Background/Purpose:
Decreases in circulating neutrophil counts have been observed in adults with
rheumatoid arthritis (RA) and children with systemic or polyarticular juvenile
idiopathic arthritis treated with the interleukin-6 (IL-6) receptor-α antagonist
tocilizumab (TCZ). However, no temporal relationship with risk for infection
has been demonstrated to date, and the mechanism of neutrophil count decrease
associated with TCZ is unclear. Previous research in RA
patients showed that TCZ had no effect on neutrophil function or survival when
assessed 4 and 12 weeks after TCZ initiation¹;
however, the effects of TCZ on neutrophil function and survival at the
neutrophil nadir (day 4 [D4] after TCZ administration) have not been assessed.

Methods:
Healthy male subjects age 18-65 years received a single intravenous dose (blinded
to subjects only) of TCZ 8 mg/kg or placebo (PBO) on day 0 (D0). Neutrophil
function and survival were assessed ex vivo in isolated polymorphonuclear
leukocytes (PMNs) on D0 predose and on D4. Neutrophil apoptosis, phagocytosis,
production of reactive oxygen species (ROS), morphology, and surface markers (adhesion
molecules CD11b, CD62L, and CD162; CD16) were assessed.

Results:
TCZ was administered to 12 subjects and PBO to 6 subjects. Neutrophil count decreased
with TCZ but not with PBO. No subjects experienced a drop in their neutrophil
count <1×10⁹/L. TCZ-treated subjects were divided into 2 groups: PMN
high (subjects with ≤50% reduction in D4 neutrophil count relative to
baseline, n=5) and PMN low (subjects with >50% reduction in D4 neutrophil
count relative to baseline, n=7). Mean neutrophil counts at D4 as percentages
of D0 levels were 102% in the PBO group, 72% in the PMN-high group, and 45% in
the PMN-low group. The functional capacity of neutrophils was unaffected by the
administration of TCZ, as demonstrated by intact respiratory burst activity and
intact phagocytosis of heat-killed S. pneumoniae at D4 (Table). Survival
of neutrophils after 20 hours of culture was unaffected in the TCZ-treated
subjects, with apoptosis rates showing no differences between PBO and TCZ
groups either under control conditions or in the presence of the prosurvival
factors granulocyte macrophage–colony-stimulating factor and tumor necrosis
factor-α (Table). Surface markers and neutrophil shape change were also similar
among the PBO, PMN-low, and PMN-high groups at D4 in both control and
stimulated PMNs (Table). No serious adverse events were reported.

Conclusion:
IL-6 blockade with TCZ resulted in reduced counts of circulating neutrophils.
However, the functional capacity and survival of neutrophils at the D4 nadir were
unaffected by TCZ treatment; this may support why, to date, no temporal
associations between decreased circulating neutrophil counts and increased risk
for infection have been observed.

Reference

1.   Wright HL
et al. Rheumatology. 2014; 53:1321-31.