Psychological Stress and the Kaleidoscope of Autoimmune Diseases

Chapter 33

Psychological Stress and the Kaleidoscope of Autoimmune Diseases Kassem Sharif1,2,3, Abdulla Watad1,2,3, Alec Krosser3, Louis Coplan3, Howard Amital1,2,3, Arnon Afek2,3, Yehuda Shoenfeld4,5 1Department

of Medicine ‘B’, Sheba Medical Center, Tel-Hashomer, Israel; 2Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel; 3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 4Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 5Laboratory of the Mosaics of Autoimmunity, Saint-Petersburg University, Saint-Petersburg, Russian Federation

INTRODUCTION Stress is defined as the complex pshycophysiological reaction of the body in which normal homeostasis is disturbed or threatened [1]. Stress is considered negative when it results in detrimental behavioral and physical symptoms [2,3]. In contrast, eustress, or positive stress, results in an action-enhancing effect. The role of stress in the clinical course of autoimmune diseases is oftentimes overlooked [4]. The association between stress and autoimmunity is elusive, and the downstream effects are thought to occur in parallel to immunologic perturbations. Hormones, neurotransmitters, and other factors are shown to influence these phenomena. The role of stress in inducing or directing the clinical course of autoimmune diseases is oftentimes overlooked. In this review, we inspect the clinical evidence regarding the role of stress on various aspects of disease entities (Fig. 33.1).

RHEUMATOID ARTHRITIS AND STRESS Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by joint swelling with destruction of the synovial membrane in diarthrodial joints [5]. RA is influenced by genetic and environmental factors [6], and various factors, including stress, may contribute its pathogenesis. Many studies support the notion that stress may precede RA by years. In one retrospective study (N = 18,309), researchers showed that two or more childhood stressful events increased a person’s risk of developing RA, confirming that more stress in childhood is related to RA incidence [7]. In another large prospective study (N = 9159), researchers found an increased risk in self-reported arthritis in people with >2 traumatic childhood experiences [8]. Even with the genetic association [9], a study of 3143 twin pairs found that RA is more prevalent in those with more combat exposure. The same study found that those with RA had significantly more Posttraumatic stress disorder (PTSD) symptoms [10]. In a separate study of 54,224 female nurses, participants with >4 PTSD symptoms had an increased risk of developing RA in the next 2 years [11]. Stress and RA activity have been studied during stressful life events (i.e., divorce, bereavement) [12–15]; a literature review involving over 3000 patients found that minor and major stressors are related to an increase in disease activity [16]. Another prospective study found that worrying preceded overall disease activity. One study of 41 women with RA saw a positive association between interpersonal stress and disease activity for the same and following week [30]. No association between daily stressors and any of the immune or Hypothalamic–pituitary–adrenal axis (HPA) axis variables was found [17]. Self-reported daily stress events were correlated with pain in one study of 35 RA patients [18]. Another study found that daily job stress was related to increased pain [19]. Stressful spousal relationships were associated with increased pain scores in RA as well [20]. Researchers found that RA patients in well-adjusted marriages had reduced pain compared with distressed marriages and unmarried patients, suggesting that nonstressful marriages are protective against pain in RA [21]. Another study also found that those with well-adjusted spousal relationships did not have any changes in these variables during stressful times [22]. Mosaic of Autoimmunity. https://doi.org/10.1016/B978-0-12-814307-0.00033-5 Copyright © 2019 Elsevier Inc. All rights reserved.

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Stress

Locus Coeruleus, Adrenal Medulla

HypothalamicPituitary-Adrenal Axis

Catecholamines

Glucocorticoids

Monocytes

APCs

Th1

IL-1b

TNFa

IFN-g

IL-12

IFN-g

Monocytes

Th2

IL-4

IL-4

IL-12

IL-10

TNFa

IL-13

IL-10

IL-4

IL-17A FIGURE 33.1  The role of stress on the various aspects of the immune system. During the stress response, catecholamines and glucocorticoids are released from their respective origins. These biomolecules exert control over various immune cells, thereby causing them to alter the production of various cytokines. The increase of IL-4 promotes Th2 cell differentiation, whereas the decrease in IL-12 and the increased IL-10 production reduce the number of Th1 cells. These changes favor a shift toward a humoral immune response. APCs, antigen-presenting cells.

