DOCTORAL THESIS SAHLGRENSKA ACADEMY

Gastrointestinal Symptoms and Fatigue in Patients with Quiescent Ulcerative Colitis Börje Jonefjäll

SAHLGRENSKA ACADEMY INSTITUTE OF MEDICINE

Gastrointestinal Symptoms and Fatigue in Patients with Quiescent Ulcerative Colitis

Börje Jonefjäll

Department of Internal Medicine and Clinical Nutrition Institute of Medicine Sahlgrenska Academy at University of Gothenburg

Gothenburg 2016

Cover illustration: Kristina Jonefjäll

Gastrointestinal Symptoms and Fatigue in Patients with Quiescent Ulcerative Colitis © Börje Jonefjäll 2016 [email protected] ISBN 978-91-628-9931-8 (PRINT) ISBN: 978-91-628-9932-5 (PDF) http://hdl.handle.net/2077/44934 Printed in Gothenburg, Sweden 2016 Ineko AB

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To Kristina, Svea, Malva and Alvin

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Gastrointestinal Symptoms and Fatigue in Patients with Quiescent Ulcerative Colitis Börje Jonefjäll Department of Internal Medicine and Clinical Nutrition, Institute of Medicine Sahlgrenska Academy at University of Gothenburg, Sweden

ABSTRACT Gastrointestinal symptoms compatible with Irritable Bowel Syndrome (IBS) and fatigue are common in patients with quiescent ulcerative colitis (UC). The causes of these symptoms remain to be clarified. The overall aim of this thesis was to characterize patients with quiescent UC to find factors that might contribute to generation of residual gastrointestinal symptoms and fatigue. Two patient cohorts were studied. In Paper I and II, patients with new onset of UC (n=98) were followed prospectively during three years with yearly follow-up visits. Symptoms compatible with IBS during clinical remission was reported by 29% of the study population. When comparing patients in clinical remission with and without IBS-like symptom, patients with IBS-like symptoms had more severe gastrointestinal symptoms, tendencies toward more severe psychological symptoms and reduced levels of quality of life, but the levels of fecal calprotectin did not differ between the two groups. The patients that would develop IBS-like symptoms while in remission during follow-up experienced more severe gastrointestinal symptoms at disease onset, but the severity and extent of inflammation at disease onset were comparable to the patients who would not report IBS-like symptoms during follow-up. IBS-like symptoms during remission were not explained by pre-existing IBS. In Paper III and IV, 298 patients with UC were investigated. The criteria for deep remission were met by 132 patients and 18% of these reported IBS-like symptoms. Poor psychological well-being, higher levels of stress and increased systemic cytokine levels, but not colonic low-grade inflammation, were associated with IBSlike symptoms. The prevalence of high fatigue was 40% among the study population. Independent risk factors for high fatigue were: probable psychiatric disorder, iron deficiency, active disease and female gender. No difference was observed comparing levels of calprotectin or systemic cytokines among patients in deep remission with and without high fatigue. Conclusions: IBS-like symptoms among patients with UC in remission are common, but not as prevalent as previously reported, which emphasizes the importance of using fecal calprotectin and endoscopy to rule out on-going inflammatory disease activity. Psychological factors and increased systemic immune activity are associated with IBS-like symptoms. Psychological distress, iron deficiency and disease activity should be investigated in patients with UC suffering from fatigue. Keywords: ulcerative colitis; irritable bowel syndrome; fatigue; calprotectin ISBN: 978-91-628-9931-8 (PRINT)

