Introduction
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by persistent synovitis, autoantibody production in many patients, and progressive structural damage. In 2020, an estimated 17.6 million people worldwide were living with RA, corresponding to an age-standardized prevalence of 208.8 per 100,000; prevalence was approximately 2.45-fold higher in women than in men.1 Typical clinical manifestations include persistent joint pain, swelling, and morning stiffness (usually >30 minutes), as well as systemic symptoms such as fatigue and low-grade fever, and may progress to joint deformity and functional impairment in advanced stages. Currently, the diagnosis of RA is primarily based on the 2010 ACR/EULAR classification criteria, which comprehensively evaluate the pattern of joint involvement, serological markers such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP), as well as levels of acute-phase reactants, supplemented by imaging examinations such as ultrasound or MRI for early detection of synovitis and bone erosion.2 RA pathogenesis reflects interactions among genetic susceptibility, environmental exposures, adaptive and innate immune responses, synovial fibroblasts, and osteoclast-mediated bone erosion rather than a single linear pathway.3,4
Joint pain, morning stiffness, and systemic symptoms such as fatigue and low-grade fever caused by RA not only severely impair patients’ physical function but also significantly affect sleep architecture and quality. In the RA literature, sleep disturbance is an umbrella term rather than a single diagnosis. It encompasses diagnosed disorders—most commonly insomnia disorder, obstructive sleep apnea (OSA), restless legs syndrome (RLS), and circadian rhythm sleep–wake disorders—as well as transdiagnostic features such as poor subjective sleep quality, short or irregular sleep duration, prolonged sleep latency, frequent awakenings, increased wake after sleep onset, low sleep efficiency, non-restorative sleep, and daytime sleepiness.5,6 Across heterogeneous cohorts and syntheses, clinically important poor or disturbed sleep is reported by roughly one-half to two-thirds of patients with RA, although estimates vary with case definition, instrument, disease activity, and comorbidity.7–9
Specific disorders require phenotype-aware interpretation. OSA and RLS have been reported more often in RA than in comparison populations, but obesity, age, sex, medication exposure, pain, and ascertainment method may confound estimates.10 A meta-analysis of eight RA studies estimated OSA prevalence at 29.8%, with extreme between-study heterogeneity and a mixture of screening and diagnostic approaches.11 In a recent non-RA sleep-clinic study, computed-tomography-derived lung volumes were correlated with one another but did not independently predict OSA severity; age and body mass index remained significant predictors.12 This finding argues against inferring OSA severity from lung morphology alone and supports standard clinical risk assessment and objective sleep testing when OSA is suspected in RA.
RA and specific sleep disorders have formed a mutually reinforcing pathophysiological network that requires systematic recognition and intervention in clinical management. Previous reviews have summarized sleep disorders across connective-tissue diseases, described sleep problems in inflammatory arthritis, or focused on the sleep–inflammation–pain axis.13–15 The present review adds a phenotype-based and explicitly bidirectional framework that integrates diagnosed disorders with non-diagnostic sleep features, compares the strength and limitations of human and experimental evidence across immune, circadian, neuroendocrine, and pain pathways, and links these mechanisms to practical assessment and treatment priorities. We therefore examine how RA may disturb sleep, how sleep loss or fragmentation may amplify inflammation and pain, where the proposed pathways interact, and which conclusions are sufficiently supported to influence clinical care.
Literature Search and Scope
A PubMed-only search was conducted for records published from database inception through September 15, 2026, using the query “((Rheumatoid Arthritis[Title/Abstract]) AND ((Sleep Disorders[Title/Abstract]) OR (Insomnia[Title/Abstract])))”, restricted to English-language publications. The search retrieved 176 unique records. No duplicates were identified by PMID, and all 176 records underwent title and abstract screening.
Studies and relevant reviews were retained if they provided clinical, risk, interventional, measurement, or mechanistic evidence directly linking rheumatoid arthritis (RA) with sleep disorders or insomnia. Records were excluded if they were unrelated to the review question, lacked RA-specific results, treated sleep only as background or an incidental variable, were protocols without results, case reports, or non-substantive publications, or reported inseparable mixed-disease data. Ninety-four records were excluded, and 82 publications were retained for the narrative synthesis.
Because this was a narrative rather than systematic review, no meta-analysis or formal risk-of-bias instrument was applied.
The Bidirectional Vicious Cycle Mechanism Between RA and Sleep Disturbances
A Self-Reinforcing Vicious Cycle
There is a complex bidirectional interaction between RA and sleep disturbances, forming a self-reinforcing vicious cycle. On the one hand, the chronic systemic inflammatory state and high disease activity associated with RA can significantly disrupt sleep architecture and quality. On the other hand, sleep disturbances themselves may act as independent risk factors that promote the onset, progression, and exacerbation of RA.6,16 Clinical studies consistently indicate that sleep disturbances in patients with RA, particularly insomnia and sleep fragmentation, are closely associated with disease activity.
