Abstract
Evidence that psychological stress can increase inflammation and worsen the course of immune-mediated inflammatory disease (IMID) is steadily accumulating. The majority of data supporting this hypothesis come from studies in patients with inflammatory bowel disease (IBD). While there is no evidence to suggest that stress is a primary cause of IBD, many, although not all, studies have found that patients with IBD experience increased stress and stressful life events before disease exacerbations. Further, the disease itself can cause psychological stress, creating a vicious cycle. In addition to reviewing the epidemiological evidence supporting a stress-IMID relationship, this article also briefly discusses how stress-related changes in neural, endocrine, and immune functioning may contribute to the pathogenesis of immune diseases, IBD in particular. The effects of different pharmacological and nonpharmacological interventions, including stress management and behavioral therapy, on stress, mood, quality of life (QOL), and activity of the underlying IMID are also summarized.
Stress, which can be defined as a threat or a perceived threat to an organism’s homeostasis, carries numerous health-related adverse effects1,2. Historically, psychological stress has been linked to the functioning of the gastrointestinal (GI) system3. Since the 1930s, both gastroenterologists and psychiatrists have implied that emotional life experiences might be associated with intestinal inflammation3,4. Since then, and despite methodological difficulties, substantial advances have been made in elucidating the relationship between stress and inflammatory bowel disease (IBD) activity, and the mechanisms by which this occurs. Several studies have also evaluated the effects of pharmacological and particularly nonpharmacological therapies on psychological stress and disease activity and course.
PSYCHOLOGICAL STRESS AND IBD — OBSERVATIONAL STUDIES
Despite numerous anecdotal reports of the effects of stress on GI functioning, it has taken several decades to clarify the influence of psychological stress on the development and severity of IBD and other immune-mediated inflammatory diseases (IMID). This is partly due to methodological limitations in this area of research. Studies testing the hypothesis that stressful events are associated with IBD are difficult to design and conduct because:
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They require a long study period to allow for a sufficient number of events to occur for correlation testing
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A high degree of patient compliance is required for the recording of life events and symptoms
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The definition of what comprises stress and a stressful life-event is variable
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There are interindividual differences in stress perception
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Some researchers have studied mixed groups of patients with ulcerative colitis (UC) and Crohn’s disease (CD)
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A wide range of outcome measures has been used
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In several reports, statistical methods have been suboptimal
Thus, available studies differ in design, participants’ characteristics, methods of classifying disease activity, and duration of followup.
Goodhand, et al1 analyzed 13 studies that evaluated the influence of stress on relapse in IBD. Of these, 9 supported the hypothesis that stress and/or adverse life events worsened disease activity, and 4 reported no effect.
A prospective study of 62 patients with UC found that chronic psychological stress, measured by the Perceived Stress Questionnaire (PSQ), increased the risk of exacerbations of the disease5. Patients who fell into the upper stress tertile on enrolment had a higher hazard ratio for exacerbation during the subsequent 5 years than those in the low tertile (Figure 1). Further, a high PSQ score at any visit more than tripled the risk of disease worsening during the next 8 months.
Multivariate time-dependent analysis involving 101 patients with CD showed that those who had low levels of stress and who were identified as using low-avoidance methods using the Coping Inventory for Stressful Situation Avoidance subscale were least likely to relapse during the study period6. On the other hand, patients with either high stress-low avoidance, high stress-high avoidance, or low stress-high avoidance scores had higher likelihood of relapse (Figure 2). That study highlighted the importance of psychological stress in induction of relapse in CD, and suggested that patients’ coping methods may affect relapse rates.
A recent prospective study, using a population-based IBD sample and directly comparing potential risk factors for disease flare, found that the rates of major life-related stressful events, high perceived stress, and negative mood were significantly different between those who experienced flare and those who were in remission (Table 1)7. Further, the flare group was more likely to have had a major stressful event in the 3-month period before the relapse (p = 0.01). Based on a numeric rating scale to describe the stress impact of these events (i.e., 0 = not at all stressful to 10 = extremely stressful), the flare group reported a higher total stress impact of major events (7.2 vs 4.9; p < 0.01) compared to those without flare.
The finding that stress might lead to disease exacerbations in patients with IBD prompts the question of whether stress affects response to treatment. Persoons, et al8 determined that the presence of a major depressive disorder at baseline predicted a lower remission rate (odds ratio = 0.166, 95% confidence intervals 0.049–0.567, p = 0.004) in patients receiving episodic infliximab treatment (5 mg/kg), and the period of time before needing retreatment with infliximab was reduced (p < 0.001).