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SAMMANFATTNING PÅ SVENSKA Ulcerös kolit (UC) är en inflammatorisk tarmsjukdom som drabbar tjocktarmen och ger upphov till inflammation i tarmslemhinnan i varierande grad. De vanligaste symtomen vid UC är blodiga, slemmiga diarréer. Mellan aktiva sjukdomsperioder kan patienterna vara helt symtomfria, s.k. remission. Vissa patienter med UC uppvisar, trots avsaknad av inflammatorisk sjukdomsaktivitet i tarmen, svårvärderade magtarmsymtom liknande dem vid Irritable bowel syndrome (IBS) vilket utgör ett kliniskt dilemma. IBS karakteriseras av återkommande smärta eller obehag i magen relaterat till avvikande tarmtömningsvanor där någon underliggande organisk sjukdom inte kan påvisas. Studier har visat att IBS-lika symtom hos patienter med UC i remission är kopplade till psykologiska faktorer men även att de möjligen avspeglar en låggradig inflammatorisk sjukdomsaktivitet. Kraftig trötthet är också ett vanligt förekommande symtom hos patienter med UC och orsaker till detta är inte fullständigt klarlagt. För att kunna ge patienter med UC som upplever IBS-liknande symtom och kraftig trötthet en optimal och korrekt behandling är det viktigt att ytterligare kartlägga vilka faktorer som bidrar till uppkomsten av dessa symtom. I delarbete I och II följdes 98 patienter med nydebuterad UC under 3 års tid med årliga kontroller. IBS-liknande symtom under remission rapporterades utav 29% av patienterna. De IBS-lika symtomen var associerade med mer uttalade magtarmsymtom generellt, nedsatt psykiskt välbefinnande och lägre livskvalitet, men de verkade inte var orsakade av låggradig inflammation i tarmen eftersom nivåer utav calprotectin i avföring var lika när man jämförde grupperna i remission med och utan IBS-lika symtom. De patienter som rapporterade IBS-lika symtom under uppföljningen upplevde mer uttalade magtarmsymtom, inklusive magsmärta, vid det första skovet av UC trots att det inte var någon skillnad i inflammatorisk sjukdomsaktivitet jämfört med de patienter som inte utvecklade IBS-lika symtom. Förekomsten av IBS-lika symtom efter insjuknandet i UC förklarades inte utav tidigare existerande IBS. I delarbete III och IV undersöktes 298 patienter med UC. Utav patienterna i djup remission upplevde 18% IBS-lika symtom. De IBS-lika symtomen var associerade med nedsatt psykiskt välbefinnande, högre nivåer av stress och ökad systemisk immunologisk aktivitet men inte låggradig inflammation i tarmslemhinnan. Kraftig trötthet rapporterades av 40% av patienterna. Riskfaktorer för kraftig trötthet var psykologisk ohälsa, järnbrist, inflammatorisk sjukdomsaktivitet och kvinnligt kön. Trötthet hos patienterna i djup remission var inte kopplat till låggradig inflammation i tarmslemhinnan eller systemisk immunologisk aktivitet. Konklusion: IBS-lika symtom hos patienter med UC i remission är vanligt förekommande och dessa symtom bör utredas med fekalt calprotectin och endoskopi för att utesluta inflammatorisk aktivitet i tarmslemhinnan. Psykologiska faktorer och stress men även ökad systemisk immunologisk aktivitet är associerat med IBS-lika symtom. Psykisk ohälsa, järnbrist och inflammatorisk sjukdomsaktivitet bör utredas hos patienter med UC som upplever kraftig trötthet.

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LIST OF PAPERS This thesis is based on the following studies, referred to in the text by their Roman numerals.

I.

Jonefjäll B, Strid H, Öhman L, Svedlund J, Bergstedt A, Simrén M. Characterization of IBS-like symptoms in patients with ulcerative colitis in clinical remission. Neurogastroenterol Motil 2013;25(9):756-e578.

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Jonefjäll B, Simrén M, Öhman L, Lasson A, Svedlund J, Strid H. The severity of inflammation at onset of ulcerative colitis is not associated with IBS-like symptoms during clinical remission. J Crohns Colitis, 2015 Sep;9(9):776-83.

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Jonefjäll B, Öhman L, Simrén M, Strid H. IBS-like symptoms in patients with ulcerative colitis in deep remission are associated with increased levels of serum cytokines and poor psychological well-being. Inflamm Bowel Dis. 2016 Nov;22(11):2630-2640

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Jonefjäll B, Simrén M, Lasson A, Öhman L, Strid H. Psychological distress, iron deficiency, active disease and female gender are independent risk factors for fatigue in patients with ulcerative colitis. Submitted

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CONTENT ABBREVIATIONS .............................................................................................. X 1 INTRODUCTION ........................................................................................... 1 1.1 Ulcerative colitis ................................................................................... 1 1.2 Irritable bowel syndrome ...................................................................... 3 1.3 IBS-like symptoms in quiescent ulcerative colitis ................................ 4 1.4 Fatigue................................................................................................... 7 1.5 Fatigue in ulcerative colitis ................................................................... 7 2 AIM ........................................................................................................... 10 3 PATIENTS AND METHODS ......................................................................... 11 3.1 Study design ........................................................................................ 12 3.1.1 Paper I and II ............................................................................... 12 3.1.2 Paper III and IV ........................................................................... 13 3.2 Assessment of clinical disease activity ............................................... 15 3.3 Definition of remission ....................................................................... 16 3.4 Inflammatory biomarkers .................................................................... 17 3.5 Anaemia and iron deficiency .............................................................. 17 3.6 ANS activity........................................................................................ 18 3.7 Questionnaires..................................................................................... 19 3.8 Statistical methods .............................................................................. 19 4 RESULTS ................................................................................................... 22 4.1 IBS-like symptoms in quiescent ulcerative colitis (Paper I - III) ........ 22 4.1.1 Prevalence of IBS-like symptoms ............................................... 22 4.1.2 Low-grade immune activity ........................................................ 24 4.1.3 Psychosocial factors, QOL and gender ....................................... 26 4.1.4 Gastrointestinal and non-GI somatic symptoms.......................... 27 4.2 Predictive factors for development of IBS-like symptoms (Paper II) . 29 4.2.1 Inflammatory activity and gastrointestinal symptoms ................ 29 4.2.2 Psychosocial factors, gender and ANS-activity .......................... 29

