ORIGINAL ARTICLE

Sleep Disturbances and Inflammatory Bowel Disease Tauseef Ali, MD* and William C. Orr, PhD†

Abstract: With an estimated 70 million Americans suffering, sleep disorders have become a global issue, and discovering their causes and consequences are the focus of many clinical research studies. Sleep is now also considered to be an important environmental and behavioral factor associated with the process of inflammation and the immune system. Increased sleepiness is considered part of the acute phase of response to tissue injury, and sleep loss activates inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-a. Clinical studies in many immunemediated diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and ankylosing spondylitis, have revealed an association of sleep disturbances with disease activity. Recent research suggests that individuals with sleep abnormalities are also at greater risk of serious adverse health, economic consequences, and most importantly increased all-cause mortality. The importance of sleep in inflammatory bowel disease has recently gained attention with some published studies demonstrating the association of sleep disturbances with disease activity, subclinical inflammation, and risk of disease relapse. A comprehensive review of sleep physiology and its association with the immune system is provided here. Experimental and clinical studies exploring this relationship in inflammatory bowel disease are reviewed, and the clinical implications of this relationship and future directions for research are also discussed. (Inflamm Bowel Dis 2014;20:1986–1995) Key Words: sleep, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, environmental risk factors

T

he pathogenesis of inflammatory bowel disease (IBD) involves a complex interplay of host, genetic, and environmental factors.1–3 These factors result in the dysfunction of the innate and adaptive immune system and manifest as chronic, relapsing, and remitting inflammatory disease of the intestinal tract. Epidemiological studies have shown a rising incidence of IBD over the past several decades, and the observed geographic variations have suggested a strong influence of environmental factors on the pathogenesis of IBD.4,5 Childhood hygiene, smoking, diet, drugs, and stress have been shown to influence intestinal permeability, alter the mucosal immune system, and disrupt the intestinal mucosa, not only predisposing patients to IBD, but also modulating the disease’s activity and outcomes. Sleep is another important environmental and behavioral factor that has been shown to be associated with inflammation and the immune system. In fact, sleep disturbances (SDs) such as increased sleepiness are considered part of the acute phase of response to tissue injury that activates the process of inflammation.6 Sleep has a profound effect on the immune system, with sleep loss activating inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-a. Clinical studies in many Received for publication April 16, 2014; Accepted May 11, 2014. From the *OU Physicians Inflammatory Bowel Disease Center, and †Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. The authors have no conflicts of interest to disclose. Reprints: Tauseef Ali, MD, OU Physicians IBD Center, WP1345, 920 Stanton L. Young Boulevard, Oklahoma City, OK 73012 (e-mail: [email protected]). Copyright © 2014 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000108 Published online 13 July 2014.

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immune-mediated diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and ankylosing spondylitis (AS), have revealed an association of SDs with disease activity.7–9 The importance of sleep in IBD has recently gained attention with some published studies demonstrating the association of SDs with disease activity, subclinical inflammation, and risk of disease relapse. The purpose of this article is to review sleep physiology and its association with the immune system. A concise review of experimental and clinical studies exploring this relationship in IBD is provided. The clinical implications of this relationship and future directions for research are also discussed.

