Among healthy adults, ongoing stressful circumstances are associated with elevations of in vivo markers of systemic inflammation, including increases in circulating levels of IL-6.17
Even brief naturalistic stressors correlate with increases in stimulated IL-6 production.18
Exposure to minor naturalistic stressors that may last from hours to weeks is associated with increases in circulating levels of IL-6, particularly in patients withRA who are depressed.2,19
Moreover, chronic daily stress predicts greater stimulated monocyte production of IL-6 and impaired capacity of adrenocorticoids to suppress IL-6 production.20
IL-6 production, in turn, is related to increased fatigue in patients with RA.20
Such stress-induced activation of inflammatory signaling is increasingly seen as having relevant clinical implications. Even short-term experimental psychological stress induces marked increases in monocyte production of TNF-α in patients with RA compared with healthy controls.21
However, such increases in the expression of proinflammatory cytokines occur primarily in patients with RA who are not taking TNF-α antagonist medications.21
Patients with RA who took TNF-α antagonists (infliximab, etanercept, or adalimumab) were protected from stress-related increases in TNF-α production, with unchanged production similar to responses in healthy controls.
The stress-induced increased TNF-α production that is seen in patients with RA who are not taking TNF-α antagonists may reflect altered TNF-α regulation at the cellular level. Infliximab, etanercept, and adalimumab work by binding to soluble TNF-α, which prevents it from attaching to its receptor, thus rendering the TNF-α biologically inactive. Finally, there is some evidence that these medications also block the activation of nuclear factor (NF)- κ, an intracellular transcription factor that initiates expression of genes specific to the production of TNF-α and other inflammatory cytokines. Acute psychological stress, as well as sleep deprivation, are known to induce the activation of NF- κ.22,23
Similar to the effects of psychological stress on inflammatory responses, disordered sleep also has key consequences for expression of proinflammatory cytokines. Sleep deprivation and disordered sleep lead to daytime elevations in circulating levels of IL-6 and TNF-α, along with increases in the cellular and genomic expression of markers of inflammation.24–26
Moreover, sleep deprivation induces an exaggerated elevation of IL-6 and TNF-α in patients who show abnormal increases in resting levels of proinflammatory cytokine activity compared with controls.27
In turn, elevated levels of IL-6 correlate with symptomatic reporting of fatigue with similar relationships between fatigue and other serum markers of proinflammatory activity (eg, IL-1ra, sTNF-RII, and neopterin).28–30
Increases of proinflammatory cytokine activity and disordered sleep are also implicated in reducing the pain threshold, which raises the testable hypothesis that disordered sleep and elevated proinflammatory cytokine activity mediate increased pain sensitivity in RA.31,32
Basic studies show that proinflammatory cytokines contribute to hyperalgesia and pain sensitivity; pain neurons in the spinal cord secrete IL-1 and application of IL-1 into the dorsal horn provoking the increased firing of pain fibers.33
Similarly, in studies with healthy adults, experimental deprivation of sleep is associated with increased pain sensitivity during the morning.32
Taken together, stress, depression, and sleep loss, and/or a failure to recover from it, may be associated with increased production of inflammatory markers in RA, which, in turn, amplifies symptomatic expression of pain and fatigue.