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Inflammatory bowel disease
Original article
Fatigue management in patients with IBD: a randomised controlled trial
  1. Lauran Vogelaar1,
  2. Adriaan van't Spijker2,
  3. Reinier Timman2,
  4. Antonie J P van Tilburg3,
  5. DirkJan Bac4,
  6. Ton Vogelaar2,
  7. Ernst J Kuipers1,5,
  8. Jan J V van Busschbach2,
  9. Christien J van der Woude1
  1. 1Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
  2. 2Department of Psychology and Psychotherapy, Erasmus MC, Rotterdam, The Netherlands
  3. 3Department of Gastroenterology and Hepatology, Sint Franciscus Gasthuis, Rotterdam, The Netherlands
  4. 4Department of Gastroenterology and Hepatology, Gelderse Vallei, Ede, The Netherlands
  5. 5Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
  1. Correspondence to Lauran Vogelaar, Department of Gastroenterology and Hepatology, Erasmus MC, ‘s Gravendijkwal 230, Room HS 306, Rotterdam 3000 CA, The Netherlands; l.vogelaar{at}erasmusmc.nl

Abstract

Objective To assess the effectiveness of solution-focused therapy (SFT) on fatigue and quality of life (QoL) in patients with fatigued inflammatory bowel disease (IBD).

Design Randomised controlled trial in two Dutch hospitals. Patients with IBD with quiescent IBD and with a Checklist Individual Strength—Fatigue (CIS—fatigue) score of ≥35 were enrolled. Patients were 1:1 randomised to receive SFT or care as usual (CAU) for 3 months. Patients were followed for a further 6 months after the SFT. Primary endpoint was defined as changes in fatigue and QoL during follow-up. Secondary endpoints included change in anxiety and depression, medication use, side effects to medication, disease activity, laboratory parameters (C-reactive protein, leucocytes and haemoglobin) and sleep quality.

Results Ninety-eight patients were included, of whom 63% were women, mean age was 40.1 years. After the SFT course, 17 (39%) patients in the SFT group had a CIS-fatigue score below 35 compared with eight (18%) of patients in the CAU group (p=0.03). The SFT group also showed a greater reduction in fatigue across the first 6 months compared with the CAU group (CIS-fatigue: p=<0.001 and CIS-total: p=0.001).

SFT was associated with a significant higher mean IBD questionnaire change at 3 months (p=0.020). At 9 months, no significant differences between the two groups were observed.

Conclusions SFT has a significant beneficial effect on the severity of fatigue and QoL in patients with quiescent IBD. However, this effect diminished during follow-up.

  • Ibd Clinical
  • Inflammatory Bowel Disease

https://doi.org/10.1136/gutjnl-2013-305191

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    Significance of this study

    What is already known about this subject?

    • Fatigue can invalidate patients with inflammatory bowel disease (IBD) and contribute to disease burden.

    • Psychological factors may influence the burden of disease.

    • Psychotherapy is effective to decrease fatigue in patients with chronic diseases.

    What are the new findings?

    • Solution-focused therapy significantly reduces fatigue and, thereby, increases quality of life in patients with IBD.

    • Solution-focused therapy decreased the fatigue level to values observed in the normal healthy population.

    How might it impact on clinical practice in the foreseeable future?

    • The results of this study augment the evidence that psychotherapy is effective to decrease fatigue in quiescent patients with IBD and, therefore, can be used to optimise treatment in such patients.

    Introduction

    Inflammatory bowel disease (IBD) can lead to severe, debilitating fatigue which may significantly impair the quality of life (QoL).1–6 Over 40% of IBD patients suffer from severe fatigue, even during disease remission.1 ,3 ,7 Although most patients have persistent fatigue, and psychological factors are known to be associated with fatigue, management strategies focussing on fatigue are lacking and intervention studies are scarce.5–18 Psychological interventions for patients with IBD have previously been applied for multiple goals, such as improving QoL, decreasing depression and decreasing flares. However, none of these studies investigated the effect on fatigue. Furthermore, due to heterogeneity between studies, it is difficult to draw conclusions on the effectiveness of these interventions on QoL.10–18

    Fatigue is also seen in other chronic conditions, such as disease remission after treatment for cancer, rheumatic disease, multiple sclerosis and chronic infectious diseases.19 ,20

    Especially in former cancer patients, in patients with rheumatic disease and in patients with multiple sclerosis, psychotherapy showed to be effective in reducing fatigue.21–24 We earlier reported in a pilot study with a small sample size that psychotherapy, especially solution-focused therapy (SFT) in patients with IBD is feasible and reduced fatigue.25 Therefore, we assessed in a randomised controlled trial whether SFT is more effective in improving fatigue and Qol than care as usual (CAU).

