Stress and the skin: exploring the associations between perceived stress and self-reported skin symptoms and signs
Thomas Jonathan Stewart
A thesis in fulfilment of the requirements for the degree of
Master of Medicine (by research)
School of Medicine
Faculty of Medicine
November 2018
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THE UNIVERSITY OF NEW SOUTH WALES
Thesis/Dissertation Sheet
Surname or Family name: Stewart
First name: Thomas
Abbreviation for degree as given in the University calendar: MRes
School: Medicine Faculty: Health
Title: Stress and the skin: exploring the associations between perceived stress and self-reported skin symptoms and signs
Abstract
Background & Aims: A connection between psychological stress and the skin has been recognised for many years. Although laboratory-based research has uncovered sound pathogenic mechanisms and clinical research has successfully linked stress with a number of skin diseases, less has been made of the skin symptoms and signs that are experienced in the non-healthcare seeking population in association with stress. This thesis aims to assess whether increased levels of perceived psychological stress are associated with presence of skin symptoms and signs in Australian university students.
Methods: A comprehensive review of the literature on the associations between stress and established skin diseases was undertaken. This review examined proposed underlying pathologic mechanisms as well as clinical studies investigating the relationships between perceived stress and skin disease. After institutional approval, an electronic cross-sectional survey using the validated Perceived Stress Questionnaire and a modified Self-Reported Skin Questionnaire, was distributed to 5000 students at a single university. The results of these questionnaires were analysed using logistic regression to assess whether increased levels of perceived psychological stress are associated with presence of the studied skin symptoms and signs.
Results: 471 participants successfully completed the survey and were included in the study. Subjects with higher levels of stress were statistically significantly more likely to report the presence of itch
2 (p<0.001), dry/sore rash (p<0.001), scaly skin (p<0.001), hair loss (p<0.001), other rashes on face (p<0.001), itchy rash on hands (p<0.001), troublesome sweating (p=0.003) or hair-pulling (p<0.001). No association was found between stress and: pimples, oily/waxy patches on scalp or flakey scalp, warts, or nail-biting. The results are discussed with reference to the existing literature on skin symptoms, signs and diseases.
Conclusion: The results support the hypothesis that an increase in perceived stress is associated with an increased likelihood of self-reporting a number of skin symptoms and signs in a nonhealthcare-seeking population. These findings may have significant implications for the self- management of skin morbidity with coexistent stress. The utility of perceived stress- and skin symptom- and sign-based tools in psychodermatology research is not yet fully elucidated.
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5 Index Page
Acknowledgements 9
List of Abbreviations 10
List of Figures and Tables 12
Chapter 1 Introduction 13-15
Chapter 2 Literature Review 16-52
2.1 Stress is still largely a concept, not easily defined 16
2.2 Historical theories of stress 17
2.3 Contemporary theories incorporating psychological concepts 18
2.4 Current working definition of stress 19
2.5 How stress has been handled in research 20
2.6 Stress response models 21
2.6.1 Posttraumatic stress disorder 23
2.7 Stress and pathology 24
2.8 Stress and the immune system 25
2.9 Central immune response to stress: But is it also in the skin? 28
2.10 Stress and skin immunity 28
2.10.1 Stress-skin components 29
2.10.2 Innate immunity 29
2.10.3 Adaptive immunity 31
2.11 Stress and dermatologic diseases 32
2.11.1 Pruritus 32
6 2.11.2 Dermatitis - Atopic 34
2.11.3 Dermatitis - Allergic contact 36
2.11.4 Dermatitis - Seborrhoeic 37
2.11.5 Urticaria 39
2.11.6 Rosacea 41
2.11.7 Acne vulgaris 43
2.11.8 Psoriasis 44
2.11.9 Alopecia Areata 46
2.11.10 Telogen Effluvium 47
2.11.11 Hyperhidrosis 48
2.11.12 Trichotillomania 49
2.11.13 Humanpapillomavirus (warts) 50
2.12 Gaps in the literature 50
2.13 Research question and hypotheses 52
2.14 Research aims and objectives 52
Chapter 3 Methods 53-59
3.1 Study population, recruitment and execution 53
3.2 Ethical considerations 53
3.3 Perceived Stress Questionnaire 54
3.4 Self-reported Skin Questionnaire 57
3.5 Inclusion criteria and final participant numbers 58
3.6 Statistics and data analysis 59
7 Chapter 4 Results 60-69
4.1 Demographic description of the study population 60
4.2 Stress levels in the study population 61
4.3 Skin symptoms and signs in the study population 62
4.4 Relationship between stress levels and skin symptoms 63
4.5 Results conclusions 69
Chapter 5 Discussion 70-80
5.1 Discussion of stress-skin associations 70
5.2 Study limitations 76
Chapter 6 Conclusions and future research 80
Chapter 7 Publications/presentations arising from this research 81
Chapter 8 Appendices 82
Chapter 9 References 99
8 Acknowledgements
Drs. Margot Whitfeld and Winnie Tong, who served as supervisors guiding me in the development, execution and construction of this thesis.
Dr Boaz Shulruf for his assistance with the statistical analyses
Robert Brown, of UNSW Student Life and Learning, who assisted in the electronic dissemination of the study survey.
9 List of Abbreviations
AA Alopecia Areata CU Chronic urticaria
ACD Allergic Contact Dermatitis DHEA-S Dehydroepiandrosterone Sulfate
ACTH Adrenocorticotrophic Hormone DNA Deoxyribonucleic acid
AD Atopic Dermatitis GI Gastrointestinal
AMP Anti-Microbial Peptides HH Hyperhidrosis
AOR Adjusted Odds ratio HPA Hypothalamic-Pituitary Adrenal
APC Antigen Presenting Cell HPV Humanpapillomavirus
BALB/c Albino, laboratory-bred stain of HREC Human research ethics committee house mouse IBM International business machines BDNF Brain-derived neurotrophic factor IFN Interferon BFRB Body-Focused Repetitive IL Interleukin Behaviours LC Langerhans Cell CGRP Calcitonin gene-related peptide NF-kB Nuclear Factor Kappa Beta CHS Contact Hypersensitivity NGF Nerve Growth Factor CI Confidence Interval OR Odds ratio CIU Chronic Idiopathic Urticaria PNS Peripheral Nervous System CNS Central Nervous System POMC Proopiomelanocortin CRF Corticotrophin-releasing Factor PSQ Perceived Stress Questionnaire CRH Corticotrophin-Releasing Hormone PTSD Posttraumatic Stress Disorder CRP C-Reactive Protein
10 SAM Sympathetic Adrenal Medullary TE Telogen Effluvium
SD Seborrhoeic DermatitisSNS TNF Tumour Necrosis Factor Sympathetic Nervous System TTM Trichotillomania SP Substance P UNSW University of New South Wales SPSS Statistical Package for the Social UV Ultraviolet Science VIP Vasointestinal peptide SRSQ Self-Reported Skin Questionnaire
11 List of Tables and Figures
Tables Pg.
1. Distribution of students by age 60 2. Frequency of skin symptoms and signs in the study population 62 3. Logistic regression analysis of stress vs. itch 63 4. Logistic regression analysis of stress vs. dry/sore rash 63 5. Logistic regression analysis of stress vs. scaly skin 64 6. Logistic regression analysis stress vs. itchy rash on hands 64 7. Logistic regression analysis stress vs. pimples 65 8. Logistic regression analysis stress vs. other rashes on face 65 9. Logistic regression analysis stress vs. warts 66 10. Logistic regression analysis stress vs. troublesome sweating 66 11. Logistic regression analysis stress vs. hair loss 67 12. Logistic regression analysis stress vs. oily, waxy patches on scalp or flakey scalp 67 13. Logistic regression analysis of stress vs. nail-biting 68 14. Statistical analysis of stress vs. hair-pulling 68 15. Compilation of p values for all skin symptoms and signs 69
Figures
1. Perceived Stress Questionnaire 55 2. Modified Self-Reported Skin Questionnaire 57 3. Distribution of students by faculty 61 4. Distribution of participants by PSQ index 62
12 Chapter 1 - Introduction
A belief in the connection between the mind and body has existed for centuries. In ancient Greece, three doctors (‘knife’, ‘herb’ and ‘word’) routinely would see a patient together, with the understanding that thoughts, feelings and attitudes affect biological functioning, and physical health can affect the mental state (Kleisiaris, Sfakianakis, & Papthanasious, 2014). Lending credence to this, modern research has increasingly suggested that the mind and body collaborate to maintain health. An example is the gut-brain axis which involves bidirectional communication between central and enteric nervous systems linking emotional and cognitive centres of the brain with peripheral intestinal functions. Psychological stress, which will refer to the psychological, emotional and behavioural response to perceived threat, harm or loss (Dougall & Baum, 2011), has been shown to affect this axis with suspected involvement in conditions such as inflammatory bowel disease (Carabotti, Scirocco, Maselli, & Severi, 2015). The skin is also an immediate stress perceiver as well as a target of stress responses (Chen & Lyga, 2014).
Not only does stress have an important role in disease states but also in cutaneous health. There is good evidence to show that the course of various skin disorders is affected by psychological stress (Champion RH, Burton JL, 1992; Narang, 2017). In many cases, it remains unclear if the exact role of stress is causative, consequential, or both. To date, the impact of stress has been predominantly examined in conditions in which inflammation is thought to be the chief aetiological mechanism e.g. psoriasis and atopic dermatitis (AD). The key pathways that have been proposed linking stress to skin conditions revolve around inappropriate activation of inflammatory cascades, autonomic dysfunction and adaptive behaviours leading to physical damage. The relevance of laboratory-based theory to the clinical setting is being increasingly realised. (Chen & Lyga, 2014; Hall et al., 2012).
‘Psychodermatology’, ‘psychoneurocutaneous medicine’ and ‘psychocutaneous medicine’ are terms used to encompass the interaction between mind and skin, with ‘psychocutaneous medicine’ possibly the most commonly used. There is not a universally accepted classification system of psychocutaneous diseases, however the most widely accepted classification is that proposed by Koo and Lee (Koo JYM, 2003). This classification consists of three groups: (1) psychophysiological disorders, (2) psychiatric disorders with
13 dermatologic symptoms and (3) dermatologic disorders with psychiatric symptoms. Psychophysiologic symptoms, which will be the main focus of this work, occur in individuals who do not have a primary psychiatric disorder but in which psychological factors (e.g. stress) appear to precipitate or exacerbate dermatologic symptoms, such as itch. The skin signs that are discussed will be what appears on the skin such as dryness or flakey skin, without requiring a medical diagnosis to be made.
Research investigating the influence of stress in skin disorders has largely focused on single, physician-diagnosed diseases in the medical clinic setting (Schut et al., 2016). Early laboratory work however, examined the effects of stress on skin in the non-diseased state (Segerstrom & Miller, 2004). The pathogenic role of stress in skin diseases is being increasingly elucidated by means of laboratory-based animal studies (Firdaus S. Dhabhar, 2013). The translation of this evidence to humans in the clinical setting is evolving. Early researchers did not have access to validated stress measurement tools which made their findings difficult to interpret outside the setting in which they were studied. Knowledge of the pathogenesis of many skin diseases is increasing and greater understanding of the pathophysiological mechanisms of skin symptoms (e.g. itch) in relation to stress may contribute to the development of improved therapeutic options (Chida, Steptoe, Hirakawa, Sudo, & Kubo, 2007).
In order to further examine the relationship between psychological stress and skin morbidity, a cross-sectional study was performed in a nonhealthcare-seeking population looking at the following hypotheses:
An association exists between perceived psychological stress and self-reported skin symptoms and signs
So as to explore these hypotheses, an electronic survey was distributed to a general student population at a large Australian university. The survey consisted of two standardised instruments, the Perceived Stress Questionnaire (PSQ) (Levenstein et al., 1993) and (2) the Self-Reported Skin Questionnaire (SRSQ) (F Dalgard, Svensson, Holm, & Sundby, 2003), to assess a group of self-reported skin symptoms and signs.
14 This thesis to follow is organised into five discrete chapters, of which this introduction is the first. The second chapter is a review of the relevant literature. The third is a description of the methods used in the cross-sectional study followed by the results in chapter four. Chapter five is a discussion of the significance and implications of the results. Finally, chapter six lists the conclusions of the thesis. The appendices include attachments relevant to the cross-sectional survey and copies of articles written as a result of, and in preparation of this research.
15 Chapter 2 - Literature review
Psychological stress is a topic of ongoing debate within academic circles but remains undisputedly, a universal and influential state of mind. Despite a lack of consensus on a complete definition or best means of measurement, significant advances have been made in the last three decades in understanding the complex interactions that occur between stress and disease states (França, Chacon, Ledon, Savas, & Nouri, 2013). There is a foundational and continually evolving body of evidence showing that stress can have important effects on physical and psychological disorders (Cohen, Janicki-Deverts, & Miller, 2007). This chapter is a literature review of the proposed connections between psychological stress and pathology, which will consider the conceptual models of stress, psychological systems that propagate the stress response, and the impact of stress on immune-mediated disease, with a focus on inflammatory skin conditions.
2.1 Stress is still largely a ‘concept’, not easily defined
The greatest challenge with studying psychological stress has always been establishing a practical definition. Review of historical and contemporary works has identified some common foundational concepts. It is generally accepted that stress is adaptive; a response to harm, actual or threatened, manifest with negative feelings or mood (Dougall & Baum, 2011). Beyond this however, there is little agreement. Some analysts have contended that stress can be positive, but others insist it is a strictly aversive state (Baum, 1990; Selye, 1984). Others have argued that simultaneous physiological and biological activation proves stress is an emotion, while others propose it to be a general state of arousal associated with taking action against a stimulus (Baum, 1990; Mason, 1971). In the past, it has been variously considered as a stimulus, response, and continuum of both. Fundamentally, stress represents a physiologic adjustment to environmental change and thus, has assumed a key role in the course of human evolution. These ideas all factor in the distillate of a few main theories which essentially converge on stress as a psychological, emotional and behavioural response to perceived threat, harm or loss (Dougall & Baum, 2011).
16 2.2 Historical theories of stress
Modern stress theory originated with Cannon’s work in the early 1900s (Cannon, 1914). He postulated that stressors provoked negative emotions which led to sympathetic nervous system (SNS) activation and disturbance of ‘homeostasis’ (C. Gross, 1998). Cannon proposed that release of sympathetic hormones (e.g. adrenaline) equipped the organism to respond to imminent harm i.e. fight-or-flight. This model did not consider measures of activation or persistence, rather focusing solely on sympathetic arousal (Cannon, 1914; Goldstein & Kopin, 2007). In the 1950s, Selye worked with hormone extracts in animal models, proposing a universal response to stress mediated by Hypothalamic-Pituitary-Adrenal axis (HPA) activation, which acted independently of the nature of the stimulus (General Activation Syndrome) (Selye, 1984). Later in the 1970s, Mason (Mason, 1971) combined Cannon and Selye’s ideas, proposing that stress affected multiple biological systems, extending that stress was an integrated catabolic reaction aimed at producing blood glucose levels sufficient to sustain resistance. Mason was the first to suggest that the nature of endocrinological responses to stress may be specific to the stimulus (Mason, 1971).
Numerous flaws have since become apparent in the earlier definitions of stress, however there is also important durability in this early work. Prolonged or excessive activation of the Sympathetic Adrenal Medullary (SAM) and Hypothalamic Pituitary Adrenal (HPA) axes are still widely recognised as the principal mediators of the pathophysiological stress response, and, in fairness, historical theories did intimate at some of the psychological aspects. For example, Cannon’s concept of critical stress levels inferred that organisms have thresholds, above which there may be pathogenic responses to threat. His thoughts around emotion also intimated at the need for a stimulus to be perceived as a threat in order to trigger a response (Cannon, 1914). Moreover, Selye’s theories of adaptive capacity to stressors being limited with eventual depletion of resources is consistent with ideas of ‘life change’ and aftereffects of stress (Selye, 1984). Whilst Selye did not at all acknowledge the importance of psychological factors in the stress response, as arguably the most prominent stress pioneer, he had an unrivaled influence on engendering later interest and popularising the topic.
17 2.3 Contemporary theories incorporating psychological concepts
Psychological models did indeed build on early biological theories but were developed mostly independently of this work. In the 1960s, Lazarus recognised the importance of the individual in the environment-stress interaction, and that an arbitrary event was not necessarily synonymous with resultant stress (Lazarus, 1966). Thus, he introduced the concept of perception and cognitive appraisal of a stressor, integrating this into his famous ‘transactional model’. The innovation was that, for stress to be experienced by an individual, it is a requirement that the event be appraised as harmful or threatening. Cognitive appraisal extended to individual coping strategies. Appraisal outcomes would then lead to negative emotions, but unlike previous models, it is the individual’s appraisal of the event and not the emotional sequelae, that predicts physiological and behavioural responses. Lazarus conceptualised stress as a dynamic process in which an individual is constantly reappraising situations as new information arises (Lazarus, 1966).
Lazarus, with Folkman, expanded on the original transactional model defining stress as the “relationship between a person and the environment, appraised as taxing or exceeding his or her resources and endangering his or her well-being”(Lazarus, RS, 1984, p.19). This update stressed the importance of integrated appraisal and coping resources. They hinted that an excessive response to stress not reconciled by coping efforts could result in disease states (Lazarus et al, 1984). McEwen et al more recently consolidated Lazarus and Folkman’s work proposing that a combination of background, psychological and environmental factors contribute to perception of an event, and introduced the concept of ‘allostatic load,’ or psychologically-induced ‘wear and tear’. Stress-induced physiological activation of SAM and HPA axes, which can be adaptive acutely or chronically, can lead to deleterious effects on other physiological systems (e.g. immune, metabolic, neurological) (Juster, McEwen, 2010; McEwen, 1998). This concept of allostatic load has provided a useful framework for organising research on stress-associated diseases.
18 2.4 Current working definition of stress
A common theme in stress concepts is adjustment to environmental change. Selye postulated that life involves perpetual change requiring adaptation. Much of this is minor and goes unnoticed, like the continual adjustments one makes to the handlebars of a bike in order to maintain a straight course. On the other hand, major stressors require more meaningful efforts to avoid potential harm, like a sudden deviation to avoid a veering car (Selye, 1984). Each adjustment involves a specific response (i.e. adjustment of handlebars) as well as a non-specific component, composed primarily of SNS and HPA arousal and physiological support for cognitive and behavioural adjustments. Activation of the nonspecific component supports adaptive coping as well as mechanisms enabling the organism to become more efficient and effective in executing the adjustments needed for successful adaptation. Together, the specific coping actions directed at threatening situations and the nonspecific activation supporting these responses may be considered ‘stress’ (Dougall & Baum, 2011; Selye, 1984).
