Alimentary Pharmacology and Therapeutics

Fatigue in out-patients with inflammatory bowel disease is common and multifactorial P. Bager*, R. Befrits , O. Wikmanà, S. Lindgren§, B. Moum–, H. Hjortswang**, N. H. Hjollund  ,àà & J. F. Dahlerup*

*Department of Medicine V (Hepatology and Gastroenterology), Aarhus University Hospital, Aarhus, Denmark.   Department of Gastroenterology and Hepatology, Karolinska University Hospital, Stockholm, Sweden. à Department of Medicine, Stockholm South General Hospital, Stockholm, Sweden. § Department of Clinical Sciences, Lund University, Gastroenterology-Hepatology Division, Malmo¨ University Hospital, Malmo¨, Sweden. – Department of Gastroenterology, Oslo University Hospital, Oslo, Norway. **Department of Endocrinology and Gastroenterology, Linko¨ping University Hospital, Linko¨ping, Sweden.    Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark. àà Department of Occupational Medicine, Hospital Unit Western Jutland, Herning, Denmark.

Correspondence to: Dr P. Bager, Department of Medicine V (Hepatology and Gastroenterology), Aarhus University Hospital, Noerrebrogade 44, 8000 Aarhus C, Denmark. E-mail: [email protected]

Publication data Submitted 8 June 2011 First decision 5 July 2011 Resubmitted 14 October 2011 Accepted 16 October 2011 EV Pub Online 7 November 2011

ª 2011 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2011.04914.x

SUMMARY Background Patients with inflammatory bowel disease (IBD) often complain of fatigue. Aim To investigate the prevalence and characteristics of fatigue among IBD outpatients in Scandinavia and to provide normative values for fatigue in IBD patients. Methods A cross-sectional study was conducted on 425 IBD patients from six outpatient centres in Denmark, Norway and Sweden. Fatigue was measured using the Multidimensional Fatigue Inventory. The patients were also screened for anaemia and iron deficiency. Each centre included approximately 5% of their IBD cohort. The patients were enrolled consecutively from the out-patient clinics, regardless of disease activity and whether the visit was scheduled. The fatigue analysis was stratified for age and gender. Results Using the 95th percentile of the score of the general population as a cutoff, approximately 44% of the patients were fatigued. When comparing the IBD patients with disease activity to the IBD patients in remission, all dimensions of fatigue were statistically significant (P < 0.05). Being anaemic or iron deficient was not associated with increased fatigue. Being a male patient with ulcerative colitis treated with corticosteroids was a strong determinant for increased fatigue. The normative ranges for IBD fatigue were calculated. Conclusions Fatigue in IBD is common regardless of anaemia or iron deficiency. Fatigue in IBD is most marked for patients 4 for CD patients and SCCAI >4 for UC patients. The remaining patients were classified as being in remission.16–18 Fatigue assessment The Multidimensional Fatigue Inventory (MFI-20) is a 20-item, self-report instrument designed to measure five dimensions of fatigue (general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue).19 Each dimension contains four questions and score range from 4 to 20 (a higher score indicates greater fatigue). The MFI-20 has been translated into Danish, Swedish and Norwegian. The instrument has been validated in both Denmark and Sweden.12, 20, 21 However, the MFI-20 has not been specifically validated in an IBD population. All of the participants completed the MFI-20 questionnaire on the day of clinical attendance. Blood samples Blood samples were collected at the visit or within a 2 week period of the visit and analysed for haemoglobin, C-reactive protein (CRP) and ferritin. The presence of anaemia and ⁄ or iron deficiency (ID) was also evaluated. The World Health Organization (WHO) definition of anaemia was applied, with haemoglobin levels below 130 g ⁄ L in males and below 120 g ⁄ L in nonpregnant females.22 Ferritin was chosen to measure ID. As ferritin is an acute-phase reactant, patients with elevated CRP were classified as having ID if the CRP level was above the upper limit of the reference at each site and if the ferritin level was below 100 lg ⁄ L For patients without elevated CRP, ID was classified if the CRP level was below or equal to the upper limit of the reference at each site and if the ferritin level was below 30 lg ⁄ L. The limits were adopted from the European guidelines published in 2007.23 Aliment Pharmacol Ther 2012; 35: 133–141 ª 2011 Blackwell Publishing Ltd

Fatigue in IBD out-patients CRP values were also used for additional analyses to determinate the presence of disease activity. Data handling Blood sample analyses and clinical assessments were performed at each centre, the anonymised data were sent to the Aarhus University Hospital, where the data analyses were performed. Ethics The study was approved by the Ethics Committees of Denmark, Norway and Sweden and by the Danish Data Protection Agency. Statistical methods Parametric and nonparametric descriptive statistics were used, and 95% confidence intervals (CI) for the proportions were calculated where relevant. The median and interquartile ranges (IQR) were used to illustrate median values and variations where relevant. The frequencies were compared using Chi-square tests. A stepwise multiple regression model was used to identify the determinants of fatigue. The Epidata and Stata 11 software packages were used for all analyses.

RESULTS Ninety-seven percentage of the screened patients were included in the analysis. The demographic and disease characteristics of the participants are presented in Table 1. There were more CD patients than UC patients and more males than females included in the study. Using the WHO definitions, anaemia was found in 14% of the UC and 23% of the CD patients. ID was present in 32% of the UC and 36% of the CD patients.24 The use of biologics was more frequent among the CD patients compared with the UC patients. The mean scores of the five dimensions of fatigue are presented in Table 2. All of the fatigue dimensions were normally distributed, with a tendency towards an absence of reduced motivation and mental fatigue. We found a statistically significant effect for gender (P < 0.001); therefore, the results are presented with gender stratification. The fatigue scores were not significantly different between the UC and CD patients, except for the CD males, who had a significantly higher reduced activity score compared with the UC males. The scores for all the fatigue dimensions were significantly higher in the patients with disease activity compared with the patients in remission. In contrast, all of the fatigue Aliment Pharmacol Ther 2012; 35: 133–141 ª 2011 Blackwell Publishing Ltd

dimensions showed no significant differences between the patients with and without anaemia. Similarly, no fatigue scores differed significantly between the patients with (N = 146) and without (N = 279) ID (as defined above). The supplementary calculations using ferritin