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4.3 Fatigue in ulcerative colitis (Paper IV) ............................................... 30 4.3.1 Prevalence and risk factors for high fatigue ................................ 30 4.3.2 Fatigue during deep remission..................................................... 32 5 DISCUSSION .............................................................................................. 33 5.1 IBS-like symptoms in patients with quiescent ulcerative colitis ......... 33 5.1.1 Prevalence of IBS-like symptoms ............................................... 33 5.1.2 Occult local inflammation ........................................................... 35 5.1.3 Systemic immune activity ........................................................... 36 5.1.4 Gender ......................................................................................... 37 5.1.5 Gastrointestinal and non-GI somatic symptoms .......................... 38 5.1.6 Psychosocial factors and quality of life ....................................... 39 5.1.7 Predictive factors for development of IBS-like symptoms ......... 40 5.1.8 Treatment of IBS-like symptoms ................................................ 42 5.2 Fatigue in ulcerative colitis ................................................................. 43 5.2.1 Prevalence of fatigue ................................................................... 43 5.2.2 Risk factors for fatigue ................................................................ 44 5.2.3 Fatigue during deep remission..................................................... 47 5.2.4 Treatment of fatigue .................................................................... 48 5.3 Study limitations ................................................................................. 49 6 CONCLUSION ............................................................................................ 51 7 FUTURE PERSPECTIVES ............................................................................. 52 ACKNOWLEDGEMENT .................................................................................... 54 REFERENCES .................................................................................................. 56

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ABBREVIATIONS ANS CI CRI CRP GI GSRS HAD IBD IBDQ IBS IL IFN IQR MFI mRNA OR PHQ PSS QOL SD SF-36 TNF UC

Autonomic nerve system Confidence interval Coping resources inventory C-reactive peptide Gastrointestinal Gastrointestinal symptom rating scale Hospital anxiety and depression scale Inflammatory bowel disease Inflammatory bowel disease questionnaire Irritable bowel syndrome Interleukin Interferon Interquartile range Multidimensional fatigue inventory Messenger ribonucleic acid Odds ratio Patient health questionnaire Perceived stress scale Quality of life Standard deviation Short form health survey-36 Tumor necrosis factor Ulcerative colitis

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1 INTRODUCTION 1.1 Ulcerative colitis Ulcerative colitis (UC) is a life-long chronic inflammatory bowel disease (IBD) affecting the colorectal mucosa, characterized by a relapsing and remitting course.1, 2 UC is most common in the developed countries of North America and Europe and the highest incidence and prevalence have been reported from the northern countries of Europe.3 The prevalence of UC in Scandinavian countries has been reported to be 161-350/105 persons4-7 and several studies have shown that the incidence has increased, from as low as 3.3 to as high as 20/105 persons over the last decades.4-6, 8-12 The median age at disease on-set have been reported to be 34-46 years, but UC can occur at any age.13 Patients with UC report reduced quality of life (QOL) and the socioeconomic burden of UC is essential due to work losses, medical treatment, need for hospitalization and surgery.3, 14 Further, patients with UC have an increased risk of colorectal cancer.15 Surgical treatment in patients with UC is often due to colorectal cancer or failure of medical therapy. Although the colectomy rates have decreased3, the IBSEN study recently reported a 10% cumulative risk of colectomy 10 years after the diagnosis of UC.16 However, patients with UC do not have a higher mortality rate than the general population.3, 14, 17 The pathogenesis of UC is not fully understood. Luminal factors (such as bacteria and environmental antigens), disturbances of the colonic wall (such as increased permeability) and a dysregulated immune system in genetically predisposed patients seem to be of importance. Altogether these factors result in a destructive host-microbiome interaction, which lead to inflammation and mucosal damage.18 Patients with active UC suffers from gastrointestinal (GI) symptoms such as diarrhoea, passage of blood and pus in stool, urgency to defecate and abdominal discomfort. The natural course of UC varies a lot. The disease can be continuously active or present with flares and periods between flares with no disease activity, so called remission.1 The inflammation in UC is normally continuous in the colon, beginning in the rectal mucosa.2 The most proximal