For example, poor sleep quality is significantly associated with higher Disease Activity Score in 28 joints (DAS28-ESR), increased subjective fatigue, and impaired physical function.17,18 Among patients experiencing aggravated pain and fatigue, sleep problems are particularly prominent and often manifest as difficulty falling asleep, frequent nocturnal awakenings, and a lack of restorative feeling upon waking.8,19 Consistent with these observations, a 30-day mobile health (mHealth) study involving 254 patients found that subjective sleep measures predicted health-related quality of life, although several associations were attenuated after adjustment for pain, fatigue, and mood. Greater day-to-day variability in self-reported total sleep time remained associated with poorer physical and psychological quality of life, whereas actigraphy-derived sleep measures showed no consistent associations.20 These findings underscore the clinical relevance of perceived sleep disturbance while also indicating that its effects are partly intertwined with pain, fatigue, and emotional symptoms. In addition, psychological comorbidities such as depression and anxiety are prevalent among RA patients, and these emotional disorders not only coexist with sleep disturbances but also further amplify inflammatory responses and pain perception through neuroendocrine and immune pathways, thereby jointly impairing patients’ quality of life.13,21
From a mechanistic perspective, sleep disturbances can activate and amplify inflammatory responses through multiple pathways, thereby exacerbating RA disease severity. Experimental and clinical evidence shows that sleep deprivation or disrupted sleep architecture can elevate levels of pro-inflammatory cytokines (such as IL-6, TNF-α, and C-reactive protein) and activate key inflammatory signaling pathways such as NF-κB, thereby increasing peripheral and central pain sensitivity and enhancing overall disease activity.14 Notably, this inflammation–sleep interaction may extend to long-term complications, as patients with RA combined with sleep disturbances exhibit a significantly increased risk of cardiovascular disease, suggesting that sleep problems represent not only a symptomatic burden but also a key mediator influencing long-term prognosis.22
Mechanisms by Which Inflammation Drives Sleep Disturbances
Transmission of Peripheral Inflammatory Signals to the Central Nervous System
Persistently elevated peripheral pro-inflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, and TNF-α, not only act locally on joints but can also transmit inflammatory signals to the central nervous system (CNS) through multiple pathways, thereby influencing sleep regulation, emotional state, and pain perception. This process mainly relies on three mechanisms: the vagal nerve pathway, active and passive transport across the blood–brain barrier, and migration of immune cells. These routes are well described in general neuroimmunology; their relative contributions in human RA remain uncertain.
The vagus nerve, an important parasympathetic pathway connecting peripheral organs with the brainstem, has afferent fiber endings widely distributed in immune-cell-rich tissues such as the liver and gastrointestinal tract. Peripheral inflammatory cytokines, particularly IL-1β, can activate receptors such as IL-1R1 on vagal afferent fibers, transmitting signals to the nucleus tractus solitarius (NTS), which subsequently projects to brain regions including the hypothalamus, amygdala, and locus coeruleus, thereby triggering neurobehavioral responses such as fever, appetite suppression, and alterations in sleep architecture. For example, once transmitted to the central nervous system via the vagus nerve, IL-1β can modulate the hypothalamic thermoregulatory center to induce fever and also influence emotional and anxiety responses through the amygdala.
Animal experiments have shown that vagotomy significantly weakens the influence of peripheral inflammation on the central nervous system, confirming the key role of the vagus nerve in inflammation–brain communication.23,24
Although the blood–brain barrier (BBB) is highly selective, its permeability may undergo dynamic changes under systemic inflammatory conditions. Cytokines such as IL-1α, IL-1β, TNF-α, and IL-6 can enter the brain parenchyma through specific and saturable carrier-mediated transport mechanisms.25 In addition, in circumventricular organs (CVOs) lacking a typical vascular blood–brain barrier, such as the organum vasculosum of the lamina terminalis (OVLT), circulating cytokines can bypass endothelial tight junctions and directly interact with the brain parenchyma or adjacent regions. These regions form an alternative barrier through ependymal cells or tanycytes, creating a regulatory interface that enables peripheral inflammatory signals to be sensed by the central nervous system and triggers downstream neuroendocrine and behavioral responses such as fever, somnolence, and reduced appetite.
