The role of stress is emerging among the factors involved in the pathophysiology of rheumatic diseases including genetic predisposition, infections and gender. A stressor is any stimulus that disturbs or threatens to disturb homeostasis. Stressors can be exogenous or endogenous and metabolic, physiologic, infectious, inflammatory, or emotional in nature. The stress system response (SSR) is the array of physiological and behavioural adaptation to restore homeostasis and is mediated through activation of the hypothalamic-pituitary- adrenal axis (HPA) and the sympathetic nervous system (SNS). Activation of HPA axis induces synthesis and release of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH and finally glucocorticoids (GC) such as cortisol. GC act in a permissive way to increase readly available energy resources to brain and heart during stress and terminate defense mechanisms to stress to prevent these responses to become destructive themself. SNS activation leads to release of norepinephrine (NE) and the sympathetic division of the autonomic system is associated with conferring an adaptative advantage during stressful situation.
The SSR in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)
There is strong evidence that major life events and chronic minor stress act as important factors in RA and are associated with the onset and course of the disease. By considering that minor and major stress activate the SSR, the activation of the HPA axis is the physiologic consequence of such stimulation. However, as introduced, also inflammatory or infectious mediators such as cytokines (i.e. Il-6, TNF-alpha) are considered stressors (even with direct effects on adrenal gl) and are involved in HPA axis activation. Therefore, the chronic stimulation of the HPA axis (i.e. chronic stress), as reported in early RA patients (pts) and perhaps during the course of the disease (high levels of IL-6), might explain the lover than expected HPA axis function as showed by low levels of cortisol and dehydroepiandrosterone (DHEA). However, the administration of GC replaces the hormonal hypoproduction of the exhausted adrenal glands (gl), as well as decreases the levels of the inflammatory (chronic/acute) stressors (i.e. cytokines) in RA pts. Almost 50–80% of SLE pts believe that stress had provoked their illness and high level of life stress precedes flares of the disease. As observed in RA, low levels of cortisol and DHEA have been found in SLE pts further suggesting an altered HPA axis function.
The SSR in fibromyalgia syndrome (FM) and in polymyalgia rheumatica (PMR)
Minor stress and emotional trauma may act as provoking factors in FM and may modulate the course of the disease. In particular, the evidence suggest that FM represents pathology developing from a structurally dysregulated SSR which may result from a detrimental cascade of negative neuroendocrine and behavioural reaction patterns. Pain is the most prominent complain in FM. Pain memory and amplification as well as chronic pain in itself, become a main stressor in FM pts and there can be little doubt that FM is associated with chronic stress.
Recent data suggest that FM is related to a neuroendocrine disorder characterised by hyperreactive ACTH release and a relative hyporesponse of the adrenal gl. The presence of mild hypocortisolism with a reduced adrenal responsiveness in face of an exaggerated endogenous ACTH upon HPA axis stimulation, suggest a mild feedback resistance to cortisol at the central level and support distinct disturbance in the SSR in FM. The abrupt onset of PMR, with symptoms reminding the steroid withdrawal syndrome or adrenal insufficiency (i.e. myalgia, malaise, pain, depression, etc), might be induced by intense stimulation and inefficient response of the HPA axis, including different acute stresses (i.e. surgery, infections, severe interpersonal stress) in elderly people that are ageing-predisposed to an unadeguate SSR. Our studies have shown that the reduced production of adrenal hormones (i.e. cortisol, DHEAS) in recent- onset and untreated PMR pts, seems mainly related to altered intraadrenal responsiveness to ACTH stimulation (i.e. increased 17-OHP).
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