    Methods

    Study design and sample size

    This randomised controlled trial was designed to evaluate the efficacy of SFT in comparison to CAU in quiescent patients with IBD with severe fatigue. This trial was conducted in accordance with the protocol International Conference on Harmonisation Guidelines for Good Clinical Practice, the Declaration of Helsinki and local national regulations governing clinical study conduct, and was registered at the medical ethical committee (MEC) of the Erasmus MC (registration number: MEC-2010-107; NL32020.078.10). The protocol was approved by the institutional review board or by the ethics committee at each centre. The study was not designed for an interim analysis, and no Data Safety Monitoring Board was assigned. All patients gave written informed consent. Patients were enrolled at two sites in The Netherlands from January 2010 to January 2011 by the principal investigator.

    The sample size calculation was based on results from a small open-label study, reporting that SFT might reduce fatigue in patients with IBD.25 A power analysis was performed using α=0.05 and β=0.80. Assuming an expected decrease of three points on the Checklist Individual Strength (CIS)-fatigue score in the intervention group versus no effect in the CAU group, the required sample size was 42 patients in each group. Assuming a dropout rate of approximately 15%, we determined to include 98 patients in the study.

    Intervention and randomisation

    Patients randomised for the intervention arm participated in a 7-session solution-focused course, focussing on coping styles for fatigue. Control subjects received CAU.

    The course consisted of six group sessions during 3 months, and was completed by a booster session at month 6. Duration of each session was 1.5 h. Each group consisted of seven patients. In the fifth session, a partner, family member, or close relative participated. The course consisted of psychoeducation about IBD and fatigue and SFT. SFT is a brief form of psychotherapy. The focus is on the existing adequate coping abilities of patients, rather than on their problems. For the purpose of this study, the SFT was modified to focus on fatigue management.25

    Patients were randomised to the treatment or control arm in blocks of 14 subjects using randomisation lists drawn from a computer-generated series of random numbers. Randomisation was conducted by the second author. The randomisation lists were anonymised for the randomisation process.

    Patients

    Men and women aged ≥18 years and diagnosed with IBD with a CIS-fatigue score of ≥35 were eligible for inclusion. Patients had to be in remission defined as a Crohn's Disease Index (CDAI) <150 or Clinical Activity Index (CAI) (ulcerative colitis index) <10 and a C-reactive protein (CRP) <10. Demographic and baseline IBD severity data, concomitant medication use were collected.

    The diagnosis of IBD (at least 6 months in duration) was radiologically or endoscopically/histologically confirmed. Pregnant or breastfeeding women were not included. Patients were also excluded if they had a history of lymphoproliferative disease or cancer, other than skin basocellular carcinoma; other gastrointestinal disease than IBD; listeriosis; HIV infection; immunodeficiency syndrome; central nervous system (CNS) demyelinating disease; chronic hepatitis B or C virus infection or untreated tuberculosis. Patients were excluded if they had poorly controlled medical conditions, including anaemia, low iron levels, diabetes mellitus, kidney disease, liver disease and unstable ischaemic heart disease; a known pre-existing condition that could interfere with the patient's participation such as psychiatric conditions or CNS trauma or active seizure disorders. Additionally, patients were excluded if they had undergone surgery in the past 12 weeks prior to the screening visit. Patients with a history of clinically significant drug or alcohol abuse in the last 2 years were not allowed to participate in this study.

    Study endpoints

    At baseline, routine laboratory values were assessed including CRP (reference value: 0–9 mg/L), leucocytes (reference value: 3.5–10×109/L), trombocytes (reference value: 150–370×109/L), haemoglobin (reference value: women 7.5–10 mmol/L; men 8.5–11 mmol/L), aspartate aminotransferase (reference value: women <31 U/L; men <35 U/L), alanine aminotransferase (reference value: women <34 U/L; men <45 U/L), alkaline phosphatase (reference value: women <98 U/L; men <115 U/L), gamma-glutamyl transferase (reference value: women <38 U/L; men <55 U/L), amylase (reference value: <107 U/L), iron (reference value: 10–30 μmol/L), ferritin (reference value: women 10–140 μg/L; men 30–240 μg/L), creatinine (reference value: 55–90 μmol/L), glomerular filtration rate (reference value: >60 mL/min/1.73 m2), thyroid stimulating hormone (reference value: 0.4–4.3 mU/L), vitamin B12 (reference value: 145–637 pmol/L), 25(OH)vitamin D (reference value: >50 nmol/L) and folic acid (reference value: 8–28 nmol/L).

