Neutrophil Activation Markers and Rheumatoid Arthritis Treatment Response to the JAK1/2 Inhibitor Baricitinib

OBJECTIVE: Neutrophils play an important role in regulating immune and inflammatory responses in patients with rheumatoid arthritis (RA). We assessed whether baricitinib, a JAK1/JAK2 inhibitor, could reduce neutrophil activation and whether a neutrophil activation score could predict treatment response. METHODS: Markers of neutrophil activation, calprotectin, and neutrophil extracellular traps (NETs) were analyzed using enzyme-linked immunosorbent assay in plasma from patients with RA (n = 271) and healthy controls (n = 39). For patients with RA, neutrophil activation markers were measured at baseline, 12 weeks, and 24 weeks after receiving placebo and 2 and 4 mg baricitinib. Whole-blood RNA analyses from multiple randomized baricitinib RA trials were performed to study neutrophil-related transcripts (n = 1,651). RESULTS: Baseline levels of plasma neutrophil markers were elevated in patients with RA compared to healthy controls (P < 0.001). Receiving baricitinib reduced levels of soluble calprotectin at 12 and 24 weeks, especially in patients with RA responding to treatment, as determined by American College of Rheumatology 20% improvement criteria. Whole-blood RNA analysis revealed similar changes in the predominant neutrophil markers calprotectin and Fcα receptor I upon reception of baricitinib in three randomized clinical trials involving patients with at various stages of disease-modifying therapy. Clustering analysis of plasma activation markers showed elevated levels of calprotectin and NETs (eg, a neutrophil activation score, at baseline, could predict treatment response to baricitinib). In contrast, C-reactive protein levels could not distinguish between responders and nonresponders. CONCLUSION: Neutrophil activation markers may add clinical value in predicting treatment response to baricitinib and other drugs targeting RA. This study supports personalized medicine in treating patients with RA, not only based on symptoms but also based on immunophenotyping.