The evidence supporting the role of sleep deprivation and circadian rhythm in the exacerbation of the symptoms of rheumatoid arthritis (RA) has accumulated in recent years. The majority of published studies that have examined the effects of sleep on autoimmune disease have focused primarily on the effects of pain, inflammation, and mental and physical fatigue on sleep quality. A correlation between sleep and inflammatory diseases has also been made from studies conducted in patients with non-autoimmune diseases such as sleep apnea.1 More direct evidence came from a nationwide cohort study conducted in Taiwan involving 65,754 patients with a sleep disorder, which found that people with a sleep disorder had a 1.49-fold greater risk of developing RA than controls.2 A similar earlier study involving approximately 85,000 adults came to a similar conclusion, demonstrating a link between non-apnea sleep disorders and increased risk for autoimmune diseases, including RA, systemic lupus erythematosus, ankylosing spondylitis, and Sjogren syndrome.3 Similarly, evidence has accumulated supporting the role of circadian rhythm in the regulation of immunologic processes, with a potential to affect the onset and intensity of disease symptoms and response to therapies.4,5
Two recent publications attempted to unravel the mechanisms and underlying pathophysiology of sleep deprivation and circadian rhythm in RA. A comprehensive review published in Rheumatology International examined the mechanisms, confounders, and consequences of the association between sleep and RA, and the potential exploitation of this relationship as a treatment strategy.1 Although the pathophysiologic mechanisms involved in sleep deprivation and RA are not well understood, there is speculation that they involve the breakdown of immunologic self-tolerance, perpetuated by impaired T-regulatory cell function, which is known to play a key role in suppressing inappropriate immune response. The suppression results in the upregulation of specific proinflammatory cytokines such as tumor necrosis factor-alpha, interleukins, and C-reactive proteins, which are known to be key drivers of RA pathogenesis.3,6,7 Although a breakdown of immunologic self-tolerance can help to explain the pathophysiologic relationship between sleep deprivation and RA, clinically, the effect of sleep and its deprivation is complex and is influenced by several demographic and disease-related variables. Age, gender, pain tolerance, mental health status, medication, comorbid diseases, and disease-related symptoms such as pain, fatigue, inflammation, and overall disease activity are some examples of factors that can affect sleep quality, disease symptoms, and quality of life.1
Closely associated with sleep pattern is circadian rhythm. The evidence that circadian rhythm is a strong regulator of immunologic processes is provided in a review published in Joint Bone Spine.4 The circadian rhythm controls several daily activities, including metabolism, endocrine and immune function, and sleep pattern, and is thought to also control the synthesis and release of proinflammatory cytokines, cell migration, and proliferation and phagocytosis at the site of inflammation. The nightly circadian release of proinflammatory cytokines and its elevation in synovial fluids correlate with morning joint stiffness and pain. In fact, it has been shown that in patients with RA, compared with controls, the circadian rhythm of interleukin-6 is different, and that serum concentration is approximately 10 times higher in patients with RA.4
The clinical implication of sleep and circadian rhythm in inflammatory processes suggests a re-evaluation of the approach to treatment. It has been suggested that RA symptoms closely follow a 24-hour circadian rhythm, with maximum pain, stiffness, and functional disability present in the early morning.4 Therefore, inhibition of the nocturnal increase in proinflammatory cytokines by initiating treatment at night may be a reasonable approach to optimizing therapy and patient outcomes. Data suggest that timing RA treatment to coincide with circadian rhythm to target the nocturnal increase in inflammatory cytokines may improve efficacy and optimize treatment results.4,8 In vivo studies with animal models support the benefit of chronotherapy to help improve RA symptoms. The most compelling evidence for the benefit of chronotherapy in human subjects has been demonstrated with prednisolone; studies show that prednisolone given at night resulted in a significantly shorter duration of morning stiffness compared with giving the dose in the morning.4 Given that RA is a complex disease driven by multiple pathways, it is unclear whether the principles of chronotherapy are applicable to all RA treatments, including disease-modifying and biologic agents.
“As a matter of fact,” said Maurice Cutolo, MD, professor of rheumatology, and director of the Research Laboratories and Clinical Academic Unit at the University Medical School of Genova, Italy “regarding the most used classical disease-modifying antirheumatic drugs (DMARDs), namely methotrexate, a novel unique action on synovial fibroblasts has shown that it upregulates important core circadian clock genes, resulting in apoptosis induction of the cells.”9
Dr Cutolo added that, “Interestingly, the daily oral administration of low-dose methotrexate vs the weekly dose has shown greater antirheumatic effects in collagen-induced arthritis rats.”10 A study in patients with RA has shown that oral split doses of methotrexate are better than an oral single dose and is similar to parenteral methotrexate in terms of efficacy.11 “Therefore, 2 anchor drugs in RA (glucocorticoids low dose and a conventional DMARD like methotrexate) following a chronotherapeutic approach seems superior to another regimen by considering a circadian-adapted administration,” said Dr Cutolo, suggesting that the daily administration of small molecule drugs (such as kinase inhibitors) should be tested in light of the circadian effects. However, further research is needed to explore these concepts.
The implication of sleep and circadian rhythm suggest that physicians should conduct a thorough clinical evaluation of sleep patterns as part of a comprehensive history in patients with RA. In fact, the European League Against Rheumatism recommends taking sleep quality into consideration when considering treatment for patients with inflammatory arthritis, including referral to sleep specialists.12 Administering RA treatment at night should be considered, at least based on the evidence from studies with prednisolone.
- Coskun Benlidayi I. Sleep impairment: an obstacle to achieve optimal quality of life in rheumatoid arthritis [September 11, 2018].Rheumatol Int. doi:10.1007/s00296-018-4155-5
- Chung WS, Lin CL. Sleep disorders associated with risk of rheumatoid arthritis [February 10, 2018].Sleep Breath. doi:10.1007/s11325-018-1639-1
- 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.
- Cutolo M. Circadian rhythms and rheumatoid arthritis [published online September 15, 2018]. Joint Bone Spine. doi: 10.1016/j.jbspin.2018.09.003
- Scheiermann C, Kunisaki Y, Frenette PS. Circadian control of the immune system. Nat Rev Immunol. 2013;13(3):190-198.
- 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.
- 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.
- Gibbs JE, Ray DW. The role of the circadian clock in rheumatoid arthritis. Arthritis Res Ther. 2013;15(1):205.
- Suzuki K, Yoshida K, Ueha T, et al. Methotrexate upregulates circadian transcriptional factors PAR bZIP to induce apoptosis on rheumatoid arthritis synovial fibroblasts. Arthritis Res Ther. 2018;20(1):55.
- Koyama A, Tanaka A, To H. Daily oral administration of low-dose methotrexate has greater antirheumatic effects in collagen-induced arthritis rats. J Pharm Pharmacol. 2017;69(9):1145-1154.
- Dhaon P, Das SK, Srivastava R, Agarwal G, Asthana A. Oral methotrexate in split dose weekly versus oral or parenteral methotrexate once weekly in rheumatoid arthritis: a short-term study. Int J Rheum Dis. 2018;21(5):1010-1017.
- Geenen R, Overman CL, Christensen R, et al. EULAR recommendations for the health professional’s approach to pain management in inflammatory arthritis and osteoarthritis. Ann Rheum Dis. 2018;77(6):797-807.