Different coping styles impacted future RA activity, pain, and functional disability in newly diagnosed RA patients as well. A passive coping style (i.e., feeling of hopelessness and relying on others to resolve the situation) predicted functional disability at 3 years follow-up [23]. Disease activity 3 and 5 years postdiagnosis was worse in with stress avoidance coping mechanisms [24] and greater perceived stress without active coping strategies increased the risk of developing psychological comorbidities [25].

STRESS AND MULTIPLE SCLEROSIS Multiple sclerosis (MS) is characterized by inflammation and demyelination of the central nervous system [26] and affects over 2.3 million people worldwide [27]. Past studies have shown that stress may play a role in the inflammatory and autoimmune processes [28].

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When MS patients were compared with hospital controls, it was found that MS patients had more adverse life events in the 2 years prior to the onset of disease [29–32]. Using MRI technology, psychological stress was correlated with the appearance of new brain lesions [33]. High levels of anxiety were strongly related to severity and number of stressful life events and were found to increase the likelihood of exacerbations [34]. Similarly, after rocket attacks on civilian centers in northern Israel during the 2006 war between Hezbollah and Israel, 18 relapses were observed in the 156 patients, compared with only 1–6 relapses in similar time periods in the previous 12 months [35]. Ackerman et al. also found that exacerbations more likely followed stressful life events [36]. Alleviating stress has shown many benefits in MS patients. A recent study found that patients who received stress management therapies developed fewer new lesions compared with controls [37]. Likewise, many studies concluded that physical exercise and mindfulness-based interventions can benefit patients with MS [38–40]. Pharmacological treatments used for depression and anxiety have shown efficacy in the treatment of MS [41–43]. Regions displaying high levels of oxidative damage in oligodendrocytes correlated with increased presence of T cells and microglia [44] cells responsible for maintaining the integrity of the Blood–brain barrier (BBB) [45]. When microglial activation was inhibited or NADPH oxidase was blocked, the BBB constituents were preserved in vitro and BBB disruption was reduced in vivo [46]. Mast cells are thought to exacerbate MS by facilitating vascular permeability and allowing extravasation of lymphocytes [47]. Acute stress induced by immobilization or forced swimming was caused to cause BBB disruption in mice [48,49]. The HPA axis has also been studied in relation to MS pathogenesis. Increased levels of glucocorticoids inhibit NF-κB activity, leading to downregulation of the inflammatory cascade. Normally, cortisol exerts an inhibitory effect on corticotropin-releasing hormone (CRH) secretion. Under chronic stress, the negative feedback loop can be disrupted, leading to increased levels of cortisol [50]. With sustained stress, hypocortisolemia may occur [51]. In response to CRH stimulation, patients with secondary progressive MS exhibit less cortisol production [52]. The decreased cortisol levels suggest an impaired ability to control inflammation.

STRESS AND INFLAMMATORY BOWEL DISEASES Crohn’s disease (CD) and ulcerative colitis (UC), the two most prevalent inflammatory bowel diseases (IBDs), involve chronic gastrointestinal inflammation [53]. Stress is thought to influence physiological functions of inflammation and normal responses to inflammatory conditions [54]. In a prospective cohort study of 62 patients with UC, Levenstein et al. [55] found a positive association of long-term perceived stress on disease exacerbation. The authors did not find this same association for stressful life events or short-term stress. Bitton et al. [56] also found a positive association between perceived stress and IBD severity. Patients who scored lower on avoidance coping and those with lower perceived stress were less likely to relapse (P = .003). A recent study found no association between the perceived stress level and markers of active intestinal inflammation, though it did find a relationship between perceived stress levels and reported GI symptoms [57]. In a later prospective study, the authors found that among CD and UC patients, higher symptom activity predicted higher perceived stress levels after 3 months [58]. Although the majority of studies on the effects of stress on IBD suggest that stress worsens IBD, not all studies came to the same conclusion and not everyone is in agreement. Bitton et al. [59] found that patients with UC and stressful events had an earlier time until relapse of the disease. Langhorst et al. [60] found that short-term stress was predictive of relapse in UC and that baseline long-term stress was not. Bernstein et al. [61] monitored patients with IBD and found that perceived stress and major life events significantly correlated with disease flares. Vidal et al. [62] showed that stressful life events were not associated with relapses in UC or CD. A consensus has not been reached regarding the role of psychiatric treatment in IBD. A study by Wahed et al. [63] found that counseling improved the psychological well-being of IBD patients and also improved the course of IBD. Another study by Boye et al. [64] found that stress management psychotherapy did not improve the disease course or reduce replaces, though it may impact quality of life. A study assessing mindfulness-based stress reduction found that it did not reduce the number of flares or the severity of the flares but, however, did prevent a change in the quality of life questionnaire during flares [65]. A multicenter trial examining 488 CD patients found that after 1 year of standard treatment and psychotherapy, patients used fewer sick days and had fewer hospital days, compared with control subjects using only standard therapy [66].