Even if cytokines do not directly enter the brain parenchyma, they can bind to receptors (such as IL-1R) on the luminal side of brain microvascular endothelial cells, inducing the synthesis and release of second messengers such as prostaglandin E2 (PGE2), which then diffuse into the brain parenchyma and activate nearby neurons, thereby mediating central responses such as fever and sleep alterations.26
Under conditions of chronic inflammation, peripherally activated immune cells such as monocytes and T lymphocytes express specific adhesion molecules (eg, VLA-4 and LFA-1), enabling them to migrate across the blood–brain barrier into the meninges, choroid plexus, and even the brain parenchyma.27 These infiltrating immune cells release pro-inflammatory cytokines within the central nervous system, continuously activating microglia and promoting the production of additional inflammatory mediators in local regions, thereby maintaining a neuroinflammatory microenvironment. For example, elevated levels of IL-6 and TNF-α are frequently detected in the cerebrospinal fluid of patients with RA, suggesting that peripheral immune cells play an important role in maintaining central inflammation.28 In addition, epigenetic reprogramming of monocytes (referred to as “trained immunity”) enables them to exhibit enhanced pro-inflammatory potential after entering the central nervous system, which may further exacerbate neuroimmune dysregulation.29
Central Nervous System Responses and “Sickness Behavior”
Under normal conditions, serotonin (5-HT) participates in sleep–wake regulation, emotional stability, and behavioral motivation. Inflammatory cytokines can influence tryptophan metabolism, directing it toward the kynurenine pathway rather than 5-HT synthesis, thereby reducing central 5-HT availability, which is closely associated with depressive-like behaviors (such as social withdrawal and reduced energy) and sleep disturbances. In addition, inflammation may downregulate the expression or function of 5-HT receptors (such as 5-HT1A and 5-HT2A), thereby altering slow-wave sleep generation and REM sleep regulation, resulting in reduced N3 (deep slow-wave) sleep and disrupted REM sleep architecture.
Both clinical and animal studies have confirmed that under inflammatory conditions, abnormal 5-HT metabolism is positively associated with sleep disturbances and increased fatigue.30,31 Most receptor- and circuit-specific evidence, however, comes from animal models or non-RA populations; changes in a particular serotonin receptor or dopamine circuit should not be assumed in an individual patient with RA. Dopamine is an important regulator of wakefulness and motivational behavior. Chronic inflammation influences dopamine (DA) metabolism, DA receptor expression, and the function of the nigrostriatal pathway through cytokine signaling, commonly resulting in reduced DA-D2 receptor expression and decreased dopamine availability.
These alterations are associated with behavioral slowing, increased fatigue, and reduced social interest, while in terms of sleep they manifest as impaired maintenance of wakefulness, leading to sleep fragmentation (frequent awakenings) and dysregulation of REM sleep. Inflammatory cytokines can also indirectly inhibit dopaminergic neuronal activity by activating microglia to release signaling molecules such as nitric oxide (NO) and PGE2, thereby further disrupting the sleep–wake rhythm.32
Normal sleep consists of two major stages, NREM and REM, among which N3 slow-wave sleep (SWS) is closely associated with energy restoration, synaptic homeostasis, and immune regulation. Substantial evidence suggests that inflammatory mediators exert a dose- and duration-dependent biphasic effect on sleep. During acute inflammation at low to moderate levels, pro-inflammatory cytokines such as IL-1β and TNF-α may exhibit sleep-promoting effects, increasing NREM or slow-wave activity.
However, when inflammation becomes persistent or reaches higher levels, this regulation shifts from sleep promotion to sleep disruption, characterized by reduced sleep continuity, increased sleep fragmentation, and impaired slow-wave activity quality. Clinically, this may manifest as a reduced proportion of N3 sleep (deep sleep) and decreased subjective sleep quality.33,34 Regarding REM sleep, its generation and maintenance depend on multi-nodal circuits involving the brainstem and hypothalamus, with the pontine–medullary circuitry playing a crucial role in REM initiation and homeostatic regulation.35,36 Under inflammatory conditions, peripheral and central inflammatory signals can alter neuronal excitability and network coupling through mediators such as cytokines and prostaglandins, thereby disrupting the homeostatic regulation and temporal distribution of REM sleep. Clinical and experimental studies commonly report prolonged REM latency, REM fragmentation, and abnormal REM proportion or density, although the direction of change may vary across diseases and models.37 It should be emphasized that these alterations in sleep architecture do not occur in isolation.
Sleep disruption itself can further activate inflammatory pathways and amplify pro-inflammatory signaling, thereby increasing pain sensitivity, negative emotional states, and fatigue, forming a vicious cycle of “inflammation–sleep–symptom burden”.38
Inflammation-induced “sickness behavior” represents a relatively conserved adaptive response characterized by fatigue, reduced activity, anhedonia or decreased motivation, and social withdrawal. Recent mechanistic studies suggest that inflammatory signals can directly reconfigure social behavior through specific neural circuits. For example, recent studies demonstrate that inflammation-related IL-1β signaling can act on specific IL-1R1-positive neurons in the dorsal raphe nucleus, driving behavioral outputs resembling self-isolation or social avoidance, thereby providing clearer circuit-level evidence for the link between inflammation and social withdrawal.39 In the reward–motivation dimension, increasing human neuroimaging and translational studies indicate that a high inflammatory phenotype is associated with reduced functional connectivity in cortico-striatal reward circuits and dopamine-related abnormalities in reward processing, thereby promoting anhedonia and reduced motivation.