There still exists great variability in the way stress is conceptualised. Most working definitions incorporate the key themes of adjustment and adaptation. Stress can perhaps be best defined as “a negative emotional experience accompanied by predictable biochemical, physiological and behavioural changes that are directed toward adaptation, either by manipulating the situation to alter the stressor or by accommodating to its effects” (Baum, 1990, p.653). In the event of a threat, both specific and non-specific responses are provoked, persisting until either the threat is removed or its effects have been reconciled. As such, stress is an adaptive process with the primary objective of changing a stressful situation or lessening and accommodating to its damaging effects. When faced with a stressor, physiological mechanisms respond by manufacturing a catabolic fight-or-flight reaction, and adverse health outcomes can result when these automatic protective responses become exaggerated or chronic. Ultimately, variability in the stress dynamic is also determined by factors that control appraisal of stressors and coping efforts (Dougall & Baum, 2011).
19 2.5 How stress has been handled in research
Operational definitions of stress have changed greatly over time. Historically, stimulus- based approaches were favoured, comparing groups exposed and not exposed to a given stressor. Stress was manufactured in the laboratory as immobilisation and mental tasks (Monroe & Slavich, 2016; Nesse, Bhatnagar, & Ellis, 2016). Self-reported life events lists were also commonly used, typically incorporating individual ratings of specific events on the degree of adjustment required for adaptation. The associations seen between life event scores and outcomes were reproducible, but modest (Goldstein & Kopin, 2007; Zimmerman, 1983). Further progress was made through the use of personal interviews enabling objective collection of data about each life event and its context, eliminating many biases inherent in self-reporting (Rosenman, Tennekoon, & Hill, 2011). This model was undeniably constrained by its relatively greater time and financial costs, however incorporation of contextual meaning resulted in a higher degree of associations observed. Using this method, life events and resulting difficulties were shown to contribute to the risk of developing several physical and mental conditions e.g. heart disease, depression (Brown, 1989).
The other major advance in stress measurement involved a greater focus on the ‘response’ to stress, with the premise being that the extent to which an event is perceived as stressful is a superior indicator to simply accounting for the event alone. It has become more widely recognised that individual differences in how events are experienced and situational factors dictating appraisals of stressors and the individuals ability to withstand them, are key determinants of responses and outcomes (Cohen, 2000; Lazarus, RS, 1984; Thompson, 2009). Researchers have been increasingly able to accurately measure cognitive, behavioural and physiological responses, before, during and after stress, correlating with health outcomes. Response variables that have been studied to date are perceptions of control, predictability, coping and availability of social support (Hassan et al., 2014; Nia, Aliloo, & Ansarin, 2010; Rosenbaum, White, & Gervino, 2012; Uchino & Garvey, 1997). As such, contemporary study designs have increasingly incorporated elements that examine the interactions of the perceiver and the situation and appraisals of the severity or likelihood of successful adaption (Dougall & Baum, 2011).
20 2.6 Stress response models
Several body systems are involved in the response to stress. Current stress models incorporate a range of processes affecting overall health, performance and well-being. The effects of stress are characterised in three main ways: (1) physiologically, (2) psychologically, and (3) adaptive behaviours (Dougall & Baum, 2011). Firstly, stressors can exert a direct influence on physiological processes (e.g. SNS, HPA axis) (Salleh, 2008; Segerstrom & Miller, 2004). Secondly, stress-altered psychological and cognitive states can affect task performance. Lastly, stress may lead to adaptive behaviours by altering the individuals motivations to accomplish tasks (e.g. exercise) or institute self-protective behaviours (Dougall & Baum, 2011). Through these various mechanisms, psychological stress has potential implications for the onset, course and management of almost all known major disease processes (Jafferany & Franca, 2016; Salleh, 2008).
Stress provokes several physiological responses to help the individual cope with threat. The effects are driven by cooperative activation of (1) Sympathetic Nervous System (SNS), (2) Hypothalamic-Pituitary-Adrenal axis (HPA), and (3) Peripheral Nervous system (PNS). In the SNS, stress-induced release of adrenaline and noradrenaline from the adrenal medulla leads to increased blood flow to vital organs (e.g. brain, heart) and diversion away from organs non-essential for fight-or-flight (e.g. GI tract), and these same catecholamines also act to enhance immune preparedness (Dougall & Baum, 2011). Concurrently, activation of the HPA axis with glucocorticoid release has multiple effects. Cortisol promotes the breakdown and conversion of amino acids into glucose, along with a state of ‘insulin resistance’ allowing for rapid utilisation by the body. It increases blood pressure and enhances the effect of catecholamines on cardiac output (Dougall & Baum, 2011; Salleh, 2008). Cortisol also plays an important role in countering the immune-stimulatory effects of the SNS. The PNS and efferent vagus also have a key role in immune modulation, as decreased vagal tone has been associated with inflammation (Chen & Lyga, 2014). Physiological stress responses can lead to organic and psychological disease states and the immune mechanisms underpinning this will be discussed in the next chapter.
Stress can have deleterious effects on task performance as, under stress, an individual’s focus and concentration naturally, is directed away from the task, consumed
21 rather by dealing with the stressor (Gilboa, Shirom, Fried, & Cooper, 2008). Exposure to a brief laboratory stressor has been shown to produce performance deficits in problem- solving both during, and following the exposure (Glass DC, 1972). Elevated stress has specifically been shown to impede performance on tasks that require divided attention, working memory, retrieval of information from memory and decision making (LeBlanc, 2009). These effects may be negligible when the task is minor but have the potential to lead to serious consequences in certain situations. Mundane daily tasks (e.g. monitoring a computer screen, balancing a bank account), are highly vulnerable to the effects of stress and are often work- or safety-related, and paying them insufficient attention can still lead to serious consequences. Stress-precipitated inattention and lack of concentration in the workplace has been linked to job loss, serious injury and even mortality (Gilboa et al., 2008; Kompier & Di Martino, 1995).
Psychological stress can provoke behavioural changes. These adaptations can increase exposure to harmful environmental factors. Studies have shown that stressed individuals are more likely to smoke cigarettes, consume alcohol in excessive amounts and lead sedentary lifestyles (De Vogli & Santinello, 2005; José, van Oers, van de Mheen, Garretsen, & Mackenbach, 2000; Kouvonen, Kivimäki, Virtanen, Pentti, & Vahtera, 2005). They are also more likely to engage in high-risk behaviours, such as unprotected sexual intercourse and intravenous drug use, which have been associated with sequelae such as heart disease, viral hepatitis and unplanned pregnancy (Chiasson et al., 2005; Kiviniemi MT, 2010). Stress-induced behaviours may also prove harmful through reduced treatment compliance. Patients experiencing higher levels of stress are less likely to satisfactorily comply with advice or medications prescribed by their physicians (Perez GK, 2011). Furthermore, stress associated with depression or anxiety has been shown to interfere with treatment of coexistent chronic diseases, increasing the risk of acute events such as myocardial infarction (Gustad, Laugsand, Janszky, Dalen, & Bjerkeset, 2014).
The multifactorial and broad influence of psychological stress on the individual demonstrates the importance of examining its effects on the body as an integrated whole, rather than concentrating on a single stress model alone such as the sympathetic-adrenal medullary system or alcohol misuse. Responses across all systems work cooperatively to facilitate adaptation by changing the situation and/or accommodating to its effects. This
22 relies on important patient-specific resilience and coping factors. By design, biological, cognitive and behavioural responses are adaptive in the short-term, but prolonged activation results in ‘wear and tear’ on the organism and increased vulnerability to adverse health outcomes (B. S. McEwen, 1998).
2.6.1 Posttraumatic Stress Disorder
Posttraumatic stress disorder (PTSD) is the prototypical stress response model. PTSD is an anxiety problem that develops in some people after extremely traumatic events such as combat, crime, an accident or natural disaster. Sufferers classically experience recurrence of three main symptom groups: (1) reliving the event, (2) emotional disconnect, with active avoidance of triggering stimuli and (3) heightened physiological arousal (American Psychiatic Association, 2013). PTSD is characterised by an abnormal physiological response profile and hyper-reactiveness to stress (Casada, Amdur, Larsen, & Liberzon, 1998). The effects of PTSD are wide-reaching, spanning across several domains of functioning.
In response to a ‘triggering’ stimulus, PTSD sufferers manifest heightened activation of biological processes. They exhibit chronic recurrent SAM activation with increased circulating levels of adrenaline, noradrenaline and their respective metabolites, as well as downregulation of adrenergic receptors (Southwick et al., 2007). Dysregulation of the HPA axis has been associated with PTSD, however the exact nature of this interaction is unclear (de Kloet et al., 2006). Cortisol suppression due to enhanced negative feedback to the adrenal glands has been shown in combat veterans (Southwick et al., 2007), whereas increased serum cortisol levels driven by an augmented adrenocorticotrophic hormone (ACTH) response to corticotrophin-releasing factor (CRF), has been found in other PTSD populations (Rasmusson et al., 2004). Serotonergic axis dysfunction is also typical in PTSD, manifest by symptoms of aggression, impulsivity and depression (Davis, Suris, Lambert, Heimberg, & Petty, 1997). PTSD has been associated with increased risk of developing angina, heart failure, asthma, bronchitis and peripheral artery disease, independent of lifestyle and behavioural factors (Spitzer et al., 2009).
23 Individuals with PTSD exhibit psychosocial symptoms and adaptive behaviours both dependent and independent of the physiologic component. Commonly reported psychosocial symptoms of PTSD include sleep difficulties, anxiety, dissociation and a propensity to startle (American Psychiatic Association, 2013). Anxiety and sleep difficulties have been associated with chronically elevated SNS activity (Williamson, Porges, Lamb, & Porges, 2014). Psychologically, PTSD is often associated with an increased risk of anger and aggressive behaviours as well as an increased propensity towards violence, but this link may be limited to concomitant alcohol abuse (Elbogen et al., 2014; Taft, Creech, & Murphy, 2017). PTSD sufferers misuse substances such as alcohol and illicit drugs at higher rates than controls (Berenz & Coffey, 2012). Avoidance behaviours increases their risk of developing psychiatric disorders such as depression and anxiety, as well as reduces their likelihood of accessing health care (Kazlauskas, 2017; Kessler, Sonnega, Nelson, & Bromet, 1995). PTSD represents not only a vehicle through which exposure to traumatic events may affect physical and psychological health, but also an independent risk factor.
Like other stress response models, PTSD morbidity is highly individualised. The delay between exposure to trauma and onset of symptoms is variable, and symptom triggers and frequency also differs greatly between sufferers. The posttraumatic stress experience occurs on a wide spectrum, spanning from having to look away during violent scenes in a movie to a catatonic reaction to fireworks. PTSD as a stress-response model illustrates the enduring importance of identifying specific factors in the individual and environment to determine risk of developing symptoms and/or disease. Risk factors that have been identified for developing PTSD are social support, perceived control and coping (Voges & Romney, 2003).
2.7 Stress and pathology
In addition to its self-evident impact on daily function such as arousal and metabolism, psychological stress can have profound effects on pathologic processes. There are several mechanisms that explain the connections between stress and disease states, of which immune dysregulation is possibly the most putative (Dougall & Baum, 2011).
24 The impact of stress is evident at several stages in the disease course. In addition to affecting onset, course and treatment of disease, there is good evidence that the experience of having chronic diseases themselves can also cause stress (Dougall & Baum, 2011). This bidirectional relationship has led analysts to propose that in many cases, a vicious cycle emerges where chronic disease first predisposes sufferers to psychosocial vulnerability which then compromises self-care, resulting in suboptimal management and worsening of their disease (Mayou, Peveler, Davies, Mann, & Fairburn, 1991). The important role of stress in disease processes will be highlighted by examining its effects on skin immunity and then predominantly, immune-mediated dermatoses.
2.8 Stress and the immune system
Psychological stress can affect the immune system through several mechanisms. The three main pathways are: (1) Sympathetic Nervous system (2) Hypothalamic-Pituitary-Adrenal axis, and (3) Parasympathetic Nervous system. The sympathetic-adrenal-medullary and hypothalamic-pituitary-adrenal axes possess direct and indirect connections with the immune system. Sympathetic noradrenergic fibres directly innervate primary and secondary lymphoid organs (Dougall & Baum, 2011) and almost all immune cells have receptors for at least one of the stress hormones. T & B lymphocytes, monocytes and macrophages display receptors for glucocorticoids (e.g. cortisol, corticosterone), substance P (SP), neuropeptide Y, prolactin, serotonin and catecholamines. The binding of stress hormones to an immune cell surface receptor (e.g. lymphocytes) triggers a cascade of reactions inside the cell that can elicit important changes in its function (Dougall & Baum, 2011; Reed & Ralson, 2016).
Stress hormones work to produce a large-scale redistribution of leukocytes, usually kept in the spleen, bone marrow and lymph nodes, out of these compartments into the bloodstream to ultimately be delivered to target organs e.g. skin, lungs (Schneiderman, Ironson, & Siegel, 2008; Segerstrom & Miller, 2004). Adrenaline and noradrenaline also influence immune activity indirectly by modulating production of proinflammatory cytokines such as IL-1, IL-2, IL-6, TNF-α, that affect various downstream target cells. Additionally, noradrenaline promotes nuclear factor kappa-beta (NF-kB) activation with increased gene expression of several mediators (IL-6, IL-8), which, in turn, further augment
25 inflammation (Firdaus S. Dhabhar, 2014; Reed & Ralson, 2016). Neuropeptide Y acts cooperatively with noradrenaline, enhancing leukocyte adhesion, platelet aggregation and macrophage activation (Reed & Ralson, 2016). Notably, these processes are bidirectional, such that cytokines feed back to the CNS and modulate the central activity of the SNS and HPA axes.
There is good evidence that the parasympathetic nervous system also modulates inflammation (Bonaz, Sinniger, & Pellissier, 2017; Pavlov & Tracey, 2012). Locally, the efferent vagus inhibits macrophage activation through parasympathetic outflow and release of acetylcholine. Acetylcholine downregulates inflammation by inhibiting production of proinflammatory cytokines such as IL-1 and TNF by macrophages (Bonaz et al., 2017; Reed & Ralson, 2016). This reflex may have systemic potential as vagus activity can be relayed to the medullary reticular formation, locus coeruleus or hypothalamus, and lymphoid organs receive vagal sensory innervation (Reed & Ralson, 2016). It is thought that stress leading to ‘vagal withdrawal’ may promote inflammation. Decreased vagal tone has been associated with the presence of increased inflammatory markers in healthy controls (Thayer & Fischer, 2009) as well as patients with cardiovascular disease (Haensel, Mills, Nelesen, Ziegler, & Dimsdale, 2008; Janszky et al., 2004).
In essence, this evolutionarily-conserved ‘stress response’ is designed to help the individual swiftly and appropriately deal with, and ultimately survive impending physical threat. An important limitation is that stress-induced enhancement of the immune system in this context can prove harmful if it exacerbates existing autoimmune or inflammatory disease due to chronic activation (Dougall & Baum, 2011).
Prolonged or exaggerated activation of the HPA and SAM axes leads to permanent changes in the stress response led by a blunted morning cortisol release on a background of increased basal secretion. The HPA axis plays a critical negative-feedback role by dampening down the ‘proinflammatory’ immune response when it is no longer required, however, under chronic stress, insufficient glucocorticoid signaling or resistance can result. This may be due to exhaustion of cortisol supply from the adrenal cortex with decreased negative feedback or hyperactivation of the HPA axis leading to overexposure of cortisol and increasing resistance of receptors to its effects (Peters, 2016; Reed & Ralson, 2016).
26 Hormonal disturbance in turn produces changes in the immunological response pattern in order to facilitate adaptation to chronic stress. Under chronic stress, anti-inflammatory cytokines such as IL-4 and IL-5 are preferentially released to suppress the initial, predominantly cellular, immune response (Firdaus S. Dhabhar, 2013; Eva M.J. Peters, 2016). Overall, there is a switch from innate non-specific immunity and an adaptive cellular Th1 weighted response, to an adaptive Th2 profile and predominance of humoral immunity (Schneiderman et al., 2008; Segerstrom & Miller, 2004).
This shift in immunological response pattern is somewhat advantageous for the organism as, not having to switch off an acute inflammatory response conserves energy and minimises collateral damage caused by excessive inflammatory reactions. However, at the same time, the nonspecific innate immune response is now suppressed and the organism is thereby poorly equipped to ward off new microbes. Moreover, errors can occur in the distinction between foreign and self, leading to the development of autoimmune disease in the non-suppressed state (Eva M.J. Peters, 2016). Some research has suggested that these stress-induced immune changes can be moderated by individual traits and coping mechanisms. Trait-negative affect may influence the magnitude of stress-induced suppression of immune function (Marsland & Cohen, 2001a), whereas a greater positive affect trait has been associated with faster skin barrier recovery after an acute psychological stressor (Robles, Brooker, & Pressman, 2009). In melanoma patients, associations were found between lymphocyte subpopulations and possession of certain coping strategies (Trapp et al., 2016).
In summary, autonomic and neuroendocrine activation in response to stress is protective up to a point, but excessive activation may have deleterious long-term sequelae. The metabolic demands of contemporary psychological stressors are minimal and as such, strong autonomic and neuroendocrine activation is often unnecessary and instead may lead to the development of immune-mediated disease and increased inflammation beyond what is required.
27 2.9 Central immune response to stress: But is it also in the skin?
The above neuroendocrine stress models are well elucidated and some of the resulting cutaneous effects are highly intuitive (e.g. pallor with vasoconstriction, increase in sweating). However, in order to understand many of the more complex interactions that occur between stress and cutaneous immunity, it is important to recognise that the immune system reacts to stress mediators at both a central and peripheral level (Eva M.J. Peters, 2016). Receptors for stress mediators are present on every cutaneous and skin-infiltrating cell in the immune system. This includes components of innate immunity such as mast cells, Langerhans cells and neutrophils, as well as adaptive immunity, such as T & B lymphocytes (Dougall & Baum, 2011; Reed & Ralson, 2016).
