RESUMEN
OBJECTIVE: Neuroinflammatory adverse events have been observed among new users of tumor necrosis factor (TNF) inhibitors. No studies to date have compared the real-world risk of TNFs with other new users of biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). The objective of this study is to describe the risk of neuroinflammatory disease after initiation b/tsDMARDs. METHODS: This new user comparative effectiveness cohort study used a large US-based electronic health records database to describe the unadjusted incidence of neuroinflammatory adverse events over a 3-year period. The cohort included patients with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, or ulcerative colitis initiating treatment with a TNF inhibitor (n = 93,661) or other b/tsDMARD (n = 38,354). RESULTS: Among 132,015 patients included in the analysis, the most common first biologic agent was a TNF inhibitor; the unadjusted incidence of neuroinflammatory events was numerically lower among new users of TNF inhibitors (incidence 1.34 per 1,000 patient-years) as compared with the combined non-TNF group (1.69 per 1,000 patient-years). There was no significant association between TNF exposure and neuroinflammatory events as compared with the combined non-TNF b/tsDMARDs overall (hazard ratio 1.01; 95% confidence interval 0.75-1.36) and within each disease group. CONCLUSION: The overall risk of neuroinflammatory events among new users of TNF inhibitors did not differ substantially as compared with new users of other b/tsDMARDs. Meta-analyses of randomized trials should be conducted to corroborate these findings, which may be affected by channeling bias.
RESUMEN
The circadian system produces ~24-hr oscillations in behavioral and physiological processes to ensure that they occur at optimal times of day and in the correct temporal order. At its core, the circadian system is composed of dedicated central clock neurons that keep time through a cell-autonomous molecular clock. To produce rhythmic behaviors, time-of-day information generated by clock neurons must be transmitted across output pathways to regulate the downstream neuronal populations that control the relevant behaviors. An understanding of the manner through which the circadian system enacts behavioral rhythms therefore requires the identification of the cells and molecules that make up the output pathways. To that end, we recently characterized the Drosophila pars intercerebralis (PI) as a major circadian output center that lies downstream of central clock neurons in a circuit controlling rest:activity rhythms. We have conducted single-cell RNA sequencing (scRNAseq) to identify potential circadian output genes expressed by PI cells, and used cell-specific RNA interference (RNAi) to knock down expression of ~40 of these candidate genes selectively within subsets of PI cells. We demonstrate that knockdown of the slowpoke (slo) potassium channel in PI cells reliably decreases circadian rest:activity rhythm strength. Interestingly, slo mutants have previously been shown to have aberrant rest:activity rhythms, in part due to a necessary function of slo within central clock cells. However, rescue of slo in all clock cells does not fully reestablish behavioral rhythms, indicating that expression in non-clock neurons is also necessary. Our results demonstrate that slo exerts its effects in multiple components of the circadian circuit, including PI output cells in addition to clock neurons, and we hypothesize that it does so by contributing to the generation of daily neuronal activity rhythms that allow for the propagation of circadian information throughout output circuits.