Journal of Crohn's and Colitis, 2015, 776–783 doi:10.1093/ecco-jcc/jjv107 Advanced Access publication June 16, 2015 Original Article

Original Article

The severity of inflammation at onset of ulcerative colitis is not associated with IBS-like symptoms during clinical remission Börje Jonefjäll1, Magnus Simrén1,2, Lena Öhman1,3, Anders Lasson4, Jan Svedlund5, Hans Strid1 Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 2University of Gothenburg Centre for Person-Centered Care (GPCC), Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 3Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 4Department of Internal Medicine, Södra Älvsborgs Hospital, Borås, Sweden 5Department of Psychiatry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 1

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Corresponding author: Börje Jonefjäll, MD, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Magtarmmottagningen, Blå Stråket 3, Göteborg S-413 45, Sweden. Tel: +46703753933; Fax: +4631822152; Email: [email protected]

Abstract Background and aims: Symptoms compatible with irritable bowel syndrome (IBS) are common in patients with ulcerative colitis (UC) in clinical remission. It has been suggested that these symptoms might arise due to post-inflammatory changes comparable with post-infectious IBS.The aim was to study factors at new onset of UC that predict development of IBS-like symptoms during clinical remission. Methods:  In total, 98 patients with new onset of UC were followed prospectively for 3 years with yearly follow-up visits. Data from the first visit at the onset of UC were compared between a group of patients who fulfilled the criteria for IBS while in remission (UCR+IBS) during follow-up and a group who did not (UCR–IBS). Results:  Among the UC patients, 87 met the criteria for clinical remission and 25 (29%) of these reported IBS-like symptoms in remission during follow-up.There was no difference in inflammatory disease activity at the initial flare or in the prevalence of previous IBS symptoms when comparing UCR+IBS and UCR–IBS patients. The UCR+IBS patients reported more severe gastrointestinal symptoms, including abdominal pain, during their primary flare. Conclusion:  The severity and extent of inflammation at onset of UC do not seem to affect the development of IBS-like symptoms in UC patients during clinical remission.The high prevalence of IBS-like symptoms is not explained by pre-existing IBS. UCR+IBS patients reported more severe gastrointestinal symptoms at disease onset, which might indicate a more sensitive gastrointestinal tract in this category of patients. Key Words: Ulcerative colitis; irritable bowel syndrome; calprotectin

1. Introduction Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) affecting the colonic mucosa causing gastrointestinal (GI) symptoms such as diarrhoea, passage of mucopus, blood in stool and urgency

to evacuate. Between episodes of active disease, UC patients can have long periods without evidence of intestinal inflammation and GI symptoms, so-called clinical remission.1 However, it is common for UC patients, while in remission, to report symptoms compatible

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Potential Risk Factors for IBS-like Symptoms in UC

UC in patients between 18 and 75 years, and the criteria for exclusion were malignancy (5  years prior to inclusion), difficulties in understanding the Swedish language, abuse of alcohol or drugs and significant heart, lung, kidney, neurological, rheumatic or psychiatric disease. This study was approved by the Regional Ethical Review Board of the University of Gothenburg, and the subjects gave verbal and written informed consent before participation.

2.2. Study design The UC patients were included in the study at disease onset and followed clinically for 3 consecutive years with yearly follow-up visits (Figure  1). Demographic data were collected at the first visit. The study subjects completed self-administered questionnaires and were interviewed and examined clinically, including endoscopic evaluation, by a physician at each visit. Between study visits, the patients were followed according to clinical routine by a limited number of physicians and standard treatment was allowed. Data from the yearly follow-up visits concerning IBS-like symptoms have previously been published by our group and are not shown in this article.9 In this study, data from the first visit at disease onset were compared between (1) patients who, during follow-up, would fulfil the criteria for IBS on at least at one of the 3-yearly follow-up visits while in clinical remission (UCR+IBS) and (2) those who would not do so (UCR–IBS).

