fibromyalgia flare up relief Earlier diagnosis of rheumatoid arthritis allows for earlier treatment with ... increase in medication is recommended with disease flare-ups.22 ...Skip to Main Content
A growing body of research indicates that the stress system, and its interactions with the immune system, play a pivotal role in the aetiology and progression of rheumatoid arthritis (RA). The stress system has multiple levels and comprises physiological, psychological and environmental components. However, most investigations in RA that involve the stress system tend to focus on the interrelationships between neuroendocrine and immune function, and related disease activity, with little regard for the role of other aspects of stress system activation, including psychological variables. This is despite the fact that psychological stressors, and related psychological variables, are known to influence RA disease activity. This article aims to explore the multiple levels of stress system activation and how they may ultimately influence disease-related outcomes in RA. Some measurement issues of psychological stress will also be examined.
Rheumatoid arthritis (RA) is an autoimmune disease whose aetiology and progression are multifactorial, including a range of immune, neuroendocrine and psychosocial variables . How these variables interact with one another and how they ultimately influence the disease process in RA is only partially known. A growing body of research indicates that the stress system, and its interactions with the immune system, play a pivotal role in RA [1–6]. The stress system has multiple levels and is comprised of neuroendocrinological [e.g. hypothalamic–pituitary–adrenal (HPA) axis], psychological and environmental components [3, 7, 8]. However, most of the investigations in RA that involve the stress system tend to focus on the interrelationships between neuroendocrine and immune function, and related disease activity, with little regard for the role of other aspects of stress system activation, including psychological variables. This is despite the fact that psychological stressors, and related psychological variables, are known to influence RA disease activity, and a few recent studies suggest that psychosocial functioning may influence disease activity, and related outcomes through neuroendocrine and immune mechanisms [9–13]. Therefore, in this article, we aim to explore the multiple levels of stress system activation and how they may ultimately influence disease-related outcomes in RA. Some measurement issues of psychological stress will also be examined that are relevant to RA.
In recent years, understanding of the interaction between the neuroendocrine (HPA axis) and immune–inflammatory systems has increased greatly [1, 14, 15]. Communication between these two systems constitutes a negative feedback control loop which regulates the immune/inflammatory response . Evidence from in vitro, animal and human studies demonstrates that activation of the immune system may constitute a stressor to which the HPA axis responds ([3, 6, 16]; Fig. 1). In fact, activation of the immune system is associated with increased circulating levels of cytokines such as interleukin (IL)-1, IL-6 and tumour necrosis factor alpha (TNF-α) . Both peripheral and central administration of IL-1 have been shown to increase circulating adrenocorticotrophic hormone (ACTH) and corticosterone in experimental animals . Similar findings have been reported for IL-6 and TNF-α . In humans, administration of IL-6 stimulates the HPA axis even more potently than maximal doses of exogenous synthetic corticotrophin-releasing hormone (CRH) . In addition, research has implicated the dysregulation of this interaction between neuroendocrine and immune mechanisms as a contributing factor to the initiation and/or perpetuation of inflammatory diseases such as RA [16, 21].
HPA axis studies including RA patients suggest that these individuals have a relatively hypofunctional axis with defective central and peripheral components [14, 16, 21, 22]. Severe RA has been shown to be associated with a loss of the circadian rhythm of plasma cortisol, and this change could be correlated with markers of disease activity . Further, a controlled study indicated that in RA subjects, diurnal cortisol secretion is at the lower limit of normal, and failed to increase in response to the stress of surgery despite high levels of IL-1 and IL-6 .
A number of studies have indicated that untreated individuals with RA have hypersecretion of ACTH without an accompanying increase in cortisol, suggesting a normal central response to inflammation, but a defect in adrenal responsiveness [16, 23, 24]. A recent study examined HPA axis functioning in active RA patients and healthy controls by recording responses to i.v. doses of human CRH . The results indicated that RA patients could not maintain their mean serum cortisol levels at the concentrations achieved the 1 last update 2020/05/27 by healthy controls in spite of persistently higher mean ACTH levels. Therefore, it appears that individuals with RA have relatively deficient cortisol production, as well as compensatory ACTH hypersecretion . In addition, a type of subclinical hypogonadism is observed in patients with stress-derived activation of the HPA axis .A number of studies have indicated that untreated individuals with RA have hypersecretion of ACTH without an accompanying increase in cortisol, suggesting a normal central response to inflammation, but a defect in adrenal responsiveness [16, 23, 24]. A recent study examined HPA axis functioning in active RA patients and healthy controls by recording responses to i.v. doses of human CRH . The results indicated that RA patients could not maintain their mean serum cortisol levels at the concentrations achieved by healthy controls in spite of persistently higher mean ACTH levels. Therefore, it appears that individuals with RA have relatively deficient cortisol production, as well as compensatory ACTH hypersecretion . In addition, a type of subclinical hypogonadism is observed in patients with stress-derived activation of the HPA axis .
