Rheumatoid arthritis reprograms circadian output pathways.

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

Preventive dental care use for children with special health care needs in Washington's Access to Baby and Child Dentistry program.

BACKGROUND: Preschool-aged children with special health care needs (CSHCN) from low-income households are at increased risk of developing poor oral health. The study goal was to assess preventive dental care use for CSHCN enrolled in Medicaid within Washington state's Access to Baby and Child Dentistry (ABCD) program. METHODS: The authors analyzed 2012 Medicaid eligibility and claims files for children younger than 6 years in the ABCD program (N = 206,488). The authors used medical diagnosis and eligibility data to identify each child's special needs status (no or yes). The outcome was preventive dental care use (no or yes). The authors used modified Poisson regression models to estimate crude and covariate-adjusted prevalence rate ratios. RESULTS: Of the 206,488 children in the study, 2.1% were CSHCN, and 114,570 used preventive dental care (55.5%). CSHCN used preventive care at rates similar to those of children without special health care needs (SHCN) (54.7% and 55.5%, respectively; P = .32). After adjustment for confounding variables, CSHCN were significantly less likely to use preventive dental care than were children without SHCN (prevalence rate ratio, 0.91; 95% confidence interval, 0.88 to 0.94; P < .001). Older preschool-aged children were significantly more likely to use preventive dental care than were younger preschool-aged children. A significantly higher proportion of preventive medical care users also used preventive dental care. CONCLUSIONS: CSHCN who were enrolled in Medicaid in Washington's ABCD program were less likely to use preventive dental care than were children without SHCN who were enrolled in Medicaid. PRACTICAL IMPLICATIONS: Future intervention research investigators should evaluate ways to improve access to preventive dental care for CSHCN. Additional strategies may be needed to improve oral health behaviors for preschool-aged CSHCN receiving Medicaid.

The circadian clock regulates inflammatory arthritis.

There is strong diurnal variation in the symptoms and severity of chronic inflammatory diseases, such as rheumatoid arthritis. In addition, disruption of the circadian clock is an aggravating factor associated with a range of human inflammatory diseases. To investigate mechanistic links between the biological clock and pathways underlying inflammatory arthritis, mice were administered collagen (or saline as a control) to induce arthritis. The treatment provoked an inflammatory response within the limbs, which showed robust daily variation in paw swelling and inflammatory cytokine expression. Inflammatory markers were significantly repressed during the dark phase. Further work demonstrated an active molecular clock within the inflamed limbs and highlighted the resident inflammatory cells, fibroblast-like synoviocytes (FLSs), as a potential source of the rhythmic inflammatory signal. Exposure of mice to constant light disrupted the clock in peripheral tissues, causing loss of the nighttime repression of local inflammation. Finally, the results show that the core clock proteins cryptochrome (CRY) 1 and 2 repressed inflammation within the FLSs, and provide novel evidence that a CRY activator has anti-inflammatory properties in human cells. We conclude that under chronic inflammatory conditions, the clock actively represses inflammatory pathways during the dark phase. This interaction has exciting potential as a therapeutic avenue for treatment of inflammatory disease.-Hand, L. E., Hopwood, T. W., Dickson, S. H., Walker, A. L., Loudon, A. S. I., Ray, D. W., Bechtold, D. A., Gibbs, J. E. The circadian clock regulates inflammatory arthritis.