Some studies further suggest that anti-inflammatory interventions or dopaminergic modulation may influence this pathway.40,41 Impairment of these motivation/reward circuits may further reduce daytime activity and social engagement and may worsen sleep architecture and subjective sleep experience through behavioral pathways such as reduced activity and circadian rhythm disruption. In addition, a bidirectional coupling exists between inflammation and the HPA axis. Pro-inflammatory cytokines can influence HPA axis reactivity and feedback regulation, potentially leading to long-term dysregulation of the stress system.
Chronic insomnia or sleep deprivation is also associated with abnormal HPA axis activity, such as altered cortisol rhythms or levels in some individuals.42,43 Therefore, in chronic inflammation-related diseases, inflammatory mediators and the HPA axis jointly act on the limbic system and prefrontal–striatal networks, potentially contributing to the co-occurrence and mutual maintenance of fatigue, emotional symptoms, and sleep–wake rhythm disturbances.
Circadian Rhythm Disruption
Circadian rhythms are integratively regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, which functions as the “master biological clock” and coordinates clock gene expression in peripheral tissues through neural and humoral signals, thereby maintaining sleep–wake rhythms, hormonal secretion rhythms, and immune homeostasis. In patients with RA, persistent inflammation not only alters immune system function but also disrupts the central circadian rhythm system, thereby aggravating disturbances in sleep architecture.
The circadian rhythm system and immune–inflammatory pathways exhibit profound bidirectional regulatory interactions. Core clock proteins (such as CLOCK and REV-ERBα) can directly bind to promoter regions of inflammation-related genes and regulate their transcription. Conversely, inflammatory signaling pathways such as NF-κB can in turn influence the expression of clock genes, forming complex feedback loops.33,44 Recent studies indicate that inflammation can directly modulate the firing rhythms of SCN neurons and their responsiveness to light signals, thereby weakening the central biological clock’s synchronization of peripheral immune rhythms.
In healthy individuals, IL-6 exhibits a pronounced circadian rhythm, with plasma concentrations typically peaking from late night to early morning. Slow-wave sleep (SWS) exerts an inhibitory effect on the production of pro-inflammatory cytokines such as IL-6. In chronic inflammatory conditions such as RA, persistently elevated inflammatory burden forms a vicious cycle with sleep disturbances.
On the one hand, disease activity leads to sleep fragmentation and reduced sleep efficiency. On the other hand, reduced sleep quality may weaken the physiological inhibitory effect of sleep on inflammation, thereby further aggravating inflammatory responses.45 In addition, during chronic inflammatory states, microglia—the resident immune cells of the central nervous system—become activated and release pro-inflammatory cytokines (such as IL-1β) and mediators such as PGE2. These molecules alter the excitability of neural circuits surrounding the SCN in the hypothalamus, further disrupting neuronal firing rhythms, leading to circadian phase shifts and reduced rhythm amplitude.
Consequently, this circadian dysregulation exacerbates disturbances in the sleep–wake cycle and may promote the progression of related pathologies.46 Therefore, inflammation-driven circadian clock dysfunction represents an important central mechanism underlying sleep disorders in RA.
Under normal physiological conditions, the HPA axis exhibits a pronounced circadian rhythm, characterized by elevated cortisol levels in the early morning and reduced levels at night, thereby exerting anti-inflammatory effects and maintaining wakefulness. However, in patients with RA, despite an increased inflammatory burden at night, cortisol secretion often appears relatively insufficient or phase-delayed, resulting in a circadian mismatch between inflammation and anti-inflammatory hormones.47 Clinical studies have found that IL-6 levels in RA patients peak during the early morning hours, while the cortisol peak is insufficient to suppress this inflammatory surge, resulting in the most pronounced joint inflammation in the morning.48 This circadian imbalance between an “inflammatory peak and insufficient cortisol response” is considered an important mechanistic basis for morning stiffness in RA. Studies have revealed that sustained sleep deprivation (eg, reducing sleep to approximately 4.3 hours for several consecutive nights) can significantly elevate peripheral blood levels of IL-6 and CRP and may increase pain sensitivity.49 These findings suggest that insufficient sleep itself represents a pro-inflammatory state.
Although the study did not directly assess the effects of inflammation on sleep architecture, other evidence suggests that in chronic inflammatory diseases such as RA, elevated nocturnal inflammatory burden can disrupt slow-wave sleep stability and inhibit the normal transition of REM sleep. As a result, patients experience worsened joint stiffness and pain upon awakening, accompanied by impaired restorative sleep function, thereby forming a vicious cycle of “inflammation–sleep disturbance–symptom exacerbation.” (Figure 1). Figure 1Bidirectional vicious cycle between rheumatoid arthritis (RA) and sleep disturbances.
