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.

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