Inclusion / Exclusion Criteria

Inclusion criteria

Patients will be recruited with active RA:

1. 2010 ACR/EULAR Rheumatoid Arthritis classification criteria for a diagnosis of RA^*
2. Patient with DMARD failure eligible for anti-TNF-α therapy as per UK NICE guidelines^**
3. Patients must have a minimum of 3 swollen joints – the joint selected for biopsy and a minimum of 2 from 28 joint count set, as assessed at biopsy visit
4. Selected joint for biopsy must be minimum grade 2 synovial thickening, as assessed at the biopsy visit
5. 18 years of age and over
6. Patients must be capable of giving informed consent and the consent must be obtained prior to any screening procedures

^* The ACR/EULAR classification for a diagnosis of RA could have been at any time in the patient’s disease history; the score does not need to be 6 or more at screening.

^** Current NICE guidelines available at the following link: http://www.nice.org.uk/guidance/ta375

Exclusion criteria

Patients will be excluded if they have any contraindication to Etanercept, Rituximab or Tocilizumab therapy:

1. Women who are pregnant or breast-feeding
2. Women of child-bearing potential or males whose partners are women of child-bearing potential, unwilling to use an effective method of contraception (recommend double contraception) throughout the trial and beyond the end of trial treatment for the duration as defined in the relevant SmPC or IB; 12 months for Rituximab, at least 3 weeks for Etanercept, and at least 3 months for Tocilizumab.
3. History of or current inflammatory joint disease or autoimmune disease other than RA
4. Prior exposure to Rituximab, any anti-TNF, Tocilizumab, or any other biologic for treatment of RA
5. Treatment with any investigational agent ≤ 4 weeks prior to baseline or < 5 half-lives of the investigational drug (whichever is the longer)
6. Intra-articular or parenteral corticosteroids ≤ 4 weeks prior to baseline synovial biopsy.
7. Oral prednisolone more than 10mg/d or equivalent ≤ 4 weeks prior to baseline synovial biopsy.
8. Active infection
9. Known HIV,  Hepatitis B, or Hepatitis C infection
10. Septic arthritis of a native joint within the last 12 months
11. Septic arthritis of a prosthetic joint within 12 months or indefinitely if the joint remains in situ
12. Latent TB infection unless they have completed adequate antibiotic prophylaxis
13. Malignancy (other than basal cell carcinoma) within the last 10 years
14. New York Heart Association (NYHA) grade III or IV congestive heart failure
15. Demyelinating disease
16. Known allergy to latex, Rituximab, Tocilizumab or Etanercept
17. Any other contra-indication to the study medications as detailed in the applicable Summaries of Product Characteristics (SmPC) including low IgG levels, at physician’s discretion
18. Receipt of live vaccine <4 weeks prior to first infusion
19. Major surgery in 3 months prior to first infusion
20. Presence of a transplanted organ (with the exception of a corneal transplant >3 months prior to screening)
21. Known recent substance abuse (drug or alcohol)
22. Poor tolerability of venepuncture or lack of adequate venous access for required blood sampling during the study period
23. Patients unable to tolerate synovial biopsy or in whom this is contraindicated (e.g. patients on anti-coagulants such as warfarin or equivalent drugs. Patients on antiplatelet agents can be included in the trial).
24. Patients currently recruited to other clinical trials
25. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study