As stated, the immune system is directly linked to the stress system, and is profoundly influenced by the effectors of the stress response [1–3, 6, 15]. The stress response is associated with the activation of several neuroendocrine systems including the HPA and hypothalamic–pituitary–gonadal (HPG) axes, and the sympathetic nervous system, but for brevity we will focus on the HPA axis [3, 5, 25–41]. The activation of the HPA axis may occur when confronted by a psychosocial stressor, which if appraised as threatening, can result in associated affective and behavioural (i.e. coping) responses, as well as elevated serum levels of cortisol (Fig. 2; [29–31]). Hence, the HPA axis provides an essential interface between the internal and external environments, and enables the individual to adapt to diverse noxious stimuli, whether they be psychological, physical or otherwise [3, 25, 26, 32]. The role of the increased cortisol release is adaptational and attempts to counteract the effects of stressors in order to re-establish homeostasis [3, 33]. However, failure to mount an appropriate HPA axis response to a stress trigger may be detrimental, and may represent a significant contributory factor in the aetiology of a variety of disease processes, including autoimmune and inflammatory disorders such as RA . Some research indicates that psychosocial stressors [34–39], and a range of other psychosocial variables (e.g. coping, personality), may influence disease onset and/or exacerbations . In fact, stress is the cause most given by patients for flare-ups in their RA . Psychosocial stressors may influence disease activity by disturbing the homeostasis of the neuroendocrine and immune systems in RA [11, 39]. However, recent research indicates that different psychosocial stressors may have differing effects on the neuroendocrine and immune systems in individuals with RA, as well as other rheumatic conditions. Acute stressors and interpersonal conflict are associated with increases in cortisol, catecholamines and prolactin [25, 42–44]. In addition, chronic stressors may generally alter baseline neuroendocrine levels [2, 29]. Furthermore, animal and human studies indicate that chronic and acute stressors have generally a suppressive effect on immune mechanisms, but a few studies have found that chronic low-intensity stressors may be immunoenhancing [2, 11, 41, 45–49]. It is possible that major and small life events may in fact operate via different neuroendocrine pathways, in turn leading to different alterations in immune mechanisms, and subsequent disease outcomes [28, 48–50]. For instance, major life events may suppress RA disease activity through cortisol and catecholamine suppression of Th1 activity . On the other hand, minor stressors may trigger an exacerbation of disease activity via the activation of post-ganglionic discharge of pro-inflammatory substances on a background of non-glucocorticoid-suppressed Th1 activity . These psychosocial stress-related alterations in neuroendocrine and immune functioning have been related to changes in disease activity and associated pain in RA and other rheumatic conditions [11, 13, 39, 41, 49].
Research for 1 last update 2020/05/27 clearly demonstrates links between psychosocial functioning and disease activity, and associated pain and disability in RA [9–13]. Further, exacerbations and overall outcomes in RA incorporate complex interactions between psychosocial and disease-related variables [10, 51]. Personality, psychological stressors, threat appraisals of RA, perceived ability to cope with RA and associated pain and disability, coping strategies, and social support have been shown to be related to pain levels, disability and RA disease activity [9, 10, 12, 28, 34–36, 51–56]. Further, research indicates that psychosocial factors may act upon RA disease activity and associated physical adjustment through neuroendocrine and immune mechanism modulation (Fig. 2; [3, 11, 13, 31]).Research clearly demonstrates links between psychosocial functioning and disease activity, and associated pain and disability in RA [9–13]. Further, exacerbations and overall outcomes in RA incorporate complex interactions between psychosocial and disease-related variables [10, 51]. Personality, psychological stressors, threat appraisals of RA, perceived ability to cope with RA and associated pain and disability, coping strategies, and social support have been shown to be related to pain levels, disability and RA disease activity [9, 10, 12, 28, 34–36, 51–56]. Further, research indicates that psychosocial factors may act upon RA disease activity and associated physical adjustment through neuroendocrine and immune mechanism modulation (Fig. 2; [3, 11, 13, 31]).
