Effects of tocilizumab on neutrophil function and kinetics

Abstract

Background

Decreases in circulating neutrophils (polymorphonuclear leukocytes, PMNs) have been reported in patients treated with the anti-interleukin-6 receptor (IL-6R) antibody tocilizumab (TCZ); the mechanism for this is unclear. We hypothesize that TCZ reduces circulating neutrophils by affecting margination and / or bone marrow trafficking without affecting neutrophil function or apoptosis.

Materials and methods

18 healthy subjects were randomized to single intravenous dose of TCZ 8 mg/kg (n = 12) or placebo (n = 6) on day 0. On day 4, each subject had autologous indium-111-labeled neutrophils re-injected, and their kinetics quantified with longitudinal profiling in a whole body gamma-counter. TCZ-treated subjects were divided into two groups according to the extent of reduction in neutrophil count.

Results

Mean day 4 neutrophil counts, as % baseline, were 101.9%, 68.3% and 44.2% in the placebo, TCZ-PMN-’high’ and TCZ-PMN-’low’ groups, respectively (p < 0.001). Following TCZ, neutrophil function, activation and apoptosis ex vivo were all unaffected. In vivo, there were no differences in early blood recovery or margination to liver / spleen and bone marrow; however, later neutrophil re-distribution to bone marrow was markedly reduced in the TCZ-PMN-low group (peak pelvic count as % day 4 count on: day 5, 188% placebo vs 127% TCZ-PMN-low, p < 0.001; day 10, 180% placebo vs 132% TCZ-PMN-low, p < 0.01), with a trend towards higher liver / spleen neutrophil retention.

Conclusions

We have demonstrated for the first time in humans that IL-6R blockade affects neutrophil trafficking to the bone marrow without influencing neutrophil functional capacity.