Stages of Sleep Polysomnographic data are used to classify sleep into 2 main categories, rapid eye movement (REM) sleep and non–rapid eye movement (NREM) sleep. Non-REM sleep is further divided into 3 stages based on increasing arousal thresholds. These sleep stages cycle through REM and NREM every approximately 90 minutes. During the first half of each night, more time is spent in slow-wave delta sleep each cycle, with increasing time in REM sleep occurring in the later portions of the night. Humans spend around 25% of their total sleep time in REM sleep. The exact biological purpose of sleep is unknown. However, slow-wave sleep is thought to be restorative and restful sleep, and REM sleep is associated with dream recall and memory consolidation. Although the ideal amount of sleep varies among individuals, most studies recommend 7 to 8 hours a night as optimal for adults. Alterations in normal sleep patterns are thought to be a significant contributor to a vast array of illnesses including depression, metabolic syndrome, inflammation, gastrointestinal diseases, and cancer.10–12 Inflamm Bowel Dis
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REGULATION OF SLEEP Sleep regulation is often described with a 2 process model.13 Process S, or the sleep homeostatic drive, linearly increases over the amount of time that an individual stays awake.14 Process C, or the circadian alerting drive, oscillates with body temperature on a cycle of approximately 24 hours.11,14 During the later hours of the day, process C enters its decline in the circadian pattern and process S has accumulated approximately 16 hours of continuous wakefulness. The combination of declining alertness and a sufficient amount of previous wakefulness facilitates the onset of sleep.14 Biological clocks have evolved based on a 24-hour cycle that allows organisms to anticipate and physiologically adjust to daily environmental changes; this circadian system provides a temporal organization of waking and sleep.11,15 The circadian clock is entrained or synchronized to the specific day–night cycle (phase) of the environment through signals such as light, meals, and social interaction. Light is the most important factor affecting the circadian rhythm. Light travels from the retina through the retinohypothalamic pathway to the suprachiasmatic nucleus and then through a monosynaptic pathway at the superior cervical ganglion to the pineal gland where it suppresses melatonin production. Melatonin is a neurohormone that synchronizes circadian rhythms both with the environment and the human body because melatonin receptors are found in nearly all human tissue. Furthermore, the 24-hour circadian rhythm is governed by 1 primary circadian clock and a system of peripheral clocks located in tissues including the pancreas, liver, and adipose tissue.16 The suprachiasmatic nucleus also serves as a “standard time,” which synchronizes peripheral tissue clocks.17 A series of “clock genes” help regulate the timing through both positive and negative feedback loops. CLOCK and BMAL-1 (Brain and Muscle Arnt-like protein) form heterodimers that accumulate throughout the day. These heterodimers then bind to the promoter regions of the genes Period (PER) and Cryptochrome (CRY) to activate their transcription. PER and CRY proteins then accumulate and form heterodimers that inhibit transcription of CLOCK and BMAL-1 proteins.18 In mammals, point mutations in these clock genes have been linked to altered circadian function and sleep abnormalities, including familiar advanced sleep phase syndrome and delayed sleep phase syndrome.19–21 Researchers have focused on determining whether similar feedback-loop clock genes are present within the gastrointestinal tract. PER2 expression has been identified in the myenteric plexus and affects the rhythmic releases of acetylcholine and nitric oxide, ultimately regulating peristalsis.22,23 Hypotheses regarding circadian rhythms affecting nutrient transport in the small intestine, gastric acid secretion, gut motility, and production of digestive enzymes have also been proposed.23

SLEEP AND HOST DEFENSE The acute phase response (APR) is a critical innate immune response that follows an inflammatory challenge. 24 Sleep is

Sleep and IBD

considered an important host defense and part of the APR to the inflammatory process. Sleep has been shown to share many immunoregulatory pathways with other APRs. The APR manifests itself in 2 ways: (1) biochemically with elevated C-reactive protein, serum amyloid A, and mannose binding protein and (2) behaviorally with fever, anorexia, and excessive sleep. This complex of responses leads to host-protective behavior, such as inhibition of microorganism growth and mobilization of leukocytes and natural killer cells.24 Interleukin (IL)-1b, TNF-a, and IL-6, the 3 major proinflammatory cytokines that are also important in IBD, are the primary triggers of the APR and are associated with excess sleep.25 The binding of pathogenic microbial molecules, also known as pathogenassociated molecular patterns, to toll-like receptors leads to the production of proinflammatory cytokines, which in turn induce NREM sleep. Therefore, enhanced NREM sleep seems to be the outcome of this inflammatory cascade.25 However, the anti-inflammatory cytokines, such as interferon (IFN)-a, IFN-b, IL-4, and IL-10, downregulate the APR and may inhibit sleep. Altered sleep responses have been recorded after viral and bacterial challenges in both animal and clinical studies. After intravenously injecting rabbits with Staphylococcus aureus to induce septicemia, researchers observed a large excess in NREM sleep within few hours of inoculation.26 Similarly, excessive stage 4 NREM sleep has been observed in patients with early stages of HIV infections, even before the onset of AIDS.27 Similarly, it has been suggested that changes in intestinal permeability during inflammation increase the exposure of bacterial products to macrophages, resulting in the release of somnogenic cytokines.28 This observation is relevant to the SDs observed in patients with IBD.