2.3.  Disease activity At each visit the disease activity of UC was evaluated using the Mayo score.19 The Mayo score contains four variables: stool frequency, rectal bleeding, endoscopic findings and the physician’s global assessment. Each variable is graded from 0 to 3 and the maximum total score is 12 points, indicating severe and active disease. All patients were examined by colonoscopy at disease onset and with sigmoidoscopy at each follow-up visit. The degree of mucosal inflammation was assessed according to the endoscopic Mayo score. Clinical remission was defined as a total Mayo score ≤2, physician’s global assessment 0 and endoscopic subscore 0, with no relapse during the 3-month period prior to the visit. The colonic extent of disease was determined at disease onset according to the Montreal classification.20

2.4.  Sample collection

2. Methods 2.1. Subjects Patients with new onset of UC were recruited to the study from two specialized IBD clinics. The criteria for inclusion were new onset of

Mayoscore Endoscopy

During the colonoscopy at disease onset, before anti-inflammatory treatment was initiated, biopsies were taken from inflamed mucosa for histology and immunological analyses. Furthermore, blood and stool samples were obtained at the onset of disease and during the consecutive follow-up visits. Biopsies and blood samples

Onset of UC

1 year

2 year

3 year

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Colonoscopy Sigmoidoscopy Sigmoidoscopy Sigmoidoscopy

Questionnaires

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Blood samples

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Stool samples

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Biopsies

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Figure 1.  Study flowchart. Patients with new onset of ulcerative colitis were followed prospectively for 3 years.

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with irritable bowel syndrome (IBS), such as abdominal pain or discomfort and disturbances in stool frequency and form.2–6 The origin of these symptoms is not known. It has been suggested that occult inflammatory disease activity, indicated by elevated levels of faecal calprotectin, may cause these symptoms,7 whereas other studies have not been able to confirm this.8,9 Furthermore, it has been reported that patients with IBD in remission with IBS-like symptoms have evidence of subclinical inflammation in colonic biopsies and increased intestinal permeability.10 However, altered intestinal permeability is not only a feature of IBD, but it has also been detected in IBS patients, and known IBS triggers, including stress and anxiety, might affect the epithelial barrier function through neuroimmune interactions.11 Indicating the importance of neuroimmune interactions, TRPV1 neuroactive nerve fibres and enteric neuropeptides such as substance P have been shown to play important roles in the pathophysiology of UC and in pain generation in both IBS and quiescent IBD.12–15 Multiple studies have shown an association between IBS-like symptoms in IBD patients and psychosocial factors such as anxiety and depression, as well as reduced quality of life.3,7,9 Central factors along the gut–brain axis as well as alterations in the autonomic nerve system (ANS) seem to be of importance for the generation of GI symptoms,16 but central factors alone do not explain the increased prevalence of IBS-like symptoms in IBD patients. Postinflammatory changes in the colon might be another important factor driving the development of IBS-like symptoms. A unifying model for post-infectious IBS and IBD-associated IBS has been proposed in which both central and peripheral factors interact and contribute to symptom generation.17 Established risk factors for developing postinfectious IBS are duration of the initial gastroenteritis, toxicity of the infecting organism, female gender, adverse life events, hypochondria, smoking and depression.18 However, risk factors for developing IBS-like symptoms in patients with IBD are not known. Hence, it is still unclear whether peripheral factors, such as severity of inflammation and the duration or extent of the initial flare at onset of disease, contribute to the development of IBS-like symptoms in UC patients in clinical remission. Furthermore, it is not known whether psychological factors, ANS activity and GI symptoms at onset of UC are of importance for the generation of IBS-like symptoms during clinical remission. Therefore, the aim of this study was to examine potential factors that might predict the development of IBS-like symptoms during clinical remission in patients with new onset of UC.

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778 for immunological analysis were stored at –80°C and stool samples were stored at –20°C until further analyses.