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Gastrointestinal Symptoms and Fatigue in Patients with Quiescent Ulcerative Colitis

extent of disease should be assessed according to the Montreal classification (i.e. proctitis, left-sided colitis or extensive colitis).19 The extent of disease varies at disease onset and can also progress over time.16 In contrast, the other major IBD; Crohn´s disease, is typically presented as a discontinuous segmental inflammation when it affects the colon.20 However, rectal sparing colitis is also seen in patients with UC and is of importance for this thesis and will be further discussed.21 The severity of disease can be evaluated using different clinical scores (for example: Truelove and Witts´ criteria 22 or Mayo Score23). To classify the patients according to extent and severity of disease is of importance to choose optimal medical treatment and to identify patients with severe colitis who should initially be treated as inpatients.24 In clinical practice, the most commonly used biomarkers for disease activity among patients with UC are calprotectin in stool and C-reactive peptide (CRP) in serum. Fecal calprotectin is a marker of increased activity of neutrophilic granulocytes seen in the acute phase of colonic inflammation.25 The level of fecal calprotectin correlates with the degree of mucosal inflammation seen at endoscopy as well as with histological inflammation among patients with UC.26-28 Studies have shown that fecal calprotectin can be used to predict endoscopic mucosal inflammation and to identify patients with endoscopic and histological mucosal healing.27-30 Further, it has been shown that elevated levels of fecal calprotectin can predict a more severe clinical course in patients with UC.31-33 CRP is a systemic acute-phase protein produced by hepatocytes. The levels of CRP is increased in many inflammatory conditions and not specific for colonic inflammation.34 Patients with UC that have elevated levels of CRP are more likely to have moderate to severe disease.35 In a Norwegian study, levels of CRP correlated to disease extent at the diagnosis of UC, but 71% of these patients had normal levels of CRP. To sum up, fecal calprotectin is the best marker for colonic inflammation but CRP, although of some clinical value, is not considered to be a reliable marker for disease activity or to be able to discriminate between UC patients with normal or mild inflammation at endoscopy.27, 34, 35 UC is treated with anti-inflammatory and immune modulating medications, depending on the disease severity, extent and activity over time. The most commonly used medications are 5-aminosalicylic acid (5-ASA), corticosteroids, thiopurines, tumor necrosis factor-α (TNF-α) inhibitors and the α4β7 integrin inhibitor. If medical treatment fails surgical treatment with

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colectomy is recommended.24 The overall therapeutic goal is to bring the patients into long-standing steroid-free remission and to prevent future relapses, thereby improving GI symptoms and QOL and reduce the risk for hospitalization and need for surgery.24

1.2 Irritable bowel syndrome Irritable bowel syndrome (IBS) is characterized by abdominal pain or discomfort which is relieved by defecation and associated with a change in stool consistency and frequency. IBS is a functional bowel disorder, which per se, means that no organic GI disease that might cause the GI symptoms should be present. The diagnostic criteria are determined by the Rome foundation for functional GI disorders and the papers in this thesis use the Rome II36 (Paper I and II) and Rome III37 (Paper III and IV) criteria for IBS. To fulfill the Rome criteria for IBS, the patients have to have abdominal discomfort or pain combined with two of the following three features; (1) relieved with defecation, (2) onset associated with a change in stool frequency, and (3) onset associated with a change in form (appearance) of stool. According to the Rome II criteria, the symptoms should have been present for at least 12 weeks during the preceding 12 months and the Rome III criteria state that the symptoms should have been present for at least 2-3 days per month during the previous 3 months and the symptoms should have been present for more than 6 months. Further, IBS can be subtyped into: IBS-D (IBS with diarrhoea), IBS-C (IBS with constipation), IBS-M (mixed IBS with both diarrhoea and constipation), and IBS-U (unsubtyped IBS).37 In a meta-analysis, the global prevalence of IBS has been reported to be approximately 11% and in the general population in European countries the prevalence varies between 2.6% and 13%.38 Although IBS is a benign disorder, these patients report reduced QOL and the socioeconomic consequences (health care costs and absence from work or school) of IBS are substantial, pointing out the importance of a correct treatment of patients with IBS.39, 40 The pathophysiology of IBS is still incompletely understood. Peripheral factors such as GI motility disturbances, dietary factors, alterations of the gut microbiota composition, increased intestinal permeability, dysregulated