SUBJECTIVE ASSESSMENT OF SDS Different patient-reported and self-administered questionnaires29–31 to assess SDs such as overall sleep quality, insomnia, and sleepiness are frequently used in research studies and clinical practice. The Pittsburgh Sleep Quality Index (PSQI) is the most widely used self-rated questionnaire assessing sleep quality and disturbances over an 1-month time interval. Nineteen individual items generate 7 “component” scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, SDs, use of sleeping medication, and daytime dysfunction.29 The sum of scores for these 7 components yields 1 global score. A global PSQI score .5 can distinguish poor sleepers from good ones, with a diagnostic sensitivity of 89.6% and specificity of 86.5%.29 The PSQI provides a clinically useful assessment of a variety of SDs that might affect sleep quality. The clinimetric and clinical properties of the PSQI suggest its utility both in clinical practice and research activities. Most clinical studies assessing sleep in patients with IBD have used this questionnaire as a tool to measure sleep quality and disturbances.32–36 The insomnia severity index is a 7-item self-report questionnaire assessing the nature, severity, and impact of insomnia over www.ibdjournal.org |

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a period of 1 month. The questionnaire evaluates the following dimensions: severity of sleep onset, sleep maintenance, and early morning awakening problems, sleep dissatisfaction, interference of sleep difficulties with daytime functioning, noticeability of sleep problems by others, and distress caused by the sleep difficulties. A 5-point Likert scale is used to rate each item (e.g., 0 ¼ no problem; 4 ¼ very severe problem), yielding a total score ranging from 0 to 28. The total score is interpreted as follows: absence of insomnia (0–7); subthreshold insomnia (8–14); moderate insomnia (15–21); and severe insomnia (22–28). In a population-based sample, a cutoff score of 10 is optimal for detecting insomnia cases with 86.1% sensitivity and 87.7% specificity.30 Although insomnia is a highly prevalent disorder associated with functional impairment, health care costs, and increased risk of depression,30,37 it has yet to be investigated in clinical studies of SDs in IBD. The Epworth Sleepiness Scale, an 8-item questionnaire, is the most widely used clinical instrument for evaluating sleepiness.31 The score can range between 0 and 24. A score greater than 10 indicates sleepiness, and a score greater than 16 indicates the possibility of severe sleepiness or even narcolepsy. Other scales, such as the Stanford Sleepiness Scale 38 (7-item questionnaire) and the Karolinska Sleepiness Scale (9-item questionnaire),39 have been used in clinical studies to asses sleepiness and have been proven simple, reliable, and validated objective tools to assess sleepiness.39,40 Because of the nature of their items and component structures, these questionnaires are not conducive to validation with modern psychometric techniques, such as item response theory models.41 Given the content and psychometric concerns with the abovementioned questionnaires, PROMIS (Patient-reported Outcomes Information System) for SD and sleep-related impairment are item banks that were recently developed to improve the available self-report instruments measuring sleep–wake function.42 PROMIS (www.nihpromis.org) is a National Institutes of Health-funded consortium that aims to build item pools and develop core questionnaires measuring key health-outcome domains manifested in a variety of chronic diseases. The SD and sleep-related impairment item banks consist of 27 and 16 items each. Respondents rate various aspects of their sleep over the past 7 days on 5-point scales. Recently, Short 8-item PROMIS SD and sleep-related impairment forms have also been described.41 The questionnaires discussed above are retrospective instruments having the advantage of being able to quickly summarize events occurring over a long period. However, distortion due to the collapse and distillation of information cannot be avoided. Incomplete or selective memories and the human tendency to focus on the worst experiences and perhaps to amplify their importance can introduce information and interview biases. These issues can be countered through the use of prospective sleep diaries.43,44 Some sleep diaries present information in a graphic format that allows the clinician to quickly survey and appreciate patterns in large amounts of data. However, more precise information is

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obtained from fill-in-the-grid or question-type formats.43,44 Efforts are being made to develop a standardized diary for prospective sleep monitoring, to facilitate comparisons across studies.45

OBJECTIVE ASSESSMENT OF SDS The nocturnal polysomnogram is the standard objective measure of sleep.46 However, the associated expense, limited number of recordings (1–2 nights), night-to-night variability in human sleep, and difficulties surrounding the measurement of sleep in the laboratory are some of the limitations of this type of study. Actigraphy is a relatively low-cost method of estimating sleep parameters, such as total sleep time and the timing and duration of prolonged awakenings.47 An actigraph is a device that records gross motor movements. Not much bigger than a wristwatch, it is attached to a limb and can be worn day or night without interfering with normal sleep or daily functioning. It can record motor activity (in the case of sleep, the lack thereof) across many days and nights, and data are analyzed by means of a computer program that can provide reasonably accurate estimates of sleep onset latency, total sleep time, and sleep efficiency (defined as total sleep time/total recording time). However, actigraphy can overestimate the amount of sleep obtained in patients with insomnia who do not move much during the night, even when they are awake. Furthermore, the various commercially available actigraphs have not been standardized. They have different sensitivities to the detection of movement and differing algorithms for converting raw data points into estimates of sleep and wakefulness.48

