Neutrophil activation markers can predict rheumatoid arthritis treatment response to the Janus Kinase 1/2 inhibitor baricitinib

Objectives Neutrophils play an important role in regulating immune and inflammatory responses in 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 ELISA in RA plasma (n=271) and healthy controls (n=39). For RA patients, neutrophil activation markers were measured at baseline, 12 weeks, and 24 weeks after treatment with placebo, 2 mg, and 4 mg baricitinib. Whole blood RNA analyses from multiple randomized baricitinib RA trials were performed to study neutrophil‐related transcripts (n=1651). Results Baseline levels of plasma neutrophil markers were elevated in RA patients compared to healthy controls (p<0.001). Baricitinib reduced levels of soluble calprotectin at 12 and 24 weeks, especially in RA patients responding to treatment, as determined by ACR20. Whole blood RNA analysis revealed similar changes in the predominant neutrophil markers calprotectin and FcαRI upon treatment with baricitinib in three randomized clinical trials involving RA patients at various stages of disease modifying therapy. Clustering analysis of plasma activation markers showed elevated levels of calprotectin and NETs, e.g., a neutrophil activation score, at baseline, could predict treatment response to baricitinib. In contrast, CRP levels could not distinguish between responders and non‐responders. Conclusions 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 RA patients, not only based on symptoms, but also based on immunophenotyping.