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Gastrointestinal Symptoms and Fatigue in Patients with Quiescent Ulcerative Colitis

intestinal immune system, disturbances in the enteroendocrine system (including increased levels of serotonin) and visceral hypersensitivity have been proposed as contributing factors for generation of GI symptoms among patients with IBS.41-44 Approximately 10% of patients with IBS report an infectious gastroenteritis prior to the development of IBS (so called post-infectious IBS) and alterations of the immune system locally in the intestinal mucosa, as well as increased systemic immune activity have been reported among patients with IBS.42, 45 Further, high prevalence of IBS-like symptoms in patients with quiescent IBD has been reported.46-53 Taken together, these data suggest common pathophysiological pathways in IBS and IBD, such as residual lowgrade immune activity and/or post-inflammatory alterations in the gut.44, 54, 55 Central nervous system factors are also of importance since IBS is associated with mood and anxiety disorders.43, 56, 57 What is cause and consequence is however hard to determine. Central factors (i.e. the brain) and peripheral factors (i.e. the gut) can however affect each other bi-directionally through the autonomic nervous system (ANS) and the hypothalamus-pituitary-adrenal axis (i.e. the brain-gut axis) and contribute to the generation of GI symptoms.43 The treatment of patients with IBS focuses on reducing the burden of GI symptoms and improving QOL. Patient education about IBS and life-style advice, such as dietary modification and increased physical activity, are essential.58-60 Moreover, the treatment should be individualized and pharmacological agents (targeting the most prominent symptoms), psychological therapies and gut-directed hypnotherapy might be appropriate depending on severity of symptoms and psychological co-morbidity.60-62

1.3 IBS-like symptoms in quiescent ulcerative colitis Residual GI symptoms during quiescent UC (i.e. remission) have been studied in several previous studies. Different definitions of GI symptoms during remission have been used, but the most common is symptoms compatible with IBS, evaluated by the Rome criteria for IBS (Table I). Reduced QOL is observed among UC patients that experience IBS-like

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symptoms during quiescent disease47, 49, 50, pointing out the importance of a correct treatment of this category of patients. The prevalence of IBS-like symptoms during remission has been reported to be 25% and 46% (Table 1).46-53 The origin of these symptoms is not fully understood. The severity of psychological symptoms, such as anxiety and depression, has been associated with IBS-like symptoms during remission47, 50 but whether this is cause or consequence has not been established. Further, persisting occult low-grade colonic inflammatory disease activity have been proposed as a possible cause, although data are contradictory.50-53, 63 The explanation for the inconsistent findings might be that previous studies use different definitions of remission: several studies have not evaluated the patients with endoscopy or at least not at the time of symptom registration and mild endoscopic inflammation have been accepted in the remission criteria and only the most recent studies have used fecal calprotectin as a biomarker for mucosal inflammation (Table 1). In recent years more strict definitions for remission (deep remission and mucosal healing) have been introduced as goal for treatment in patients with IBD.64 However, in contrast to a dualistic view of the pathogenesis of residual GI symptoms during remission, a biopsychosocial unifying model have been proposed for IBD-associated IBS and post-infectious IBS, where central factors (such as psychosocial distress and life stress) and peripheral factors (such as altered bacterial flora) interact and through the immuneinflammatory system in the intestinal mucosa influence the generation of GI symptoms.65, 66 The link between the central and peripheral factors is further supported since psycho-neuro-endocrine immune modulation through the brain-gut axis has been proposed to be central in the pathogenesis of both IBS and IBD.44, 67, 68

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Gastrointestinal Symptoms and Fatigue in Patients with Quiescent Ulcerative Colitis

Table 1. Overview of studies concerning IBS-like symptoms in patients with UC in remission. Study

Definition

Prevalence

(year)

IBS

IBS

Endoscopy

Calprotectin

Isgar46

(1983)

Manning69

33% (n=33)

Yes ⃰

No

Simrén47

(2002)

Own criteria

33% (n=14)

Yes †

No

Minderhoud48

(2004)

Rome II36

32% (n=23)

No

No

Ansari49

(2008)

Rome II36

46% (n=23)

Yes ⃰

No

Keohane50

(2010)

Rome II36

39% (n=17)

No

Yes

Berrill51

(2013)

Rome III37

32% (n=18)

No

Yes

Jelsness-Jørgensen52 (2013)

Rome II36

25% (n=15)

No

Yes

Fukuba53

Rome III37

26% (n=10) ⃰

Yes †

No

(2014)

15% § ⃰ Mild inflammation accepted in the criteria for remission. †Endoscopy was not performed exclusively adjacent to symptom registration. §Endoscopic normal mucosa included in the criteria for remission.