EFFECTS OF SLEEP DEPRIVATION It is difficult to study the effects of sleep loss on the immune system. In sleep deprivation studies, it is also difficult to control for confounding factors such as stress, feeding, thermoregulation, and increased locomotor activity. All of these factors can affect sleep and immune functions. Despite these limitations, an emerging body of evidence suggests that sleep loss indeed affects our immune systems. Scientists have studied the activity of the immune system, such as measuring natural killer cell activity or plasma cytokine levels. In experimental models of sleep deprivation, rats with 20 days’ sleep loss developed septicemia and died.49 Bacterial cultures from their blood revealed facultative anaerobes, suggesting intestinal migration of bacteria leading to infection and sepsis. Furthermore, animal studies have revealed a robust 24-hour diurnal rhythmicity exhibited at the cellular, tissue, organ, and behavioral levels of the organism.50 Recent studies have found that the core molecular transcriptional–translational circadian regulatory feedback loop is housed at the cellular level, and that this 24-hour molecular clock regulates the diurnal timing of the expression of many clock-controlled genes.51 Undergoing repeated phase shifts of the light–dark cycle has been shown to increase mortality in aged mice.52 Hence, the chronic disruption of circadian rhythms may impose a serious challenge to health. The various molecular and clinical effects of sleep loss are described below and summarized in Table 1.

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TABLE 1. Effects of Sleep Loss on the Immune System Study Subjects Molecular effects Healthy Volunteers (n ¼ 19)53 Healthy volunteers (n ¼ 12)54

Healthy volunteers (n ¼ 20)55 Healthy volunteers (n ¼ 8)56 Healthy volunteers (n ¼ 42)57 Clinical effects Healthy volunteers (n ¼ 19)58 Healthy volunteers (n ¼ 25)59

Period of Sleep Deprivation

40 h of sleep deprivation 48 h of sleep deprivation

64 h of sleep deprivation 77 h of sleep deprivation 4 d PSD 4 d TSD

24 h sleep deprivation after vaccination 6 nights of PSD

Sleep diary for 14 d Healthy volunteers (n ¼ 153)60 Sleep quality of shift Maastricht Cohort Study. workers Employees of 45 different companies (n ¼ 12,095)61

Effectors

E-Selectin, ICAM-1, VCAM-1, CRP, IL-6, IL-1ra DNA synthesis of lymphocytes; adherence and alkaline phosphatase activity of granulocytes WBC, NK activity, T-cell types Phagocytic activity of lymphocytes sTNF-a RI sTNF-aR II IL-6

Outcomes

Increase in E-Selectin, ICAM, IL-1 and IL-1ra; no change in VCAM; Decrease in CRP and IL-6 Marked reductions of DNA synthesis after stimulation with phytohemagglutinin. No changes were noted in granulocyte adherence or alkaline phosphatase activity Increase in WBC and NK cell activity And reduced CD4 and CD16 count Decrease in phagocytosis Increase in sTNF-a RI and IL-6 in TSD but not in PSD No effects on sTNF-aRII in PSD and TSD

Antibody titers of HAV at day 28 2-fold higher HAV antibody titer in those who slept at post immunization night postvaccination compared with those who stayed awake Antibody titers of influenza Antibody titers in subjects who were immunized in vaccine at day 10 a state of sleep debt were less than half those postimmunization measured in the subjects with normal sleep times Nasal drops of rhinovirus and Participants with less than 7 h of sleep were at 3-fold development of clinical cold higher risk of developing cold Common clinical infections Three-shift workers reported the highest prevalence for all 3 infections (common cold, flu-like illness, and gastroenteritis)

CRP, C-reactive protein; HAV, hepatitis A vaccine; IL-1ra, cytokine interleukin-1 receptor antagonist; sTNF-a RI and RII, soluble TNF alpha receptor I and II.

