Sleep and Cytokines in Rheumatoid Arthritis

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The prevalence of sleep disturbance can be quite high in autoimmune disorders; for example, 50% of multiple sclerosis patients report clinically relevant sleep complaints (Fleming and Pollak 2005) as do 61% of systemic lupus patients (Tench, McCurdie, White, and D'Cruz 2000). Perhaps the highest prevalence is in rheumatoid arthritis (RA) patients, between 50 and 75% of patients complain of difficulties initiating or maintaining sleep (Drewes 1999). Fatigue is a debilitating symptom in each of these conditions, and studies show that poor sleep is significant predictor of fatigue, often more so than other disease-specific variables (Nicassio, Moxham, Schuman, and Gevirtz 2002). Although the underlying causes of sleep difficulties can include medication effects as well as chronic pain, studies with RA patients are indicating that inflammatory cytokines might be important promoters of sleep dysregulation.

RA is a chronic autoimmune disorder in which patients develop bilateral polyarticular pain. This disorder can be highly debilitating, with significant pain and fatigue early in the disease; subsequent bone resorption and possible deformation of joints, typically in the hands occur later in the disease. The etiology of the disease is unknown, but RA disease progression is driven primarily by inflammatory cytokines, including TNF, IL-1, and IL-6. Biologic agents, such as etanercept, infliximab, and humira, work by specifically neutralizing the activity of TNF, which in turn down-regulates expression of other inflammatory cytokines (Feldmann and Maini 2001). Very high levels of inflammatory cytokines are found in synovial fluid in the joints of RA patients, and systemic levels are also increased. RA patients typically show high plasma levels of IL-6, the magnitude of which correlates with subsequent disease progression; and plasma IL-6 levels decrease drastically following treatment with biologic agents (Charles et al. 1999). Thus, inflammatory cytokines that are involved in disease progression are the same cytokines that interact with sleep processes.

RA patients report frequent difficulties with sleep; polysomnography studies show that RA patients have trouble falling asleep and have poorer sleep efficiency with multiple awakenings during the night as compared to healthy controls (Hirsch et al. 1994). The sleep of RA patients also shows frequent alpha-EEG arousals during SWS (Mahowald, Mahowald, Bundlie, and Ytterberg 1989; Drewes, Svendsen, Taagholt, Bjerregard, Nielsen, and Hansen 1998). Although poor sleep is often speculated as due to nocturnal pain, the latter may not be the primary causative agent. Sleep impairments, measured via polysomnography, are found not only in RA patients experiencing a pain flare, but also in those who are not experiencing pain (Drewes et al. 1998). Furthermore, treatment with nonsteroidal anti-inflammatory medications reduced pain severity but did not improve sleep in a sample of RA patients (Lavie, Nahir, Lorber, and Scharf 1991). In turn, poor sleep may contribute to morning levels of fatigue and pain in RA (Nicassio and Wallston 1992; Drewes et al. 1998). No study to date has studied the roles of cytokines on sleep, fatigue, and pain in this population. There is a striking absence of studies examining the role of inflammatory processes in mediating these links between sleep and disease symptoms in RA patients. Such studies are needed to advance our understanding of sleep and its association with other RA symptoms.

It is known that a poor night's sleep can increase pain sensitivity the following morning. In a sample of healthy men, experimental disruption of NREM sleep over three nights induced increased pain sensitivity and muscle tenderness (Moldofsky and Scarisbrick 1976), a finding more recently replicated in healthy middle-aged women (Lentz, Landis, Rothermel, and Shaver 1999). To date, there is no study examining experimental sleep deprivation, even for brief periods of time in RA patients. However, poor sleep is associated with increased morning tenderness in the peripheral joints of RA patients who are experiencing an acute pain flare (Moldofsky, Lue, and Smythe 1983). The biological mechanisms that underlie the link between poor sleep and increases of pain and fatigue are as of yet unexplored in RA, although elevations in proinflammatory cytokine activity are implicated (Moldofsky 2001). As noted above, RA patients with poor sleep who were given a single dose of infliximab showed dramatic improvements in sleep efficiency and sleep latency immediately following administration. Furthermore, these improvements occurred before these subjects improved on clinical markers such as joint pain and swelling (Zamarron et al. 2004). This is consistent with the hypothesis of cytokine dysregulation of sleep, since the medication produces rapid decreases in inflammatory cytokines and blocks the activity of TNF.

Sleep research with RA patients provides a valuable opportunity to test relationships between sleep and cytokines, particularly because cytokines play such a major role in the severity of the disease. A variety of factors such as medication types, degree of disease progression, and the presence of depressed mood and fatigue in this population make these studies difficult. However, inclusion of cytokine assessment in these studies would provide valuable corroboration as to whether inflammatory cytokines contribute to sleep deficits seen in RA and by extension, impact pain sensitivity, fatigue, and lethargy during the day.

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