Rheumatoid arthritis (RA)-associated pain, stiffness, fatigue, functional impairment, and systemic inflammation can disrupt sleep through peripheral-to-central inflammatory signaling and altered neuroendocrine and neurotransmitter regulation. Conversely, insufficient or fragmented sleep may amplify pro-inflammatory signaling, pain sensitivity, and hypothalamic–pituitary–adrenal axis dysregulation, thereby worsening RA symptoms and disease activity. Depression and anxiety may further strengthen this cycle, whereas sleep-targeted interventions may help reduce symptom burden.
The symbol “↑” indicates an increase; all arrows and labels denote proposed or associated pathways rather than established causal effects in RA. Created with BioRender.com.Cycle diagram titled, Bidirectional vicious cycle mechanism between rheumatoid arthritis left parenthesis RA right parenthesis and sleep disturbances. Top left heading reads, Rheumatoid arthritis.
A large circle lists: Chronic systemic inflammation; Joint pain and stiffness; Physical function impairment; Fatigue; Pro-inflammatory cytokines; Immune cell migration. Text near an arrow reads, Peripheral inflammatory signals to the CNS, with a label, BBB. Near the top center, text reads, Central nervous system.
A curved arrow across the top reads, RA affects sleep. A box near the top right lists: Disrupted sleep regulation; Altered tryptophan dopamine metabolism; Reduced 5-HT dopamine availability; Disrupted sleep-wake cycle. Top right heading reads, sleep disturbances.
A large circle lists: Insomnia; Circadian rhythm disruption; Poor sleep quality. Inside the same circle, text reads: Exacerbated inflammatory response; Increased pain sensitivity; Increased cardiovascular risk; HPA axis dysfunction. Center text reads, Bidirectional vicious cycle.
Bottom center text reads: Inflammatory pathway activation; rising to Pain sensitivity; Worsened morning stiffness; RA progression. A small label nearby reads, NF-kB. Bottom left box heading reads, Depression and anxiety disorders, with text: Amplified inflammation and pain perception, reduced quality of life.
Bottom right box heading reads, Interventions, with text: Improved sleep quality; Regulation of immune and neuroendocrine networks; Reduced inflammatory burden. A large curved arrow along the bottom reads, Sleep disturbances worsen RA.A cycle diagram of rheumatoid arthritis and sleep disturbances with symptoms, pathways and interventions.Abbreviations: 5-HT, 5-hydroxytryptamine; BBB, blood–brain barrier; CNS, central nervous system; HPA, hypothalamic–pituitary–adrenal; NF-κB, nuclear factor kappa B.
Mechanisms by Which Sleep Disturbances Exacerbate Inflammation and Pain
Loss of the Regulatory Role of Sleep in Immune Homeostasis
Normal sleep is an essential physiological process for maintaining immune homeostasis and inflammatory balance, as it suppresses excessive pro-inflammatory signaling and promotes nocturnal immune recovery and regulation. Sleep helps suppress pro-inflammatory pathway activity while enhancing anti-inflammatory signaling and immune tolerance, thereby maintaining balanced responses to internal and external stimuli. During sleep, the functions of immune cells such as T cells and natural killer cells are optimized, and the expression of pro-inflammatory cytokines is rhythmically regulated, thereby reducing unnecessary inflammatory output.34
However, sleep deprivation, sleep fragmentation, or chronic sleep insufficiency can disrupt this homeostatic mechanism, leading to markedly elevated levels of peripheral pro-inflammatory cytokines. Sleep deprivation or fragmentation (including continuous sleep loss) has been confirmed by systematic reviews to be significantly associated with elevated circulating inflammatory markers such as IL-6 and CRP, suggesting that insufficient sleep itself can activate inflammatory responses.49 Animal studies have shown that long-term sleep deprivation in mice results in significant increases in circulating pro-inflammatory cytokines (such as IL-6 and IL-17A) and chemokines, accompanied by the mobilization of neutrophils and other inflammatory cells, indicating that sleep loss can induce pronounced inflammatory responses.50 The elevation of these inflammatory markers not only reflects systemic inflammatory activation but also indicates that immune homeostasis is shifting toward a pro-inflammatory state.
At the molecular level, sleep deprivation can activate several canonical inflammatory transcription pathways, including NF-κB, JAK/STAT, MAPK, and AP-1 signaling cascades, which are key regulatory nodes for pro-inflammatory gene expression. Experimental sleep deprivation models show that activation of these pathways is accompanied by increased mRNA expression of pro-inflammatory cytokines, enhanced monocyte responsiveness to TLR4 stimulation, and increased secretion of IL-6 and TNF-α.51 Meanwhile, sleep deprivation is also associated with reduced endogenous melatonin production, and insufficient melatonin may further release the inhibitory control over inflammatory pathways such as NF-κB, thereby enhancing inflammatory responses.52
This inflammatory activation is not limited to the peripheral circulation but is also evident in the CNS and peripheral immune organs. For example, in mouse models of prolonged sleep deprivation, peripheral pro-inflammatory cytokines rapidly accumulate and drive neutrophil mobilization and inflammatory responses, resembling a cytokine storm–like pathological state.50,53 Moreover, insufficient sleep may affect hematopoietic function and promote epigenetic reprogramming of immune cells, leading monocytes and macrophages to exhibit a pro-inflammatory phenotype associated with “trained immunity” under chronic inflammatory conditions. Once established, this phenotype may enhance the body’s exaggerated responsiveness to inflammatory stimuli and persist even after sleep recovery, thereby further increasing the inflammatory burden.