    Furthermore, faecal calprotectin concentration was measured using the Bühlmann calprotectin test (calprotectin ELISA test). Levels <200 μg/g were regarded as compatible with disease remission.26 ,27

    The primary objective of the study was to assess the effect of SFT on fatigue and QoL at month 6. This was measured with the CIS,28 Fatigue Severity Scale-9 (FSS-9),29–31 Inflammatory Bowel Disease Questionnaire (IBDQ),32 ,33 Short Form-36 (SF-36)34 ,35 and EuroQol (EQ-5D)36 at baseline, month 3, month 6 and month 9.

    The secondary objective was to investigate the effect of SFT on anxiety and depression, sleep quality, disease activity, medication use, side effects to medication and laboratory parameters (CRP, leucocytes and haemoglobin). Measurements of these items were performed at baseline, month 3, month 6 and month 9 with the Hospital Anxiety and Depression Scale (HADS),37 Pittsburgh Sleep Quality Index (PSQI),38 CDAI39 ,40 or CAI,41 a questionnaire focusing on current medication use and side effects, and laboratory parameters on full blood.

    The CIS is a 20-item patient-reported validated instrument, measuring severity of fatigue, motivation, activity level, and concentration. The severity of fatigue, measured with the subscale ‘fatigue’, was used as an outcome measure. Patients with a score of 35 or higher on this subscale were considered to be fatigued. The CIS is a renewed format of the Multifactorial Fatigue Index (MFI), 5 questions are different formulated, all other questions are the same. The CIS is standardised and uses a cut-off score for fatigue by contrast with the MFI.

    The FSS-9 is a self-administered questionnaire. A total score of ≥4 is considered as indicative of chronic fatigue. Furthermore, the FSS-9 is sensitive to different gradations of fatigue severity.

    The HADS is a self-assessment questionnaire, measuring anxiety and depression. Scores of 10 or higher are considered to reflect a clinical level of anxiety and/or depression.

    The PSQI was developed to measure sleep quality during the previous month. A PSQI global score >5 is considered to indicate significant sleep disturbance.

    The medication questionnaire listed all possible IBD medications registered in The Netherlands. Patients could mark their drugs in this list and state whether they experienced side effects.

    The questionnaires were verified by medical records, and in case of missing values by enquiries from the principal investigator.

    Data and statistical analysis

    Mixed modelling, also known as random effect modelling, multilevel or hierarchical linear regression analysis was applied for longitudinal analysis of the data. At first, saturated models were postulated with the CIS-fatigue, CIS-total, FFS-total, EQ-5D, IBDQ-total, SF-36 physical and mental scales, PSQI, HADS, CDAI/CAI, medication and side effects to medication, CRP, leucocytes and haemoglobin as dependent variables. The saturated models included age, gender, linear time, quadratic time, the logarithm of time and their interaction with treatment and age and gender as fixed effects. The deviance statistic42 using restricted maximum likelihood43 was applied to determine the covariance structure, that is, whether a random slope and intercept-time covariance was needed in addition to a random intercept. Then the saturated models were reduced by eliminating insignificant fixed effects, respecting that interaction effects must be nested under their respective main time effect. The significance of the difference between the saturated models and the parsimonious final models were determined with the deviance statistic using ordinary likelihood. Potential gender differences and differences between Crohn's disease (CD) and ulcerative colitis (UC) were analysed by adding these effects and interactions with time to the parsimonious models.

    For baseline characteristics, the χ2 test was used for dichotomous variables and the independent samples t test for continuous variables.

    Frequencies of response at months 3, 6 and 9 were compared between groups by using the χ2test.

    Data were analysed with SPSS Software for Windows, V.20 (SPSS, Chicago, IL).

    Results were considered significant when two-sided p values were less than 0.05. Effect sizes were calculated by dividing the effects by the estimated SDs at baseline.44 The data was anonymised for the investigators conducting data analysis.

    Results

    Patient flow diagram

    Overall, 98 patients were enrolled in the study, 49 in the SFT group and 49 in the CAU group (figure 1). One patient declined further participation after randomisation.

    Figure 1
    Figure 1

    CONSORT flow diagram.

    Baseline characteristics

    Tables 1 and 2 show the clinical characteristics of each group. Baseline characteristics were similar between the two groups, indicative of successful randomisation. The mean age of the patients was 40.1 years (10.3 SD), 37% was male, 58 (59%) patients were diagnosed with CD, and 40 (41%) with UC. Means (SD) of baseline questionnaire scores are shown in table 3. For fatigue scores no differences were observed for gender or age.

