In vivo blockade of tumor necrosis factor-alpha in patients with rheumatoid arthritis: longterm effects after repeated infusion of chimeric monoclonal antibody cA2

Abstract

Objective: To investigate the longterm consequences of tumor necrosis factor-alpha (TNF-alpha) blockade in patients with rheumatoid arthritis (RA), to compare changes after repeated infusion of cA2 monoclonal antibody with those occurring after the initial treatment, and to investigate significant correlations of cellular or serological changes to the duration of clinical benefit for each patient.

Methods: A clinical trial testing TNF-alpha monoclonal antibody cA2 in treatment of RA showed this therapeutic agent is highly effective. A dosage of 1 mg/kg or 10 mg/kg cA2, given in a single infusion, was compared to placebo. After clinical relapse all patients were (re)treated with 3 or 10 mg/kg cA2. In parallel to this clinical study, we investigated cellular and molecular changes induced by in vivo blockade of TNF-alpha.

Results: After an initial transient increase, T lymphocyte counts were not significantly different from starting values throughout the observation period. Monocyte counts as well as serum interleukin 6 (IL-6) and soluble intercellular adhesion molecule 1 (sICAM-1) concentrations remained decreased for several weeks after infusion. After a repeated infusion, increases in numbers of T cells and decreases in monocytes and IL-6 and sICAM-1 concentrations were evident again. Changes in cell counts, however, were smaller, especially in the group initially treated with the low dose (1 mg/kg), despite a higher retreatment dosage of 3 or 10 mg/kg cA2. Similarly, in this group decrease of IL-6 and sICAM-1 concentrations was less pronounced, was delayed to Day 7 after infusion, and lasted for a shorter period than seen after initial treatment.

Conclusion: We conclude that in vivo TNF-alpha blockade leads to prolonged cellular and serological changes. This effect appears to be less pronounced after repeated infusion of cA2 compared to the initial treatment, mainly in the low dose group.