Early in 2006, the FDA approved Rituximab for the treatment of moderate to severe rheumatoid arthritis that has not responded to TNF blockers. Rituximab is a chimeric monoclonal antibody of human and mouse origin that recognizes CD 20. CD 20 is a surface molecule of unknown function that specifically is expressed on the surface of mature B-cells but not pro B-cells or plasma cells. The drug effectively binds to and causes the depletion of B-cells within the peripheral blood and lymph nodes. Originally, rituximab was used for the treatment of B-cell lymphomas, and during these treatments it was noted that patients with concomitant autoimmune disease saw improvement of their autoimmune symptoms following treatment with rituximab. These observations led to studies of the drug in treating numerous autoimmune diseases such as autoimmune hemolytic anemia, immune thrombocytopenia purpura, systemic lupus erythematosus, and rheumatoid arthritis.
Edwards and colleagues published a randomized, double-blind, controlled trial of 161 patients with active rheumatoid arthritis in the New England Journal of Medicine in June of 2004. The control group was treated with methotrexate alone, whereas the study groups were treated with either rituximab alone, rituximab plus cyclophosphamide, or rituximab plus methotrexate. All rituximab arms showed significantly greater improvement in disease symptoms, with the greatest improvements in the rituximab plus methotrexate arm. More recently, the results of a phase 2B trial known as the “Dose-ranging assessment international clinical evaluation of rituximab in RA (DANCER)” trial, which involved 486 patients, and the results of phase 3 trial known as “the randomized evaluation of long-term efficacy of rituximab (REFLEX)” trial were published in abstract form in two annual scientific meetings. Each study showed that rituximab significantly improved disease symptoms when compared with placebo. The dose approved by the FDA is two doses of 1000mg given intravenously, separated by two weeks, and the FDA notes that it is to be given with methotrexate. The approval recommends that 200mg of intravenous methylprednisolone be given intravenously at the time of each infusion. Although the literature does not yet clearly answer the question as to when repeat treatments will be indicated, the manufacturers (Genentech and Biogen) note that the interval will likely be 6 to 9 months between courses of therapy. We await the publication of the follow-up reports from the prior Rituximab studies to assist in determining the most efficacious and safest interval. Infusion reactions are a very common side effect, especially with the first infusion, which is why rituximab is often given following corticosteroids. An increased risk of infection does not appear to be a major side effect of rituximab.
At the end of 2005, the FDA approved abatacept for treatment of moderate to severe rheumatoid arthritis in patients who did not respond to other disease- modifying anti-rheumatic drugs. Abatacept is a genetically engineered fusion of the extracellular portion of cytotoxic T-lymphocyte antigen-4 (CTLA-4) with Fc portion of IgG. The molecule is designed to interfere with an interaction between antigen presenting cells and T-lymphocytes called co-stimulation. Co-stimulation of T-lymphocytes by antigen presenting cells is necessary for the development of a proper adaptive immune response; however, in this setting the drug is thought to interfere with the process leading to autoimmunity.
In September of 2005, Genovese and colleagues published a randomized double-blind phase 3 trial of Abatacept for the treatment of rheumatoid arthritis in the New England Journal of Medicine. This trial, titled “the abatacept trial in treatment of anti-TNF inadequate responders (ATTAIN)”, studied 393 patients who were randomized to either abatacept (at 10 mg/kg) plus disease modifying agents or placebo plus disease modifying agents. In this group of anti-TNF failures, abatacept caused a statistically significant improvement in clinical symptoms and physical function when compared with placebo. Dosing is approximately 10 mg/kg by intravenous infusion at 2 and 4 weeks following the initial infusion, then monthly thereafter. Dosage is calculated as follows:
|Body weight of patient||Dose|
|<60 kg||500 mg|
|60 to 100 kg||750 mg|
|>100 kg||1 g|
The drug is contraindicated in patients who are taking TNF antagonists. Adverse effects include headaches, upper respiratory tract infections, nasopharyngitis, and an overall increased risk of infection.
Armamentarium for rheumatoid arthritis—how do these agents fit in?
It is an exciting advance in rheumatology to have two new biologic medications, especially since it is estimated that 25-30% of patients will have an inadequate response to anti-TNF agents. Abatacept is approved by the FDA for patients who have failed methotrexate or other disease-modifying agents such as biologics. At this point, it is likely that most rheumatologists will reserve abatacept for patients who have failed anti-TNF therapy. Rituximab is approved for patients who have failed biologic therapy. Therefore, neither of these agents is likely to be “first-line” at this moment. After rheumatologists get more of a feel for the efficacy and tolerability of these agents in clinical practice, these medications may be considered earlier in the RA treatment algorithm.
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