Addition of Rituximab to Leflunomide in Patients With Active Rheumatoid Arthritis
Condition: Rheumatoid Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

Detailed description: 
      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)
    

Intervention name(s): Rituximab; Placebo
Intervention type(s): Biological; Drug
Intervention description(s): 1000 mg Rituximab infusion; infusion of Sodium citrate, Polysorbate, Sodium chloride
Other intervention name(s): Mab Thera
Intervention MeSH terms: Rituximab
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Active rheumatoid arthritis; leflunomide; rituximab; inadequate clinical response to leflunomide