Previous research indicates that psychosocial variables have complex relationships with both neuroendocrine and immune processes . However, there is a paucity of research that has examined the interrelationships between psychosocial, neuroendocrine and immune variables, and their contribution to susceptibility and exacerbation of illness, including RA. Nonetheless, findings to date suggest that psychosocial variables, such as psychological stress [13, 50, 58–61], appraisals , depression [3, 62, 63], beliefs in coping abilities [13, 48, 64] and social support [13, 39, 44] may contribute to illness by disrupting stress system hormone release, which in turn affects immune mechanisms on bodily processes, including susceptibility to and exacerbation of illnesses such as RA (Fig. 2; [8, 31, 65, 66]).
A recent study examined the relationships between small undesirable events, interpersonal stressors, depression, coping efficacy, neuroendocrine function and disease status in women with RA and osteoarthritis (OA) controls . The results indicated that changes in prolactin (PRL) levels in RA patients were positively associated with changes in depression, interpersonal conflict, coping inefficacy and clinician ratings of disease activity, while no significant relationships were found between PRL levels and the psychosocial and disease variables for OA . This is one of the first studies simultaneously to demonstrate links between psychosocial, neuroendocrine and disease activity variables in women with RA.
fibromyalgia flare up reliefhow to fibromyalgia flare up relief for Another investigation examined within-subject relationships between self-reported pain, minor daily stressors, negative affect, soluble interleukin-2 receptor (sIL-2R) levels and disease activity in individuals with RA over consecutive days . Previous research has demonstrated declines in sIL-2R levels to relate to improvements in joint inflammation over 1 yr among RA patients . Changes in negative affect were unrelated to joint inflammation, although increases in negative affect were associated with increases in joint pain and decreases in sIL-2R levels . It was concluded that immune alterations may intermediate the relationship between psychological stress and RA . Recently, a prospective study investigated the relationships between interpersonal stress, spousal support, sIL-2R, total T-cell activation and disease activity for married women with RA . Interpersonal stress ratings were taken over consecutive weeks and related to disease activity through comparing disease activity ratings and immune markers taken at baseline and in a highly stressful week . Results showed significant elevations in disease activity from baseline to the stressful week, including the immune markers. Women with better spousal relationships did not show increases in disease activity after an episode of interpersonal stress, while women with more critical spouses showed a significant increase in sIL-2R from baseline to stress. These studies seem to provide evidence for the role of psychosocial stressors, and related psychosocial variables, in disease activity (see Fig. 2). Also, they further indicate that psychological variables may influence disease processes via immune function pathway interference.
At present, there is a paucity of research that has implemented a fully integrated approach which explores the complex interrelationships between psychosocial variables, neuroendocrine and immune function, and disease activity and related outcomes. However, based on previous findings, it may be hypothesized that psychological stressors ultimately influence disease activity and related outcomes through neuroendocrine and immune mechanisms [11, 13]. The complexities in measurement and theory on both psychological and biological sides of the stress and illness equation may contribute to the delay in a comprehensive and testable biopsychosocial model of RA disease activity and outcome. Based on research to date, albeit disparate, we propose an integrated biopsychosocial model of how stressors may impact on RA disease activity and related outcomes (Fig. 2; ). Psychosocial stressors do not influence RA activity directly, but rather through a cycle of psychosocial responses which may either modify or exacerbate [8, 12, 13, 35, 48] the effects of the psychosocial stressor on RA-related outcomes (Fig. 2; [31, 68–70]). Cognitive appraisals of the threat posed by the stressor, and available resources, play a central role in the impact of stressors on psychosocial and physical outcomes [13, 69]. None of these processes are considered to be linear, but rather involve cycles and feedback loops over time.