Furthermore, insufficient sleep not only impairs the role of sleep in maintaining immune homeostasis but also alters the functional phenotype of immune cells. Trained immunity is a form of innate immune memory driven by metabolic and epigenetic reprogramming. It is primarily manifested in monocytes and macrophages as an enhanced inflammatory response to secondary heterologous stimuli.
Its essence lies in epigenetic modifications that promote pro-inflammatory gene expression.54 Although direct evidence is still lacking that sleep deprivation can chronically trigger trained immunity. Clinical studies have demonstrated that sleep deprivation significantly alters the distribution of circulating monocyte subsets and induces a more pro-inflammatory expression pattern (eg, increased non-classical monocytes). These alterations are associated with upregulated systemic inflammatory signaling and may reflect rapid reprogramming of immune cells toward a pro-inflammatory phenotype.55 If this pro-inflammatory immune remodeling persists under chronic inflammatory conditions, it may exacerbate the body’s exaggerated responses to inflammatory stimuli and maintain an increased inflammatory burden even after sleep recovery.
Dysregulation of the Neuroendocrine System
The hypothalamic–pituitary–adrenal (HPA) axis is a core neuroendocrine pathway responsible for responding to physiological stress and maintaining homeostasis, regulating the secretion of hypothalamic corticotropin-releasing hormone (CRH), pituitary adrenocorticotropic hormone (ACTH), and adrenal glucocorticoids such as cortisol. Normal sleep stabilizes the circadian rhythm of cortisol by suppressing baseline activation of the HPA axis, whereas sleep fragmentation, chronic sleep insufficiency, or persistent insomnia can lead to increased HPA axis reactivity, disrupted cortisol rhythms, and reduced glucocorticoid receptor sensitivity. This condition is characterized by relative resistance to glucocorticoid-mediated negative feedback regulation, weakening the anti-inflammatory effects of glucocorticoids and allowing pro-inflammatory signaling to remain insufficiently suppressed, thereby sustaining inflammatory processes.
For instance, research has shown that chronic stress may impair HPA axis feedback regulation and induce glucocorticoid receptor resistance, resulting in abnormal cortisol rhythmicity and persistent pro-inflammatory states, a phenomenon especially prominent in chronic inflammatory and autoimmune disorders such as rheumatoid arthritis.56 Furthermore, sleep fragmentation, sleep deprivation, and chronic insomnia may increase HPA axis reactivity and alter cortisol secretion patterns, including elevated cortisol levels during the early morning and nighttime, indicating that impaired HPA axis negative feedback regulation is frequently observed in sleep disorders and may contribute to sustained inflammatory activity.
The sympathetic nervous system (SNS), a key component of the autonomic nervous system, cooperates with the HPA axis in the regulation of physiological stress responses. During sleep insufficiency or disrupted sleep structure, SNS activity becomes persistently elevated and hyperactive, characterized by increased basal norepinephrine levels and decreased heart rate variability. Clinical and experimental studies show that individuals with sleep disturbances frequently display elevated sympathetic tone and enhanced stress reactivity, which are linked to increased cardiovascular risk and indicate a significant role of the SNS in modulating inflammatory responses.
In chronic inflammatory states, SNS regulation of immune cells may gradually shift from a relatively anti-inflammatory profile toward a pro-inflammatory one, promoting the release of inflammatory mediators such as TNF-α and IL-6 and contributing to persistent inflammatory activation.57
The locus coeruleus (LC) is the principal brainstem source of norepinephrine and is normally most active during wakefulness and relatively quiet during NREM and REM sleep. General insomnia neurobiology and experimental animal studies implicate excessive LC–noradrenergic activity in hyperarousal, microarousals, sleep fragmentation, and REM suppression.58–61 This evidence supports a plausible arousal mechanism, but whether sustained LC activation occurs specifically in RA or directly drives RA inflammation has not been established.
Pain Facilitation and Central Sensitization
Sleep disturbances can enhance subjective responses to experimental pain stimuli, manifested as increased ratings of suprathreshold heat pain and cold pressor pain, a phenomenon validated in multiple sleep restriction models. However, this increase in pain sensitivity may not depend on classical pro-inflammatory cytokines in peripheral circulation, such as TNF-α and IL-8. Systematic reviews continue to support an association between sleep disturbances and pain facilitation, although the mechanisms may involve central sensitization or dysregulation of neural modulation rather than purely peripheral inflammatory drivers.62
Sleep disturbances can also enhance pain facilitation processes while weakening endogenous pain inhibitory capacity. Clinical studies show that compared with normal sleep, individuals with fragmented or insufficient sleep exhibit enhanced temporal summation of pain, indicating faster accumulation of central pain responses to repeated stimuli. At the same time, multiple studies have reported impaired conditioned pain modulation (CPM), indicating reduced efficiency of endogenous pain inhibitory systems.
