Chronobiology: How Sleep Deprivation Is Influencing Rheumatoid Arthritis Outcomes

The treatment of RA with biologic agents has improved slowing of radiographic progression toward low disease activity significantly. There is, however, an increasing need to improve quality of life for these patients, including sleep quality. Enhancing the efficacy of RA treatment to achieve low disease activity and improve patient-reported outcome is emerging as the new standard of care.

There is evidence that circadian concepts—chronobiologic principles—can be used to improve the efficacy of current therapeutic regimens for those with RA.21 Chronobiologic principles imply that timing of treatments to the circadian rhythm (chronotherapy) can optimize results. The most compelling evidence for successful RA chronotherapy is with glucocorticoids. The coordination of glucocorticoid administration with the nocturnal rise in blood IL-6 concentrations results in substantially reduced morning stiffness and pain, compared with the same dose taken in the morning. Modified-release prednisone enables bedtime administration with release of glucocorticoids at the optimal time for suppression of proinflammatory cytokines. Indeed, the Circadian Administration of Prednisone in RA (CAPRA-1) clinical study found that modified-release prednisone increased subjective sleep quality scores on a visual analog scale and reduced IL-6 levels and morning stiffness substantially more than conventional glucocorticoids.22

In a further study, CAPRA-2 compared modified-release prednisone with placebo and showed that the modified-release drug increased treatment response rates and physical functioning and reduced morning stiffness, severity of RA, and fatigue.

In addition to optimizing relief of the core symptoms of RA, chronotherapy might also relieve important comorbid conditions such as depression and sleep disturbances.22 A small-scale study involving 6 patients with RA evaluated the effect of infliximab on sleep and alertness. The study found that abnormalities in sleep and alertness improved the day after the first infusion of infliximab. This prompt response, not related to amelioration of joint discomfort, suggests a key role for TNF-α in sleep disturbance. Similarly, in a study of tocilizumab in 15 patients with RA experiencing sleep disturbances, improvement in sleep quality and reduction in daytime sleepiness were reported.1

It has been argued that increased relief of pain and stiffness, resulting from improved treatment efficacy with chronotherapy, might also alleviate the psychological impact of RA that manifests as depression and anxiety. Indeed, a well-described but not fully understood link has been postulated between peripheral inflammation and affective disorders such as depression and anxiety.22The mechanisms for this association are thought to involve neuroimmune processes in the central nervous system, which are triggered by signaling from the periphery by a number of routes, including peripheral sensory afferent activation, cytokine transport to the central nervous system, or leukocyte infiltration of the central nervous system. In preclinical models, peripheral inflammation has been found to cause long-lasting depression-like behavior. Chronotherapeutic tailoring of RA treatment with nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, or glucocorticoids to suppress proinflammatory peripheral mediators might therefore have the additional benefit of reducing symptoms by reducing neuroimmune periphery-to-brain signaling.22 Further research is needed to explore these concepts.

Summary and Clinical Applicability

Sleep deprivation is common in those with RA and is associated with poor health outcomes. It may also be a driver for RA disease processes. Chronotherapy that targets the nocturnal rise in inflammatory mediators in the blood of patients with RA may have an important complementary role in RA treatment to improve both radiographic progression of disease and patient-reported outcomes, including fatigue and depression. The prevalence of sleep disorders in those with RA is high, and clinicians should consider evaluating this important problem to improve not only quality of life for patients but also to influence disease outcome by improving sleep quality.


1. Westhovens R, Van der Elst K, Matthys A, Tran M, Gilloteau I. Sleep problems in patients with rheumatoid arthritis. J Rheumatol. 2014;41(1):31-40.

2. Her M, Kavanaugh A. Patient-reported outcomes in rheumatoid arthritis. Curr Opin Rheumatol. 2012;24(3):327-334.

3. Rendas-Baum R, Bayliss M, Kosinski M, et al. Measuring the effect of therapy in rheumatoid arthritis clinical trials from the patient’s perspective. Curr Med Res Opin. 2014;30(7):1391-1403.