Molecular Effects of Sleep Deprivation

Clinical Effects of Sleep Deprivation

Experimental studies provide growing evidence of the sensitivity of the sleep-wake system to activation of host-response mechanisms. After 40 hours of total sleep deprivation, the blood levels of E-selectin, intracellular adhesion molecule-1 and IL-1 increased significantly in healthy volunteers.53 Forty-eight hours of sleep deprivation markedly reduced lymphocyte DNA synthesis after stimulation with phytohemagglutinin.54 White blood cells, granulocytes, monocytes, natural killer cell activity, and the proportion of lymphocytes in the S phase of the cell cycle increased after 60 hours of sleep deprivation in healthy young adults.55 The same study showed reduced CD4 and CD16 counts after sleep deprivation.55 Seventy-seven hours of sleep deprivation also decreased the phagocytic activity in healthy volunteers.56 Increased production of IL-6 and soluble TNF a- receptor I has been shown in healthy human subjects undergoing 4 days of sleep deprivation.57 Data have suggested both an intrinsic circadian rhythmicity and sleep–wake homeostasis influence on the release and circadian rhythm of leptin, an adipocyte-derived hormone.62 Leptin has been recently described as an important inflammatory adipocytokine in IBD.63

Different clinical studies have examined the effects of sleep deprivation on functional immunity. The antibody response to vaccination can provide a valid tool to assess the influence of sleep on adaptive immune systems in humans. In a study of 19 healthy adults, acute sleep deprivation for only 1 day after immunization to hepatitis A vaccine resulted in significantly decreased antibody titers. Subjects who slept at night after receiving the vaccination had 2-fold higher hepatitis A vaccine antibody titers after 4 weeks compared with those staying awake.58 Similarly, in another vaccination study of 25 healthy subjects, influenza vaccine was administered after 4 nights of restricted sleep. Sleep restriction continued for another 2 nights after the vaccination. After 10 days of vaccination, antibody titers from sleep-restricted subjects revealed half of the level of influenza antibodies as was seen in controls.59 Individuals with less than 7 hours of sleep per night have also been found to have an almost 2-fold increased risk of developing colds.60 Similarly, shift workers who are typically considered a chronically sleepdeprived population have also been shown to have increased incidence of infections.61 www.ibdjournal.org |

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Effects of Sleep Restriction on the Gastrointestinal Tract Unlike the effects of sleep on cardiovascular and respiratory system, sleep-related changes in gastrointestinal physiology are not extensively described in the literature. However, it is becoming increasingly clear that changes in gastrointestinal functions during sleep play an important role in the pathophysiology of various gastrointestinal disorders. There seems to be an interdependent relationship between sleep and the pathogenesis of several gastrointestinal disorders.64 Sleep disturbances, such as sleep restriction and sleep apnea, can result in tissue hypoxia, oxidative stress, sympathetic activation, and systemic inflammation, leading to activation of inflammatory cytokines such as TNF, IL-1, and IL-6.65 Alterations in these cytokine levels have been demonstrated in certain gastrointestinal diseases, such as IBD, gastroesophageal reflux disease, liver disorders, and colorectal cancer. Sleep disturbances that are brought on by these disorders are shown to contribute to the severity of these same gastrointestinal diseases.66 For example, sleep disorders are common in patients with gastroesophageal reflux disease.67 Sleep deprivation decreases the threshold for esophageal acid perception in patients with gastroesophageal reflux disease.68 Patients with duodenal ulcers demonstrate a failure to inhibit acid secretion during the first 2 hours of sleep,69 and patients suffering from irritable bowel syndrome (IBS) have also been shown to have disturbed sleep patterns.70 Patients with IBS with lower amounts of quality sleep were prone to lower thresholds for rectal sensitivity and altered anal sphincter function.71,72 Circadian clock genes have been shown to regulate the physiology of the gastrointestinal tract. Disruption of the intestinal epithelial barrier enables the translocation of proinflammatory bacterial products, such as endotoxin, across the intestinal wall and into systemic circulation, a process that has been linked to pathologic inflammatory states.73 Circadian disruption has been shown to promote alcohol-induced gut leakiness, endotoxemia, and steatohepatitis. Hence, circadian organization is also critical for the maintenance of intestinal barrier integrity. Similarly, risk of colorectal adenomas seems to be increased in patients with

shorter sleep duration, even after adjusting for age, gender, race, smoking, family history of colorectal cancer, and waist-to-hip ratio.74 Table 2 describes the effects of SDs on different gastrointestinal disorders and possible mechanisms.