This means that the body is less able to utilize the intrinsic mechanism of “pain inhibiting pain” to buffer nociceptive experiences when encountering painful stimuli.63 These manifestations of central sensitization are closely associated with increased inflammation related to sleep disturbances, neuroplastic changes in the nervous system, and interactions between cognitive and emotional factors, collectively contributing to sustained increases in pain sensitivity (Figure 2). Figure 2Mechanisms by which sleep disturbances exacerbate inflammation and pain in rheumatoid arthritis (RA). Candidate mechanisms linking sleep disturbances to inflammation and pain amplification in rheumatoid arthritis.
Sleep loss and fragmentation disturb immune and circadian homeostasis and are associated with altered T-cell and natural killer-cell function, monocyte Toll-like receptor 4 responsiveness, pro-inflammatory cytokine production, intracellular inflammatory signaling, and melatonin secretion. In parallel, sleep disturbances can dysregulate hypothalamic–pituitary–adrenal axis and sympathetic/locus coeruleus–noradrenergic activity, alter cortisol rhythms, sustain hyperarousal, and weaken anti-inflammatory control. These immune and neuroendocrine changes may increase peripheral nociceptive input, impair endogenous pain inhibition, and promote central sensitization, thereby increasing pain sensitivity.
The symbol “↑” and red upward arrows indicate increases or upregulation, whereas blue downward arrows indicate decreases or downregulation; all other arrows denote proposed directional relationships between candidate mechanisms rather than inevitable or RA-specific causal effects. Created with BioRender.com.A) Disruption of immune homeostasis. Left side labeled, Normal sleep, shows a balance scale above labels, T cell and, NK cell, leading to, Circadian regulation and then to, Inflammatory homeostasis.
Right side labeled, Sleep deprivation slash fragmentation, shows an unbalanced scale and the text, up arrow Pro inflammatory cytokines, feeding into four labeled pathways, NF kappa B, JAK slash STAT, MAPK and, AP 1. Below are labels, Monocytes and, TLR4, with an up arrow next to TLR4. A clock icon is shown above the text, Melatonin production, with a downward arrow.
B) Neuroendocrine system dysregulation. Left subsection titled, Hypothalamic minus Pituitary minus Adrenal axis, shows brain to adrenal icons with the text, Insufficient sleep and, up arrow HPA axis. Downward arrows lead to, Glucocorticoid resistance and, Disrupted cortisol rhythm, then to, Anti inflammatory effects, with a downward arrow and then to, Persistent inflammation, with an upward arrow nearby.
Right subsection titled, Sympathetic nervous system left parenthesis SNS right parenthesis, includes the label, Sleep disturbance and a box listing, Sustained SNS activation, Hyperarousal and, up arrow Norepinephrine. Nearby text shows, TNF alpha and, IL 6, each with an up arrow. A dashed divider separates a lower area labeled, Locus coeruleus, with a box listing, LC neuron hyperactivity, Hyperarousal and, REM suppression.
At the bottom are labels, Anxiety and, Pain sensitivity, connected by arrows. C) Increased pain sensitivity left parenthesis central sensitization right parenthesis. The top shows labels, Central nervous system and, Sleep disturbance.
Arrows lead to a cluster labeled, Peripheral inflammation minus driven and to a human body silhouette with highlighted regions. Text near the arrow to the silhouette reads, Central sensitization slash neuroregulatory imbalance.A three part diagram linking sleep disturbance with immune disruption, neuroendocrine dysregulation and pain.Abbreviations: AP-1, activator protein 1; HPA, hypothalamic–pituitary–adrenal; JAK/STAT, Janus kinase/signal transducer and activator of transcription; LC, locus coeruleus; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa B; NK, natural killer; RA, rheumatoid arthritis; REM, rapid eye movement; SNS, sympathetic nervous system; TLR4, Toll-like receptor 4.
Therapeutic Implications
Treat-to-target control of RA may improve sleep indirectly by reducing inflammation, pain, stiffness, and fatigue. Cytokine-blocking studies provide suggestive but inconclusive support for an inflammation–sleep pathway in RA. TNF-α and IL-1β also regulate physiological NREM sleep; thus, any benefit may reflect normalization of dysregulated signaling rather than a simple cytokine-lowering effect.64,65 Small studies of infliximab, etanercept, other anti-TNF agents, and tocilizumab reported improvements in subjective sleep or sleep efficiency, but objective findings were inconsistent.66–70 In larger studies, certolizumab improved a secondary patient-reported sleep outcome that correlated with disease activity, whereas anti-TNF use was not associated with better sleep scores in a large cross-sectional cohort.71,72 Therefore, current evidence cannot distinguish direct sleep effects from improvements mediated by reduced inflammation, pain, fatigue, mood symptoms, or disability.
