Stress is widely recognized as an important risk factor in the aetiology of inflammatory rheumatic diseases [1
]. An adaptational stress response involves the activation of both the hypothalamus-pituitary-adrenal axis (HPA axis) [6
] and the autonomic nervous system (ANS) [7
], and both stress axes are thought to communicate bidirectionally with the immune system [7
]. Because many rheumatic diseases are characterized by immune-mediated joint inflammation, stressful events might contribute to the aetiology, maintenance and exacerbation of rheumatic diseases [11
]. Recent advances in psychoneuroimmunology have provided insight into the complex mechanisms by which stressors might acutely affect the body's immune system [13
]. However, little attention has been paid to whether and how different short-term experimental stressors influence the separate pathways of the physiological stress response system (ANS, HPA axis, immune system) in patients with inflammatory rheumatic diseases.
Perception of an external stressful stimulus prompts the activation of various physiological systems that together define the body's stress response, which is aimed at re-establishing homeostasis. The physiological stress response is mainly coordinated by the hypothalamus, with activation of the ANS and the pituitary and adrenal glands (HPA axis) resulting in the release of catecholamines and cortisol, respectively [1
]. These stress hormones, supposedly acting via β- and α-adrenergic as well as glucocorticoid receptors, down-regulate immune and inflammatory processes; however, these processes also influence the central nervous system (CNS) [7
]. Circulating cytokines (for example, tumor necrosis factor α (TNF-α), interleukin (IL)-6 and IL-1) and activated immune cells, markers of inflammation, activate both (intermediates of) the HPA axis and the ANS. Chronically elevated levels of cytokines, as occur during long-term inflammation, might lead to changes in HPA axis and ANS activity [21
]. Moreover, the bidirectional relationship between the CNS and immune system implies that the physiological response to real-life stressors could contribute to the pathophysiology of inflammatory diseases [1
]. How these three systems, the ANS, the HPA axis and the immune system, act in response to a stressful event in rheumatic disorders is not well understood.
Although the laboratory setting is not a natural
environment, it allows control of key factors in the delivery of stress and observation of its effects and reduces many sources of bias and individual differences [16
]. The literature on acute psychoneuroimmunological and psychoendocrinological responses to experimental stress in healthy individuals is still increasing. Studies of healthy populations suggest that experimental psychological and physical stressors not only activate the ANS [23
] and the HPA axis [24
], but also influence the immune system by activating innate immunity, as reflected by increased numbers of natural killer (NK) cells and the production of pro-inflammatory IL-6 [15
]. Moreover, these different physiological systems (ANS, HPA axis and immune system) seem to work in an interdependent fashion [25
Despite the possible detrimental physiological effects of stress in patients with inflammatory rheumatic diseases, such as an altered disease course, little is known about acute-phase reactants of experimentally induced stress (both autonomic, neuroendocrine and immune). Reviews of acute physiological stress responses have either focussed on one [16
] or two [2
] stress response systems only (for example, ANS and/or neuroendocrine system), and included either only patients with rheumatoid arthritis [2
] or a heterogeneous group of both healthy participants and various patient populations [16
]. In addition, studies of the relationship between stress and inflammatory rheumatic diseases have often used experimental stressors that do not necessarily mimic real-life stressors. Different types of time-limited experimental stressors have been identified, namely, physical stressors (autonomic function tests, exercise), physiological stressors (corticotropin-releasing hormone (CRH) and (nor)epinephrine infusions, insulin tolerance test and dexamethasone suppression test) and psychological stressors (cognitive tests, public speaking) [2
]. Many studies have investigated the effects of these types of stress on components of the stress response system, such as the ANS or the HPA axis, but external validity of these studies of stress is questionable. The prevalence of cardiovascular dysfunction is high after standard tests of autonomic function [26
], such as the Valsalva manoeuvre, deep breathing, orthostatic tests, and sustained handgrip. While these tests may trigger autonomic responses, it is not known whether they activate the stress response system and alter neuroendocrine or immune function. HPA axis function has been investigated extensively by challenging specific parts of the HPA axis by means of infusion of CRH, synthetic glucocorticoids, or cytokines [27
]. Although alterations in HPA axis responsiveness at a hypothalamic, pituitary or adrenal level have been reported, more subtle changes in HPA functioning have also been suggested to occur [27
]. While injection studies might shed some light on possible altered neuroendocrine responses, the anti-inflammatory effects of exogenously administered glucocorticoids are not necessarily mirrored by increased secretion of endogenous glucocorticoids in response to a real-life stressor. Thus the question remains to what extent different types of experimental stressors that mimic real-life stressful events (for example, psychological stressors and physical exercise) are able to induce an autonomic, neuroendocrine and immune response in patients with inflammatory rheumatic diseases.
To the best of our knowledge this is the first review to investigate whether and how different experimental stressors mimicking real-life stressful events (psychosocial, cognitive, exercise and sensory stressors) influence physiological responses at the three levels (ANS, HPA-axis, immune system) in patients with prototypic inflammatory rheumatic diseases (for example, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).