Objectives In patients with rheumatoid arthritis (RA), baricitinib not only improves arthritis symptom severity, but also patients’ neuropsychological symptoms, such as depression and fatigue. However, the cellular mechanisms through which baricitinib can affect neural activity is unexplored. While the blood-brain barrier (BBB) permeability of this drug remains unclear, Janus kinase inhibitors (JAKi) might reach the area postrema (AP), which is a unique brain region with a weak BBB function. Our recent study demonstrated microglial activation during experimental arthritis in the AP. Therefore, we sought to assess the effect of baricitinib on microglia in the AP using collagen-induced arthritis mouse model. Methods Microglia number and morphology in the AP were assessed by immunostaining for ionized calcium-binding adaptor molecule-1 (Iba-1). Data were collected on post-immunization day 35 (early phase) and 84 (late phase), and compared between baricitinib- and vehicle-treated mice. The effect on signal transducers and activators of transcription (STAT3) in the AP was also immunohistochemically examined. Behavioral outcomes were assessed by examining feeding behaviors and sucrose preference tests. Results In the early phase, activated microglial levels in the AP were decreased by baricitinib, accompanied by the inhibition of phosphorylated-STAT3 and recovery of food intake and sucrose preference. On the other hand, baricitinib did not affect microglial morphology in the late phase. Conclusion Our results demonstrate that baricitinib can affect brain cells, specifically microglia, in the brain region with a weak BBB and mitigate aberrant behaviors during autoimmune arthritis, pointing to the potential therapeutic effect of JAKi on brain pathologies underpinning RA.

Background Rheumatoid arthritis (RA) is complicated by psychiatric symptoms. There are many reports of abnormalities in the brains of RA patients and models of arthritis. However, it is unclear when these abnormalities appear and where they are distributed. In this study, we analyzed the spatiotemporal gene expression changes in the brains of mice with collagen-induced arthritis. Methods Mice were divided into three groups: i) collagen-induced arthritis (all mice developed arthritis on day 35): complete Freund’s adjuvant (CFA) and type II collagen at initial immunization, and incomplete Freund’s adjuvant (IFA) and type II collagen at booster immunization; ii) C(+/-) (50% mice developed arthritis on day 35): only IFA at booster immunization; and iii) C(-/-) (no arthritis): only CFA at initial immunization and only IFA at booster immunization. Whole brains were collected at 10 stages of arthritis and divided into six sections. RT-PCR was performed using RNA extracted from the divided brains, and the expressions of proinflammatory cytokines and glial markers were semi-quantified. At the same time, the arthritis score, body weight, and food and water intake were recorded and analyzed for correlation with brain gene expression. Results After booster immunization, a transient increase in ITGAM and IL-1β was observed in multiple areas. Interestingly, IL-6 was persistently expressed before the onset of arthritis in the olfactory bulb (OB), which correlated with body weight loss and decreased food intake. This characteristic change in the OB was similarly observed in the C(+/-), but not in the C(-/-). Furthermore, in the C(+/-), non-arthritis mice showed the same changes in the OB as the arthritis mice. This elevation of IL-6 persisted throughout the chronic phase to day 84. Conclusion Persistent elevation of IL-6 in the OB from the early stage of arthritis may be an important finding that might explain the neuropsychiatric pathophysiology of RA, which is present in the early stages of disease, and presents as a variety of symptoms over time. These findings also support the idea that the OB may be affected in early disease and persistently under particular peripheral immunoinflammatory conditions, as has been reported in a variety of neurodegenerative diseases.