4. Gossec L, Dougados M, Dixon W. Patient-reported outcomes as end points in clinical trials in rheumatoid arthritis. RMD Open. 2015;1(1):e000019.

5. Colten HR, Altevogt BM, eds. Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. Washington, DC: The National Academies Press;2006.

6. Ibarra-Coronado EG, Velazquéz-Moctezuma J, Diaz D, Becerril-Villanueva LE, Pavón L, Morales-Montor J. Sleep deprivation induces changes in immunity in Trichinella spiralis-infected rats. Int J Biol Sci. 2015;11(8):901-912.

7. Sangle SR, Tench CM, D’Cruz DP. Autoimmune rheumatic disease and sleep: a review. Curr Opin Pulm Med. 2015;21(6):553-556.

8. Sariyildiz MA, Batmaz I, Bozkurt M, et al. Sleep quality in rheumatoid arthritis: relationship between the disease severity, depression, functional status and the quality of life. J Clin Med Res. 2014;6(1):44-52.

9. Xu Y, Zhang L, Huang A, Zhao Y, Liu Y. An investigation of sleep disturbance and related factors in rheumatoid arthritis patients [in Chinese]. Zhonghua Nei Ke Za Zhi. 2015;54(11):927-930.

10. Purabdollah M, Lakdizaji S, Rahmani A, Hajalilu M, Ansarin K. Relationship between sleep disorders, pain and quality of life in patients with rheumatoid arthritis. J Caring Sci. 2015;4(3):233-241.

11. Hegarty RS, Treharne GJ, Stebbings S, Conner TS. Fatigue and mood among people with arthritis: carry-over across the day. Health Psychol. 2016 Feb 11. [Epub ahead of print]

12. Katz P, Margaretten M, Trupin L, Schmajuk G, Yazdany J, Yelin E. Role of sleep disturbance, depression, obesity, and physical inactivity in fatigue in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2016;68(1):81-90.

13. Kang JH, Lin HC. Obstructive sleep apnea and the risk of autoimmune diseases: a longitudinal population-based study. Sleep Med. 2012;13(6):583-588.

14. Hsiao YH, Chen YT, Tseng CM, et al. Sleep disorders and increased risk of autoimmune diseases in individuals without sleep apnea. Sleep. 2015;38(4):581-586.

15. Palma BD, Gabriel A Jr., Colugnati FA, Tufik S. Effects of sleep deprivation on the development of autoimmune disease in an experimental model of systemic lupus erythematosus. Am J Physiol Regul Integr Comp Physiol . 2006;291(5):R1527-R1532.

16. Haack M, Sanchez E, Mullington JM. Elevated inflammatory markers in response to prolonged sleep restriction are associated with increased pain experience in healthy volunteers. Sleep. 2007;30(9):1145-1152.

17. Wright KP Jr, Drake AL, Frey DJ, et al. Influence of sleep deprivation and circadian misalignment on cortisol, inflammatory markers, and cytokine balance. Brain Behav Immun. 2015;47:24-34.

18. Garbazza C, Bromundt V, Eckert A, et al. Non-24-hour sleep-wake disorder revisited – a case study. Front Neurol. 2016;7:17.

19. Besedovsky L, Lange T, Born J. Sleep and immune function. Pflugers Arch. 2012;463(1):121-137.

20. Scheiermann C, Kunisaki Y, Frenette PS. Circadian control of the immune system. Nat Rev Immunol. 2013;13(3):190-198.

21. Gibbs JE, Ray DW. The role of the circadian clock in rheumatoid arthritis. Arthritis Res Ther. 2013;15(1):205.

22. Buttgereit F, Smolen JS, Coogan AN, Cajochen C. Clocking in: chronobiology in rheumatoid arthritis. Nat Rev Rheumatol. 2015;11(6):349-356.