Combination of rituximab (RTX) with several different chemotherapeutic regimes has proven synergistic effects in patients with either lymphoma or autoimmune diseases. First data of uncontrolled trials with the combination of RTX and leflunomide (LEF) are available.

Rituximab provides lasting improvement in the signs and symptoms of rheumatoid arthritis (RA) after two infusions per treatment course in tumor necrosis factor (TNF) inhibitor inadequate responder (IR) patients. Importantly, MabThera® has been shown to inhibit radiographic progression in this highly pre-treated patient population. Rituximab is licensed for adult patients with severe active RA in combination with methotrexate after inadequate response to previous treatment, including TNF alpha- Inhibitors.

In daily practice the combination with methotrexate is often limited to side effects or contraindications to Methotrexate (MTX). Therefore there is an unmet medical need for evidence for the combination of RTX with other Disease modifying anti-rheumatic drugs (DMARDs)than MTX.

Leflunomide is a DMARD that selectively inhibits de novo pyrimidine synthesis by blocking the enzyme dihydro-orotate dehydrogenase, thereby preventing DNA synthesis. The efficacy and safety of leflunomide in patients with active RA have been demonstrated in three phase III studies. Leflunomide was shown to be better than placebo and at least as effective as methotrexate in improving individual signs and symptoms of RA; these responses were seen as early as 4 weeks and were maintained for up to 2 years. Leflunomide was also effective in slowing disease progression as assessed by radiographic analysis of joint damage, and in improving functional activity as measured by the Stanford Health Assessment Questionnaire Disease Activity Index. An open label extension study of patients treated with leflunomide demonstrated that these improvements are maintained for up to 5 years in a subset of patients, with no new or unexpected adverse events emerging compared with the initial phase III studies.

In Europe leflunomide is often used in daily clinical practice as an alterative to MTX in patients with active RA.

Recently published data of a small open label trial (Vital et al. 2008) and data of a German non-interventional study (NIS) (Wendler et al. 2009) demonstrated the effectiveness of the addition of RTX to leflunomide in patients with active RA. The proportion of patients achieving EULAR (European League against Rheumatism) moderate to good response was 61% for RTX alone, 65 % for RTX plus MTX and 79% for RTX plus leflunomide in the German NIS. In the Leeds study of Vital et al.

33% of the patients achieved ACR (American College of Rheumatology)50 response (ACR 20: 68%, ACR 70: 20%) despite multiple pre-treatments, including patients with inadequate response to three TNF-Inhibitors.

The low rate of serious adverse drug reactions in the different groups of the German NIS demonstrated the safety of the combination of RTX and leflunomide (n=90) (1.6 / 1.1 / 0,5% for RTX+MTX / RTX+LEF / RTX Mono, 5.1 / 6,7 / 3,8% experienced infusion reactions)

Inclusion Criteria:

Male and female patients, 18 to 75 years of age, with active rheumatoid arthritis (RA) who have had an inadequate response to disease modifying anti-rheumatic drugs, not more than 3 non-biological DMARDs including leflunomide, and not more than one inadequate response to anti-TNF-therapy, and currently have active disease despite at least 3-month treatment with leflunomide. 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 diagnosed according to the revised 1987 ACR criteria for the classification of rheumatoid arthritis.
• Willingness and capability to give written informed consent, and willingness to participate and to comply with the study protocol.
• Not more than 2 non-biological DMARDs other than leflunomide in history, which are washed out at least 4 weeks prior to first rituximab infusion
• Previous use of anti-TNF therapy is allowed. Patient will only be allowed to be pre-treated with a maximum of two anti-TNF therapies and only one stopped due to inadequate response. The second anti-TNF could be stopped for instance due to intolerance, e.g. injection site reactions. Anti-TNF treatment must be discontinued prior to baseline considering the different characteristics of the specific compound: Use of infliximab, adalimumab, certolizumab, golimumab within 8 weeks of baseline, use of etanercept within 4 weeks of baseline.

Exclusion Criteria:

• RA functional class IV: limited in ability to perform usual self-care, work, and other activities
• Male and female patients with other chronic inflammatory articular disease or systemic autoimmune disease
• Any active infection, a history of recurrent clinically significant infection, a history of recurrent bacterial infections with encapsulated organisms (Hepatitis B, C and 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 be tested at screening)
• Primary or secondary immunodeficiency
• History of cancer with curative treatment not longer than 5 years ago except basal-cell carcinoma of the skin that had been excised
• Evidence of significant uncontrolled concomitant diseases or serious and / or uncontrolled diseases that are likely to interfere with the evaluation of the patient'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) or severe,uncontrolled cardiac disease.
• Women lactating, pregnant, nursing or of childbearing potential with a positive pregnancy test or planned pregnancy.
• Women of childbearing potential without adequate contraception (medically acceptable methods (pearl Index < 1) are contraceptive implant, contraceptive injection, intrauterine device (IUD), or oral contraceptives taken for at least 3 months,which the patient agrees to continue using during the study, or a double-barrier method which 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 / questionable reliability) as well as neurotic personality.
• Participation in another investigational study within 4 weeks prior to the screening visit.
• 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 to inadequate 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 within the last 2 weeks or corticosteroids at instable doses within the last 2 weeks
• Intolerance or contraindication to drugs required for the treatment of the side effects of rituximab
• Previous treatment with any investigational medicinal product within last 3 months prior 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 upper limit of normal
• IgG (immunoglobulin G) level < 5g/l