2.10 Stress and skin immunity
Research has confirmed skin as both an immediate stress perceiver and a chief target of stress responses. As the body’s most external and largest organ, the skin plays a key role in barrier and immunologic function, maintaining homeostasis between external and internal environments. Skin receives sensory input from external stressors (e.g. heat, pain, mechanical stress) and three types of receptors (nociceptors, thermoreceptors and mechanoreceptors) are responsible for transmitting these signals to the spinal cord and then to the brain. The CNS processes and then responds to these signals, which in turn coordinates stress responses in the skin. Skin and its appendages are not only targets of stress mediators, but also a local source of these factors which engineer various immune and inflammatory responses. Stress has effects on cutaneous innate and adaptive immune function through the SAM and HPA axes, peripheral (peptidergic) sensory nerves and skin resident cells (Alexopoulos & Chrousos, 2016; Eva M.J. Peters, 2016). This section will provide an overview of the key players mediating the interactions between psychological stress and skin immunity at the central and local levels.
28 2.10.1 Stress-skin components
Skin possesses the requisite architecture to be highly responsive to psychological stress. This is intuitive as it would be redundant to be equipped to respond to a threat (lion hunting you) without being able to survive the aftereffects (skin laceration). Human skin expresses Corticotrophin-Releasing Hormone (CRH) and its receptors. CRH-R1α is the predominant receptor type in skin and is displayed on all major cell populations in the epidermis, dermis and subcutis. CRH-R2α is expressed mostly in hair follicles, sebaceous and eccrine glands, muscle and blood vessels (Slominski et al., 2006). CRH protein, as well as mRNA and protein products for CRH-R1 and 2 have been found in stressed murine models (Stinnett, Westphal, & Seasholtz, 2015). Skin produces proopiomelanocortin (POMC) and POMC-derived peptides, precursors to ACTH and other polypeptide products (Rousseau et al., 2013). Human hair follicles synthesize cortisol as well as several other neuroendocrine mediators such as catecholamines, prolactin and melatonin (Hall et al., 2012). Skin is highly innervated by sensory nerves that produce and respond to various neurotrophins and neuropeptides (e.g. SP). Important innate factors such as mast cells also reside within the skin (Alexopoulos & Chrousos, 2016; Chen & Lyga, 2014).
2.10.2 Innate immunity
The innate immune response consists of components that contribute to the immediate and generic immune defense in the skin. Innate components most vulnerable to the effects of psychological stress are the epidermal skin barrier, antimicrobial peptides, peripheral sensory neurons and mast cells (Hall et al., 2012)(Alexopoulos & Chrousos, 2016).
The stratum corneum is the outermost skin layer and provides important barrier protection against infection and fluid loss. In humans, increased perceived stress has been shown to impair function and delay recovery of the epidermal barrier (Choe et al., 2018; Orion & Wolf, 2012). Choi et al proposed that glucocorticoid-driven reduced synthesis of epidermal lipids may explain this effect (Choi et al., 2005). Antimicrobial peptides, another evolutionarily-conserved pillar of the innate cutaneous immune response, are downregulated in mice subjected to sensory stress, who when subsequently exposed to
29 Streptococcus pyogenes, developed more severe infections compared with controls (Aberg et al., 2007). Stress stimulates mast cell activation and release of IL-6 which can cross the blood brain barrier and secondarily activate the HPA axis. IL-6 can induce lymphocyte activation and increase antibody production via CD4+ T cells (Hall et al., 2012). Mast cells and leukocytes residing in the dermis are activated by and display receptors for CRH. Asadi et al showed that SP, a known local stress responder, can induce expression of CRH receptor-1 and stimulate human mast cells (Asadi et al., 2012). Mast cells play a critical role in neurogenic inflammation. In mice, restraint stress causes enhanced degranulation of mast cells compared with non-stressed controls. Pre-exposure sensory neuron destruction was also found to inhibit mast cell degranulation supporting a role for stress-induced neurogenic inflammation independent of the HPA axis (Singh, Pang, Alexacos, Letourneau, & Theoharides, 1999).
Neuropeptides and neurotrophins released by cutaneous peripheral (sensory) nerve terminals serve as local stress responders that mediate neurogenic inflammation (Botchkarev et al., 2006). Based on available research, Nerve growth factor (NGF) appears to play a vital role in local protection. NGF promotes the proliferation of keratinocytes which provides protection against UV-induced apoptosis, as well as proliferation, migration and differentiation of fibroblasts into myofibroblasts, which could play a key role in wound healing (Chen & Lyga, 2014). NGF contributes to stress-induced cutaneous hyperinnervation and promotes neurogenic inflammation by stimulating cytokine release (IL-6) from mast cells (Marshall, Gomi, Blennerhassett, & Bienenstock, 1999). In a murine model, stress induced an increase in NGF and its receptor which in turn increased the number of SP- positive sensory neurons (Eva Milena J. Peters et al., 2004). Substance P is a key propagator of NGF effects and has been shown to be the main mediator of the brain-hair-follicle axis, by stimulating mast cell degranulation and increasing macrophage infiltration (Eva M.J. Peters et al., 2007). SP augments CRH-induced mast cell degranulation under stress, critical for neuroinflammation (Singh et al., 1999). SP also induces neutrophils, as well as release of various cytokines from monocytes and T cells, such as IL-1, IL-6 and IL-12, leading to T cell proliferation and inflammation (Mashaghi et al., 2016; C. Smith, Barker, Morris, MacDonald, & Lee, 1993). Downstream, these innate elements work cooperatively with the adaptive
arm.
30 2.10.3 Adaptive immunity
Stress has the potential to influence the development of the adaptive immune response at several stages. Through the actions of various mediators, stress has been shown to alter the numbers, distributions and function of immunologic cells (Segerstrom & Miller, 2004). This effect is no more evident than with APCs. Stress has been shown to reduce the density of Langerhans cells (LC) in the skin of humans and mice (Kleyn et al., 2008). Corticosteroids can induce apoptosis of LCs and impair their expression of costimulatory molecules e.g. CD25, CD205 (Hoetzenecker et al., 2004). Glucocorticoids can inhibit dendritic cell production of IL- 12, which may skew the Th1/Th2 balance toward Th2 (Panina-Bordignon et al., 1997; Kristina Seiffert & Granstein, 2006). Adrenaline has been shown to inhibit antigen presentation in epidermal cell preparations (K. Seiffert et al., 2002). Neuropeptides have also been shown to exert their own influence. Calcitonin gene-related peptide (CGRP) inhibits LC ability to present antigen to lymphocytes in vitro(Hosoi et al., 1993). Treatment of LCs with CGRP can reduce antigen presentation to Th1 T cells with deferred presentation to Th2 T cells (Ding, Stohl, Wagner, & Granstein, 2008). SP has been demonstrated to bind to human LCs thus impairing proliferative responses (Staniek et al., 1997). Adaptive factors act independently and in concert with innate elements, both centrally and peripherally, to propagate the effects of stress on immune function. In addition to enhancing innate cutaneous immune responses, short-term stress experienced at the time of re-exposure to an antigen can also affect adaptive immune responses in skin. Dhabhar et al found that compared with non-stressed controls, mice that were acutely stressed at the time of re-exposure to an antigen demonstrated a significantly larger number of infiltrating leukocytes at the site of the immune reaction (F. Dhabhar & McEwen, 1996). Other studies have similarly shown enhancement of the recall phase of cell- mediated immunity by various stressors administered at the time of antigen re-exposure, in mice, rats, hamsters and non-human primates (Bilbo et al., 2002; Coe, Lubach, & Ershler, 1989; Wood, Karol, Kusnecov, & Rabin, 1993). It has also been shown that short-term stress can enhance CHS responses in mice, but the variability of outcomes between studies suggests the sensitising agent and dose, nature and timing of stressor, and model type is important in this interaction (Bowers, Bilbo, Dhabhar, & RJ, 2008; F. S. Dhabhar & McEwen, 1999; Flint, Miller, & Tinkle, 2000; Nakano, 2007; Popov, Mirkov, & Kataranovski, 2012).
31 Similarly, studies investigating the impact of chronic stress on skin immune responses have shown chronic restraint stress to produce either suppression or enhancement of CHS responses in mice (Bowers et al., 2008; F. Dhabhar & McEwen, 1997). There appears to be a good basis for an association between stress and changes in adaptive immunity, however further work is required to better define the specifics of these interactions.
In conclusion, psychological stressors and stress-related molecules (e.g. glucocorticoids, adrenaline, and noradrenaline) have been shown to impact various cell behaviours, costimulatory molecule expression and cytokine profiles of immune cells in skin adaptive immune responses, including dendritic cells and lymphocyte immune cell subsets. Research has shown that the skin is not only a target of psychological stress but also an active participant in the stress response, through production of local HPA axis components, peripheral nerve endings and resident skin cells (e.g. mast cells). There are bidirectional communication pathways between the brain and skin, which play key roles in integrating these interactions.
2.11 Stress and dermatologic diseases
This section will discuss a selection of skin diseases that are common, encompass the symptoms and signs included in the surveys and are traditionally classified as psychocutaneous disorders. The proposed mechanisms underlying these associations are predominantly ‘inflammatory’, however also include autonomic dysfunction (e.g. hyperhidrosis) and adaptive behaviours (e.g. trichotillomania). Pruritus will be discussed separately as a medically-definable skin symptom. Warts will also be discussed as, immune function, which is known to be stress-reactive is also heavily involved in the natural history of humanpapilloma virus infection.
2.11.1 Pruritus
Pruritus is the unpleasant sensation that leads to the need to scratch. It is a medically- definable symptom. One third of the population experiences itch each week and it alters
32 quality of life and is frequently associated with psychiatric comorbidity, of which stress has been shown to be both precipitative and consequential (Laurent Misery et al., 2018). There are six broad aetiological categories: dermatological, systemic, neurological, psychogenic mixed and other, with skin diseases being the leading cause (Laurent Misery et al., 2018; Ständer et al., 2007) and the others will not be discussed. Several common skin diseases such as atopic dermatitis and psoriasis have itch as a principal symptom. Stress has been implicated in the worsening of pruritic symptoms in atopic dermatitis (Mochizuki et al., 2018). Itch also frequently occurs independently of identified organic disease, with a study reporting that 6.5% of patients attending a university dermatology department had somatoform pruritus, in which pruritus symptoms suggest an underlying medical diagnosis but no organic cause can be identified (Weisshaar et al., 2012). A high proportion of these patients are believed to have a psychological contribution to their condition and, ‘psychogenic pruritis’ has been defined as an itch disorder where itch is at the centre of the symptomatology and psychological factors may play a role in the triggering, intensity, aggravation, or persistence of the pruritus (Laurent Misery et al., 2018).
Although all the neurologic pathways mediating itch are not fully understood, however it is generally accepted that transmission of signals along histamine-sensitive and nonhistamine-sensitive peripheral C-nerve fibres is involved. Histamine sensitive fibres transmit acute itch and nonhistamine nerve fibres have a role in transmission of chronic itch (Azimi, Xia, Lerner, & General, 2017). Signal transmission is effected through the action of several neural mediators on sensory nerves such as histamine, opioids, substance P, nerve growth factor, interleukins and prostaglandins (Metz & Ständer, 2010; Yosipovitch, 2007). The itch stimulus travels via primary afferent C neurons to the cerebral cortex where multiple sites in the brain are activated including sensory and motor function, as well as emotion (Davidson & Giesler, 2010; Ikoma, Steinhoff, Ständer, Yosipovitch, & Schmelz, 2006). Scratching acts to inhibit the itch sensation by activation of inhibitory local circuits in the CNS resulting in the release of endogenous opiates (Sun et al., 2018; Yosipovitch et al., 2008). Chronic pruritus can lead to central sensitisation for itching (Ikoma et al., 2006). Thus, there appear to be several inputs, pathways and moderators of the itch sensation, which may contribute to its complex psychological and physical temperament.
33 Heightened psychological stress has been shown to be associated with higher levels of itch in the general population as well as in those with skin diseases e.g. atopic dermatitis (Oh et al., 2010; Yamamoto et al., 2009). As discussed previously, stress induces the release of various mediators (SP, NGF, interleukins), which are also possibly responsible for mediating the itch sensation under the influence of stress. Certain intrinsic personality factors, such as perceived self-efficacy, combined with stressful life events may render affected individuals more prone to developing pruritis (Florence, Robert, Lars, & Stuart, 2012; França & Jafferany, 2017). Coping has also been shown to be a mediator of the relationship between stress and itch in patients with atopic dermatitis and may serve problem solving and or emotional regulation functions (Grandgeorge & Misery, 2015; Schut et al., 2015). Beyond stress-enhanced mast cell degranulation, research has really only scratched the surface in elucidating the highly complex and multidimensional interactions that occur between stress and itch.
2.11.2 Dermatitis - Atopic
Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disorder that affects up to 20% of children and 3% of adults worldwide, and the incidence appears to be rising (Nutten, 2015). Hallmark features of AD are dry skin and severe itch that is associated with cutaneous hyperreactivity to environmental stimuli. Multiple factors are thought to be involved in pathogenesis, including skin barrier abnormalities, defects in innate immunity, Th2-skewed adaptive immune response and altered skin resident microbial flora (Kuo, Yoshida, De Benedetto, & Beck, 2013). It is still under debate whether skin inflammation is initiated by barrier dysfunction or immune dysregulation. There is good evidence to show that several psychological conditions and symptoms, such as impaired psychosocial functioning, depression and anxiety are more common among patients with AD (Gochnauer, Valdes-Rodriguez, Cardwell, & Anolik, 2017). The association between psychosocial distress and AD, proposed to be immunologically-based, may be influenced by perceived disease severity and other factors that negatively affect quality of life e.g. sleep loss (T. S. Kong, Han, Lee, & Son, 2016; Wittkowski, Richards, Griffiths, & Main, 2007)
34 Psychological stress has been connected with AD pathogenesis mostly through skin barrier dysfunction and immune dysregulation. The barrier function of the skin is comprised of corneocytes packed with keratin filaments embedded in a matrix of filaggrin breakdown products (Elias & Wakefield, 2014). This barrier blocks entry of environmental irritants, allergens and microbes and prevents excessive water loss. Filaggren deficiency is a major factor in barrier dysfunction, as well as imbalances between stratum corneum protease and anti-protease activity, tight junction abnormalities, microbial colonisation and release of proinflammatory cytokines (Leung, 2013). The epidermis of AD patients is characterised by a genetically impaired skin barrier function with increased transepidermal water loss (Seidenari & Guisti, 1995). Amit et al showed a decline in permeability barrier recovery in parallel with an increase in perceived psychological stress in AD patients (Amit, Chren, & Sands, 2001). Stress-aggravated itch (discussed in more detail in ‘pruritis’ 2.11.1) with resultant scratching may also contribute to morbidity through inflicted physical damage to epidermal integrity (Suarez, Feramisco, Koo, & Streinhoff, 2013).
Immune dysregulation utilises barrier dysfunction to contribute to AD pathogenesis. In normal skin, keratinocytes and antigen presenting cells express innate immune receptors (e.g. Toll-Like Receptors), which, when stimulated, lead to release of inflammatory mediators such as antimicrobial peptides (AMP) and various cytokines and chemokines, and enhancement of tight junctions, as a means of protection (Suarez et al., 2013). Patients with AD exhibit reduced Toll-Like Receptor 2/9 functioning which confers defective innate immune-mediated epidermal barrier repair (De Benedetto, Agnihotri, McGirt, Bankova, & Beck, 2009). Enhanced allergen entry through a defective skin barrier leads to skew in immune profile towards Th2 (Agrawal & Woodfolk, 2014). Furthermore, psychological stress has been shown to selectively preference Th2-immune responses through its effects on the HPA and SAM axes (Segerstrom & Miller, 2004). In AD, a predominance of Th2-type cytokines has been shown to lead to suppression of IL-17 and IL-22-mediated AMP production (H. H. Kong, 2015). These immunological changes are suspected to lead to an alteration in the skin microbiome with resulting heightened inflammation (B. E. Kim & Leung, 2018).
Research has examined the impact of cognitive and personality factors on stress- exacerbated atopic dermatitis. Atopic dermatitis sufferers exhibit a propensity for certain
35 personality traits that may increase susceptibility to the development or exacerbation of atopic dermatitis symptoms, especially under stress. Atopic dermatitis patients have shown significantly higher scores in trait anxiety and stress vulnerability, and significantly lower scores in positive self-concept, compared with controls (Buske-Kirschbaum et al., 2004). Schut et al showed a significant relationship between perceived stress and itch in atopic dermatitis patients, which was fully mediated by negative itch-related cognitions (Schut et al., 2015). Opportunistically, psychological interventions targeting stress have also been shown to exert positive effects on skin status, itch and scratching behaviour, in AD (Chida et al., 2007). In summary, there appears in the literature to be a strong immunological basis for the AD-stress dynamic, influenced by behavioural and cognitive factors. Despite this, AD remains largely managed by contemporary dermatologists without regard to psychosocial factors (França & Jafferany, 2017).
2.11.3 Dermatitis - Allergic Contact
Allergic contact dermatitis (ACD) is a T-cell-mediated, delayed-type hypersensitivity response to exogenous agents. Point prevalence of allergic contact dermatitis is around 20% (Mortz, Bindslev-Jensen, & Andersen, 2013). Acute ACD lesions consist of pruritic, erythematous, indurated, scaly plaques, typically localised to the skin areas that come in contact with the allergen. The agents most frequently implicated include nickel, tetraethylthiuram disulfide, and fragrances (Cahill et al., 2012). Disturbances in physical and psychosocial functioning have been reported in subjects with allergic contact dermatitis (Kieć-Swierczyńska et al., 2008). ACD has an appreciable effect on quality of life, especially when it affects the hands, face, or is occupationally-related (Kadyk, McCarter, Achen, & Belsito, 2003). The effects of psychological stress on contact hypersensitivity has been well- investigated in murine models (Hall et al., 2012). In these models, significant increase in the swelling response to allergen following restraint stress has been reported, however the nature of the response appears to depend on several factors such as type and dose of sensitising agent, as well as the nature and timing of the stressor (Bowers et al., 2008; Flint et al., 2000; Popov et al., 2012) (Firdaus S. Dhabhar, 2014).
