteinaemia at the time of the screening visit, e.g. in nephrotic syndrome or impaired renal function, as shown by:

    • Serum Creatinine > 150 umol / L