2.5.  Inflammatory biomarkers

2.6.  IBS-like symptoms Subjects experiencing IBS-like symptoms were identified by using the Rome II Modular Questionnaire.23 To fulfil the Rome II criteria for IBS, a patient had to have abdominal discomfort or pain combined with two of the following three features: (1) relieved by defaecation; (2) onset associated with a change in stool frequency; and (3) onset associated with a change in form (appearance) of the stool. The symptoms should have been present for at least 12 weeks during the preceding 12 months. The patients were interviewed by the physician at disease onset (visit 1), using the Rome II Questionnaire for IBS as a basis for the interview, to determine whether they had experienced IBS symptoms in their lives prior to onset of UC symptoms. At each yearly follow-up visit, patients completed the Rome II Questionnaire by themselves. Previous IBS symptoms were not a criteria for exclusion in this study since there was a risk of recall bias as well as the possibility that previous IBS symptoms might have been secondary to low-grade activity of UC prior to a definitive diagnosis of an IBD.

2.8.  Psychological factors To assess psychological factors, the Hospital Anxiety and Depression scale (HAD) and the Coping Resources Inventory (CRI) were used. The HAD scale consists of 14 items, each using a Likert scale (0–3) with subscales for anxiety (seven items) and depression (seven items).26 The higher the scores the more severe are the symptoms of anxiety and depression, respectively. In clinical practice a value between 0 and 7 is considered normal, a value between 8 and 10 is considered a possible case of anxiety/depression and a value ≥11 is considered a probable case of anxiety/depression. The CRI is a 60-item self-report measure of a person’s coping resources, subdivided into five domains (cognitive, social, emotional, spiritual/philosophical and physical).27 The different domains reflect the patient’s ability to respond to, handle and recover from stressful situations The patient responds to each item on a four-point Likert scale, where higher scores indicate stronger coping abilities. In addition to the five domain subscale scores, a total resource score is computed.

2.8.  Assessment of ANS activity Cardiac efferent ANS activity was assessed using heart rate variability (HRV) analysis of 24-hour Holter electrocardiogram data, recorded in patients in remission 3–4 months after being diagnosed and enrolled in the study. The technique is non-invasive, easy to perform and, if used under standardized conditions, highly reproducible.28 The cardiac autonomic function can be used as a proxy measure of GI autonomic activity, since a correlation has been shown between GI functions, controlled by the ANS, and cardiac autonomic activity.29,30 The recording period commenced with two 10-minute episodes of controlled respiration (15 breaths/min) to standardize results, since breathing affects the heart rate and therefore influences HRV.31 The first episode was performed in supine position and the second episode immediately after assuming standing position, before the subject was discharged for 24-hour continuous Holter monitoring. A  three-channel cardiac Holter monitor (Lifecard CF, Delmar Reynolds, Washington, USA) was used as the recording device. The root mean square of successive normal R–R interval differences (RMSSD), and low- to high-frequency ratio (LF/HF) were calculated from the HRV data. The RMSSD is considered to indicate parasympathetic activity32 and was analysed throughout the full 24-hour recording. The frequency components provide information on the distribution of power as a function of frequency.33 The LF/HF ratio is considered to reflect sympathovagal balance, and after standing up it mainly reflects sympathetic activity.33 We analysed LF/HF from the second 10-minute episode, i.e. immediately after assuming a standing position. The analysis was performed using an Impresario Analyzer, Software Version 2.6.1801 (Delmar Reynolds, Washington, USA).

2.7.  Gastrointestinal symptoms The severity of GI symptoms was assessed using the Gastrointestinal Symptom Rating Scale (GSRS).24,25 The GSRS contains 15 questions and uses a seven-grade Likert scale.1–7 The higher the score, the more pronounced are the symptoms. The GI symptoms are reported as a total GSRS score and can also be divided into five separate domains by combining the different questions to further characterize the GI symptoms (diarrhoea, constipation, abdominal pain, indigestion

2.9. Statistics Categorical variables were expressed as percentages and compared using Fisher’s exact test (two-sided). Continuous data were expressed as median and interquartile range and comparisons between two groups were performed with the Mann–Whitney U test. A p-value

The severity of inflammation at onset of ulcerative colitis is not associated with IBS-like symptoms during clinical remission.

Symptoms compatible with irritable bowel syndrome (IBS) are common in patients with ulcerative colitis (UC) in clinical remission. It has been suggest...
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