36 In their murine models Nakano et al showed that an adaptive immune response was a fundamental requirement for acute stress-induced immunoenhancement in CHS (Nakano, 2007). Zhang et al demonstrated that restraint stress induced a series of immunological changes such as increased NF-kB DNA-binding activity and IL-18 mRNA expression in splenic lymphocytes, leading to enhancement of contact hypersensitivity response, suggesting that these changes were possibly mediated by the sympathetic nervous system (J. Zhang et al., 2010). Saint-Mezard et al recently proposed that release of noradrenaline by sympathetic nerve termini during a stress exerts an adjuvant effect on dendritic cells by promoting enhanced migration to lymph nodes, resulting in increased allergen-specific T cell responses (Saint-Mezard et al., 2016). Kitagaki et al showed that CHS symptoms could be reproduced with subsequent stress in the absence of further hapten application in mice, signifying development of a ‘de novo’ disease state (Kitagaki, Hiyama, Kitazawa, & Shiohara, 2014). Reproduction of these findings in human models has not yet been explored.
2.11.4 Dermatitis - Seborrhoeic
Seborrhoeic dermatitis (SD) is a chronic relapsing-remitting dermatitis that occurs across the lifespan. It is typically characterised by well-demarcated erythematous plaques with greasy- looking, yellow scales distributed on areas rich in sebaceous glands e.g. scalp, central face, upper trunk. The pathogenesis is not fully understood, however, studies have identified several predisposing factors including fungal colonization, sebaceous gland activity, as well as several factors that confer individual susceptibility. Sebum gland activity strongly correlates with SD; however, it does not appear to be a primary cause. Sebum glands may exert their influence through altered lipid composition providing a favourable milieu for malassezia. In SD patients, free fatty acids and cholesterol have been shown to be elevated and may promote malassezia growth (Ostlere, Taylor, Harris, Rustin, & Wright, 1996; B. Ro & Dawson, 2005). Malassezia has been shown to have lipase activity, which hydrolyses sebum triglycerides and releases unsaturated fatty acids such as oleic and arachidonic acid (DeAngelis, Sanders, Johnstone, Reeder, & Coleman, 2007). These metabolites cause aberrant keratinocyte differentiation resulting in stratum corneum abnormalities and disrupted epidermal barrier function which triggers an inflammatory response (Warner,
37 Schwartz, Boissy, & TL, 2001). Malassezia is detected on normal skin in healthy adults and topical application of oleic acid does not induce visible changes in non-SD subjects but causes flaking on non-lesional skin of SD patients, suggesting intrinsic epidermal barrier defects may be involved (DeAngelis, Gemmer, Kaczvincksy, Kenneally, & Schwatz, 2005).
Altered corneodesmosomal hydrolysis in SD may disrupt lipid organisation and disturb the desquamation process, leading to aberrant barrier function (Warner et al., 2001). In support of this, barrier abnormalities have been detected in dandruff-affected scalps by electron microscopy that included intercellular Malassezia yeasts, changes in corneocyte shape and corneodesmosomes, and disrupted lipid lamellar structure (Turner, Hoptroff, & Harding, 2012; Warner et al., 2001). Because no clear differences have been found in Malassezia levels between individuals with or without SD, it is likely that an immune or inflammatory reaction may add to predisposition (Dessinioti & Katsambas, 2013). A study found elevated levels of human leukocyte antigens and increased levels of total serum IgA and IgG antibodies have been detected in SD patients (Bergbrant, Johansson, Robbins, Scheynius, & Faergemann, 1991; Borda & Wikramanayake, 2015). However, no increase in the titers of antibodies against Malassezia was detected, suggesting that the elevated Ig production occurs rather as a response to yeast metabolites (Bergbrant et al., 1991; Borda & Wikramanayake, 2015; Parry & Sharpe, 1998). The strong inflammatory reaction provoked by these metabolites includes infiltration of natural killer cells and macrophages, with concurrent local activation of complement and an increased local keratinocyte production of inflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-8 and TNF-α in affected skin areas (Faergemann, Bergbrant, Dohsé, Scott, & Westgate, 2001). Activation of innate immunity through Toll-like receptors (TLRs) also seems to play a role. Keratinocytes infected with Malassezia furfur upregulate TLR-2, as shown by RNA analysis(Dattner, 2018). The lack of increase in anti-Malassezia antibodies also indicates a change in cellular immune response instead of humoral response (Ashbee, Ingham, Holland, & Cunliffe, 1994).
Stress and psychological comorbidity is recognised anecdotally to be linked with exacerbation of SD. However, formal clinical studies examining this link are few. Araya et al showed that 28.3% of patients reported emotional stress as the trigger of their SD flare (Araya, Kulthanan, & Jiamton, 2015). Misery et al showed SD is often preceded by a stressful
38 event, however, like the Araya study, patients were not compared with controls (L Misery et al., 2007). Peyri et al found that the most prevalent profile of a SD sufferer prior to flare was a history of stress, depression or fatigue (Peyrí & Lleonart, 2007). Gul et al showed neurotic personality characteristics were more frequent in SD patients (Gul, Karaaslan, & Çolgecen, 2017). There have been reports that sleep deprivation, a common consequence of stress, can exacerbate SD symptoms (Araya et al., 2015). A large UK study did not find any association between other stress adaptations such as smoking or alcohol consumption, and seborrhoeic dermatitis (Sanders, Pardo, Franco, Ginger, & Nijsten, 2018). Perhaps owing to the uncertainty about the relationship between stress and SD, no substantial attempt at explaining stress-SD pathogenesis was eminent in the literature.
2.11.5 Urticaria
Urticaria is a vascular skin reaction that classically presents as itchy, well-demarcated erythematous plaques. Chronic urticaria occurs when disease is present for at least 6 weeks. It affects up to 1% of the general population (Weller et al., 2010; Zuberbier, Balke, Worm, Edenharter, & Maurer, 2010). No external or allergic cause or contributing disease process can be identified in 80-90 % of patients. Most of the research in this area has been done in Chronic Idiopathic Urticaria (CIU) (synonymous with chronic spontaneous and symptomatic urticaria), which refers to chronic urticaria in which appearance of lesions is not triggered by any consistent or identifiable factors and it specifically excludes the physical urticaria syndromes and other inducible forms. Patients with CIU experience impairment in mental and physical health, and daily activities, shown to be comparable to moderate-to-severe psoriasis (Mendelson et al., 2017). There are several theories regarding the pathogenesis of CIU, none of which have been conclusively proven. The most well-founded mechanisms appear to involve histamine-releasing factors and defects in basophil signaling and/or function (Asero, Tedeschi, Marzano, & Cugno, 2017; Caproni et al., 2005).
Inappropriate activation and degranulation of mast cells as the key event in pathogenesis is well established. However, the triggering stimuli and interplay of effector mechanisms remain unclear. The original autoimmunity hypothesis is well documented but appears to be viable in only a minority of patients (Asero et al., 2017). More recently, it
39 received new support following the detection of autoreactive CD4+ T cells that proliferate in response to FcεRE in CU patients (Auyeung, Mittag, Hodgkin, & Harrison, 2016). Basopaenia is a well-established associate of CU and basophils from CU patients show different phenotypes that seem independent of the presence of autoantibodies or FcεRI (Eckman, Hamilton, Gober, Sterba, & Saini, 2008). Eosinophils activated by IgG autoantibodies have been detected in CU patients and may induce mast cell degranulation via tissue factor hyperexpression (Cugno et al., 2009). Inflammation also appears to have an important role, with various inflammatory markers (e.g. lipocalin-2, TNF-alpha. IL-6) consistently shown to be higher in patients versus controls (Trinh et al., 2016). More recently it was shown that serum from CU patents can induce significant activation of mast cells without high-affinity IgE receptor, suggesting an alternative pathomechanism (Cugno et al., 2016). It is most likely these different mechanisms are interlinked acting either synergistically or sequentially to produce mast cell degranulation and wheal formation.
CIU patients often report more severe symptoms during periods of psychological stress. However, evidence that psychosocial factors are in some way causative is lacking (Ben-Shoshan, Blinderman, & Raz, 2013). Studies exploring the pathologic links between stress and CIU are still in their relative infancy. The important role of mast cells in CU occurrence was shown in previous studies (Ucmak et al., 2013). It has been acknowledged that tryptase-positive chymase-negative mast cells might serve as an important source of IL- pro-inflammatory IL- 6 in CU (Nettis et al., 2001). IL-6 has been shown to increase in connection with psychological stress in CU patients (Ucmak et al., 2013). It is known that the increasing secretions of IL-6 occur during various immune-inflammatory processes including hypersensitivity reactions and autoimmune diseases (Papanicolaou, Wilder, Manolagas, & Chrousos, 1998). Varghese et al showed a significant correlation between stress scores and markers of systemic inflammation such as CRP and IL-18 in CIU patients, accompanied by lowering of basal cortisol levels, compared with controls (Varghese et al., 2016). One study showed decreased levels of serum dehydroepiandrosterone sulfate (DHEA-S) in patients with CU. DHEA-S is involved in neuroimmunomodulation and the response to stress, and may play a role in modulating vulnerability of the organism to the negative impact of stress (Kasperska-Zajac, 2011).
40 Research has also looked at other factors that might modulate the interactions between stress and CIU. Yang et al showed insomnia might be an important psychosomatic symptom predisposing to chronic urticaria. They showed good ego-function, coping strategies and family support were associated with decreased frequency of urticaria, and positive coping tendencies and good family support may have preventative effects (Yang, Sun, Wu, & Wang, 2005). CIU patients report higher levels of alexithymia (a personality construct characterised by the subclinical inability to identify and describe emotions in the self), than controls and their defense mechanisms are more likely to be categorised as defensive, with conscious self-image management reported alongside high manifest anxiety (Hunkin & Chung, 2012). Chung et al showed emotion-focused coping was associated with severity of CIU (Chung, Symons, Gilliam, & Kaminski, 2010). Patients with acute urticaria use emotion-focused coping and seek social support to a greater degree than patients with chronic urticaria (Zelic, Rubesa, Brajac, Peitl, & Pavlovic, 2016). Relaxation therapies, stress management could be useful in the complex approach to CIU (Manolache, 2013). However, some believe there may be a resistance of CU ‘psychosomatic’ patients to undertake psychological treatment (Berrino et al., 2006).
2.11.6 Rosacea
Rosacea is a chronic inflammatory skin disorder seen mostly in fair-skinned females. Estimates of prevalence range from 1 to 10% in fair-skinned populations (Elewski et al., 2011; McAleer, Fitzpatrick, & Powell, 2010). It affects the central face predominantly, presenting as any combination of flushing, erythema, telangiectasia, papulopustular eruption and rhinophyma. The original standard classification of rosacea identified the most common groupings of signs and symptoms and designated them as: subtype 1, erythematotelangiectatic; subtype 2, papulopustular; subtype 3, phymatous; and subtype 4, ocular (Gallo et al., 2018). Patients with rosacea report negative psychosocial effects such as low self-esteem and self-confidence, and decreased social interactions (Huynh, 2013). They report a number of factors that worsen their symptoms such as heat, sun, alcohol, spicy foods and medications, and it has long been suspected that emotion is related to flushing (Su & Drummond, 2012). Pathogenesis is still not fully understood, however,
41 proposed contributing factors include abnormalities in innate immunity, inflammatory reactions to cutaneous microorganisms, ultraviolet damage and vascular dysfunction (Rainer, Kang, & Chien, 2017).
Dysfunction of the innate immune system may contribute to the development of rosacea through the production of abnormal cathelicidin peptides. Cathelicidins exert vasoactive and inflammatory actions and have been detected at increased levels in skin from patients with rosacea (Yamasaki & Gallo, 2009). Skin microbes have been described as an inciting factor for inflammation, as well as Demodex folliculorum, a mite that resides in sebaceous follicles (Zhao, Wu, Peng, & Cheng, 2010). Bacillus olenorium, helicobacter pylori and staphylococcus epidermidis and their interactions with innate immunity have also been implicated (Lazaridou et al., 2011). Sun is often cited as an exacerbating factor in rosacea and ultraviolet B radiation has been shown to induce angiogenesis in mice and stimulate production of reactive oxygen species, and may incite activation of the innate immune system (Bielenberg et al., 1998; Brauchle, Funk, Kind, & Wener, 1996; Yamasaki & Gallo, 2009). Study data confirming this association are lacking however, with fewer than one- third of patients reporting exacerbations with sunlight (Crawford, Pelle, & James, 2004). Flushing and increased blood flow have also been associated with exacerbations. Mechanisms supporting neurovascular dysregulation in rosacea are not well understood but some suggest that activation of transient receptor potential Vanilloid-1 and transient receptor potential Ankyrin-1 may stimulate release of vasoactive peptides (Aubdool & Brain, 2011).
In addition to the aforementioned factors, studies have shown stress to be associated with worsening of rosacea symptoms (Drummond & Su, 2017; Sowińska- Gługiewicz, Ratajczak-Stefańska, & Maleszka, 2005; Su, 2008). Limited available research offers some potential insights into pathogenesis. It has been shown that stress can precipitate increased SNS activity leading to cutaneous vasodilatation. CRH, known to be elevated under stress, induces degranulation of mast cells that release vasodilatory mediators e.g. histamine and nitric oxide (Woo, Lim, Cho, & Park, 2016). Also, CRH can stimulate production of pro-inflammatory IL-6, IL-8, IL-18, which regulates mitogen-activate protein kinase, and NF-kB-light-chain-enhances of activated B cells leading to erythema (Woo et al., 2016). Stress adaptation behaviours may also contribute to pathogenesis
42 through obesity, smoking and alcohol, all of which have been implicated separately (Li, Cho, Drucker, Qureshi, & Li, 2017a, 2017c, 2017b). Su et al showed that stress perception and susceptibility to emotional arousal may even vary between rosacea subtypes, producing differential effects on axon reflex responses and blushing (Su, 2008). Cognitive behavioural therapy and task concentration training have been shown to be beneficial in managing stress in rosacea sufferers (Härtling, Klotsche, Heinrich, & Hoyer, 2016; Su, 2008).
2.11.7 Acne Vulgaris
Acne vulgaris is an inflammatory disorder of pilosebaceous follicles most synonymous with adolescence and young adulthood. It affects around 85% of the adolescent population and can occur throughout the lifespan, with up to 54% of adult females affected (Lynn, Umari, Dellavalle, & Dunnick, 2016; Perkins, Maglione, Hillebrand, Miyamoto, & Kimball, 2012). Acne manifests along a spectrum of open and closed comedones, inflammatory papules, pustules and nodules. Acne typically occurs on areas with hormonally-sensitive sebaceous glands, including the face, neck, chest, upper back, and upper arms. Due to its chronicity, and high visibility, acne often has negative psychological impact, interfering in domains such as dress, social interactions and schoolwork (Lasek & Chren, 1998). Sufferers can experience quite significant psychological morbidity, rarely resulting in suicide (Sundström et al., 2010). Pathogenesis is thought to involve a complex interplay between abnormal keratinisation, genetics, sebum production, inflammation and Propionibacterium acnes (Kumar et al., 2016). Patients frequently attribute worsening of their acne symptoms to increased stress. Studies formally exploring this interaction have started to emerge in the last 15 years.
In 2003, an important study by Chiu et al showed an association between perceived stress levels and acne severity in university students (Chiu, Chon, & Kimball, 2003). This prompted work into the possible pathogenic mechanisms. Several studies have uncovered important roles for the peripheral HPA axis and substance P. CRH and its receptor have been detected on sebocytes (Zouboulis et al., 2002). It has been shown that CRH promotes lipogenesis through upregulation of 3β-hydroxysteroid dehydrogenase isomerase and induces proinflammatory IL-6 and IL-11 production in keratinocytes, contributing to inflammation (Zbytek et al., 2002; Zouboulis et al., 2002). SP-positive nerve fibres have been
43 shown to be increased proximate to sebaceous glands and acne lesions in facial acne (Tyrka, Price, Kao, Marsella, & Carpenter, 2011). SP has several actions that can potentiate acne symptoms. It promotes proliferation and differentiation of sebaceous glands as well as induces expression of Peroxisome Proliferator-Activated Receptor gamma which stimulates lipogenesis (Lee et al., 2008). SP also stimulates release of proinflammatory IL-1, IL-6 and TNF-α from sebocytes and can activate mast cells (Singh et al., 1999). Currently, there is a solid basis for a pathogenic link, however consensus is lacking and more studies are needed.
Adaptive behaviours and cognitive factors have been preliminarily explored in the stress-acne dynamic. Social distress has been correlated with self-reported acne severity and found to be a barrier to sport or exercise participation (Loney, Standage, & Lewis, 2008). This may have important implications for the development of obesity and insulin resistance, both of which have been associated with increased risk of acne vulgaris (Aizawa & Niimura, 1995; Jon Anders Halvorsen, Vleugels, Bjertness, & Lien, 2012). Studies that have shown no association between stress and acne severity suggest the risk of psychosomatic disease depends on tolerance and methods of coping with stress. Poor self-concept and perfectionistic and compulsive personality traits correlated strongly with self-excoriative behaviours in women with facial acne (Gupta, Gupta, & Schork, 1996). As the mechanisms underpinning this relationship become better elucidated and the influence of other factors increasingly explored, greater clarify should follow.
2.11.8 Psoriasis
Psoriasis is a chronic systemic inflammatory disorder. It has no gender predilection and can occur at any age (Parisi, Symmons, Griffiths, & Ashcroft, 2013). It most commonly manifests clinically as erythematous cutaneous plaques affecting the scalp, extensor elbows and knees, and gluteal cleft. Other symptoms include pruritis, burning, stinging, sensitivity, pain and bleeding. Pathologically, psoriasis is characterised by inflammation, hyperkeratosis, increased epidermal proliferation, angiogenesis and abnormal keratinisation. Pathogenesis is generally understood to be multifactorial, involving a complex interplay of genetics, environmental and behavioural components. Psoriasis can have a significant impact on daily functioning and psychological well-being. Elevated rates of low self-esteem, sexual
44 dysfunction, decreased work productivity, anxiety and depression have been reported (Kimball, Jacobson, Weiss, Vreeland, & Wu, 2005). The literature supports an association between psoriasis and psychosocial stress (Hunter, Griffiths, & Kleyn, 2013; Stewart, Tong, & Whitfeld, 2018)(Appendix 5), the exact features of which remain uncertain, but appears to be mediated by a combination of immunological, behavioural and cognitive factors (Leibovici & Menter, 2016).