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1.4 Fatigue Fatigue is a complex and multidimensional symptom with both physical and mental components.70 The symptom fatigue is a commonly reported in the general population71, 72 and among primary care patients.73 Persistent fatigue might reflect underlying somatic and/or psychiatric disease or might even be a side effect of medical treatment70. Studies have shown that high levels of fatigue is common among patients with chronic inflammatory conditions, such as IBD74-81, rheumatoid arthritis82, multiple sclerosis83, and cancer.84 Inflammation has been suggested as a possible link between fatigue, pain and depression.85 Moreover, patients with various functional disorders such as fibromyalgia86, IBS87, 88, and naturally, chronic fatigue syndrome89, report high levels of fatigue. Interestingly, low-grade inflammation and/or immune abnormalities and co-existing psychological distress are considered to be potential important factors in the pathogenesis of all of these functional disorders.90-92

1.5 Fatigue in ulcerative colitis Fatigue is a common clinical feature among patients with IBD. The prevalence of high fatigue has been reported to be 29-40% in patients with IBD with inactive disease74-76, 79 and as high as 68% in patients with active disease (Table 2).75, 76, 81 Patients with high fatigue report reduced QOL.74, 75, 93, 94 Disease activity, perceived stress, psychological distress, sleep quality, disease-related worries and female gender have all been correlated with fatigue.75-81, 94-96 Factors important for fatigue among IBD patients with inactive disease are not fully understood. Anaemia and iron deficiency have been suggested as important contributing factors for fatigue in patients with IBD. However, existing data concerning the association between anemia, as well as levels of hemoglobin, and fatigue in patients with IBD are conflicting75, 78-80, and two previous studies report no correlation between fatigue and iron deficiency.79, 80

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Gastrointestinal Symptoms and Fatigue in Patients with Quiescent Ulcerative Colitis

Moreover, the measurement and definition of iron deficiency in patients with IBD are problematic since serological markers for iron deficiency, such as ferritin and transferrin saturation, are affected by inflammation. Therefore, use of several markers in combination has been suggested to provide the most reliable assessment of iron deficiency in IBD.97, 98 This has been taken into account in the work of this thesis. Table 2. Overview of studies regarding prevalence of high fatigue in patients with UC. Study

Patients

Prevalence of

Factors associated with

high fatigue

fatigue

IBD ⃰ 40%

QOL

UC (n=304)

UC 38%

QOL

CD (n=368)

(36%⃰ / 68%†)

Disease activity

(year) Minderhoud et al. (2003)

74

CD (n=46)

Romberg-Camps et al. (2010)

UC (n=34)

75

IBDU

Anaemia

(n=35) Jelsness-Jørgensen et al. (2011-2012)

78, 93, 96

Female gender

UC (n=92)

UC 50%

QOL

CD (n=48)

CD 52%

IBD symptoms Altered sleep Hemoglobin levels Disease-related worries

Graff et al. (2011)

76

UC (n=158)

UC 47%

QOL

CD (n=160)

(30%⃰ / 67%†)

Disease activity Sleep quality Psych distress Stress

Bager et al. (2012)

79

Goldenberg et al. (2013)

80

UC (n=174)

IBD 44%

Active disease

CD (n=251)

(29%⃰ / 57%†)

Female gender

UC (n=137)

IBD 46%§

Active disease

UC 47%†

Psych distress

CD (n=143)

Grimstad et al.

UC (n=60)

81

CD (n=21)

(2015)

Age

⃰ Inactive disease. †Active disease. §Among non-anaemic patients. CD, Crohn´s disease.

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Low-grade immune activity might also be a factor of importance for fatigue among patients with quiescent UC since patients with different chronic inflammatory conditions report high levels of fatigue.74, 85 Further, among patients with IBS, fatigue is a common symptom and low-grade immune activity is considered to be a potential contributing factor for symptom generation in IBS.88, 90, 99 Moreover, IBS-like symptoms during remission among patients with UC are common 46-53 and have been associated with higher levels of fatigue100, suggesting possible common pathophysiological pathways. Low-grade immune activity among patients with quiescent UC suffering from fatigue has not been studied previously.

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Gastrointestinal Symptoms and Fatigue in Patients with Quiescent Ulcerative Colitis

2 AIM The overall aim of this thesis was to characterize patients with UC to find factors that might contribute to generation of residual gastrointestinal symptoms during quiescent disease and fatigue. A deeper knowledge concerning the pathophysiology of these symptoms could lead to a better treatment and increased QOL for patients with UC in apparent remission. Additionally, specific aims were: 

To determine the prevalence of IBS-like symptoms during clinical remission and investigate associated psychosocial factors and low-grade inflammatory activity among patients with new onset of UC in a three year follow-up period (Paper I).



To assess potential risk factors, at onset of UC, for development of IBS-like symptoms during clinical remission in a three year follow-up period (Paper II).



To evaluate presence of subclinical local and systemic inflammation and psychosocial factors in UC patients that experience IBS-like symptoms during deep remission (Paper III).



