Stress system response and rheumatoid arthritis: a multilevel approach

J. G. Walker, G. O. Littlejohn1, N. E. McMurray and M. Cutolo2

School of Behavioural Science, The University of Melbourne,
1 Centre for Inflammatory Diseases, Monash Medical Centre, Melbourne, Australia and
2 Division of Rheumatology, Department of Internal Medicine, University of Genoa, Genoa, Italy

Correspondence to: M. Cutolo, Division of Rheumatology, Department of Internal Medicine, University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy.


    Abstract
 Top
 Abstract
 Introduction
 Neuroendocrine and immune...
 Activation of the stress...
 The relationship between...
 Definition and measurement of...
 Conclusions
 References
 
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.

KEY WORDS: Rheumatoid arthritis, Stress system, Stressors, Psychosocial factors, Neuroendocrine functioning, Immune functioning


    Introduction
 Top
 Abstract
 Introduction
 Neuroendocrine and immune...
 Activation of the stress...
 The relationship between...
 Definition and measurement of...
 Conclusions
 References
 
Rheumatoid arthritis (RA) is an autoimmune disease whose aetiology and progression are multifactorial, including a range of immune, neuroendocrine and psychosocial variables [1]. 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 [16]. 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 [913]. 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.


    Neuroendocrine and immune mechanisms implicated in RA
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 Abstract
 Introduction
 Neuroendocrine and immune...
 Activation of the stress...
 The relationship between...
 Definition and measurement of...
 Conclusions
 References
 
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 [2]. 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. 1Go). 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-{alpha}) [17]. Both peripheral and central administration of IL-1 have been shown to increase circulating adrenocorticotrophic hormone (ACTH) and corticosterone in experimental animals [18]. Similar findings have been reported for IL-6 and TNF-{alpha} [19]. In humans, administration of IL-6 stimulates the HPA axis even more potently than maximal doses of exogenous synthetic corticotrophin-releasing hormone (CRH) [20]. 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].



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FIG. 1.  The hypothalamic–pituitary–adrenocortical axis in RA. Stress and inflammatory cytokines stimulate the production of corticotrophin-releasing hormone (CRH) in the hypothalamus: the release of CRH leads to the production by the pituitary of adrenocorticotrophic hormone (ACTH), followed by secretion of glucocorticoids by the adrenal cortex, affecting the immune cells. DHEAS, dehydroepiandrosterone sulphate (adapted from Cutolo [1]).

 
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 [21]. 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 [22].

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 [16]. 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 [16]. In addition, a type of subclinical hypogonadism is observed in patients with stress-derived activation of the HPA axis [1].


    Activation of the stress system
 Top
 Abstract
 Introduction
 Neuroendocrine and immune...
 Activation of the stress...
 The relationship between...
 Definition and measurement of...
 Conclusions
 References
 
As stated, the immune system is directly linked to the stress system, and is profoundly influenced by the effectors of the stress response [13, 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, 2541]. 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. 2Go; [2931]). 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 [3]. Some research indicates that psychosocial stressors [3439], and a range of other psychosocial variables (e.g. coping, personality), may influence disease onset and/or exacerbations [28]. In fact, stress is the cause most given by patients for flare-ups in their RA [40]. 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, 4244]. 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, 4549]. 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, 4850]. For instance, major life events may suppress RA disease activity through cortisol and catecholamine suppression of Th1 activity [41]. 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 [41]. 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].



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FIG. 2.  A proposed integrated biopsychosocial model of how stressors may impact on RA disease activity and related outcomes. A range of psychosocial variables may modify or exacerbate the effects of psychosocial stressors on disease-related outcomes. Research indicates that neuroendocrine and immune mechanisms mediate the interrelationships between stressors and RA-related outcomes (adapted from Walker et al. [31]).

 

    The relationship between psychosocial variables and neuroendocrine and immune mechanisms in RA
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 Abstract
 Introduction
 Neuroendocrine and immune...
 Activation of the stress...
 The relationship between...
 Definition and measurement of...
 Conclusions
 References
 
Research clearly demonstrates links between psychosocial functioning and disease activity, and associated pain and disability in RA [913]. 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, 3436, 5156]. Further, research indicates that psychosocial factors may act upon RA disease activity and associated physical adjustment through neuroendocrine and immune mechanism modulation (Fig. 2Go; [3, 11, 13, 31]).

Previous research indicates that psychosocial variables have complex relationships with both neuroendocrine and immune processes [57]. 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, 5861], appraisals [13], 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. 2Go; [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 [13]. 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 [13]. This is one of the first studies simultaneously to demonstrate links between psychosocial, neuroendocrine and disease activity variables in women with RA.