Immunologically, psoriasis is characterised by chronic excessive Th1/Th17 immunity and neurogenic inflammation (Cai, Fleming, & Yan, 2012). Experimental stress has been shown to lead to increasing circulating levels of CD4+ T cells, including skin homing forms (Buske-Kirschbaum, Kern, Ebrecht, & Hellhammer, 2007; Hall et al., 2012). CD4+ T cells produce proinflammatory cytokines such as IL-17 which activate the HPA axis within a vicious cycle leading to hyporesponsiveness and blunted cortisol response chronically. This leads to secondary upregulation of inflammatory cytokines (IL-6) and further inflammation (Evers et al., 2010; Kunz-Ebrecht, Mohamed-Ali, Feldman, Kirschbaum, & Steptoe, 2003). Locally, psoriatic lesions exhibit an increased number of peptidergic nerve fibers showing contacts with mast cells (Eva M.J. Peters, 2016). Psoriatic tissues express high levels of NGF compared with controls (Bracci-Laudiero & Pincelli, 1995; Siba P. Raychaudhuri, Jiang, & Farber, 1998). NGF contributes to inflammation by activating T lymphocytes and inducing chemokine expression from keratinocytes (Lambiase et al., 1997; S. P. Raychaudhuri, Farber, & Raychaudhuri, 2000). NGF can also contribute to keratinocyte proliferation and mast cell activation (Marshall et al., 1999). Downstream of NGF signaling, substance P and SP-positive neurons are increased in psoriatic skin (Naukkarinen, Nickoloff, & Farber, 1989). Levels of other stress-related neuropeptides (e.g. CGRP, VIP and BDNF) have also been shown to differ in psoriasis versus controls (Brunoni et al., 2015; Chan, Smoller, Raychaudhuri, Jiang, & Farber, 1997).
Adaptive stress-related behaviours in psoriasis patients may contribute to pathogenesis through pathoimmunological mechanisms. Cigarette smoking, alcohol consumption and obesity are all well-recognised risk factors for psoriasis. Smoking has generally been shown to accelerate the formation of autoantigens in the skin and trigger innate immune responses (Sopori, 2002). Chronic stress has been associated with excessive eating and sedentary lifestyle and in turn, obesity. Obesity is a chronic low grade
45 inflammatory condition that is thought to play a role in the course of psoriasis through the secretion of proinflammatory adipokines (Adiponectin, Omentin, Chemerin) and cytokines such as TNF-alpha, IL-6, IL-8, IL-17) (Bai et al., 2018). Human behaviours are fundamentally dictated by cognitive factors, which also have been shown to influence individual stress reactivity. High levels of worrying and scratching have been independently related to an increase in psoriasis severity and itch during period of high stress (Verhoeven et al., 2009), and patients with psoriasis who are high worriers were shown to be less likely to clear their disease with psoralen and ultraviolet A therapy, than their low worry counterparts (Fortune et al., 2003).
The psychosocial sequelae of psoriasis have been widely accepted for decades, and stress has also been regularly cited as exacerbating and even triggering the onset of psoriasis (Leibovici & Menter, 2016), with recognition in treatment guidelines (Gisondi et al., 2017). Several pathophysiological mechanisms have been put forward in an attempt to explain this, including release of nerve-related factors (e.g. CRGP, SP) from peripheral sensory nerves and dysregulation in the functioning of the HPA and SAM axes. These actions likely have downstream effects on mast-cell activity, leukocyte distribution and trafficking, and potentially function of APCs in the skin, culminating in clinically-apparent neurogenic inflammatory response (Hunter et al., 2013; A. Zhang, Nguyen, & Koo, 2018). Cognitive and behavioural factors are also believed to influence this process. Systematic reviews have supported a role for stress in the exacerbation and/or onset of psoriasis symptoms (Hunter et al., 2013; Stewart et al., 2018), however questions continue to be raised about the legitimacy of this relationship signifying a need for further research (Snast et al., 2018).
2.11.9 Alopecia areata
Alopecia areata (AA) refers to non-scarring hair loss usually localised to the scalp but can occur anywhere on the body. It is the most common hair loss disorder seen in young adults and the cosmetic effect can cause severe emotional distress (Hunt & McHale, 2007). AA is understood to involve an interaction between genetic, autoimmune, hormonal and psychological factors, as well as neurologic dysfunction. Pathogenesis likely involves autoimmune-mediated disruption of the hair cycle, leading to the inhibition of normal
46 growth (Dainichi & Kabashima, 2017). There have been cases of stress clearly preceding AA onset and/or flare in the literature (Paus & Arck, 2009). Perceived stress has been shown to have marked hair growth-inhibitory effects, including premature induction of hair follicle regression in a mouse model (Eva M.J. Peters et al., 2007). What remains less clear is whether perceived stress can also induce hair shaft shedding and if this theory is transferrable to humans.
The literature supports an association between stressful events and AA (Paus & Arck, 2009). This association appears to mostly involve emotional trauma related to family dysfunction and those who attribute a stressful significance to the events (Gulec, Tanriverdi, Duru, & Akcali, 2004; Taheri, Behnam, Tousi, Azizzade, & Sheikhbatan, 2012; Willemsen, Vanderlinden, Roseeuw, & Haentjens, 2009). CRH receptors and ACTH have been shown to be upregulated in lesional hair follicles (Katsarou-Katsari, Singh, & Theoharides, 2001; H. S. Kim et al., 2006). Zhang et al proposed in their study that a positive correlation of HPA hormone levels with skin Th1 cytokines suggests that altered HPA activity may occur as a consequence of the immune response associated with AA (X. Zhang et al., 2009). Abnormalities have been seen in peptidergic innervation of lesional AA hair follicles compared with controls (Hordinsky & Ericson, 1996). Toyoda et al showed that SP is endogenously released by dermal nerve fibres around lesional hair follicles and that it may play an important part in epithelial-mesenchymal-neuroectodermal interactions in AA(Toyoda, Makino, Kagoura, & Morohashi, 2001). NGF has been shown to inhibit hair growth in ex vivo cultures, and SP can disrupt the immune protection of the transient portion of the anagen hair follicle, which has been proposed as a possible trigger for AA in humans (Gilhar, Paus, & Kalish, 2007; Eva M.J. Peters et al., 2007). Individual factors may also be important as significant differences have been found in emotional intelligence, which related strongly to control of stress, between AA and controls (Monselise et al., 2013).
2.11.10 Telogen Effluvium
Telogen effluvium (TE) is a diffuse nonscarring hair loss that occurs as a result of an abnormal shift in follicular cycling that leads to premature shedding of hair. It is one of the
47 most common forms of nonscarring hair loss, presenting as a diffuse reduction in hair density (Fatani et al., 2015). TE is generally divided into acute and chronic variants. Chronic TE is much less common and is most frequently seen in women aged 30-60 years (Whiting, 1996). In most cases the course of TE is self-limiting with hair loss starting 2-3 months after the inciting event and ceases once the inciting factor is eliminated (Grover & Khurana, 2013). A wide variety of inciting factors have been linked to TE, including serious illness, major surgery, childbirth, rapid weight loss, nutritional deficiency, drugs and emotional stress. In some cases, the inciting factor is unclear or multiple triggers are identified. Although the pathogenesis of TE is not completely understood, it is generally accepted that a physiologic event stimulates a change in follicular cycling due to an insult to the anagen bulb. Immediate anagen release is the favoured hypothesis in TE related to stress, where a significant proportion of anagen follicles are stimulated to enter telogen prematurely (Headington, 1993).
In the literature, psychological stress has been frequently implicated as a precipitating factor in telogen effluvium (TE) and diffuse hair loss. Studies have mainly examined populations of women with mixed aetiologies of hair loss (e.g. telogen effluvium, androgenic alopecia, alopecia areata, female pattern hair loss) (Jain, Kataria, & Dayal, 2000; Malkud, 2015; Poonia, Thami, Bhalla, Jaiswal, & Sandhu, 2018). Grace and colleagues proposed a key role for mast cells in pathogenesis of TE, showing that they were present in significantly higher counts in scalp biopsies of TE-affected patients, compared with alopecia areata and androgenic alopecia (Grace, Sutton, Abraham, Armbrecht, & Vidal, 2017). As an interesting note on the potential effects of stress-induced behavioural changes on TE, in one study, cadmium levels, of which cigarettes are the most prevalent source, were shown to be significantly higher in chronic TE patients compared with controls (Abdel Aziz, Sh Hamed, & Gaballah, 2015).
2.11.11 Hyperhidrosis
Hyperhidrosis refers to eccrine sweat gland overactivity causing sweat secretion in amounts greater than physiologically needed for thermoregulation. It is most commonly a chronic idiopathic condition affecting the axilla, palms and/or soles. It is thought to be caused by an
48 exaggerated autonomic response to normal emotional stress (Iwase et al., 1997). Hyperhidrosis patients have been shown to report increased sweat scores in comparison with controls at times of elevated emotional stress (K. M. Gross, Schote, Schneider, Schulz, & Meyer, 2014; Krogstad, Mork, & Piechnik, 2006). Karaca et al examined temperament and character profile in patients with primary hyperhidrosis, finding that ‘fear of uncertainty’ was significantly greater, and ‘novelty seeking’, lower in HH patients compared with controls (Karaca et al., 2007). It is thought however that most individuals suffering from primary hyperhidrosis lack overt psychopathology (Karaca et al., 2007; Ruchinskas, Narayan, Meagher, & Furukawa, 2002).
2.11.12 Trichotillomania
Trichotillomania (TTM) or ‘hair-pulling’ disorder is a repetitive body-focused disorder frequently associated with skin-picking. It is included in the group of ‘obsessive-compulsive and related disorders’ in the DSM V (American Psychiatic Association, 2013). Patients with TTM may present with bald spots in various body sites, including scalp, face, arms, legs and pubic area. The scalp is the most common pulling site, but eyelashes and eyebrows are often involved. Hair-pulling is associated with significant distress and psychosocial impact (Özten et al., 2015; Walther, Ricketts, Conelea, & Woods, 2015). Sufferers of these types of disorders are generally aware of their behaviours and give various explanations. They may report anxiety or emotional distress until they are able to pick their skin, which relieves these feelings (Bohne, Keuthen, Wilhelm, Jenike, & Baer, 2002; K. Phillips & Taub, 1995). Some report that it is simply a common habit, and others find the actions pleasurable (Bohne et al., 2002). There is some evidence that genetic factors and abnormalities in neurotransmitter systems may be involved in pathogenesis of TTM. Neuroimaging studies have found an increase in gray matter density in several brain regions involved in affect regulation, motor habits, and top-down behavioral inhibition in TTM patients compared with controls (Chamberlain et al., 2008).
49 2.11.13 Humanpapillomaviruses (warts)
Human papilloma viruses (HPV) infect epithelial tissues of skin and mucous membranes, with the most common manifestation being cutaneous warts in children and young adults. Cutaneous warts manifest as common, plantar or flat warts anywhere on the body. Infection with HPV occurs by direct skin contact, with maceration or sites of trauma predisposing to inoculation. Patients with genital warts have been shown to suffer a heavy psychological burden, owing to self-image and sexual-related concerns (Mortensen, 2010). Aetiology of warts is accepted to be infective, however stress may play a role in virus persistence and capacity to clear HPV infection. Moscicki et al found that women who perceived themselves to be highly stressed were more likely to have persistence of HPV infection. Furthermore, they found that women who reported self-destructive coping strategies such as excessive alcohol consumption, cigarette smoking or illicit drug use when stressed, were more likely to develop an active HPV infection (Moscicki, 2016). Any effect would most plausibly be immune-mediated, supported by Wu et al who showed increased psychological stress was associated with higher antibody titres in their male HPV-vaccinated population (Wu, Zimmerman, & Lin, 2016).
2.12 Gaps in the literature
Research into stress and disease, including skin disease, has dramatically increased over the last 30 years. Great strides have been made over this time and consequently, there are several areas rich for further exploration, as the push from the bench to the bedside moves forward.
As societies understanding of stress has evolved to incorporate a transactional model, so too has the robustness of stress measurement in study design. Early methodologies utilised life event scales (e.g. Holmes-Rahe Social Readjustment scale (Holmes TH, 1967)) and/or patient self-reports, which were unable to fully capture the individuals’ unique perception and handling of the stressor, and have generally not been valid indicators for somatic disease. Improvements in the reliability of stress measurement
50 has been possible through the development of validated perceived stress instruments, such as the Perceived Stress Questionnaire (Levenstein et al., 1993).
Early research mostly examined patients with assigned dermatologic diagnoses in hospitals and dermatology clinics. Laboratory-based studies, particularly animal models, have increasingly uncovered pathogenic mechanisms underlying the associations between stress and skin diseases. This provides impetus for looking at broader ways in which stress might affect the skin, including its effects on skin morbidity in nonhealthcare-seeking populations. The development of a validated tool such as the Self-Reported Skin Questionnaire, has allowed for advancement in the assessment of self-reported skin complaints in the general population (F Dalgard et al., 2003), rather than the healthcare seeking population.
Many people have preconceived ideas about whether the course of certain skin diseases is contributed to by stress. Thus, by looking at the effects of stress more broadly on the skin, and focusing on symptoms and signs without the confines of disease classifications, may help to clarify the validity of some of these preconceived notions. Examples of symptoms included in this thesis are itch, dry/sore rash and pimples, which may be mediated by pathways in the skin both within and outside the parameters of defined dermatologic diseases. Also, by asking about symptoms and signs, a broader range of morbidity can be examined. When assessing how stress may affect the skin, using a validated tool which looks at primary symptoms such as itch or sweating, and descriptive features such as scaly rash or hair loss, may enable determination of review associations without the need for medical terms or any pejorative terminology.
By combining these standardised and validated tools, it is possible to prospectively measure perceived stress and self-reported skin symptoms in a nonhealthcare-seeking population.
51 2.13 Research questions and hypotheses
Research question
- Are increased levels of perceived psychological stress associated with the presence of self-reported skin symptoms and signs in a university student cohort?
Hypothesis
- Increased levels of perceived psychological stress are associated with presence of skin symptoms and signs in Australian university students
2.14 Research aims and objectives
This research aims to better characterise the relationship between perceived psychological stress and underexplored skin symptoms and signs, and, as a consequence, contribute to greater awareness and improved management of stress-responsive dermatoses.
52 Chapter 3 – Methods
3.1 Study population, recruitment and execution
The study was conducted through the University of New South Wales (UNSW) School of Medicine during the second semester of 2016. The study population were students aged 18- 30 years at the University of New South Wales, which enabled convenience randomised sampling. By enrolling a younger age group, it was anticipated that their skin complaints were less likely to be influenced by sun damage or systemic disease. Five thousand students from all faculties were randomly selected and emailed an invitation (Appendix 1) to participate in an electronic survey (Appendix 2). Students with mental health disorders were not excluded. Random selection of students and study dissemination was facilitated through UNSW ‘Student Life and Learning.’
SurveyMonkey, an online survey development cloud-based software, was utilised to construct, host, implement and collect the survey data. The survey collected information on participant demographics, perceived stress levels and skin symptoms and signs (Appendix 2). Electronic informed consent was obtained from all participants (Appendix 3). All participants were also sent a separate participant information statement (Appendix 4). Data was collected anonymously, meaning pairing of name and other personal identifiers to data was not possible at any stage. The University of New South Wales Human Research Ethics Committee approved the study (HREC no. 16565).
3.2 Ethical considerations
The study design was ethically sound. The research was independent and impartial. No funding of any kind was sought and participants were advised in the survey introduction and participant information that the study was to form part of the chief investigator’s Master of Medicine degree. Respect for intellectual property is observed as permission from the original authors was obtained for use of their study instruments ((Florence Dalgard (email)
53 and Susan Levenstein (email)). A non-discriminative approach is observed as the survey is sent to students belonging to all faculties of the university.
Informed consent was obtained as participants were sent detailed information at the beginning of the study package and progression to the questionnaire was not possible without electronic consent being provided first (Appendices 1 & 2). The electronic document was sent on 3 occasions over 3 successive weeks. Contact of any kind was not made with non-respondents. It was clearly explained that it was a voluntary, anonymous questionnaire so as to minimise any coercion. Participants were free to withdraw at any time without consequences. This was clearly stated in the survey introduction and participant information (Appendix 4).
Participant confidentiality was wholly preserved as they were not required to provide any identifying information (e.g. name, date of birth, residential address). This anonymous data was sourced from the data collection software by the chief investigator only. Participants were instructed to provide an email address only if they wished to receive a study report. Receipt of a participants email address was taken as implied consent. Only the chief investigator had password-protected access to this information. No identifying electronic data was obtained.
The study design was constructed primarily so as to ‘do no harm’. No direct physical contact with participants or intervention was required so there was no reasonable potential for physical harm. Any psychological stress that might arise from participation in the study was reconciled by providing participants with information for appropriate referral services. The results of the study will be honestly and accurately compiled into a report and submitted for publication in a medical journal so as to further knowledge in this area.
3.3 Perceived Stress Questionnaire (PSQ)
To assess psychological stress levels in the student population, we used the Perceived Stress Questionnaire (PSQ) (Figure 1) (Levenstein et al., 1993). The PSQ is a 30-item questionnaire that measures self-reported psychological stress. It evaluates individuals perceived stress levels through the application of questions covering six broad psychological domains: (1)
54 harassment (2) overload, (3) irritability, (4) lack of joy, (5) fatigue and (6) worries and tension. It was originally validated in the Italian and English languages.
Figure 1: Perceived Stress Questionnaire
For each sentence, circle the number that describes how often it applied to you during the last month. Work quickly without bothering to check your answers and be careful to consider only the last month. Almost Sometimes Often Usually never 1. You feel tired 2. You feel that too many demands are being made on you 3. You are irritable or grouchy 4. You have too many things to do 5. You feel lonely or isolated 6. You find yourself in situations of conflict 7. You feel you’re doing things you really like 8. You feel tired 9. You fear you may not manage to attain you goals 10. You feel calm 11. You have too many decisions to make 12. You feel frustrated 13. You are full of energy 14. You feel tense 15. Your problems seem to be piling up 16. You feel you’re in a hurry 17. You feel safe and protected 18. You have many worries 19. You are under pressure from other people 20. You feel discouraged 21. You enjoy yourself 22. You are afraid for the future 23. You feel you’re doing things because you have to not because you want to 24. You feel criticized or judged 25. You are lighthearted 26. You feel mentally exhausted 27. You have trouble relaxing 28. You feel loaded down with responsibility 29. You have enough time for yourself 30. You feel under pressure from deadlines Score 5 minus(-) circled number for items 1, 7, 10, 13, 17, 21, 25, 29. Score circled number for all other items.
