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Inhibition of Tumor Necrosis Factor



- Discussion:
    - these agents bind TNF and block inflammation by inhibiting the subsequent effects of this cytokine;
    - infliximab:
          - a chimeric monoclonal antibody against TNF-(alpha)
          - variable region of a murine antibody grafted to the constant region of a human antibody;
          - given intravenously every two months;
          - in the report by Lipsky PE, et al. (2000), the authors treated 428 patients
                 who had active RA despite methotrexate therapy with placebo or infliximab;
                 - IV doses of 3 or 10 mg / kg of body weight q 4 or 8 weeks in combo w/ oral methotrexate for 54 weeks;
                 - the authors noted the combination of infliximab and methotrexate was well tolerated and resulted in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alone (clinical response, 51.8% vs. 17.0%; P<0.001);
                 - the quality of life was also significantly better with infliximab plus methotrexate than w/ methotrexate alone;
                 - radiographic evidence of joint damage increased in the group given methotrexate, but not in the groups given infliximab and methotrexate (mean change in radiographic score, 7.0 vs. 0.6; P<0.001);
                 - radiographic evidence of progression of joint damage was absent in infliximab-treated patients whether or not they had a clinical response;
                 - the authors concluded the patients with persistently active RA despite methotrexate therapy, repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage.
                 - ref: Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. 
    - etanercept (enbrel)
          - soluble receptor
          - dimer consisting of a TNF receptor joined to the Fc domain of a human IgG1 molecule;
          - given subcutaneously twice a week;
          - in the report by Bathon JM, et al (2000), the authors followed 632 patients with early RA with either twice-weekly subQ etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months.
                  - as compared with patients who received methotrexate, patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20%, 50%, and 70% improvement in disease activity during the first six months (P<0.05)
                  - among patients who received the 25-mg dose of etanercept, 72% had no increase in the erosion score, as compared with 60% of patients in the methotrexate group (P=0.007). This group of patients also had fewer adverse events (P=0.02) and fewer infections (P=0.006) than the group that was treated with methotrexate
                  - A Comparison of Etanercept and Methotrexate in Patients with Early Rheumatoid Arthritis



Tumor necrosis factor blockers in rheumatoid arthritis.