SLEEP AND IBD SDs have been observed in many immune-mediated and chronic inflammatory disorders. The impact of sleep on the immune system, especially the activation of inflammatory cytokines accompanying sleep restriction, suggests an association of SDs and disease activity of inflammatory immune-mediated diseases such as RA,9 SLE,7 and AS.8 One study even showed the benefits of anti-TNF therapy on the sleep quality of patients with AS.75 These studies have focused attention on the association of SDs and IBD. With the activation of inflammatory cytokines, especially the most common cytokines associated with IBD, TNF-a, IL-1, and IL-6, accompanying sleep restriction, a positive correlation between the disease activity and SD would be anticipated. A concise review of experimental and clinical studies exploring this relationship is presented below.

Experimental studies Disturbed sleep, especially disturbed sleep during active disease, is a well-established clinical observation. Studies of SDs revealed associations between SD and gastrointestinal symptoms, but the causality and directionality of these associations are unknown. The theory that SDs can actually worsen inflammation, leading to a more severe course of disease, has not been established. Although animal studies have shown a strong association between sleep deprivation and immune system activation, only 2 studies have examined immune system activation and the process of colonic inflammation in animal models. In the first study, the investigators demonstrated that chronic shifting of the light-day cycle led to a drastic increase in weight loss and intestinal histopathology in animals challenged by dextran sodium sulphate– induced colitis compared with control animals.76 The study indicated that circadian disruption may represent an important predisposing factor that could provoke the onset or worsening of inflammation.

TABLE 2. Sleep Disturbances and Different Noncolitic Gastrointestinal Disorders Gastrointestinal Disorder

SDs

Pathophysiologic Effects

GERD Peptic ulcer

Sleep restriction Sleep apnea

Worsening of reflux Increased risk of bleeding

Alcohol-related liver disease IBS

Circadian disruption

Increased risk of hepatic steatosis

Poor sleep quality

Colorectal adenomas

Shorter duration of sleep

Lower sensitivity to anorectal balloon dilation Increased risk of adenomas

GERD, gastroesophageal reflux disease.

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Possible Mechanism

References

Increased visceral hyperalgesia Tissue hypoxia, systemic inflammation, sympathetic activation Increased intestinal permeability and endotoxemia Alteration in autonomic nervous system regulation Decreased nocturnal melatonin production

68 66 73 71 74

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The same group published another study assessing the effects of acute and chronic intermittent sleep deprivation on the dextran sodium sulphate–induced colitis model and discovered that both acute and chronic intermittent sleep deprivation exacerbated colonic inflammation, as evidenced by marked increased in tissue myeloperoxidase activity.77 The effects of sleep deprivation on colonic inflammation were dose-dependent, with more severe inflammation in the chronic intermittent sleep deprivation group.

Clinical Studies Zimmerman was the first to publish data about SDs in the patient population with IBD.78 This was a small observational study of age-matched male patients with IBS and IBD, assessing the relationship between intestinal and extraintestinal symptoms, including SDs. An increase in SDs, as measured on a 5-point Likert scale, were noted in participants with IBS and IBD, and compared with healthy controls. The presence of diarrhea in patients with IBD and acid reflux in patients with IBS predicted the presence of SDs. The exclusion of female patients and the use of age-matched controls excluded gender and age effects. Failure to control for other potential confounding variables and the absence of standardized sleep measurement tools were some of the other limitations of this study.78 Another study used a mail-in survey to evaluate the effects of SDs and quality of life in a larger sample of patients with inactive IBD. Respondents with IBD reported significantly prolonged sleep latency, frequent sleep fragmentation, higher rate of using sleeping pills, decreased day-time energy, increased tiredness, and poor overall sleep quality compared with healthy respondents.32 The same group also published objective sleep evaluation through polysomnography in patients with IBD with inactive disease. They reported decreased sleep efficiency, as evidenced by increased stage I sleep and arousal indices.33 Assessment of sleep in asymptomatic patients has also been performed by means of wrist actigraphy.79 In a small study, decreased sleep efficiency and longer sleep onset latency were found in 4 asymptomatic patients with IBD, when compared with 8 age- and sex- matched healthy controls. There was almost no difference in melatonin rhythm among patients with IBD when compared with controls. Melatonin rhythm is a “gold-standard” measure of the circadian clock in humans. The relationship between disease activity and sleep quality has also been studied. In a large ongoing prospective cohort study known as the Manitoba IBD Cohort Study, patients with active IBD (77%) were found to have lower sleep quality compared with patients who have inactive disease (49%).36 Interestingly, the sleep quality of patients with inactive disease was also lower than the estimated prevalence of poor sleep in general adult population (32%). The study found a significant positive correlation of sleep quality and daytime dysfunction, and between perceived stress and psychological distress. There was also a strong negative correlation between sleep quality, number of sleep hours per night, and IBD-related quality of life.36 The investigators recently published