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 [11]. Previous research has demonstrated declines in sIL-2R levels to relate to improvements in joint inflammation over 1 yr among RA patients [67]. 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 [11]. It was concluded that immune alterations may intermediate the relationship between psychological stress and RA [11]. 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 [39]. 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 [39]. 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. 2Go). 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. 2Go; [31]). 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. 2Go; [31, 6870]). 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.


    Definition and measurement of stress
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 Abstract
 Introduction
 Neuroendocrine and immune...
 Activation of the stress...
 The relationship between...
 Definition and measurement of...
 Conclusions
 References
 
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 [49]. 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 [68]. This further complicates the task of distinguishing and measuring different dimensions of stress, and determining whether stressors are disease related [38]. 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
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 [55]. 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, 3436].

Many measures of major life events have been modelled on the Social Readjustment Scale [72] which identifies major life stressors in an ascending order of severity, such as death of a spouse to taking a vacation [7476]. Formats vary from self-report questionnaires [76] to semi-structured interviews [74]. Most record the frequency of occurrence of major life events over the past 12 months [76], 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 the psychosocial stressor which are known to be critical moderators in the psychosocial stress response. Further, major life stressors are difficult to measure prospectively because of their infrequent occurrence, and retrospective studies may be prone to memory and mood biases [38].

Minor life events
Minor life events, such as daily hassles [77] and interpersonal stressors [38], may be significant sources of strain for individuals with RA, who are already contending with a chronic and potentially debilitating illness, and may precipitate further RA flare-ups [78, 79]. A greater occurrence of minor stressors has been shown to be related to increased disease activity, joint tenderness and pain in RA [37, 49, 80, 81], and associated alterations in neuroendocrine and immune functioning [11, 13, 39, 48, 50].

There are many measures available with most defining minor stressors as low-intensity events that are typically chronic in nature. Chronic stressors are recurrent events which indicate ongoing sources of strain, and appear to be related to significant increases in risk of disease and exacerbations in RA [36, 58]. One of the most commonly adopted measures of minor events is the Inventory of Small Life Events (ISLE) [37] which has been used extensively with RA populations, and has good reliability and validity [13, 37, 39]. It is a self-report questionnaire that measures the frequency of minor events across a number of domains, including interpersonal domains, such as spouse and co-workers, during 1 week or month [37]. Items were selected on the basis of having a discrete beginning and observable changes in everyday events in order to minimize confounding effects of personality or mood [37]. Further, events rated as associated with RA are not scored to reduce possible confounding with RA-related stressors [13, 37]. However, the ISLE does not include a measure 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 [39]. 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 [83]. 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' appraisals of the threat or meaning of the event, as well as other psychosocial variables (e.g. coping behaviours, personality, social support, helplessness) (see Fig. 2Go) that may moderate the stress response and possible associated changes in immune mechanisms and disease activity. There are a large number of instruments that measure stress system-related psychosocial variables which are reliable, and have been validated and used extensively with RA populations [8488].


    Conclusions
 Top
 Abstract
 Introduction
 Neuroendocrine and immune...
 Activation of the stress...
 The relationship between...
 Definition and measurement of...
 Conclusions
 References
 
Research indicates that different types of psychosocial stressors may influence neuroendocrine and immune mechanisms in differing ways. Hence, care needs to be taken when operationalizing definitions and selecting measurements of psychosocial stressors. Investigations of different dimensions of psychosocial stressors, and inclusion of associated appraisals of the situation and stress system-related psychosocial variables, will offer important insights into the role of stress in the course of RA.

A full understanding of the relationships between stressors and RA requires a holistic approach that integrates different levels of the stress response [89]. Interdisciplinary investigations adopting a biopsychosocial framework will further enlighten us as to the role of psychological stressors in the exacerbation of RA disease activity and which mechanisms (e.g. psychosocial, neuroendocrine, immune) mediate the effects of stressors. Longitudinal studies that move beyond correlational designs are needed to explore the complex interrelationships and possible causal pathways between psychosocial stressors and related psychosocial moderators, neuroendocrine and immune mechanisms, disease activity and associated physical adjustment.

The type of stressor and the individual differences in stress appraisal and reactivity may prove to be important prognostic factors in disease onset and/or progression for RA patients, and generally for patients with autoimmune diseases. Therefore, therapies that focus on stress management, enhancing social supports and facilitating a greater sense of control over RA symptoms may prove to be important adjuncts to traditional pharmacotherapy interventions in RA [38, 9092].


    Acknowledgments
 
We gratefully acknowledge the assistance of Dr Mariella Presta (Rheumatology–GENOA).


    References
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Submitted 6 April 1999; revised version accepted 4 June 1999.