The stress response system is made up of psychological, affective and neuroendocrine components that can be activated by a range of physical and psychosocial stressors. A stressor is any event that activates the stress response system, which, in turn, attempts to return the organism to a homeostatic state [1, 3, 71]. Often, biological approaches focus solely on physiological aspects of the stress response, and the type of stressor is incidental to the model except when they differ in intensity of the elicited response . Nonetheless, a number of investigations have examined the effects of psychosocial stressors on RA [10, 13, 35, 39]. The concept of stress is pivotal in RA as living with a painful, chronic and somewhat unpredictable disease can be a significant source of stress in itself . This further complicates the task of distinguishing and measuring different dimensions of stress, and determining whether stressors are disease related . Researchers have taken different conceptual and measurement approaches when investigating the role of psychosocial stressors in RA disease activity, and adjustment outcomes. Psychosocial stressors may vary along a number of important dimensions, such as major or minor events, acute or chronic, anticipated or not, single or multiple events, sudden or gradual onset, and interpersonal, to name but a few [29, 38, 49, 72]. We will discuss briefly examples of stressors most commonly used in RA research.
Major life events tend to be defined as severe stressors of great intensity, while minor life events are daily hassles or stressors of less intensity. Major stressors are often acute in nature. The impact of major life events on RA is conflictual with a number of studies finding no relationship between major stressors and RA disease outcomes . Nonetheless, some research indicates that major life events (e.g. death of a spouse) may be implicated in the onset and exacerbation of RA, as well as higher levels of distress, and changes in functional disability [35, 36, 52, 73]. Major life events might represent one of the factors involved in the pathogenesis of RA [36, 49]. It has been hypothesized that severe life events may disturb the homeostatic balance between neuroendocrine and immune mechanisms to the extent that a substantial subgroup of individuals may be susceptible to developing RA [28, 34–36].
Many measures of major life events have been modelled on the Social Readjustment Scale  which identifies major life stressors in an ascending order of severity, such as death of a spouse to taking a vacation [74–76]. Formats vary from self-report questionnaires  to semi-structured interviews . Most record the frequency of occurrence of major life events over the past 12 months , and some also incorporate subjective measures of the perceived desirability or significance of the event [74, 75]. Surprisingly, many of these measures fail to acknowledge the importance of individuals'' appraisals of threat posed by the minor events. This may be rectified by including items that target the degree of perceived stress experienced in each domain of minor events . There are a number of other instruments that measure the perceived severity and frequency of minor events over daily, weekly or monthly periods [25, 77, 82]. Measurement of minor life events poses fewer difficulties in comparison to major life stressors. Minor stressors typically occur frequently so they can be measured prospectively in order to determine the relationships between fluctuations in the stressors and changes in neuroendocrine and immune functioning, and RA status [38, 49]. Prospective studies of the role of stressors in RA also reduce the risk of recall errors, and possible biases of recalling events that help the individual in explaining current health status . In addition, prospective studies allow for repeated measures over time which assist in determining whether psychosocial events are isolated or chronic recurrent sources of strain [38, 49].
Assessment of psychosocial stressors is important, but we also must consider the key elements that make up the stress response, including individuals''Leary A. Stress, emotion, and human immune function.
Seyle H. The stress of life. New York: McGraw-Hill, 1956.
Walker JG, Littlejohn GO, McMurray NE. A proposed biopsychosocial model of adjustment to rheumatic conditions. Aust NZ J Med 1999 (Abstract); in press.
fibromyalgia flare up reliefhow to fibromyalgia flare up relief for Buckingham JC, Loxley HD, Christian HC, Philip JG. Activation of the HPA axis by immune insults: Roles and interactions of cytokines, eicosanoids, and glucocorticoids.
Besedovsky HO, Del Rey A. Immune-neuro-endocrine interactions: Facts and hypothesis.
Baker GHB. Life events before the onset of rheumatoid arthritis.
Latman NS, Walls R. Personality and stress: An exploratory comparison of rheumatoid arthritis and osteoarthritis.
Marcenaro M, Prete C, Badini A, Sulli A, Magi E, Cutolo M. Rheumatoid arthritis, personality, stress response style and coping with illness. A preliminary survey.
Zautra AJ, Guarnaccia CA, Dohrenwend BP. Measuring small life events.
Zautra AJ. Investigations of the ongoing stressful situations among those with chronic illness.
Zautra AJ, Hoffman JM, Matt KS et al. An examination of individual differences in the relationship between interpersonal stress and disease activity among women with rheumatoid arthritis.