To investigate association of inflammatory disease activity, subclinical inflammation and residual GI symptoms during deep remission, psychological distress, anaemia and iron deficiency with fatigue among patients with UC (Paper IV).

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3 PATIENTS AND METHODS Two different patient cohorts (the DEBUT cohort and the SIUC (Symptoms and Inflammation in Ulcerative Colitis) cohort) were evaluated in the 4 papers included in this thesis (Table 3). Patients with UC were recruited prospectively at four specialized IBD clinics in the Västra Götaland Region, Sweden. The majority of the patients were enrolled at Sahlgrenska University Hospital/Sahlgrenska and South Älvsborgs Hospital, Borås (Paper I-IV) and a smaller group was recruited from Kungälv Hospital and North Älvsborgs Hospital/Trollhättan (paper III and IV).

Table 3. Summary of the main characteristics of the four papers.

Patient cohort No. of patients

Paper I

Paper II

Paper III

Paper IV

DEBUT

DEBUT

SIUC

SIUC

94

98

298

298

Study design

Prospective

Prospective

Cross-Sectional

Cross-Sectional

Main focus

IBS during

Predictive

IBS during

Fatigue

remission

factors of IBS

deep remission

Evaluation of

Sigmoidoscopy

Colonoscopy

Sigmoidoscopy

Sigmoidoscopy

inflammation

Calprotectin

Calprotectin

Calprotectin

Calprotectin

CRP

hs-CRP

hs-CRP

Mucosal

Systemic

Systemic

cytokines

cytokines

cytokines

Evaluation of

Anxiety

Anxiety

Anxiety

Anxiety

psychosocial

Depression

Depression

Depression

Depression

QOL

Coping

QOL

QOL

factors

Stress SIUC, Symptoms and Inflammation in Ulcerative Colitis; IBS, Irritable Bowel Syndrome; hs-CRP, high sensitive C-reactive peptide; QOL, Quality of Life

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Gastrointestinal Symptoms and Fatigue in Patients with Quiescent Ulcerative Colitis

The criteria for inclusion in the studies were verified diagnosis of UC according to Lennard-Jones criteria (new onset of UC in paper I and II).101 The criteria for exclusion were: malignancy within 5 years prior to inclusion, difficulties in understanding Swedish language, abuse of alcohol or drugs, previous surgery with resection of the colon or the small intestine, significant heart-, lung-, kidney-, neurological, rheumatic or psychiatric disease (Paper I-IV). Further, in Paper III and IV, patients with co-existing celiac disease were excluded. The studies were approved by the Regional Ethical Review Board in Gothenburg. All of the subjects gave verbal and written informed consent before participation.

3.1 Study design 3.1.1 Paper I and II

These two studies were applied on the DEBUT-cohort, into which 98 patients with new onset of UC were prospectively recruited between the year of 2004 and 2007. The patients were evaluated at the time of diagnosis and at three yearly follow-up visits (Figure 1). Data collection was finished in 2010. In Paper I, 94 patients were included to characterize patients experiencing IBS-like symptoms during clinical remission and evaluate factors associated with IBS-like symptoms. Inflammatory activity, GI symptoms severity, IBS-like symptoms, psychological distress, and QOL was assessed at the three yearly follow-up visits (Figure 1). Data from the first visit at disease onset was not included in this paper since all of the patients at that time had active disease. Four of the patients that were recruited to the DEBUT-cohort were not included in this paper since they underwent a colectomy prior to the first yearly follow-up visit. In Paper II, the aim was to identify risk factors at disease onset for development of IBS-like symptoms during remission. Inflammatory activity, extent of disease, psychological distress, coping ability and previous IBS symptoms were registered at the first visit, at disease onset, and was compared between patients who during the yearly follow-up visits fulfilled the criteria for IBS, or did not, while in clinical remission. Moreover, activity

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of the autonomic nerve system (ANS) was registered in patients in remission 3-4 months after being diagnosed and enrolled in the study. Out of the 98 patients, 87 met the study criteria for clinical remission during at least one of the follow-up visits and data from the first visit at disease onset of these patients were further analyzed in the study.

Onset of UC

1 year

2 year

3 year

Mayoscore

X

X

X

X

Endoscopy

Colonoscopy

Sigmoidoscopy

Sigmoidoscopy

Sigmoidoscopy

Questionnaires

X

X

X

X

Blood samples

X

X

X

X

Stool samples

X

X

X

X

Biopsies

X

Figure 1. Study flow chart of the DEBUT-cohort (Paper I and II) .

