Interrelationship Between Depression, Sleep, and RA
Sleep disturbance is thought to contribute to pain, fatigue, and depressed mood in patients with RA, and a number of studies show that subjective sleep complaints correlate with fatigue, functional disability, greater joint pain, and more depressive symptoms in these patients.8
Indeed, sleep difficulties, pain, depressed mood, and fatigue appear to cluster in RA; depression is associated with greater pain, whereas sleep difficulties are associated with fatigue, depression, and pain.3,9,10
The relationship between sleep disturbance and other symptoms is complex (Figure
). For example, sleep disturbance may be a symptom of depression or it may precipitate feelings of depression because it interferes with normal activities. Alternately, both sleep disturbance and depression may be manifestations of an underlying biological disturbance. To date, research on RA “sickness symptoms” has been primarily descriptive and cross-sectional, which has limited conclusions about how disordered sleep may influence and be influenced by other symptoms.
Prospective or experimental studies that simultaneously assess multiple symptoms using state-of-the-art measurement techniques are needed to advance our understanding of sleep and its association with other RA symptoms. Nevertheless, some data suggest that sleep disturbance makes a unique contribution to symptomatic pain in RA. One study showed that poor sleep is temporally associated with an overnight increase in tenderness in the peripheral joints in patients with RA who are experiencing an acute flare-up.11
On the other hand, noxious stimuli and pain are thought to interfere with sleep.8
Indeed, Nicassio and colleagues12
found that pain leads to subjective complaints of poor sleep, which, in turn, contributes to fatigue and depressive symptoms in patients with RA. However, Drewes and colleagues10
report that sleep is similarly disrupted in patients with RA with and without an active pain flare-up, which suggests that factors other than pain may cause disordered sleep in patients with RA.
Animal models, cell culture data, and anti-inflammatory cytokine antagonist treatments provide converging evidence that dysregulation of the proinflammatory cytokine network underlies synovial inflammation in patients with RA.13
Increases in monocyte production of interleukin (IL)-1 and tumor necrosis factor-α (TNF-α) correlate with destruction of cartilage and bone. In addition, plasma levels of IL-6 and TNF-α longitudinally predict increases of disease activity in patients with RA, and both IL-6 and TNF-α play key roles in the onset and pathogenesis of RA. Finally, proinflammatory cytokines show potent additive effects. TNF-α strongly induces production of IL-1 and IL-6, which, in turn, promotes a cascade of processes, such as leukocyte infiltration of synovial tissue, collagenase and prostaglandin E production, and bone resorption.
Blocking the action of TNF-α via antagonists is currently a major pharmacological strategy in the treatment of RA. For example, anti–TNF-α antibodies drop the bioactivity of IL-1 by 90% in synovial cultures. Moreover, clinical studies have shown that treatment with TNF-α receptor antagonists (eg, infusion of infliximab(Drug information on infliximab)
) rapidly binds TNF-α and induces decreases in plasma levels of IL-1 receptor antagonist (IL-ra) and IL-6 (within hours) after intravenous administration.14
Along with the rapid (within hours) decline in circulating levels of proinflammatory cytokines, infliximab infusion induces acute (within hours) symptomatic effects, including alleviation of pain, morning stiffness, and fatigue.15
Subsequently (within 2 to 4 weeks), infliximab infusion reduces joint tenderness and swelling.13,14
Finally, some data suggest that TNF-α antagonists may affect behavioral symptoms in patients with RA; in an open study, infliximab induced acute (within hours) improvements of sleep as measured by polysomnography, which raises the possibility that inflammatory responses may initiate and perpetuate behavioral complications in RA.16