IMMUNE AND INFLAMMATORY RESPONSES TO EXPERIMENTAL AND ACUTE PSYCHOLOGICAL STRESS
Psychological stress is a subjective experience that is difficult to evoke and to objectively define in a controlled experimental environment. One of the methods used to assess the effects of stress on human GI function is the dichotomous listening test, in which different types of music are played simultaneously into each of the subject’s ears at the same time as they take an IQ test. When applied for 50 minutes to patients with UC, this experimental stress test has been shown to increase production of systemic and rectal mucosal inflammatory cytokines and mediators thought to be important in the pathogenesis of IBD9.
PATHOGENESIS OF STRESS-RELATED CHANGES IN THE GI TRACT
Although the underlying mechanisms by which psychological stress can affect immune function at both systemic and gut mucosal levels are yet to be fully understood, recent evidence points to changes in the hypothalamic-pituitary-adrenal (HPA) axis (Figure 3)9. Production of corticotropin-releasing factor (CRF) by the hypothalamus, stimulated by stress, promotes the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. ACTH stimulates production of cortisol, the principal glucocorticoid, from the adrenal cortex9,10. Activation of the autonomic nervous system in response to stress causes stimulation of the sympathetic, and inhibition of the parasympathetic nervous systems, which communicate through the brain-gut axis with the nervous system in the gut, also known as the enteric nervous system.
The enteric nervous system not only controls and regulates the motility, exocrine and endocrine functions, and microcirculation of the GI tract, but also interacts directly with the mucosal immune system. Nerve fibers of the autonomic nervous system create tight effector junctions with lymphocytes and macrophages9,11. Further, receptors for hormones and neuropeptides of the HPA axis such as ACTH, corticosteroids, substance P, and CRF are found on various inflammatory cells. The effects of stress on the immune and inflammatory systems are multifactorial, and depend on both the intensity of the stressor and the duration of the stressful event12.
THE INFLUENCE OF STRESS ON RHEUMATOID ARTHRITIS AND PSORIASIS
Both psychological distress and personality variables have been shown to be involved in the disablement process in rheumatoid arthritis13. There is also evidence, mainly from case-control studies, that stress might trigger psoriasis14,15.
According to a recent study involving 169 outpatients with psoriasis and 169 matched controls, 54% of patients with psoriasis experienced at least one stressful event (47% for onset, 64% for recurrence), compared with 20% of controls (p < 0.0001)14. Family issues were mentioned by 43% of psoriatic patients, personal problems by 26%, and job/financial difficulties by 32%. All 3 types of stressful event were significantly more common in patients with psoriasis compared to controls. Similarly, Naldi, et al15 found stressful life events to be a risk factor for a first episode of acute guttate psoriasis.
THERAPEUTIC IMPLICATIONS
If psychological stress affects the natural history of IBD, then stress-reduction therapies might have beneficial effects. Unfortunately, appropriately designed controlled studies are difficult to conduct in a blinded manner. Further, results of published studies should be interpreted with caution as they have used different patient populations, measures of disease activity, and psychological approaches1,9.
Unfortunately, there have been no good trials of the effects of pharmacological treatments, such as antidepressants, in IBD. Of several trials using psychotherapy, including cognitive behavioral therapy, a minority suggested any improvement in the course of patients’ IBD, although several did indicate an improvement in their psychological status1,16,17,18,19,20,21,22,23,24,25,26,27,28,29. However, using a retrospective case note review, Wahed, et al30 recently compared the course of IBD in 24 patients during the year before (Year 1) and the year after (Year 2) referral for supportive outpatient psychological counselling to 24 matched IBD controls. Patients receiving counselling had significantly fewer relapses and outpatient attendances, and lower steroid and other relapse-related medication use during Year 2 compared to Year 1. There were no differences in any of these outcomes between Years 1 and 2 in the control group (Figure 4). Thus, IBD-focused counselling might improve not only psychological well-being but also the course of IBD in individuals with psychological stress.
Reductions in disease activity achieved with antiinflammatory, immunomodulatory, and anti-tumor necrosis factor therapies improve quality of life (QOL) and possibly mood in patients with IBD. For example, a subanalysis of patient-reported outcomes from the Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM) study demonstrated that maintenance with adalimumab provided sustained improvement in health-related QOL in patients with moderate to severe CD up to Week 5631.
CONCLUSION
Although the 2-way interconnections between psychological stress and IMID need further definition, psychological stress does appear to play a role in the natural history of some, if not all, IMID. Additional well designed studies are needed to clarify the mechanisms underlying the stress-IMID relationship, in the hope that they can be used to devise new therapeutic approaches. In the meantime, identifying and addressing the needs of patients with psychological stress and maladaptive coping strategies may influence not only their quality of life and mood, but potentially alter the course of their chronic inflammatory disease.
Footnotes
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Supported by an unrestricted grant from Abbott Canada.