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the changes in fatigue and sleep problems that these patients experienced over the 2-year period and the association of fatigue and sleep problems with disease activity.35 The mean levels of fatigue were strongly associated with disease activity, with the participants with inconsistently inactive disease having the lowest level of fatigue at each time point. Adjusting for disease activity, disease type, and age, poor sleep quality (P , 0.001) was associated independently with an increase in fatigue over time. Ananthakrishnan et al80 conducted a longitudinal internetbased cohort study of 3173 patients and discovered a 2-fold increased risk of disease relapse in patients with poor sleep. The quality of sleep was measured using the PROMIS sleep questionnaire consisting of 4 questions regarding the patient’s sleep over the past 7 days, with responses to questions on a 5-point Likert scale.80 Interestingly, the investigators found no significant risk of relapse in patients with ulcerative colitis in clinical remission who also experienced poor sleep. Recently, a study of SDs among 96 pediatric patients with Crohn’s disease and depression was conducted.81 As expected, the study revealed significantly greater SDs in depressed youth. The study also indicated that sleep difficulties increased with worsening disease activity. Another prospective cohort study from Israel recently showed a significant correlation between disease activity and SDs in patients with Crohn’s disease.82 Our group is involved in an ongoing prospective cohort study with the primary aim of studying the association of SDs and risk of relapse in patient with sleep problems. In our first study, we discovered SDs in 100% of patients with clinically active IBD. An abnormal PSQI had a positive predictive value for histologic inflammatory activity of 83%.34 We followed these patients for 6 months. Five patients were in clinical remission and had normal PSQI scores: none of these patients experienced a relapse after 6-month follow-up. In contrast, 67% of patients who were in clinical remission but had abnormal PSQI scores relapsed (risk ratio ¼ 3; 95% confidence interval (1.5–6.1); P ¼ 0.03).83 A summarized report of the published clinical studies examining the association of IBD and sleep is presented in Table 3.

CLINICAL IMPLICATIONS OF SDS IN IBD Epidemiological Relevance There is a bimodal age distribution of ulcerative colitis and Crohn’s disease, with a first and larger peak occurring around ages 16 to 25 years and a second smaller peak at around age 60 years. It is thought that certain environmental factors, such as diet, chemicals, and drugs, can trigger the first attack in a genetically susceptible individual with immune dysfunction. These environmental factors can lead to changes in the mucosal integrity and bring about the onset of a vicious cycle of chronic inflammatory process. With experimental studies investigating the role of sleep loss on intestinal motility and mucosal integrity, it is logical www.ibdjournal.org |

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TABLE 3. Clinical Studies Examining the Association of IBD and Sleep Study Author

Study Type

Association between SDs and IBD Adult studies Zimmerman78 Case-control age and sexmatched controls

Ranjbaran32

Case-control study

Keefer et al33

Case-control study

Burgess et al79

Case-control study

Pediatric studies Pirinen84

Sleep Evaluation

Results

55 IBD 5-point Likert scale for Higher mean scores of SDs in 53 IBS difficulty in falling IBD (P ¼ 0.004) and patients 56 healthy controls asleep; poor sleep with IBS (P ¼ 0.041) compared with controls Diarrhea as a predictor of poor sleep among patients with IBD and not IBS (P , 0.025) 80 inactive IBD PSQI Poor sleep quality in IBD and 24 IBS IBS patients compared with 15 healthy controls controls (P , 0.0001) IBD-Q score inversely correlated with sleep quality (r2 ¼ 0.55, P ¼ 0.02) 16 inactive IBD PSQI Poor sleep quality in IBD and 9 IBS ESS IBS patients compared with 7 healthy controls Polysomnogram controls (P , 0.05) Sleep efficiency under 85% and increased stage 1 and arousal indices 4 inactive IBD (3 Wrist actigraphy Longer sleep onset latency CD, 1 UC) (23 min versus 6.32 min) and 8 age- and sexlower sleep efficiency and matched (78 min versus 87 min) among controls cases compared with controls (P , 0.05) Similar circadian rhythm except 1 patient

Limitations

Only male patients Self-reported single center study No validated sleep questionnaire

A self-administered, mail-in questionnaire Lack of control of confounding factors

Small sample size, differences in the age group of study and control population and first night effect on PSG