Cytokine inhibitors should be used for established RA indications rather than as primary insomnia therapy. Future trials should include both subjective and objective sleep outcomes.
Sleep management should begin with phenotype-specific assessment rather than a single global sleep score. Clinicians should ask about sleep timing, latency, awakenings, snoring or witnessed apneas, restless legs symptoms, daytime sleepiness, mood, analgesics, glucocorticoids, and sedatives; objective testing is appropriate when OSA, periodic limb movements, or another sleep disorder is suspected. Cognitive behavioral therapy for insomnia (CBT-I) remains first-line for chronic insomnia and is being adapted for RA, but it is only one component of care.15,73 Other actions include positive-airway-pressure therapy for confirmed OSA, evaluation and correction of iron deficiency in RLS when indicated, circadian scheduling and morning light for selected rhythm problems, graded daytime activity, mood treatment, medication-timing review, and coordinated pain rehabilitation.
Sleep outcomes should be reassessed even when RA disease activity improves.
Interactions, Modifiers, and Strength of Evidence
Pain catastrophizing, depression, anxiety, reduced activity, and social stress can reinforce the sleep–pain cycle. Evidence from chronic-pain populations, including cohorts outside RA, suggests that catastrophizing can intensify the association between pain and insomnia and that sleep may partially mediate links between depression and chronic pain.74,75 Female sex, older age, body mass index, and unhealthy sleep patterns can also confound or modify observed associations.12,76 RA susceptibility is strongly polygenic, but direct evidence for shared genetic variants that jointly determine RA and sleep comorbidity remains limited.77
The evidence hierarchy is uneven. The most compelling human evidence consists of replicated cross-sectional associations, meta-analytic evidence for disturbed sleep and inflammation, prospective data linking subjective sleep variability with quality of life, and experimental evidence that short-term sleep restriction can increase pain. The next tier comprises small, frequently uncontrolled treatment studies in which sleep is a secondary outcome and may improve because RA activity, pain, or fatigue improves.
The least certain tier includes specific BBB-trafficking, trained-immunity, microglial, neurotransmitter-receptor, and LC pathways extrapolated from non-RA or animal studies. Mechanisms probably interact: inflammation can alter arousal and circadian timing; poor sleep can increase sympathetic activity and pain; and pain and mood can feed back on both sleep and inflammatory appraisal. This network model is biologically coherent, but it does not establish that every pathway is active in every patient.
Limitations
Current evidence has important limitations. Most RA studies are cross-sectional, use heterogeneous questionnaires or screening thresholds, and cannot separate cause from confounding by pain, fatigue, mood, obesity, medications, or disease activity. Longitudinal and interventional studies with objective sleep measures are scarce.
Many cellular and neural pathways are supported primarily by acute sleep-deprivation experiments, non-RA populations, or animal models, and existing treatment studies are small or treat sleep as a secondary outcome.
Conclusions and Perspectives
Sleep management should begin with phenotype-specific assessment rather than a single global sleep score. Clinicians should ask about sleep timing, latency, awakenings, snoring or witnessed apneas, restless legs symptoms, daytime sleepiness, mood, analgesics, glucocorticoids, and sedatives; objective testing is appropriate when OSA, periodic limb movements, or another sleep disorder is suspected. Cognitive behavioral therapy for insomnia (CBT-I) remains first-line for chronic insomnia and is being adapted for RA, but it is only one component of care.
Other actions include positive-airway-pressure therapy for confirmed OSA, evaluation and correction of iron deficiency in RLS when indicated, circadian scheduling and morning light for selected rhythm problems, graded daytime activity, mood treatment, medication-timing review, and coordinated pain rehabilitation.15,73 Sleep outcomes should be reassessed even when RA disease activity improves.
RA and sleep disturbances form a clinically important reciprocal network involving symptoms, behavior, inflammation, circadian timing, neuroendocrine regulation, and pain processing. The added value of this review over earlier broad summaries is its separation of diagnosed sleep disorders from transdiagnostic sleep features, explicit ranking of evidence strength, integration of subjective and objective sleep findings, and translation of the bidirectional model into phenotype-specific clinical decisions.
For clinical care, sleep should be assessed routinely as a multidimensional patient-important outcome. RA activity and pain should be optimized while insomnia, OSA, RLS, circadian disturbance, and mood disorders are evaluated and treated on their own merits. Future studies should use repeated patient-reported measures together with actigraphy or polysomnography, prespecify sleep endpoints in RA treatment trials, test whether sleep-directed interventions alter pain or inflammatory outcomes, and stratify by sleep phenotype, sex, age, adiposity, mood, medication, and disease activity.
These designs are needed to determine which links in the proposed cycle are causal and clinically modifiable.