Addition of Rituximab to Leflunomide in Patients With Active Rheumatoid Arthritis

Inclusion Criteria: Male and female patients, 18 to 75 years of age, with active rheumatoid arthritis (RA) whohave had an inadequate response to disease modifying anti-rheumatic drugs, not more than 3non-biological DMARDs including leflunomide, and not more than one inadequate response toanti-TNF-therapy, and currently have active disease despite at least 3-month treatment withleflunomide. Active disease is defined as DAS 28 >3.2 and at least swollen joint count (SJC) ≥ 3 and tender joint count (TJC) ≥ 3 included in the 28 joint count.

• Male and female patients with rheumatoid arthritis for at least 3 months diagnosedaccording to the revised 1987 ACR criteria for the classification of rheumatoidarthritis.

• Willingness and capability to give written informed consent, and willingness toparticipate and to comply with the study protocol.

• Not more than 2 non-biological DMARDs other than leflunomide in history, which arewashed out at least 4 weeks prior to first rituximab infusion

• Previous use of anti-TNF therapy is allowed. Patient will only be allowed to bepre-treated with a maximum of two anti-TNF therapies and only one stopped due toinadequate response. The second anti-TNF could be stopped for instance due tointolerance, e.g. injection site reactions. Anti-TNF treatment must be discontinuedprior to baseline considering the different characteristics of the specific compound:Use of infliximab, adalimumab, certolizumab, golimumab within 8 weeks of baseline, useof etanercept within 4 weeks of baseline.

Exclusion Criteria:

• RA functional class IV: limited in ability to perform usual self-care, work, and otheractivities

• Male and female patients with other chronic inflammatory articular disease or systemicautoimmune disease

• Any active infection, a history of recurrent clinically significant infection, ahistory of recurrent bacterial infections with encapsulated organisms (Hepatitis B, Cand HIV (human immune deficiency virus) - will be tested at screening)

• Chronic, latent and acute infections of the lung

• Positive result of a Tuberculosis specific Interferon gamma release assay (will betested at screening)

• Primary or secondary immunodeficiency

• History of cancer with curative treatment not longer than 5 years ago exceptbasal-cell carcinoma of the skin that had been excised

• Evidence of significant uncontrolled concomitant diseases or serious and / oruncontrolled diseases that are likely to interfere with the evaluation of thepatient's safety and of the study outcome

• Neuropathy that can interfere with filling out the patient's questionnaires

• History of a severe psychological illness or condition

• Known hypersensitivity to any component of the product or to murine proteins

• Severe heart failure (New York Heart Association Class III and IV) orsevere,uncontrolled cardiac disease.

• Women lactating, pregnant, nursing or of childbearing potential with a positivepregnancy test or planned pregnancy.

• Women of childbearing potential without adequate contraception (medically acceptablemethods (pearl Index < 1) are contraceptive implant, contraceptive injection,intrauterine device (IUD), or oral contraceptives taken for at least 3 months,whichthe patient agrees to continue using during the study, or a double-barrier methodwhich must consist of a combination of any of the following: diaphragma,cervical cap,condom, or spermicide)

• History of alcohol, drug or chemical abuse (defined as impaired / questionablereliability) as well as neurotic personality.

• Participation in another investigational study within 4 weeks prior to the screeningvisit.

• Previous treatment with any B-cell depleting agents including rituximab

• Intolerance to ingredients of rituximab or murine proteins

• Pre-treatment with abatacept, tocilizumab or other anti-TNF biologicals.

• Inadequate response to more than one anti-TNF-therapy

• Pre-treatment of more than two anti-TNF, only one is allowed to be stopped due toinadequate response. The second anti-TNF could be stopped due to intolerance, e.g.injection site reactions

• Corticosteroids at doses exceeding 10 mg per day of prednisolone or equivalents withinthe last 2 weeks or corticosteroids at instable doses within the last 2 weeks

• Intolerance or contraindication to drugs required for the treatment of the sideeffects of rituximab

• Previous treatment with any investigational medicinal product within last 3 monthsprior to baseline

• Receipt of a live vaccine within 4 weeks prior to treatment

• Intra- articular or parenteral corticosteroids within 4 weeks prior to screening visit

• Haemoglobin < 8.5 g / dl (equivalent to < 5,28 mmol/l Haemoglobin)

• Neutrophil counts < 1.500 / μl (equivalent to 1,5 / nl)

• Platelet count < 75.000 / μl (equivalent to 75 / nl)

• Lower than 500 / μl (equivalent to 0,5 / nl) lymphocytes

• Serum creatinine > 1.4 mg / dl for women or 1.6 mg / dl for men

• Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) > 2.5 times upperlimit of normal

• IgG (immunoglobulin G) level < 5g/l