SEVRA-TRIAL Safety and efficacy of vaccination with T cell-dependent and T cell-independent primary and recall antigens in patients with rheumatoid arthritis treated with anti TNF-á antibodies (adalimumab) and anti B cell therapy (Rituximab).

1. Able and willing to give written informed consent;

2. A diagnosed according to the revised 1987 criteria of the American College of Rheumatology (ACR) for at least 3 months;

3. Age 18-85 years;

4. Eligible for anti-TNF á therapy (according to the Dutch guidelines) or eligible for rituximab therapy;

5. Use of concurrent dmard therapy is allowed, provided the dose and frequency have been stable for at least 28 days. Subjects may be taking nonsteroidal anti-inflammatory drugs, provided the dose and frequency have been stable for at least 28 days. Subjects may be receiving prednisone therapy  10 mg/day provided that the dosage has been stable for at least 2 months prior to entry.

1. A positive PPD skin test (> 4 mm induration);

2. Pregnancy;

3. Breastfeeding;

4. A history of or current acute inflammatory joint disease of different origin e.g. mixed connective tissue disease, seronegative spondylarthropathy, psoriatic arthritis, Reiter’s syndrome, systemic lupus erythematosus or any arthritis with onset prior to age 16 years;

5. Acute major trauma;

6. Therapy within the previous 60 days with: any experimental drug,alkylating agents, e.g. cyclophosphamide, chlorambucil, monoclonal antibodies (including infliximab and etanercept), growth factors, or other cytokines;

7. Therapy within the previous 28 days with: parenteral or intra-articular corticoid injections, oral corticosteroid therapy exceeding a prednisone equivalent of 10 mg daily;

8. HIV infection;

9. History of severe allergic or anaphylactic reactions to vaccines;

10. Vaccination with KLH, Pneumovax, Meningovax, Polio or tetanus toxoid in the past 12 months;

11. Fever (orally measured > 38 °C), chronic infections or infections requiring anti-microbial therapy Other active medical conditions such as inflammatory bowel disease, bleeding diathesis, or severe unstable diabetes mellitus;

12. Manifest cardiac failure (stage III or IV according to NYHA classification);

13. Progressive fatal disease/terminal illness;

14. Congenital or acquired (known HIV-positive status) immunodeficiency;

15. History of lymphoproliferative disease or treatment with total lymphoid irradiation;

16. White cell count less than 3.5 x 109/l;

17. Platelet count less than 100 x 109/l;

18. Haemoglobin of less than 5.3 mmol/l;

19. Body weight of less than 45 kg;

20. History of drug or alcohol abuse;

21. Any concomitant medical condition which would in the investigator’s opinion compromise the patient’s ability to tolerate, absorb, metabolize or excrete the study medication;

22. Inability to give informed consent;

23. Mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study and/or evidence of an uncooperative attitude.