Individual PSQ items were scored by each participant, by placing a circle around the applicable number belonging to each item in the tool. Participants were instructed: “for each sentence, circle the number that describes how often it applied to you during the last
55 month. Work quickly without bothering to check your answers and be careful to only consider the last month”(Levenstein et al., 1993, p.32.).
Once completed by the study participant, the total score is compiled electronically as, either by the circled number for negative items (e.g. you feel tired) or by 5 minus (-) the circled number for positive items (e.g. you feel rested). All 30 items are added together to produce a total raw score for each participant. A PSQ index was then calculated by subtracting 30 from the raw score and dividing the result by 90 ((PSQ = (raw score– 30)/90)). The PSQ index ranged from 0 to 1, representing lowest and highest levels of perceived stress, respectively.
The PSQ was validated in a diverse Italian population of varying ages, occupations and stages of life; including students (Levenstein et al., 1993). The PSQ demonstrated good construct and predictive validity when compared with a number of other instruments. It correlated well with the Perceived Stress Scale (Cohen, Kamarck, & Mermelstein, 2016), with which it is conceptually similar. It correlates highly with the somatic symptoms subscale from Kellner’s Symptom questionnaire (Kellner, 1987), which was validated in a student population. Not shared with any other predictive measures, the PSQ had ‘harassment’ as the factor most closely related to actual physical outcomes.
Test-retest reliability of the general PSQ at 7-10 days was examined among 101 of the study population (in-patients, health workers, students). Test-retest reliability of the general PSQ after an interval of 8.03 (+/- 1.64 days) was 0.82, when non-native speakers were excluded, it increased to r = 0.86. Levenstein et al make the point that this method of simple self-reporting would likely be more reliable in English-speaking countries, as, in Italy, the word ‘stress’ is a “recent foreign borrowing of perhaps as yet unsettled significance” (Levenstein et al., 1993, p.26).
The PSQ correlates highly with minor physical symptomatology in basically healthy individuals and may be superior to alternate measures for predicting healthy outcomes (Levenstein et al., 1993). Kocalevent et al reaffirmed the construct validity of the PSQ in the context of the evolving transactional view of stress (Kocalevent et al., 2007). The PSQ is generalizable and has been validated in Spanish (Sanz-Carrillo, Garcia-Campayo, Rubio,
56 Santed, & Montoro, 2002), Greek (Karatza, Kourou, Galanakis, Varvogli, & Darviri, 2014), Swedish (Rönnlund et al., 2015) and Chinese populations (Luo et al., 2018).
3.4 Self-reported Skin Questionnaire
To assess skin complaints, we used a modified version of Self-Reported Skin Questionnaire (SRSQ) (Figure 2) (F Dalgard et al., 2003). This version added three new symptoms (oily, waxy or flakey patches on the scalp, nail-biting and hair-pulling) and removed one symptom (other skin problems) from the original version. The modified SRSQ has not been validated. We used this version as it had been used recently (2015) with success in a predominantly English-speaking university student cohort (Schut et al., 2016). It has also been used successfully in an Arabic population (Bin Saif et al., 2018).
Figure 2: Modified Self-reported skin Questionnaire
During the last week, have you had any of the following complaints (please answer every question, placing a cross in the appropriate box)? No Yes, a little Yes, quite a lot Yes, very much Itchy skin Dry/sore rash Scaly skin Itchy rash on hands Oily, waxy or flakey patches on scalp Pimples Other rash on face Warts Troublesome sweating Loss of hair Nail-biting Hair-pulling
The questionnaire on which the modified SRSQ is based, is validated (F Dalgard et al., 2003). Validity was assessed using two samples of an urban adult Norwegian population (100 health-seeking and 100 nonhealthcare-seeking patients). Participants first filled out the SRSQ and were then examined (full skin examination) by a dermatologist without regard to
57 their presenting complaint, who completed a separate form documenting any observed clinical dermatologic signs.
In order to calculate the validity, both test answers and clinical signs were dichotomised, to compare complaint categories ‘yes, quite a lot’ and ‘yes, very much’ with ‘moderate’ and ‘severe’. Dalgard et al used Spearman rank correlation as another means of validating their methods. Inter-rater agreement was done through examination of 16 patients independently by two dermatologists and was shown to be ‘good’ for the global clinical assessment (k =0.67).
In the nonhealthcare-seeking population, Dalgard et al reported the sensitivity was highest for questions on rash on the hands (75%), pimples (50%), warts (100%), and troublesome sweating (75%). The positive predictive value was highest for the question on pimples (57%), and was acceptable for scaly skin (42%), hand rash (50%), and face rash (40%). All of the above were retained in the modified version.
Dalgard et al demonstrated that their total skin complaint score (mean of the answers to all 12 items) is valid and reliable for the assessment of the skin morbidity in adult health-seeking and nonhealthcare-seeking populations. The SRSQ provides good generalisability and transferability having been used successfully across different ethnic groups including Norwegian, Danish, American and Arabic (Bin Saif et al., 2018; Florence Dalgard, Holm, Svensson, Kumar, & Sundby, 2007; Miller, Zarchi, Ellervik, & Jemec, 2016; Schut et al., 2016).
3.5 Inclusion criteria and final participant numbers
The survey was sent out to 5000 students. From the 541 students who attempted the study survey, 70 had to be excluded. Reasons for exclusion were incomplete data (n=57) and/or failure to meet the inclusion criteria (i.e. older than 30 years or not a current student of UNSW) (n=13). This left a final evaluable number of 471.
58 3.6 Statistics and data analysis
All statistical analyses were performed using SPSS statistics, version 22 (IBM, 2015).
Answers to each of the individual SRSQ items were dichotomised in such a way that the answer ‘no complaints’ was compared with the other three answers, ‘a little’, ‘quite a lot’ and ‘very much’. This determined only whether the symptom/sign occurred in the student or not, allowing for the computation of odds ratios (OR). The outcome measure was not analysed as a continuous variable due to the relatively small sample size and it was thought that dichotomising would allow for greater clarity in interpretation of the results.
Binary logistic regression was then used to calculate the likelihood of occurrence of the skin symptom or sign with a single unit increase in perceived stress (PSQ index), with outcomes measured by odds ratios. Other factors (e.g. age, gender, ethnicity, degree etc.) thought to potentially confound the association between stress as the predictor and each skin complaint as the outcome, were corrected for in the regression analyses. Influence of confounders directly on skin symptoms or signs was not within the scope of this thesis.
Bonferroni correction was conducted to minimise type 1 error, by dividing the original significance threshold value (p<0.05) by the number of analyses on the dependent variable (12) (Armstrong, 2014). The modified significance threshold was 0.0041. Nagelkerke pseudo R2 value estimates the variance in the dependent variable (skin symptom) which is explained by the independent variable (perceived stress), with larger R2 values indicating that more the variation is explained by the model, to a maximum of 1.
59 Chapter 4 – Results
We enrolled 471 students in the study. In this section, the study population demographics will first be described and then results of statistical analysis for associations between levels of perceived stress (as measured by the PSQ) and individual skin complaints.
4.1 Demographic description of the study population
There were 151 (32%) males and 320 (68%) females in the study. 0 (0%) respondents selected ‘other’. The mean age of students participating in the study was 20.98 years. Participant ages by category is displayed below in Table 1. 191 (40%) students identified as Caucasian, 262 (55.5%) as Asian, 9 (2%) as Middle Eastern, 1 (0.2%) as Pacific Islander, 8 (1.5%) as Hispanic and 19 (4%) as ‘Other’. 16 (3.5%) students identified as belonging to more than one ethnicity.
Table 1: Distribution of students by age Age (years) Number of respondents 18 15 (3%) 19 188 (40%) 20 96 (20.5%) 21 34 (7%) 22 30 (6.5%) 23 25 (5.5%) 24 29 (6%) 25 17 (3.5%) 26 6 (1.5%) 27 4 (1.5%) 28 7 (1.5%) 29 10 (2%) 30 10 (2)
For faculty, 102 (21.5%) students were enrolled at the School of Medicine, 95 (20%) at Engineering, 73 (15.5%) at Art & Social Sciences, 72 (15%) at Business School, 57 (12%) at Science, 26 (5.5%) at School of Law, 24 (5%) at Art & Design and 22 (4.5%) at Built
60 Environment. Faculty representation by percentages are displayed graphically below in Figure 3.
Figure 3: Distribution of students by faculty
Student representation by faculty Built Environ. Art & Design 5% 5%
Medical 22%
Engineering 20% Science 12% Art & Soc. Sciences 15% Law 6% Business 15%
With regards to degree type, 379 (80%) students were enrolled in a Bachelors degree, 7 in a (1.5%) Graduate diploma/honours program, 67 (14%) in a Masters degree and 18 (4%) in a Doctorate/PhD. For year of university study, 111 (23.5%) students were in their first year of study, 284 (60.5%) in second year, 20 (4%) in third year, 23 (5%) in fourth year, 12 (2.5%) in fifth year, 16 (3.5%) in sixth year and 5 (1%), more than 6 years.
4.2 Stress levels in the study population
95 students scored in the lower third on the PSQ index and fell into the ‘low stress’ group, 317 students fell into the ‘moderate stress’ group (middle third), and 59 students scored in the upper third on the PSQ index and fell into the ‘high stress’ group (Figure 4).
61
Figure 4: Distribution of participants by PSQ index
Distribution of participants by PSQ Index 350 317 300
250
200 n=471 150 95 100 59 50
0 Lower third Middle third Upper third PSQ Index Percentile (%)
4.3 Skin symptoms and signs in the study population
‘Pimples’ was the most common self-reported skin symptom (85%), followed by ‘itchy skin’
(57.5%) and ‘Oily waxy patches on scalp and/or flakey scalp’ (47.5%). ‘Itchy rash on hands’ was the least frequent self-reported symptom (19%) (Table 2).
Table 2: Frequency of skin symptoms and signs in the study population Skin symptom or sign n=471 Skin symptom or sign n=471 1. Itchy skin 272(58%) 7. Troublesome sweating 185(39%) 2. Dry/sore rash 220(47%) 8. Hair pulling 94(20%) 3. Scaly skin 224(47.5%) 9. Pimples 399(84.5%) 4. Other rashes on face 118(25%) 10. Warts 47(10%) 5. Loss of hair 152(32%) 11. Oily waxy patches on scalp 226(48%) and/or flakey scalp 6. Itchy rash on hands 90(19%) 12. Nail-biting 164(35%)
62 4.4 Relationship between stress levels and skin symptoms
Statistical analysis of each skin complaint’s (e.g. itch) association with measured stress levels is presented individually in the following tables. Associations that reached statistical significance (p<0.0041) are presented in red font in the ‘Significance’ column.
Itch
The self-report of ‘itch’ was found to be statistically significantly associated with increased stress levels (p<0.001) (Table 3).
Table 3: Logistic regression analysis of stress and itch B test Standard Degrees Significance Adjusted Odds 95% CI for AOR Error of Ratio (AOR) Lower Upper freedom limit limit PSQ index 2.94 0.66 1 <0.001 18.83 5.18 68.48 Age (18 years) 0.07 0.05 1 0.16 1.08 0.97 1.20 Gender (female) -0.08 0.21 1 0.70 0.92 0.61 1.39 Ethnicity (caucasian) 0.21 0.21 1 0.31 1.23 0.82 1.85 Faculty (medicine) -0.57 0.79 1 0.47 0.56 0.12 2.66 Degree level (PhD) -0.48 0.39 1 0.21 0.61 0.29 1.31 Study year (first) 0.56 0.71 1 0.43 1.75 0.44 7.05 Nagelkerke R square: 0.091
Dry/sore rash
The self-report of ‘dry/sore rash’ was found to be statistically significantly associated with increased stress levels (p<0.001) (Table 4).
Table 4: Logistic regression analysis of stress and dry/sore rash B test Standard Degrees of Significance Adjusted Odds 95% CI for AOR Error freedom Ratio (AOR) Lower Upper limit limit PSQ index 3.62 0.67 1 <0.001 37.49 9.99 140.54 Age (18 years) 0.07 0.05 1 0.17 1.07 0.97 1.19 Gender (female) 0.33 0.21 1 0.12 1.39 0.91 2.10 Ethnicity (caucasian) 0.22 0.22 1 0.30 1.24 0.83 1.87 Faculty (medicine) 0.10 0.80 1 0.90 1.10 0.23 5.26 Degree level (PhD) 0.15 0.38 1 0.69 1.16 0.55 2.46 Study year (first) 0.92 0.68 1 0.17 2.51 0.66 9.50 Nagelkerke R square: 0.0127
63 Scaly skin
The self-report of ‘scaly skin’ was found to be statistically significantly associated with increased stress levels (p<0.001) (Table 5).
Table 5: Logistic regression analysis of stress and scaly skin B test Standard Degrees Significance Adjusted Odds 95% CI for AOR Error of Ratio (AOR) Lower Upper freedom limit limit PSQ index 2.47 0.63 1 <0.001 11.82 3.41 40.99 Age (18 years) 0.04 0.05 1 0.42 1.04 0.94 1.15 Gender (female) 0.17 0.20 1 0.40 1.19 0.79 1.78 Ethnicity (caucasian) 0.15 0.10 1 0.45 1.16 0.78 1.73 Faculty (medicine) -0.74 0.86 1 0.39 0.48 0.09 2.58 Degree level (PhD) -0.28 0.37 1 0.45 0.75 0.36 1.57 Study year (first) 0.11 0.63 1 0.86 1.11 0.33 3.81 Nagelkerke R square: 0.058
Itchy rash on hands
The self-report of ‘itchy rash on hands’ was found to be statistically significantly associated with increased stress levels (p<0.001) (Table 6).
Table 6: Logistic regression analysis of stress and itchy rash on hands B test Standard Degrees Significance Adjusted Odds 95% CI for AOR Error of Ratio (AOR) Lower Upper freedom limit limit PSQ index 2.75 0.79 1 <0.001 15.76 3.33 74.56 Age (18 years) 0.01 0.06 1 0.84 1.01 0.89 1.15 Gender (female) -0.19 0.26 1 0.45 0.82 0.50 1.36 Ethnicity (caucasian) 0.64 0.27 1 0.02 1.89 1.12 3.19 Faculty (medicine) -0.30 1.11 1 0.79 0.74 0.08 6.53 Degree level (PhD) -0.39 0.49 1 0.42 0.67 0.26 1.75 Study year (first) -0.78 0.92 1 0.40 0.46 0.07 2.81 Nagelkerke R square: 0.072
64 Pimples
The self-report of ‘pimples’ was found to not be statistically significantly associated with increased stress levels (p=0.07) (Table 7).
Table 7: Logistic regression analysis of stress and pimples B test Standard Degrees Significance Adjusted Odds 95% CI for AOR Error of Ratio (AOR) Lower Upper freedom limit limit PSQ index 1.57 0.88 1 0.07 4.82 0.86 27.03 Age (18 years) -0.08 0.06 1 0.23 0.92 0.81 1.05 Gender (female) 0.09 0.27 1 0.74 1.10 0.64 1.88 Ethnicity (caucasian) -0.23 0.29 1 0.41 0.79 0.45 1.38 Faculty (medicine) 19.66 15105.47 1 0.99 344304514 0 Degree level (PhD) -0.27 0.47 1 0.56 0.76 0.31 1.90 Study year (first) 0.44 0.82 1 0.59 1.55 0.31 7.80 Nagelkerke R square: 0.047
Other rash on face
The self-report of ‘other rash on face’ was found to be statistically significantly associated with increased stress levels (p<0.001) (Table 8).
Table 8: Logistic regression analysis of stress and other rash on face B test Standard Degrees of Significance Adjusted Odds 95% CI for AOR Error freedom Ratio (AOR) Lower Upper limit limit PSQ index 3.78 0.76 1 <0.001 43.72 9.81 194.79 Age (18 years) 0.03 0.05 1 0.56 1.03 0.92 1.15 Gender (female) 0.13 0.24 1 0.60 1.13 0.70 1.83 Ethnicity (caucasian) 0.06 0.24 1 0.79 1.06 0.66 1.71 Faculty (medicine) 0.69 0.88 1 0.43 1.99 0.36 11.10 Degree level (PhD) 0.80 0.41 1 0.05 2.24 1.00 4.97 Study year (first) 1.32 0.66 1 0.46 3.73 1.02 13.64 Nagelkerke R square: 0.123
Warts
The self-report of ‘warts’ was found to not be statistically significantly associated with increased stress levels (p=0.07) (Table 9).
65
Table 9: Logistic regression analysis of stress and warts B test Standard Degrees of Significance Adjusted Odds 95% CI for AOR Error freedom Ratio (AOR) Lower Upper limit limit PSQ index 1.91 1.05 1 0.07 6.73 0.86 52.78 Age (18 years) -0.04 0.08 1 0.56 0.95 0.82 1.11 Gender (female) -0.32 0.33 1 0.33 0.72 0.38 1.38 Ethnicity -0.03 0.34 1 0.34 0.72 0.37 1.41 (caucasian) Faculty (medicine) 1.04 1.12 1 0.35 2.84 0.32 25.58 Degree level (PhD) 1.60 0.54 1 0.01 4.95 1.72 14.23 Study year (first) 1.77 0.84 1 0.04 5.85 1.12 30.51 Nagelkerke R square: 0.078
Troublesome sweating
The self-report of ‘troublesome sweating’ was found to be statistically significantly associated with increased stress levels (p=0.003) (Table 10).
Table 10: Logistic regression analysis of stress and troublesome sweating B test Standard Degrees Significance Adjusted Odds 95% CI for AOR Error of Ratio (AOR) Lower Upper freedom limit limit PSQ index 1.89 0.63 1 0.003 6.61 1.91 22.87 Age (18 years) 0.05 0.05 1 0.37 1.05 0.95 1.16 Gender (female) -0.08 0.21 1 0.68 0.92 0.61 1.38 Ethnicity (caucasian) -0.25 0.21 1 0.23 0.78 0.52 1.17 Faculty (medicine) -1.35 1.10 1 0.22 0.26 0.03 2.24 Degree level (PhD) -0.52 0.39 1 0.19 0.60 0.28 1.29 Study year (first) -1.57 0.76 1 0.04 0.21 0.05 0.92 Nagelkerke R square: 0.057
Hair loss
The self-report of ‘hair loss’ was found to be statistically significantly associated with increased stress levels (p<0.001) (Table 11).