STRESS AND SYSTEMIC LUPUS ERYTHEMATOSUS Systemic lupus erythematosus (SLE) is an autoimmune disease that results in attacks on multiple body systems, including the joints, skin, lungs, kidneys, and nervous system [67,68]. Environmental factors, including stressors, may act as to induce and exacerbate SLE.

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Roberts et al. [69] conducted a longitudinal cohort study of 54,753 women and found that trauma exposure and PTSD were associated with increased incidence of SLE, with a stronger incidence if there was concomitant trauma with PTSD. Stress, and its association with SLE and lupus flares, is a well-studied phenomenon [70–75]. Patients carrying the serotonin receptor 1A–1019 G allele, which has been linked to stress-related behaviors, were more susceptible to self-perceived stress and thus had an increased risk for lupus flares [70]. Kozora et al. [73] found that patients with SLE had more major life stresses (P < .002) than controls. Dobkin et al. [74] found that the global physical health scale scores in SF-36 were significantly lower in SLE patients than in healthy women. Lupus patients with higher Perceived Stress Scale scores have also been found to show cognitive impairment and experience a higher prevalence of forgetfulness and difficulty concentrating [76]. Greco et al. [77] found improvement in pain, psychological functioning, and perceived physical functioning using biofeedback-assisted cognitive behavioral treatment compared with symptom monitoring or usual medical care [77]. Williams et al. [78] found that by using workshops to reduce stress, the perceived stress levels and quality of life increased among patients. Although no significant differences were found for biological indicators of stress (cortisol or Dehydroepiandrosterone (DHEA) levels), stress-reduction interventions improved depression, fatigue, and pain [78].

STRESS AND AUTOIMMUNE THYROID DISEASE Loss of self-tolerance and subsequent production of autoantibodies against self-thyroid antigens result in varied production of thyroid hormones.

Stress and Graves’ Disease Winsa et al. [79] found that patients with Graves’ disease (GD) had more negative life events compared with matched controls in the 12 months preceding diagnosis (OR 6.3). Similarly, Kung et al. [80] demonstrated that more negative events were experienced by GD patients than controls. Yoshiuchi et al. [81] inspected the role of stress in GD for men and women and found that stressful events in the last 12 months increased risk of disease development exclusively in women. Radosavljevic et al. [82] evaluated 100 GD patients and found that subjects had significantly higher stressful life events in the last 12 months as compared with the healthy controls. Matos-Santos et al. [83] investigated three groups of 31 patients: GD, toxic goiter, and healthy controls. Patients with GD had a significantly higher number of stressful life events compared with toxic goiter and healthy controls. The addition of another control group was aimed to account for thyrotoxicosis. In a study of patients treated with iodine-131, patients with stressful events reached a hypothyroid status significantly earlier than controls. Thus, stress has been shown to potentiate the development of hypothyroidism in patients receiving a standard dose of radioiodine [84]. Fukao et al. [85] examined the effect of emotional stress and patients’ personality traits on hyperthyroid status in antithyroid-treated GD patients who are currently at euthyroid levels. They found that higher stress scores were associated with higher levels of Thyroid-stimulating hormone (TSH) receptor antibodies and larger thyroid volume after treatment termination.

Stress and Hashimoto’s Disease Martin au Pan et al. aimed to investigate whether stress and pregnancy could induce Hashimoto’s disease [86]. The authors enrolled 95 patients with Hashimoto’s thyroiditis (HT) and 97 with benign thyroid nodules as controls, and no significant differences were noted between the two groups [86]. The evaluation of the role of stress remains a challenge because HT is slow in onset and patients are usually discovered only when they develop overt hypothyroidism [87].