    View this table:
    Table 1

    Disease phenotype

    View this table:
    Table 2

    Laboratory parameters at baseline

    View this table:
    Table 3

    Baseline questionnaire scores

    Outcomes

    Tables 4 and 5, and figures 2 and 3 show the main endpoints.

    View this table:
    Table 4

    Final mixed models

    View this table:
    Table 5

    Estimates and effects sizes for SFT group and care as usual group

    Figure 2
    Figure 2

    Mean Checklist Individual Strength-Fatigue scores.

    Figure 3
    Figure 3

    Mean Inflammatory Bowel Disease Questionnaire-total scores.

    Primary outcomes

    Random effects

    The EQ-5D model only needed a random intercept, no random slope. In all other models, a random slope was significant. The FFS-total and IBDQ-total models also needed a random covariance between intercept and slope; for these models, an unstructured covariance structure was postulated.

    Fixed effects

    The final models for CIS-fatigue, CIS-total, IBDQ-total and SF-36 physical all included linear and logarithmic time effects and interactions with the treatment (table 4). Quadratic time effects were not significant and were dropped from the models.

    At 3 months, scores were significantly better in the SFT group than in the CAU group. This effect was medium for CIS-fatigue and for CIS-total, and small for IBDQ-total. For CIS-fatigue and CIS-total this effect was maintained at 6 months. At 9 months, the effects were not significant any more (table 5, figures 2 and 3).

    At 3 months, significantly more patients of the SFT group (39%), compared with the CAU group (18%), scored below the cut-off score of 35 on the CIS-fatigue (p=0.03). At 6 months, this was 34% and 21%, respectively (p=0.19). At 9 months, 30% of the SFT group and 26% of the CAU group showed lower scores than 35 on the CIS-fatigue scale (p=0.66).

    In the EQ-5D model, only the intercept showed a significant fixed effect. The FSS-total model also included a logarithmic time effect but no treatment effect. The SF-36 mental scale included an intercept and a treatment main effect, but no time effects, which is in accordance with the nearly significant difference at baseline. The final models are presented in table 4. The estimates at the time points are given in table 5.

    Secondary outcomes

    Hospital Anxiety and Depression Scale

    During follow-up, both groups showed a similar decrease in HADS-anxiety without differences between the two groups (estimated at baseline for both groups: 7.35 and at 9 months 5.93; decrease: 1.42; p<0.001). HADS-depression showed at baseline (SFT: 6.1; CAU: 6.1), at 3 months (SFT: 5.0; CAU: 5.9; p=0.03) and at 9 months (SFT: 5.5, CAU: 5.3, p=0.70).

    Medication use and side effects

    Overall, no significant differences were seen over time with respect to medication use and side effects to medication in the groups separately or between the two groups.

    However, the use of corticosteroids decreased over time in both groups (SFT: 19–4.3%, CAU: 16–9.3%), but this was not significantly different between the two groups (p=0.41).

    Disease activity

    During follow-up the CDAI and CAI showed no significant differences between the groups or in the two groups separately.

    Laboratory parameters

    Laboratory parameters (CRP, leucocytes and haemoglobin) remained stable during the study period and no differences were observed between the SFT group and the CAU group.

    Discussion

    With this randomised controlled trial, we demonstrate that SFT for fatigued IBD patients is effective in reducing fatigue and improving QoL. A significant proportion of SFT-treated patients returned to fatigue levels seen in the normal population (CIS-fatigue <35).

    Lowering fatigue and thereby improving QoL is important in managing IBD, because fatigue and impaired QoL are related to an increased risk for relapse or symptoms of the disease,9 ,45–55 and it was shown that psychological intervention to improve QoL results in a significant drop in healthcare usage.56–58

    Importantly, at 3 months, a significant lower depression score was seen in the SFT group compared with the CAU group. During follow-up, no differences were seen with respect to sleep quality, anxiety, medication use and disease activity.

    Of interest is that during follow-up, fatigue levels in the CAU group improved. This was not completely expected, because previous longitudinal studies showed no improvement on fatigue and QoL over time.8 ,9 However, regression to the mean is a well-known phenomenon which could explain the improvement in the CAU group.

    Several other factors might explain our results. First, both groups were examined at baseline by a physician, and were informed about the study and the design of the treatment. This direct medical attention may have reduced fatigue levels and, thereby, improved their QoL. Attention effect was earlier described in previous studies that showed lowering of stress, increased QoL or decreased fatigue in control patients on the waiting list.12 ,14 ,15 ,59–61 Previously, it was reported that hope is related to patients’ well-being.62–64 Therefore, the hope for future fatigue treatment may have reduced fatigue levels.