66 Table 11: Logistic regression analysis of stress and hair loss B test Standard Degrees of Significance Adjusted Odds 95% CI for AOR Error freedom Ratio (AOR) Lower Upper limit limit PSQ index 3.26 0.72 1 <0.001 25.94 6.30 107.24 Age (18 years) 0.04 0.05 1 0.49 1.04 0.93 1.16 Gender (female) 0.48 0.24 1 0.04 1.62 1.02 2.59 Ethnicity 0.72 0.23 1 0.002 2.06 1.30 3.26 (caucasian) Faculty (medicine) 1.54 0.81 1 0.06 4.67 0.96 22.76 Degree level (PhD) 0.94 0.39 1 0.02 2.57 1.19 5.54 Study year (first) 0.84 0.67 1 0.21 2.32 0.62 8.69 Nagelkerke R square: 0.179
Oily, waxy patches on scalp and/or flakey scalp
The self-report of ‘oily, waxy patches on scalp and/or flakey scalp’ was found to not be statistically significantly associated with increased stress levels (p=0.15) (Table 12).
Table 12: Logistic regression analysis of stress and oily, waxy patches on scalp and/or flakey scalp B test Standard Degrees Significance Adjusted Odds 95% CI for AOR Error of Ratio (AOR) Lower Upper freedom limit limit PSQ index 0.86 0.61 1 0.15 2.38 0.72 7.87 Age (18 years) -0.07 0.05 1 0.17 0.93 0.84 1.03 Gender (female) 0.21 0.20 1 0.31 1.23 0.83 1.84 Ethnicity (caucasian) 0.14 0.20 1 0.49 1.15 0.77 1.70 Faculty (medicine) -20.95 15023.04 1 0.99 <0.01 <0.01 Degree level (PhD) 0.67 0.38 1 0.07 1.96 0.94 4.10 Study year (first) 1.14 0.63 1 0.07 3.12 0.90 10.82 Nagelkerke R square: 0.05
Nail-biting
The self-report of ‘nail-biting’ was found to not be statistically significantly associated with increased stress levels (p=0.03) (Table 13).
67 Table 13: Logistic regression analysis of stress and nail-biting B test Standard Degrees Significance Adjusted Odds 95% CI for AOR Error of Ratio (AOR) Lower Upper freedom limit limit PSQ index 1.40 0.65 1 0.03 4.06 1.14 14.40 Age (18 years) 0.01 0.05 1 0.78 1.01 0.91 1.12 Gender (female) -0.15 0.21 1 0.47 0.86 0.56 1.31 Ethnicity (caucasian) -0.91 0.21 1 <0.01 0.40 0.26 0.61 Faculty (medicine) -0.01 0.87 1 0.99 0.99 0.18 5.48 Degree level (PhD) 0.49 0.39 1 0.20 1.63 0.77 3.29 Study year (first) -0.59 0.70 1 0.40 0.55 0.14 2.18 Nagelkerke R square: 0.07
Hair-pulling
The self-report of ‘hair-pulling’ was found to be statistically significantly associated with increased stress levels (p<0.001) (Table 14).
Table 14: Logistic regression analysis of stress and hair-pulling B test Standard Degrees Significance Adjusted Odds 95% CI for AOR Error of Ratio (AOR) Lower Upper freedom limit limit PSQ index 2.71 0.77 1 <0.001 15.07 3.29 67.01 Age (18 year) -0.13 0.07 1 0.05 0.87 0.76 1.00 Gender (female) -0.58 0.25 1 0.02 0.56 0.34 0.91 Ethnicity (caucasian) 0.03 0.26 1 0.90 1.02 0.62 1.71 Faculty (medicine) 0.10 1.11 1 0.93 1.11 0.125 9.85 Degree level (PhD) 1.24 0.46 1 0.01 3.45 1.41 8.42 Study year (first) 0.92 0.82 1 0.26 2.52 0.50 12.70 Nagelkerke R square: 0.077
68 4.5 Results conclusions
In summary, logistic regression analysis has shown statistically significant associations between increased stress levels and itch, dry/sore rash, scaly skin, itchy rash on hands, other rashes on face, troublesome sweating, hair loss, or hair-pulling (Table 15).
Table 15: Compilation of p values for all skin symptoms and signs p-value Odds Ratio Confidence Interval (95%) Itchy skin <0.001 18.83 5.18-68.48 Dry/sore rash <0.001 37.49 9.99-140.54 Scaly skin <0.001 11.82 3.41-40.99 Itchy rash on hands <0.001 15.76 3.33-74.56 Pimples 0.07 4.82 0.86-27.03 Other rash on face <0.001 43.72 9.81-194.79 Warts 0.07 6.73 0.86-52.78 Troublesome sweating 0.003 6.61 1.91-22.87 Hair loss <0.001 25.94 6.30-107.24 Oily, waxy patches on 0.15 2.38 0.72-7.87 scalp and/or flakey scalp Nail-biting 0.03 4.06 1.14-14.40 Hair-pulling <0.001 15.07 3.29-67.01
Statistically significant associations were not found between increased stress levels and pimples, warts, oily waxy patches on scalp and/or flakey scalp, or nail-biting (Table 15). The meaning of these results in the context of current understanding of the relationship between stress and skin symptoms and signs, will be discussed in the next chapter.
69 Chapter 5 – Discussion
In this chapter, interpretation of the findings is carried out with inference as to how they might fit into the existing body of evidence (summarised in Chapter 2). First, there is a discussion of the specific findings of the study, followed by a comment on important study limitations.
5. 1 Discussion of stress-skin associations
The main purpose of this study was to investigate the relationship between perceived psychological stress levels and self-reported skin symptoms and signs. The study results support the hypothesis that increased perceived stress levels are associated with a range of skin symptoms and signs including itch, dry/sore rash, scaly skin, itchy rash on hands, troublesome sweating, hair loss and hair-pulling. Perceived stress was not shown to be associated with pimples, oily, waxy patches on scalp and/or flakey scalp, warts or nail-biting.
Amongst the skin symptoms with the strongest association with perceived stress was itch. This was not surprising as an association between stress and itch has been shown previously, both dependent and independent of comorbid dermatologic disease (Murota & Katayama, 2017; Yamamoto et al., 2009). A direct association between stress and itch has been reported in the general and student populations (Schut et al., 2016; Yamamoto et al., 2009), and stress worsening associated itch has been shown in atopic dermatitis, psoriasis and chronic urticaria (Murota & Katayama, 2017; Ograczyk-Piotrowska, Gerlicz-Kowalczuk, Pietrzak, & Zalewska-Janowska, 2018; Verhoeven et al., 2008).
Stress has been shown experimentally to induce the release of several neurogenic mediators (i.e. SP, NGF), which could individually, or in combination, mediate the itch sensation under the influence of stress (Laurent Misery et al., 2018). It has been suggested that having a pre-existing pruritic skin condition may lower the subjects threshold for perception of itch stimuli (Edwards, Shellow, Wright, & Dignam, 1976). Additionally, high levels of itch appear to correlate with high subjective reactivity to stress (Niemeier, Nippesen, Kupfer, Schill, & Gieler, 2002), suggesting a key role for personality and cognitive factors in this interaction. Personality traits identified in other itch populations that might
70 reasonably be expected in our respondents are type D, neuroticism and conscientiousness, which overlap with traits found to be common in university students and survey responders (Chaytor, Spence, Armstrong, & McLachlan, 2012; Fan & Yan, 2010; Marcela, 2015; Schut, Bosbach, Gieler, & Kupfer, 2014; Yilmaz et al., 2016).
As the questionnaire enquired about isolated itch and itch associated with exacerbation of pruritic dermatosis, the positive respondents for itch in the study population were likely to have been made up of students both with isolated itch and pruritic skin conditions. 86% of participants self-reporting ‘itch’ also reported at least one other skin symptom or sign, with 67% of respondents reporting two or more symptoms or signs, in addition to itch. This might suggest that presence of itch in this cohort was more likely to be associated with pruritic skin conditions, rather than occurring in isolation. Our findings also allude to itch having highly complex pathogenic relations with stress both dependent and independent of the pathogeneses of pruritic dermatoses. It is also possible that some of the students that responded affirmatively to the query of ‘itch’ did not develop itch alone but rather, were made more aware of it or their pruritic dermatosis through increased levels of stress.
The significant association found between increased levels of psychological stress and self-reported hair loss in the study was consistent with other student population studies (Bin Saif et al., 2018; Schut et al., 2016). Peters and colleagues showed that increased psychological stress in university students, arising due to a major exam being perceived as stressful, can shift the immune response towards a Th1 profile, with the potential to hamper hair growth (Eva M.J. Peters et al., 2017), although, whether this association is seen with active hair loss in addition to reduced hair growth is not clear. Extensive translational research in murine models has indicated possible roles for CRH and ACTH overexpression, NGF, SP and T-cell imbalances in this relationship (Paus & Arck, 2009). Whilst fundamental, the majority of foundational work being in animal models somewhat limits the interpretation and application of the study findings.
Hair loss can be caused by disorders of hair, scalp as well as systemic conditions. One of the most common causes is telogen effluvium, characterised by a wave of hair-fall occurring on average 8-12 weeks after a stressful event (Malkud, 2015b). Another common
71 cause is alopecia areata, most commonly manifest by discrete patches or areas of hair loss on the scalp or body, reported by many to be precipitated by emotional stress (Paus & Arck, 2009). Other less common causes (in relation to this study) include male-pattern hair loss, iron deficiency, thyroid disease and medications (T. Phillips, Slomainy, & Allison, 2017). This study did not attempt to define each of the respondent’s specific causes for hair loss, and the large number of conditions manifest by hair loss shows the diversity of ways in which hair loss may be both a precipitant and outcome of psychological stress. Documented discordances between physicians’ estimations and patients’ self-assessment of hair loss underscores the importance of self-reporting in future psychodermatological hair research (Macquart-Moulin et al., 1997).
The difficulty in interpreting many of the stress-skin associations investigated in this study is that the vast majority of existing research in this area has focused on specific diseases, not skin symptoms and signs. Despite this fact, the association found in this study between increased levels of psychological stress and ‘scaly skin’ or ‘itchy rash on hands’ is consistent with other studies using the same design (Bin Saif et al., 2018; Schut et al., 2016). It is acknowledged that these skin symptoms and signs cannot reliably be translated to skin diseases, however it is worth mentioning that skin conditions which frequently exhibit these symptoms include psoriasis, atopic dermatitis, and seborrhoeic dermatitis, all of which have been shown to be associated with psychological stress in the literature (Chida, Hamer, & Steptoe, 2008; Hunter et al., 2013; L Misery et al., 2007)
Significant associations found between increased stress and ‘dry/sore rash’ or ‘other rashes on the face’ in this, and an Arabic study using the same design (Bin Saif et al., 2018), may have been strongly influenced by both cohorts having a large number of medical students (22%, 100%) as respondents. Medical students may possess a relatively better grasp of the contextual meaning of these terms compared with students studying non- health-related courses. The US study with the same design (Schut et al., 2016), did not find any association between increased stress and these skin symptoms, which might be explained by the different ethnic make-ups of the three populations. 54% of students enrolled at Temple University in 2015 identified as Caucasian (Temple University, 2015), whereas 54% of respondents in our study identified as Asian (40% caucasian) and presumably close to 100% of students in the Arabic study were of Middle-Eastern origin.
72 Dalgard et al showed that East Asian and Middle East/North African men, both less prevalent in the US study, more frequently self-report ‘dry/sore skin’ (Florence Dalgard et al., 2007). This might be related to occupation or ethnic predisposition.
This study’s finding of no significant association between increased levels of stress and presence of pimples was initially surprising, but other studies using the same design had similar results (Bin Saif et al., 2018; Schut et al., 2016). An affirmative response to ‘pimples’ in the study questionnaire certainty cannot be taken to constitute a diagnosis of acne vulgaris, although it may be the most ‘transferrable’ of the surveyed skin symptoms and signs. Survey enquiry about pimples has been assessed in a validation study comparing patient self-reports with a dermatologist diagnosis of acne vulgaris, and the overall agreement, sensitivity and specificity was the most favourable of any of the studied items, at 74%, 83% and 43% respectively (Jon Anders Halvorsen et al., 2008). There are other causes of ‘pimples’ including rosacea and demodex folliculitis, however acne vulgaris is the most likely diagnosis in this study population based on age of cohort and prevalence of the possible diagnoses in the general population (Bhate & Williams, 2013).
This finding was somewhat at odds with some studies in the literature which have showed associations between psychological stress and acne vulgaris in adolescent populations (Jon A. Halvorsen, Dalgard, Thoresen, Bjertness, & Lien, 2009) (Yosipovitch et al., 2007). There are several potential mechanisms to support a link. CRH-induced steroidogenesis in sebocytes as well as cytokine production (IL-6, IL-11) in keratinocytes contributing to inflammation (Zbytek et al., 2002; Zouboulis et al., 2002). SP, a potential initiator of neurogenic inflammation, upregulated in the vicinity of sebocytes, has been proposed as a central player in stress-induced acne (Tanghetti, 2013).
84% of the cohort self-reporting pimples suggests that any lack of association was not related to non-representative prevalence. The study cohort being post-adolescents and female-predominant (68%), may have also played a part, as acne vulgaris is most prevalent in male adolescents (Bhate & Williams, 2013). It is also possible that the study respondents had milder forms of disease or simply did not have acne vulgaris. Yosipovitch et al has suggested that acne pathogenesis primarily as it relates to sebum production is distinct in
73 mild compared with severe disease, and this may carry also for the role of psychological stress in this process (Yosipovitch et al., 2007).
The association found between increased stress levels and troublesome sweating in this study was consistent with other studies using the same design in America (Schut et al., 2016) and the United Arab Emirates (Bin Saif et al., 2018), suggesting climate, which is markedly different between Sydney (Australia), Philadelphia (USA) and Riyadh (Saudi Arabia), may not have had a defining influence on the association. Translation of self- reported symptom to diagnosis was less corruptible in this instance as studies have showed hyperhidrosis can be accurately diagnosed via questionnaire (Keller, Bello, Vibert, Swergold, & Burk, 2009). An association between stress and hyperhidrosis is supported in the literature. Krogstad et al showed that emotional stress significantly increased self-assessed sweating in both hyperhidrosis and control groups, with stress influencing patients more than controls. Sweat score varied significantly in the patient group, and dynamic responses to stress tended to return to baseline more slowly, compared with controls (Krogstad et al., 2006).
There is a sound basis for this association as ‘emotional’ sweating is thought to be regulated by the cerebral cortex (Schlereth, 2009). With histologically and functionally- normal sweat glands demonstrated in primary hyperhidrosis, the cause is hypothesised to be an abnormal or exaggerated central autonomic response to normal emotional stress (Sato, Kang, Saga, & Sato, 1989a, 1989b). This receives indirect support from studies which show significant differences in baseline sweating between HH patients and controls (Krogstad et al., 2006), and have proposed a genetic component in HH (K. Ro, Cantor, Lange, & Ahn, 2002). It is likely that cognitive factors exert a relatively important influence in the pathogenesis of hyperhidrosis. Identifying this association in this study is important also as it demonstrates that immune-mediated pathways, which dominate current psychodermatology theory, are not the only mechanisms through which stress might influence skin symptoms.
Hair-pulling was shown to be associated with increased stress levels in this, and other studies using the same design (Bin Saif et al., 2018; Schut et al., 2016), highlighting the important role of adaptive behaviours in the human response to stress. Perceived stress has
74 been strongly associated with body focused repetitive behaviours (BFRB), to which ‘hair- pulling’ belongs, and BFRBs have been found to be highly prevalent among females and medical students (Grant, Leppink, & Chamberlain, 2015; Siddiqui, Naeem, Naqvi, & Ahmed, 2012), both represented in high proportions in this study population. Stress connections with hair-pulling have not yet been fully elucidated but there is limited evidence that abnormalities in neurotransmitter systems may be involved (Krooks, Weatherall, & Holland, 2018).
It is important to note that hair-pulling to the point of removing the hairs may represent a symptom of trichotillomania, which is a psychiatric disorder classified by the American Psychiatric Association (American Psychiatic Association, 2013). A study of US college students found the lifetime prevalence of TTM to be around 0.6% (Christenson, Pyle, & Mitchell, 1991). Almost 20% of our cohort self-reported hair-pulling, suggesting students with psychiatric hair-pulling disorders possibly were more inclined to answer the questionnaire. As stated in the methods chapter, the questionnaire design did not exclude respondents with mental health diagnoses, so it is likely that the students who responded affirmatively to hair-pulling in the study were comprised of ‘hair-twirlers’ all the way up to sufferers of trichotillomania, and other hair-pulling psychoses.
Onychophagia, or nail-biting, classified in the DSM-5 as an ‘other specified obsessive compulsive and related disorder,’ (American Psychiatic Association, 2013) may have been susceptible to the same factors. Excluding students with psychiatric conditions would have potentially removed a large proportion of the population affected by these symptoms.
The symptom ‘warts’ generally encompasses common and genital warts and the aetiology is widely accepted to be infectious in nature (herpes simplex viruses, human papillomavirus). There is no good evidence to suggest psychological stress affects the course of warts. The finding of no association between stress and warts in the study was not unexpected, and was in line with studies in other student populations (Bin Saif et al., 2018; Schut et al., 2016). The questionnaire did not differentiate between common and genital warts so it was not possible to ascertain how respondents with genital warts only, interpreted this item.
75 The immune response to HPV recruits innate and adaptive immunity. Stress generally stimulates an innate immune response (e.g. antimicrobial peptides, NGF, SP) (Alexopoulos & Chrousos, 2016; Hall et al., 2012) and causes a shift in the adaptive response from Th1 (cytotoxic) to Th2 (humoral) profile (Segerstrom & Miller, 2004). HPV has the capacity to evade the innate response, thus delaying the activation of adaptive immunity, and it is cytotoxic T lymphocytes which are the principal effectors against HPV (Amador- Molina, Hernández-Valencia, Lamoyi, Contreras-Paredes, & Lizano, 2013; Scott, Nakagawa, & Moscicki, 2001).
Based on this, stress may, but most likely does not have a clinically significant effect on the course of warts. Warts served as a primarily non-inflammatory process for which less evidence is available regarding the role of stress. The predicted finding of no association possibly provided some indirect evidence that the survey was generally being answered thoughtfully and honestly by the respondents.