Affleck G, Pfeiffer C, Tennen H, Fifield J. Attributional processes in rheumatoid arthritis patients.
Elenkov IJ, Papanicolaou DA, Wilder RL, Chrousos GP. Modulatory effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications.
Besedovsky HO, Del Rey AE, Sorkin E. Immune-neuroendocrine interactions.
fibromyalgia flare up reliefhow to fibromyalgia flare up relief for Herbert TB, Cohen S. Stress and immunity the 1 last update 2020/05/27 in humans: A meta-analytic review.
Kieclot-Glaser JK, Glaser R, Cacioppo JT et al. Marital conflict in older adults: Endocrinological and immunological correlates.
Dorian B, Garfinkel PE. Stress, immunity & illness—a review.
Leonard BE, Song C. Stress and the immune system in the etiology of anxiety and depression.
fibromyalgia flare up reliefhow to fibromyalgia flare up relief for Monjan AA, Collector MI. Stress-induced modulation of the immune response.
Zautra AJ, Okun M, Robinson S, Lee D, Roth S, Emmanual J. Life stress and lymphocyte alterations among rheumatoid arthritis patients.
Zautra AJ, Hamilton NA, Potter P, Smith B. Field research on the relationships between stress and disease activity for 1 last update 2020/05/27 in rheumatoid arthritis.
Rogers MP, Trentham DE, McCune WJ et al. Effect of psychological stress on arthritis on rats.
Zautra AJ, Burleson MH, Smith CA et al. Arthritis and perceptions of quality of life.
Evers AWM, Kraaimaat FW, Geenen R, Bijlsma JWJ. Psychosocial predictors of functional change in recently diagnosed rheumatoid arthritis patients.
Manne SL, Zautra AJ. Coping with arthritis.
Revenson TA, Felton BJ. Disability and coping as predictors of psychological adjustment to rheumatoid arthritis.
Smedstad LM, Moum T, Vaglum P, Kvien TK. The impact of early rheumatoid arthritis on psychosocial distress.
Smith for 1 last update 2020/05/27 TW, Peck JR, Ward JR. Helplessness and depression in rheumatoid arthritis.
fibromyalgia flare up reliefhow to fibromyalgia flare up relief for Daruna JH, Morgan JE. Psychosocial effects on immune function: neuroendocrine pathways.
Cohen S, Frank E, Doyle WJ, Skoner DP, Rabin BS, Gwaltney JM. Types of stressors that increase susceptibility to the common cold in healthy adults.
Glaser R, Rice J, Sheridan J. Stress-related immune suppression: Health implications.
Kiecolt-Glaser JK, Glaser R, Shuttleworth M. Chronic stress and immunity in family caregivers of Alzheimer''s the long-term stressors that take a toll: Comment on Cohen et al. (1998).
Cutolo M. Macrophages as effectors of the immunoendocrinologic interactions in autoimmune rheumatic diseases.
Holmes T, Rahe R. The social readjustment rating scale.
Anderson KO, Bradley LA, Young LD, McDaniel LK, Wise CM. Rheumatoid arthritis: Review of psychological factors related to etiology, effects, and treatment.
Brown GW, Harris TO. Life events and illness. New York: Guilford Press, 1989.
Miller PM, Salter DP. Is there a shortcut? An investigation into the life event interview.
Sarason IG, Johnson JH, Siegel JM. Assessing the impact of life changes: Development of the life experiences survey.
Lazarus RS, Folkman S. Daily hassles and uplifts scale manual. California: Consulting Psychologists Press, 1989.
DeLongis A, Folkman S, Lazarus RS. The impact of daily stress on health and mood: Psychological and social resources as mediators.
Depue RA, Monroe SM. Conceptualization and measurement of human disorder in life stress research.
Affleck G, Tennen H, Urrows S, Higgins P. Person and contextual features of daily stress reactivity: Individual differences in relations of undesirable daily events with mood disturbance and chronic pain intensity.
Potter PT, Zautra AJ. Stressful life events''altmetric-embed''https://academic.oup.com/rheumatology/crossref-citedby/1783281''s objective of excellence in research, scholarship, and education by publishing worldwide
This PDF is available to Subscribers OnlyView Article Abstract & Purchase Options
fibromyalgia flare up reliefhow to fibromyalgia flare up relief for For full access to this pdf, sign in to an existing account, or purchase an annual subscription.