Inhibition of Tumor Necrosis Factor

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- 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 PE. Lipsky et al. N Engl J Med 2000;343:1594-602, 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
                        percent vs. 17.0 percent; 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.   Peter E. Lipsky et al. N Engl J Med 2000;343:1594-602
    - 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 JM Bathon et al (NEJM, Nov 30, 2000 Vol. 343, No. 22), 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 percent, 50 percent, and 70 percent improvement in disease activity during the first
                            six months (P<0.05)
                  - among patients who received the 25-mg dose of etanercept, 72 percent had no increase in the erosion score,
                            as compared with 60 percent 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;

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Tumor Necrosis Factor Blockers in Rheumatoid Arthritis
      David S. Pisetsky, M.D., Ph.D. The New England Journal of Medicine -- March 16, 2000 -- Vol. 342, No. 11

A Comparison of Etanercept and Methotrexate in Patients with Early Rheumatoid Arthritis
      Joan M. Bathon   JM Bathon et al (NEJM, Nov 30, 2000 Vol. 343, No. 22)

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