3.1.2 Paper III and IV

These two studies was performed on the SIUC-cohort in which 298 patients with UC was enrolled. Data were collected between September 2012 and April 2014. The primary aim was to identify patients in deep remission (i.e. no inflammation at endoscopy) in order to investigate patients with and without IBS-like symptoms during deep remission (Paper III) and to identify factors associated with fatigue during active disease and during deep remission (Paper IV). Therefore, all of the patients were evaluated with rigid sigmoidoscopy and the patients with normal mucosa with fecal calprotectin >200 μg/g (indicating presence of visible inflammation in the mucosa28, 29 ) were further investigated with flexible sigmoidoscopy within two weeks (Figure 2). Five patients were not possible to classify due to lack of stool sample and one patient were excluded due to concomitant celiac disease (elevated levels of transglutaminase antibodies was detected and the diagnosis of celiac disease was later confirmed on duodenal biopsies).102

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Gastrointestinal Symptoms and Fatigue in Patients with Quiescent Ulcerative Colitis

In Paper III, the patients were divided into three groups; those who did not meet the criteria for deep remission were classified with active disease and those who met the criteria for deep remission were further divided into those who fulfilled the Rome III criteria for IBS37 (n=24) or not (n=108) (one patient were not possible to classify due to incomplete Rome III questionnaire). In the first step, the three groups were characterized and compared according to demographic data, disease duration and extent, current treatment, severity of GI and non-GI somatic symptoms, and QOL. Thereafter, factors that might contribute to the generation of residual GI symptoms during remission were examined by comparing the two groups in deep remission with and without IBS-like symptoms regarding colonic inflammation, systemic immune activity, psychological distress and perceived stress.

Figure 2. Study flow chart of the SIUC-cohort (Paper III and IV). ⃰ Five patients were not able to classify due to lack of stool sample and one patient were excluded due to celiac disease (elevated transglutaminase antibodies102).

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In Paper IV, 155 patients were classified with active disease and 133 in deep remission (four patients were excluded from analyses due to incomplete Multidimensional Fatigue Inventory (MFI), since fatigue was the primary outcome studied in this paper), (Figure 2).70 The study population was first investigated to determine the prevalence of high fatigue (MFI General fatigue score ≥13 (this cutoff is based on the 95th percentile of a group of healthy controls in a previous Dutch study74)) and to characterize the type of fatigue reported by evaluating the scores of the different MFI domains. To investigate the patients with high fatigue and identify possible risk factors for high fatigue, the UC patients with high fatigue were compared with patients with mild/no fatigue (MFI General fatigue score 1.23, 103

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Gastrointestinal Symptoms and Fatigue in Patients with Quiescent Ulcerative Colitis

Table 4. Assessment of clinical disease activity of ulcerative colitis with the Mayo score. Mayo score Stool frequency 0=Normal number of stools for this patient. 1=1-2 stools more than normal. 2=3-4 stools more than normal. 3=5 or more stools more than normal. Rectal bleeding 0=No blood seen. 1=Streaks of blood with stool less than half the time. 2=Obvious blood in stool most of the time. 3=Blood alone passed. Findings of endoscopy 0=Normal or inactive disease 1=Mild disease (erythema, decreased vascular pattern, mild friability) 2=Moderate disease (marked erythema, absent vascular pattern, friability, erosions) 3=Sever disease Physician´s global assessment 0=Normal 1=Mild disease 2=Moderate disease 3=Severe disease

3.3 Definition of remission In Paper I clinical remission was defined as a total Mayo score ≤ 2 with an endoscopic subscore ≤ 1 with no relapse during the 3-month period prior to visit. In Paper II the definition for clinical remission was adjusted to a total Mayo score ≤ 2 with an endoscopic subscore = 0 and physician´s global assessment = 0, with no relapse during the 3-month period prior to visit. In Paper III and IV, the criteria for remission were even stricter. The Mayo score was adjusted if needed after the flexible sigmoidoscopy was performed (Figure 2) and deep remission was defined as an adjusted total Mayo score ≤ 2, physician´s global assessment = 0, rectal bleeding = 0 and an endoscopic subscore = 0, with no relapse during the 3-month period prior to visit.

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3.4 Inflammatory biomarkers The patients provided stool and blood samples in connection to study visits (Paper I-IV). Levels of calprotectin were measured in stool samples as a marker for colonic mucosal inflammation. In Paper II, biopsies were obtained from inflamed mucosa at the initial colonoscopy and expression levels of mRNA for the cytokines interleukin (IL)-8, IL-17A and interferon (IFN)-γ were analyzed as immunological markers for mucosal UC activity at disease onset. As marker for systemic inflammation at disease onset, the levels of CRP were assessed in Paper II. In Paper III and IV, high sensitive-CRP (i.e. test able to detect levels