Sopping Up Tumor Necrosis Factor: A New Treatment for Rheumatoid Arthritis?
ABSTRACT & COMMENTARY
Synopsis: Use of a genetically engineered protein consisting of the tumor necrosis factor binding portion of a human tumor necrosis factor receptor, coupled to the constant portion of a human immunoglobulin G heavy chain resulted in marked, dose-dependent, improvement for the three-month duration of the trial.
Source: Moreland LW, et al. N Engl J Med 1997;337: 141-147.
Tumor necrosis factor receptor fusion protein (TNFR-Fc) is a novel biological which was engineered from parts of two human proteins. The active portion is believed to be the tumor necrosis factor receptor bearing the binding site for TNF. It is coupled to the product of the gene for the constant region of a human immunoglobulin G protein. The resulting fusion protein was used in a double blind randomized controlled trial to assess its usefulness in treating rheumatoid arthritis. Adult patients with rheumatoid arthritis who had failed at least one disease modifying antirheumatic drug (DMARD) had all DMARDs withdrawn for a month before baseline measurements were made. There were 180 patients randomized to 4 groups: placebo, 0.25 mg/m2, 2 mg/m2, and 16 mg/m2 of TNFR-Fc given by subcutaneous injection twice a week.
Use of non-steroidal anti-inflammatory drugs, prednisone in a stable dose of 10 mg or less per day, and analgesics were permitted during the trial. Withdrawals due to lack of efficacy were much more frequent in the placebo group (43% of withdrawals) than in the highest dose TNFR-Fc group (5% of withdrawals). All measures were statistically significantly better after three months of treatment and encompassed swollen joint counts, tender joint counts, morning stiffness duration, physician’s and patient’s global assessments, pain as assessed by visual analog scale, quality of life from the Health Assessment Questionnaire, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level. Using American College of Rheumatology criteria for 50% improvement, only 7% of the placebo group improved 50% by the end of three months vs. 57% of the highest dose TNFR-Fc group. Using criteria for 20% improvement, only 14% of the placebo group improved by 20% or more, while 75% of the highest dose TNFR-Fc group improved that much. The TNFR-Fc was remarkably well-tolerated, and only one withdrawal from the TNFR-Fc group was due to a possible drug-related adverse eventa local reaction at an injection site. Some upper respiratory were reported and were described as mild and self limited despite continuation of the TNFR-Fc. No antibodies to TNFR-Fc were detected in the serum of any of the subjects.
COMMENT BY JERRY M. GREENE, MD
This is welcome news indeed. One of my patients wanted to know when he could start taking TNFR-Fc. Unfortunately, he will have to wait to see if the Food and Drug Administration approves its use for people with rheumatoid arthritis, which would be its first indication. If approved, it will still be no panacea. The twice weekly subcutaneous injections may put off some patients. In addition, it is not a cure for RA. The beneficial effects were gradually lost upon discontinuation of the injections. While the lack of an antibody response was encouraging it remains to be seen whether neutralizing antibodies develop with long-term treatment. Nevertheless, if major toxicity, not evident in this relatively short-term trial, does not develop with chronic use, TNFR-Fc has the potential to be a welcome addition to the pharmacopeia.
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