STRESS AND TYPE 1 DIABETES MELLITUS Type 1 diabetes mellitus (T1DM) is a chronic disease characterized by insulin deficiency as a consequence of autoimmune destruction of pancreatic β-cells. Genetic susceptibility and environmental factors have been shown to precipitate T1DM [88]. Stressful events have been suggested to play a role in the onset of both type 1 and type 2 diabetes. From as early as the 17th century, Thomas Willis, an English physician, linked the disease onset to prolonged sorrow [89]. A Swedish case control study set to investigate the role of psychological stress on the emergence of diabetes. New onset T1DM children, aged 0–14, were enrolled in the investigation and the findings suggested that stressful events in

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the vulnerable age group 5–9 may be associated with disease development [90]. In another report, 67 T1DM patients 0–14 years of age were compared to 61 matched healthy control subjects. When compared with controls, T1DM patients showed more statistically significant negative stressful events during the first 2 years of life (P = .039). This indicates that negative events may be a risk factor for T1DM [91]. The influence of stressful life events and glycemic control has been the focus of various reports. Lloyd et al. [92] examined the occurrence of stressful experiences in 55 adult patients with T1DM, mean age 27.6 ± 8.9 years old, average duration of diabetes 12.7 ± 8.0 years. Subjects with poor glycemic control (HbA1c > 7.7%) were significantly more likely to report severe personal stressors 1 month before HbA1c measurements compared with patients whose glycemic control remained fair or improved (43% and 25% vs. 7% and 0%, P = .000). A metaanalysis of randomized controlled trials on the effectiveness of psychological therapies in improving glycemic control in patients with T1DM was performed [93], totaling 543 participants (children and adolescents). The mean standardized effect sizes were −0.35, 95% CI -0.66 -0.04, P = .03, translating to a reduction in glycosylated hemoglobin of 0.48%, a level sufficient to decrease the microvascular complications of diabetes [94]. This demonstrates that psychological treatment can help improve glycemic control in children and adolescents.

SYSTEMIC SCLEROSIS AND STRESS Systemic sclerosis (SSc) is a chronic multisystemic connective tissue disease. Scleroderma is divided into diffuse and limited cutaneous forms based on the extent of skin involvement [95]. Stress has been proposed to play a factor in disease pathogenesis, progression, and exacerbation. Chen et al. [96] investigated the occurrence of stressful events prior to SSc onset in 40 patients and found that SSc subjects reported a higher number of stressful life events in all measured categories than controls (P < .05), highlighting the association between stress and SSc onset. Another report found that prior to disease onset, 72% of the SSc respondents reported increased psychological stress, 50% reported emotional and personal problems, and 40% had a history of anger and anxiety [97]. Few studies discuss the association between stress and SSc. Further investigations of the association between stress and SSc are needed.

STRESS AND PEMPHIGUS Pemphigus entails a collection of various autoimmune conditions characterized by blistering. Robust reports have implicated the role of certain environmental causes, including infections, dietary factors, and emotional stress, in pemphigus disease onset and propagation [98]. Several case reports highlight the role of stress in modulating various aspects of disease onset and exacerbation [99– 101]. Brenner et al. [100] report two cases of pemphigus developing after war-related stress. Tamir et al. [101] documented a 68-year-old woman who did not improve with standard treatment; however, the addition of anxiolytics resulted in gradual healing. Additionally, one prospective epidemiological study showed stressful events graded as “important” life events occurred in numerous patients 1–6 months prior to first signs or worsening of pemphigus, highlighting the role of stressful events in the disease course [102]. The exact pathomechanism of stress and pemphigus remains obscure. However, during stress, the skin is a prominent target for CRH, cortisol, catecholamines, and substance P [103]. Exposure of animals to stress has shown increased cutaneous inflammation, perifollicular accumulation of antigen-presenting cells, and mastocyte degranulation [104]. Taken together, these observations underscore the putative role of stressful events in inducing and worsening disease activity.

CONCLUSION The relationship between stress and autoimmune diseases appears to be complex and intricate. A formidable amount of evidence supports the association and role of stress in influencing various aspects of autoimmune diseases including disease onset, severity of disease, and exacerbations. Active management of stress through various psychological techniques demonstrates significant benefits on disease outcomes and quality of life. Given the interrelation between these two factors, clinical physicians should encourage patients with autoimmune disease to seek stress management practices as part of their daily routines.

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330  SECTION | V  The Novel Environmental Factors Associated With Autoimmunity

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