Infliximab treatment shifts the balance between stimulatory and inhibitory Fcγ receptor type II isoforms on neutrophils in patients with rheumatoid arthritis

Objective Human neutrophils express both activating and inhibitory Fcγ receptors (FcγR), and their relative expression determines the inflammatory response to immune complexes. Tumor necrosis factor α (TNFα) up‐regulates the expression of stimulatory FcγRIIa on neutrophils in vitro, and amplifies immune complex–induced activation of neutrophils in vivo. This study was undertaken to determine whether TNFα blockade in patients with rheumatoid arthritis (RA) alters the balance of activating FcγR and inhibitory FcγR and thereby decreases inflammation. Methods We used fluorescence‐activated cell sorting and Western blotting to examine FcγR expression on neutrophils in 24 patients with RA, preceding their first infusion of infliximab and immediately prior to ≥3 subsequent infusions. Results In 13 of 24 patients (54.2%), there was a decrease in the expression of the predominant activating FcγR, FcγRIIa, after treatment with infliximab, an effect that persisted over ≥3 months of treatment. Although prior to initiation of infliximab therapy the inhibitory FcγR, FcγRIIb, was undetectable in neutrophils from 23 of 24 patients with RA, FcγRIIb protein was detected by Western blotting in 9 patients (37.5%) at the time of the third infliximab infusion. The induction of inhibitory FcγRIIb was always associated with decreased levels of FcγRIIa, and improvement following infliximab therapy, measured using the Health Assessment Questionnaire, was significantly associated with down‐regulation of FcγRIIa. Conclusion Our findings indicate that TNFα inhibition may reduce inflammation in patients with RA by restoring the balance of activating and inhibitory FcγR and thereby raising the threshold for immune complex–mediated activation of neutrophils.