    Second, patients completed questionnaires with a focus on fatigue and QoL. Some patients stated that filling in the questionnaires made them think about the relationship between their illness and fatigue. This may have started a cognitive reappraisal of their fatigue, reducing the perceived impact of the fatigue. And third, the last SFT session was at 6 months without follow-up plans. It may be that patients felt left without support after treatment, and this may result in increased fatigue and decreased QoL. The phenomenon of diminished treatment effect during follow-up was also seen in previous studies evaluating psychotherapy to improve QoL or to reduce fatigue.14 ,60 This suggests that a booster session a couple of months after the last treatment session might increase the long-term effectiveness of the treatment.65

    The effect of the treatment on fatigue and QoL was most pronounced at month 3, and remained significant during the first 6 months of the study. After finishing the SFT, the fatigue levels seemed to incline again, although they remained lower than before the SFT was started. It is known that psychotherapy necessitates repeated treatment sessions in the long term.66 Therefore, it seems that a longer period of treatment with more follow-up sessions is needed for a more sustained effect on fatigue and QoL. This was shown in a previous study which included two booster sessions after the intervention that resulted in a more sustained effect on QoL. Additionally, a longer follow-up showed a further diminished effect in the control group.12

    Earlier studies investigating the effects of psychotherapy on stress, QoL or fatigue showed that the intervention group improved on psychological distress, QoL or fatigue during the intervention, but this improvement often ended after treatment.14 ,15 ,17 ,18 ,67 ,68

    By contrast with our study, these studies had a small sample size, and did not include validated fatigue questionnaires. Our study had a greater sample size and included validated QoL questionnaires and also validated fatigue questionnaires, which give a more evident outcome on these parameters.

    This study has a number of limitations. At inclusion, we screened for disease activity using calprotectine, however, we do not have follow-up results for this measurement. For measuring disease activity during follow-up we used the CDAI and CAI. Although these questionnaires are validated and used widely in trials, they are more prone to subjective results of disease activity and, therefore, we were not able to answer the question whether SFT reduces the number of relapses, which was demonstrated earlier.69

    Another limitation is that the results of the CAU group may be affected by attention. This probably influenced outcomes of the CAU group.

    Although it is difficult to exclude all attention to the patients, it is worth investigating this possible influence with a control group not receiving information about the intervention.

    Another limitation of our study is the follow-up time of 6 months, because it was previously demonstrated that a longer follow-up period of 18 months leads to a decrease of QoL in the CAU group, while QoL increased in the intervention group during that follow-up.12

    Conclusion

    SFT has a significant positive effect on fatigue and QoL in patients with IBD, and offers a management strategy for these patients. Although very effective, this effect declined during follow-up. Because of the burden of fatigue in patients with IBD, we argue that this fatigue management, especially in groups, should be part of the IBD treatment.

    Further research should focus on when and for how long fatigue management should be implemented. This includes a cost-effectiveness analysis of this intervention.

    Acknowledgments

    We thank Bernadette Lourens—Rafaela for contributing to the study by data processing and for her assistance in data collection, and Lieneke Homans, Katinka Oerlemans for practical assistance.

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    Footnotes

    • Contributors All authors have read and approved the final manuscript. LV: participated in the conception and design, acquisition of data, analysis and interpretation of data and drafting of the manuscript. AS: participated in the conception and design of the study and critical revision of the manuscript for important intellectual content. RT: participated in the conception and design of the study, performed the statistical analysis and critical revision of the manuscript for important intellectual content. AT: acquisition of data, critical revision of the manuscript for important intellectual content. DJB: acquisition of data, critical revision of the manuscript for important intellectual content. TV: participated in the conception and design, critical revision of the manuscript for important intellectual content. EK: participated in the conception and design, critical revision of the manuscript for important intellectual content. JB: participated in the conception and design, critical revision of the manuscript for important intellectual content. CW: had full access to all data of the study and takes responsibility for the integrity of the data and the accuracy of the data analysis, study concept and design, acquisition of data, and critical revision of the manuscript for important intellectual content.

    • Competing interests All authors state that there are no potential conflicts of interest during the work under consideration for publication. CW has participated in the advisory board of Centocor, MSD, FALK Benelux, Abbott laboratories and Ferring during the last 3 years and received financial compensation for these activities.

    • Patient consent Obtained.

    • Ethics approval The protocol was approved by the institutional review board or by the ethics committee at each centre: Erasmus MC and Gelderse Vallei hospital.

    • Provenance and peer review Not commissioned; externally peer reviewed.