5.2 Study limitations
There were several limitations in this study that warrant discussion to qualify the findings. These related chiefly to factors in the study design, as well as representativeness of the sample population, and will be discussed below.
Use of ternary coding (male, female, other) for gender posed a potential source of bias. This is likely to have had little to no effect however as no respondents (0/471) identified as ‘other’ gender. As students were likely answering the survey ‘on the run’ on mobile devices it would have been impractical to offer all 33 gender identities recognised by the Australian sex survey. Moreover, use of non-binary gender coding was not routine in non-gender-related surveys circulated at UNSW in 2016 (Quality Indicators for Learning and Teaching, 2016), and the UNSW HREC committee did not propose that it be added. The 2016 Australian Bureau of Statistics census (ABS, 2016) reported that 5.4 per hundred- thousand people (0.000054%) identified as non-binary sex, which theoretically equates to 0.27 persons of the 5000 sent a study invitation. The use of a ternary coding system also conformed to designs of parallel studies, allowing for ease of lateral data merger (Bin Saif et
76 al., 2018; Schut et al., 2016). Any non-response bias potentially introduced through the use of ternary gender coding was corrected for in statistical analyses.
The perceived stress questionnaire asked respondents to nominate one of four discrete levels of perceived stress for each item (1. almost never, 2. sometimes, 3. often, 4. usually) (Levenstein et al., 1993). By virtue of this design, the PSQ assumed that no respondents will have ‘no stress’, which is almost certainly false based on the known complex pervasive nature of stress. It is most likely that respondents who perceived zero stress in the month leading up to participating in the study, nominated ‘almost never’, which may have artificially inflated the levels of stress reported in the study.
Use of a ‘modified version’ of the SRSQ may have weakened the validity and reliability of the dataset. This modified version has been used successfully in English and non-English-speaking populations (Bin Saif et al., 2018; Schut et al., 2016), and it is important to note that the skin symptoms associated with inflammation, including pimples and dry skin, which are the main focus of this thesis, were largely conserved from the original validated tool (F Dalgard et al., 2003). The only items that was not included was ‘other skin problems’.
Self-reporting of skin symptoms and signs via the modified SRSQ meant that participants were not physically examined or given specific dermatologic diagnoses. This hampered interpretation and clinical extrapolation of the study results as, previously mentioned, the vast majority of existing literature has focused on specific dermatologic diseases assigned to patients attending dermatology outpatient clinics.
In adolescents, the prevalence of self-reported complaints has been shown to be higher than those found during clinical examination by a skin specialist (Jon Anders Halvorsen et al., 2008). Moreover, the association with reduced quality of life (as reflected by an increased score on a Quality of life index) is stronger for self-reported skin problems than dermatologist-diagnosed conditions (Quandt et al., 2008). Skin diseases themselves have been shown to cause significant stress and impairment in quality of life (Sanclemente et al., 2017) and thus, in the absence of longitudinal design, a causal relationship between stress and skin symptoms was not able to be established.
77 5000 questionnaires were originally sent via email, of which 4,965 were delivered, and 3251 students opened the email, of which 541 attempted the survey, and 471 were enrolled in the study. The low response rate (10.8%), which is generally expected with surveys (Rindfuss, Choe, Tsuya, Bumpass, & Tamaki, 2015), produces a potential ‘non- response bias.’ Non-respondents of the survey may have been less interested in, or affected by stress, too busy or less understanding of the value or purpose of the research (Bates, Dahlhammer, & Singer, 2006; R. Groves, Presser, & Dipko, 2004; Saleh & Bista, 2017; Wenemark, 2010).
The study population was predominated by respondents of younger age, with around 63.5% aged between 18-20 years. This was expected as, according to Australian higher education data from 2016, most higher education students were in the 18-20 age group (Australian Government: Department of Education and Training, 2017). Moreover, the survey was deliberately sent to students aged 30 years or less and respondents to online surveys tend to be younger, even after controlling for confounding factors such as internet access and computer skills (Couper, Conrad, & Tourangeau, 2007). In addition, it was anticipated that by excluding respondents aged over 30 years, of which there were statistically likely to be few, that skin disorders more prevalent in older populations (e.g. rosacea and actinic damage) would be omitted.
Most of the respondents in the study were female (68%). The gender breakup at UNSW has been reported as 53.5% male and 46.5% female (Australian Government: Department of Education and Training, 2017), showing that women disproportionately responded to the survey. This is not unexpected when viewing survey research, known to exhibit typical demographic patterns. Women have been reliably shown to be more likely to participate in surveys than males (W. G. Smith, 2008). Moreover, women are more likely to seek health care generally, and thus may be disproportionately attracted to health-related surveys (A. E. Thompson et al., 2016).
22% of respondents in the study belonged to the medical faculty, which is a much greater proportional representation, compared with the <7% in the UNSW student population (Australian Government: Department of Education and Training, 2017). This is not unexpected as people have been shown to be more likely to participate in a survey of
78 interest or relevance to them (R. M. Groves, Presser, & Dipko, 2004). Medical students have been shown to score highly on traits of agreeableness and conscientiousness (Chaytor et al., 2012; Lievens, Coetsier, De Fruyt, & De Maeseneer, 2002), both of which have been shown to overlap with those who respond to surveys (Fan & Yan, 2010).
Directed efforts were made to minimise non-response bias. Students were sent reminders and offered a small incentive in the form of participation in a raffle for a Westfield shopping voucher (Fekete, Segerer, Gemperli, & Brinkhof, 2015; van Otterloo, Richards, Seib, Weiss, & Omer, 2011). This incentive was approved by the Human research and ethics committee. Despite this, it has been shown that younger people (20-30 years) are less interested in incentives than older participants (Saleh & Bista, 2017). To mitigate potential non-response bias, due to age, sex and other factors, the relationships between stress levels and each skin symptom/sign were examined controlling for potential
confounding factors e.g. sex, age, degree.
Whilst the original study had a number of limitations this does not diminish the overall value of the research. Several of the limitations were inherent in the study design, offset by important benefits, such as affording access to a nonhealthcare-seeking population and potential for higher response rate. All reasonable efforts were made to minimise these potential confounders and it is critically important that these limitations are duly considered when interpreting the results.
79 Chapter 6 – Conclusions and future research
Conclusions
The hypothesis, that increased levels of perceived psychological stress are associated with the presence of skin symptoms and signs in Australian university students was supported, with study findings suggesting that increased levels of perceived stress are associated with the presence of itch, dry/sore rash, scaly skin, itchy rash on hands, troublesome sweating, hair loss or hair-pulling. This association may have been mediated by any combination of, dysregulation of biological stress-response apparatuses, students heightened awareness of skin symptoms under stress and/or stress-adaptive behaviours. Several limitations were present in this work despite directed efforts to mitigate them and, in many ways, the final design provided other important advantages.
Future research
Associations between stress and skin conditions are becoming increasingly evident. Demonstrating causality continues to be a challenge in this type of research. Further longitudinal-design research investigating the biochemical changes that occur in the ‘stressed state’ is needed to explain why the skin symptoms and signs observed in this research might be seen. This may also provide a better understanding of the relationship between stress and many skin diseases, hence perhaps shedding light on the pathogeneses of these disorders. With a view to this, a longitudinal study is currently underway to assess the inflammatory changes that occur in acne vulgaris under the influence of psychological stress.
80 Chapter 7 – Publications and presentations arising from this research
1. Stewart TJ, Tong W, Whitfeld MJ. Associations between psychological stress and psoriasis: A systematic review. Int J Dermatol. 2018; DOI: 10.1111/ijd.13956.
2. Stewart TJ, Schut C, Whitfeld M, Yosipovitch G. A cross-sectional study of psychological stress and skin symptoms in Australian university students. Australas J Dermatol. 2017; doi:10.1111/ajd.12640.
3. A cross-sectional study of psychological stress and skin symptoms in Australian university students. Oral presentation in ‘Education and research’ session at GP17, Sydney 26-29 October 2017.
4. A cross-sectional study of psychological stress and skin symptoms in Australian university students. Oral presentation in ‘Stress and the skin’ session at the Association of Psychocutaneous Medicine of North America annual meeting, Orlando 2nd March 2017.
5. Stewart TJ, Schut C, Whitfeld M, Yosipovitch G. A cross-sectional study of psychological stress and skin symptoms in Australian university students. Poster session presented at the Australasian College of Dermatologists Annual Scientific Meeting, Sydney 6-9 May 2017.
81 Chapter 8 – Appendices
Appendix 1
Dear Student,
I am writing to let you know about a research project that you may like to take part in. The research is being undertaken by the UNSW Faculty of Medicine to learn about the effects of stress on skin diseases. The reason for this is to help people with stress-induced skin diseases.
If you take part in the research we would ask you to complete a brief online survey about your levels of stress and skin symptoms. The estimated duration is 10 minutes. Your answers will remain anonymous and will not be shared with anyone else.
Participating students who would like to be entered into a draw will have the chance to win one of three $50 Westfield gift cards.
In order to participate please follow this link: https://www.surveymonkey.com/r/TZJLLWT Stress and Skin Survey
www.surveymonkey.com
Taking part in research is voluntary. You may choose not to take part. If you decide not to take part your decision will have no effect on your relationship with The University of New South Wales or the study team.
If you would like more information please contact Dr Thomas Stewart at [email protected] or 0427341699.
This research has been reviewed and approved by The University of New South Wales Human Research Ethics Committee. If you have any complaints or concerns about the research project please email [email protected] or phone +61 2 9385 6222 quoting the following number: HC16565.
Thank you very much for your participation in our survey!
Yours sincerely,
Dr Thomas Stewart & Dr Margot Whitfeld UNSW Faculty of Medicine
82 Appendix 2
Survey Template
1. What is your gender?
- Male - Female - Other
2. What is your current age? (to the nearest year)
- 18 - 23 - 27 - 19 - 24 - 28 - 20 - 25 - 29 - 21 - 26 - 30 - 22
3. Which best describes your current academic degree?
- Bachelors - Graduate diploma/honours - Masters - Doctorate/PhD
4. Which best describes your current year of study?
- First - Fifth - Second - Sixth - Third - Seventh or higher - Fourth
5. In which faculty are you enrolled?
- Art & Design - Business - Medicine - Arts & Social sciences - Engineering - Science - Built environment - Law - Undeclared
6. What is your racial/ethnic identification?
- Caucasian - Aboriginal/Torres Strait Islander - Asian - Pacific Islander - African - Hispanic - Middle Eastern - Other
83 7. Perceived Stress Questionnaire
For each sentence, circle the number that describes how often it applied to you during the last month. Work quickly without bothering to check your answers and be careful to consider only the last month. Almost Sometimes Often Usually never 1. You feel tired 2. You feel that too many demands are being made on you 3. You are irritable or grouchy 4. You have too many things to do 5. You feel lonely or isolated 6. You find yourself in situations of conflict 7. You feel you’re doing things you really like 8. You feel tired 9. You fear you may not manage to attain you goals 10. You feel calm 11. You have to many decisions to make 12. You feel frustrated 13. You are full of energy 14. You feel tense 15. Your problems seem to be piling up 16. You feel you’re in a hurry 17. You feel safe and protected 18. You have many worries 19. You are under pressure from other people 20. You feel discouraged 21. You enjoy yourself 22. You are afraid for the future 23. You feel you’re doing things because you have to not because you want to 24. You feel criticized or judged 25. You are lighthearted 26. You feel mentally exhausted 27. You have trouble relaxing 28. You feel loaded down with responsibility 29. You have enough time for yourself 30. You feel under pressure from deadlines
84 8. Self-Reported Skin Questionnaire
During the last week, have you had any of the following complaints (please answer every question, placing a cross in the appropriate box)? No Yes, a little Yes, quite a lot Yes, very much Itchy skin Dry/sore rash Scaly skin Itchy rash on hands Oily, waxy or flakey patches on scalp Pimples Other rash on face Warts Troublesome sweating Loss of hair Nail-biting Hair-pulling
85 Appendix 3
Stress and Skin
Study Information & Consent
The purpose of this research study is to investigate the relationship between self-rated stress and skin diseases.
What you should know:
1. You are being invited to participate.
2. The decision to take part is completely up to you.
3. You can choose not to take part in the study.
4. You can agree to take part now and later change your mind up until submitting the questionnaire. After submission, your responses cannot be withdrawn as they will not be identifiable.
5. Whatever your decision you will not be disadvantaged in any way.
6. Ask any questions you might have before and after you decide.
7. By clicking to proceed, you are not waiving any of the legal rights you otherwise would have as a participant in a research study,
The estimated duration of your participation is 10 minutes.
The study procedures consist of answering questions about your stress level and skin symptoms.
There are no reasonably foreseeable risks or discomforts related to participation in this study.
The benefit you will obtain from the research is knowing that you have contributed to the understanding of the relationship between stress and skin symptoms.
At the end of the survey you will have the option to provide an email address should you want to be entered into a draw to win one of three $50 Westfield shopping vouchers.
The alternative to participation is not to participate.
86 Please contact the research team with any questions, concerns or complaints about the research, and for any research-related injuries, by calling Dr Thomas Stewart (+61427341699) or emailing [email protected].
This research has been reviewed and approved by the University of New South Wales Human Research Ethics Committee (HREC). Please contact them at (02) 9385 7257 or email them at: [email protected] for any of the following: questions; concerns or complaints about the research; questions about your rights; to obtain information or to offer input.
Confidentiality: All efforts will be made to limit the disclosure of your personal information to people who have an absolute need to see this information. This includes information about your age, gender, ethnicity, degree and skin conditions. However, the study team cannot guarantee complete secrecy. There are several organisations that may impact and copy your information to make sure the study team and following the rules and regulations regarding research and the protection of human subjects. These organisations include the human research ethics committee and University of New South Wales and its affiliates and agents.
We thank you for your support,
Dr Thomas Stewart and Dr Margot Whitfeld
87 Appendix 4
Participant information sheet
UNSW Faculty of Medicine
ONLINE PARTICIPANT INFORMATION STATEMENT
Stress and the skin Dr Margot Whitfeld
The research study is being carried out by the following researchers: Role Name Organisation Chief Investigator Dr Margot Whitfeld St Vincents Clinical School Co-Investigator/s Dr David Connor St Vincents Clinical School Dr Winnie Tong Student Investigator/s Dr Thomas Stewart St Vincents Clinical School Research Funder n/a
What is the research study about? You are invited to take part in this research study. You have been invited because you are a university student aged 18-30 years studying at UNSW in 2016.
To participate in this project, you need to meet the following inclusion criteria: • UNSW university student aged 18-30 years enrolled in 2016.
The research study is aiming to establish the relationship between psychological stress and skin symptoms.
Do I have to take part in this research study? Participation in this research study is voluntary. If you don’t wish to take part, you don’t have to. Your decision will not affect your relationship with The University of New South Wales or study team.
This Participant Information Statement and Consent Form tells you about the research study. It explains the research tasks involved. Knowing what is involved will help you decide if you want to take part in the research.
Please read this information carefully. Ask questions about anything that you don’t understand or want to know more about. Before deciding whether or not to take part, you might want to talk about it with a relative or friend.
If you decide you want to take part in the research study, you will be asked to: 88 • Tick a consent box on the survey • Keep a copy of this Participant Information Statement
What does participation in this research require, and are there any risks involved? If you decide to take part in the research study, you will be asked to complete a short questionnaire about your levels of stress and any skin symptoms you might be experiencing. Aside from giving up your time, we do not expect that there will be any risks or costs associated with taking part in this study. You will be asked to complete an online questionnaire, which will ask you questions about psychological stress and skin symptoms. We expect this activity might take up to 10 minutes.
Will I be paid to participate in this project? There are no costs associated with participating in this research study, nor will you be paid. However, you will be entered into a draw for the chance of winning one of three $50AUD Westfield shopping vouchers.
What are the possible benefits to participation? Participants will gain the knowledge that they have contributed to the understanding of the relationship between stress and skin diseases.
What will happen to information about me? By ticking the consent box on the survey, you consent to the research team collecting and using information about you for the research study. We will keep your data for 7 years. We will store information about you securely on the SurveyMonkey database and it will also be exported to the password-protected computer of the chief investigator as back up. Your information will only be used for the purpose of this research study and it will only be disclosed with your permission.
It is anticipated that the results of this research study will be published and/or presented in a variety of forums. In any publication and/or presentation, information will be published in a way such that you will not be individually identifiable.
How and when will I find out what the results of the research study are? You have a right to receive feedback about the overall results of this study. You can tell us that you wish to receive feedback by leaving your email at the end of the study. This feedback will be in the form of a one-page summary. You will receive this feedback after the study is finished.
What if I want to withdraw from the research study? Submitting your completed questionnaire is an indication of your consent to participate in the study. You can withdraw your responses any time before you have submitted the questionnaire. Once you have submitted it, your responses cannot be withdrawn because they are anonymous and there we will not be able to tell which one is yours.
89 What should I do if I have further questions about my involvement in the research study? The person you may need to contact will depend on the nature of your query. If you want any further information concerning this project or if you have any problems which may be related to your involvement in the project, you can contact the following member/s of the research team:
Research Team Contact Name Dr Margot Whitfeld Position Chief Investigator Telephone (02) 9966 9667 Email [email protected]
If at any stage during the project you become distressed or require additional support from someone not involved in the research please call Healthdirect on 1800 022 222 or your local GP or public hospital.
What if I have a complaint or any concerns about the research study? If you have any complaints about any aspect of the project, the way it is being conducted, then you may contact:
Position Human Research Ethics Coordinator Telephone + 61 2 9385 6222 Email [email protected] HC Reference Number HR16565
90 Appendix 5
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98 Chapter 9 – References
Abdel Aziz, A. M., Sh Hamed, S., & Gaballah, M. A. (2015). Possible Relationship between Chronic Telogen Effluvium and Changes in Lead, Cadmium, Zinc, and Iron Total Blood Levels in Females: A Case-Control Study. International Journal of Trichology, 7(3), 100– 106. https://doi.org/10.4103/0974-7753.167465
Aberg, K. M., Radek, K. a, Choi, E. H., Kim, D. K., Demerjian, M., Hupe, M., … Elias, P. M. (2007). Psychological stress downreglates epidermal antimicrobial peptide expression and increases severity of cutaneous infections in mice. J Clin Invest, 117(11), 3339–3349. https://doi.org/10.1172/JCI31726DS1
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