Objective: We applied systems biology approaches to investigate circadian rhythmicity in rheumatoid arthritis (RA).\nMethods: We recruited adults (age 16â??80 years old) with a clinical diagnosis of RA (active disease [DAS28 > 3.2]).\nSleep profiles were determined before inpatient measurements of saliva, serum, and peripheral blood mononuclear\nleukocytes (PBML). Transcriptome and proteome analyses were carried out by RNA-SEQ and LC-MS/MS. Serum samples\nwere analysed by targeted lipidomics, along with serum from mouse collagen induced-arthritis (CIA). Bioinformatic\nanalysis identified RA-specific gene networks and rhythmic processes differing between healthy and RA.\nResults: RA caused greater time-of-day variation in PBML gene expression, and ex vivo stimulation identified a time-ofday-\nspecific RA transcriptome. We found increased phospho-STAT3 in RA patients, and some targets, including\nphospho-ATF2, acquired time-of-day variation in RA. Serum ceramides also gained circadian rhythmicity in RA, which\nwas also seen in mouse experimental arthritis, resulting from gain in circadian rhythmicity of hepatic ceramide synthases.\nConclusion: RA drives a gain in circadian rhythmicity, both in immune cells, and systemically. The coupling of distant\ntiming information to ceramide synthesis and joint inflammation points to a systemic re-wiring of the circadian\nrepertoire. Circadian reprogramming in response to chronic inflammation has implications for inflammatory\nco-morbidities and time-of-day therapeutics.
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