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Heat of the night: sleep disturbance activates inflammatory mechanisms and induces pain in rheumatoid arthritis

Nature Reviews Rheumatology volume 19, pages 545–559 (2023)Cite this article

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Abstract

Sleep has a homeostatic role in the regulation of the immune system and serves to constrain activation of inflammatory signalling and expression of cellular inflammation. In patients with rheumatoid arthritis (RA), a misaligned inflammatory profile induces a dysregulation of sleep–wake activity, which leads to excessive inflammation and the induction of increased sensitivity to pain. Given that multiple biological mechanisms contribute to sleep disturbances (such as insomnia), and that the central nervous system communicates with the innate immune system via neuroendocrine and neural effector pathways, potential exists to develop prevention opportunities to mitigate the risk of insomnia in RA. Furthermore, understanding these risk mechanisms might inform additional insomnia treatment strategies directed towards steering and reducing the magnitude of the inflammatory response, which together could influence outcomes of pain and disease activity in RA.

Key points

  • Patients with rheumatoid arthritis (RA), a chronic inflammatory disorder, frequently complain of symptoms of insomnia and pain.

  • Inflammation can induce sleep disturbance, and in turn sleep disturbance increases inflammation in a feedforward loop, which is sustained by sympathetic arousal mechanisms and a downregulation of glucocorticoid receptor sensitivity.

  • Sleep disturbance can also increase pain sensitivity, as mediated by increases in inflammation; in patients with RA, sleep loss induces heightened pain responses and activation of arthritis-related joint pain.

  • Interventions that treat insomnia have the potential to interrupt the effects of sleep disturbance on inflammation, pain sensitivity and symptomatic progression in patients with RA.

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Fig. 1: Model depicting the impact of sleep disturbance and inflammation on pain and disease activity in patients with RA.
Fig. 2: Schematic model of neural sites and effector mechanisms involved in sleep regulation of inflammation.

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Acknowledgements

The work of the authors is funded by National Institutes of Health (NIH) — National Institute on Drug Abuse (NIH/NIDA) R01DA0329922 (to M.T.S. and M.R.I.), by NIH – National Heart, Lung, and Blood Institute (NIH-NHLB) R01 HL079955 (to M.R.I.), and the Norman Cousins Center for Psychoneuroimmunology.

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  1. Department of Psychiatry and Behavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Michael R. Irwin

  2. Cousins Center for Psychoneuroimmunology, UCLA Semel Institute for Neuroscience and Human Behaviour, Los Angeles, CA, USA

    Michael R. Irwin

  3. Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine I, University Hospital, Regensburg, Germany

    Rainer H. Straub

  4. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

    Michael T. Smith

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  1. Michael R. Irwin
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  2. Rainer H. Straub
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  3. Michael T. Smith
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All authors contributed to all aspects of the preparation of this manuscript.

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Correspondence to Michael R. Irwin.

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Nature Reviews Rheumatology thanks Filip Swirski, Monica Andersen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

C-reactive protein

(CRP). An acute phase protein that is synthesized by the liver in response to the production of IL-6 by macrophages or T cells.

Electroencephalography

(EEG). A measure that tracks the electrical activity of the brain; one use is to graphically represent stages of sleep, which are defined by differences in waveform shape, frequency and amplitude.

Electromyography

A measure that tracks the electrical activity of muscle; it can be used, together with the EEG, to define stages of sleep, such as rapid eye movement sleep, in which low muscle tone or activity is accompanied by random and rapid eye movements.

Epigenetic ageing

An estimate of biological age given by evaluating changes in DNA methylation at particular genomic locations, which is found to be more predictive of mortality risk than chronological age.

Experimental sleep disruption

Imposing a loss of sleep during the night, for either part of the night (in other words, partial night sleep deprivation) or for the entire night (in other words, total night sleep deprivation).

Glucocorticoid resistance

A state of decreased sensitivity to the anti-inflammatory effects of glucocorticoids, which can be caused by ongoing increases in inflammation as well as by a genetic predisposition.

Glucocorticoids

Neuroendocrine hormones that belong to the steroid hormone class, which suppress inflammation and antiviral immune responses, in addition to having a role in the metabolism of protein, fat and glucose.

Hypothalamic–pituitary–adrenal axis

(HPA axis). A neuroendocrine system that links the hypothalamus, pituitary and adrenal glands and functions to regulate the immune system in response to circadian signalling, behavioural states such as sleep and peripheral inflammatory signals.

Parasympathetic nervous system

A component of the autonomic nervous system that comprises nerve fibres that innervate visceral tissues to regulate actions of the body when it is at rest, mainly through the release of the neurotransmitter acetylcholine.

Rapid eye movement

(REM). A stage of sleep, also known as paradoxical sleep, that is characterized by desynchronized electroencephalogram activity in a manner similar to waking, accompanied by random and rapid movement of the eyes together with low muscle tone. REM sleep is viewed as the sleep period in which there is a propensity to dream.

REM density

A measure specific to REM sleep and refers to the number of eye movements during REM sleep, which increases throughout the night along with a reduction in the drive to sleep. In other words, REM density is higher during the circadian or sleep period with arousal, and decreased in the night following sleep deprivation, which increases the drive to sleep.

Sleep continuity

The relative distribution of uninterrupted sleep, as opposed to wakefulness, during the night, as measured by sleep efficiency and wake time after sleep onset (the amount of time spent awake after turning off the lights and initiating sleep).

Sleep duration

The amount of time spent asleep during the night, measured either by subjective report or objectively, using polysomnography or actigraphy. Short sleep duration is defined as less than the reference amount of 7 h per night and is typically characterized as being less than 6 h of sleep per night. Long sleep duration is typically characterized as being more than 8 h of sleep per night.

Sleep efficiency

Time spent asleep as a percentage of the total time spent in bed.

Sympathetic nervous system

(SNS). A component of the autonomic nervous system that comprises nerve fibres that innervate lymphoid tissues, as well as nearly all other body tissues. The SNS regulates immune cell traffic and immune responses during sleep and in response to stress through the release of noradrenaline.

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Irwin, M.R., Straub, R.H. & Smith, M.T. Heat of the night: sleep disturbance activates inflammatory mechanisms and induces pain in rheumatoid arthritis. Nat Rev Rheumatol 19, 545–559 (2023). https://doi.org/10.1038/s41584-023-00997-3

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