Small sample size, no validated disease severity index

160 IBD Sleep self-report and More troubled sleeping and Self-reported assessment of 236 age-/gendersleep questions of overtiredness among IBD disease severity and SDs matched control the child behavior adolescents with severe disease Effect of steroids not assessed in and parents of checklist, and youth compared with mild disease and the group with severe disease both groups self-report controls (P , 0.01) Association between SDs and disease activity Adult studies Prospective 318 IBD PSQI 82% active CD and 72% active Cross sectional data and lack of Graff36 cohort study 160 CD ESS UC patients with PSQI . 5 control group 158 UC compared with 51% inactive CD and 47% inactive UC (P , 0.001) Day-time sleepiness also worse in patient with active disease in both CD and UC (P , 0.01) Strong correlation between sleep quality and disease activity, perceived stress, psychological distress, and quality of life (P , 0.001)

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TABLE 3 (Continued) Study Author

Study Type

Graff et al35

Prospective cohort study

312 IBD 159 CD 153 UC

PSQI

Ali34

Prospective cohort study

41 IBD 23 CD 18 UC

PSQI

Gingold-Belfer et al82

Prospective cohort study

108 CD

PSQI

Cross sectional case-control study

96 CD PSQI 19 healthy controls

Pediatric study Benhayon et al81

Patients

Sleep Evaluation

Association between SDs and disease relapse 3173 IBD Ananthakrishnan80 Internet-based longitudinal 2079 CD cohort study 1094 UC

PROMIS SD questionnaire

Ali T, 2013

PSQI

Prospective cohort study

70 IBD

Results

Limitations

Fatigue was associated with No objective measures of disease disease activity pattern activity (P ¼ 0.0002) After controlling for disease activity, type and age, poor sleep quality was independently associated with changes in fatigue over time (regression coefficient ¼ 0.30; P , 0.001) 100% SDs in active disease and Small sample size 72% in inactive disease (OR, 2.8, P ¼ 0.007) PPV for 83% for histologic inflammation in inactive group Significant correlation between Only patients with CD using the CDAI and PSQI scores CDAI score (subjective (P , 0.001) measures of disease activity) More SDs in depressed youth with CD Qualitative SDs predicted by disease activity, pain and anxiety Quantitative SDs predicted by disease activity

Small sample size Causality cannot be established

Impaired sleep associated with 2- Validity of PROMIS fold increase risk of disease questionnaire (only 4 relapse in patients with CD in questions regarding past 7 d clinical remission sleep on a Likert scale) 2-fold increased increase of Small sample size disease relapse in patients with IBD at 6 mo

CD, Crohn’s disease; OR, odds ratio; PPV, positive predictive value; UC, ulcerative colitis.

that SDs in early adulthood could be an important contributing factor to the onset of IBD.

and anxiety.81 Investigators proposed that treatment of 1 of the 3 can affect the outcome of the other 2. Assessment and management of SDs can play an important therapeutic role.

Disease Monitoring Studies have shown that poor sleep quality is associated with disease activity. Recently, our group discovered a positive predictive value of 83% for subclinical inflammation in patients with poor sleep quality. Poor sleep quality was also associated with a 3-fold increased risk of disease relapse in 6 months. This relapse risk was confirmed in another study.80 Assessment of SDs can play an important role in disease monitoring and optimizing medical management to prevent disease relapse.

Therapeutic Importance A recent study described a “tripartite relationship” among SDs, disease activity, and psychiatric disorders such as depression

MANAGING SLEEP DISTURBANCES IN IBD It is anticipated that if SDs are indeed part of the pathogenesis of IBD, then treatment to improve the quality of sleep should have a salubrious effect on patients with IBD. As a follow-up to our work showing the prevalence of SDs, we are embarking on a program to investigate the effects of a behavioral intervention program to treat SDs in patients with IBD.

FUTURE DIRECTIONS Future research should use more objective sleep measures, including polysomnography and actigraphy, to further characterize www.ibdjournal.org |

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Ali and Orr

the changes in sleep architecture in patients with IBD. The field would also benefit from additional studies using more objective measures of IBD activity, such as calprotectin or histologic and endoscopic evaluation. Our group performed the first prospective study, but our number of participants was small. Our results should be confirmed by larger trials. Treatment of SDs and any corresponding impact on disease outcome must be studied more carefully. Recently, we proposed an algorithmic approach to the assessment of sleep disorders.85 A study of improved sleep hygiene and its effect on disease outcome are currently ongoing.

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