Fatigue in inflammatory bowel disease: Prevalence, risk factors, assessment, outcomes, and management

Table 1 Various scales for assessment of fatigue in patients with inflammatory bowel disease

Scales for fatigue assessment used in patients with IBD	Validated in IBD
Functional assessment of chronic illness therapy-fatigue[49-55]	Yes
Daily fatigue impact scale[56,57]	Yes
Modified fatigue impact scale[56,57]	Yes
Fatigue severity scale[56]	Yes
Inflammatory bowel disease fatigue scale[58-63]	Yes
Multidimensional fatigue inventory[58,59,64-67]	Yes
Patient-reported outcomes measurement information system® fatigue short form 7a (SF-7a) scale[68,69]1	Yes
Multidimensional assessment of fatigue[58,59]	No
Fatigue questionnaire[66,70,71]	No
Brief fatigue inventory[64]	No
PedsQLTM multidimensional fatigue scale[72,73]1	Yes
Multidimensional fatigue scale[74]1	No

¹Assessment of pediatric patients.

IBD: Inflammatory bowel disease.

Table 2 Summary of studies on the various therapies for the management of fatigue in inflammatory bowel disease

Ref.	Country, study design, No. of patients	Patient characteristics and number	Intervention	Outcome
Pharmacotherapy for control of disease activity
Grimstad et al[98], 2016	Norway, prospective, n = 82 (UC: 100%)	Treatment-naïve adult patients with active UC	Conventional treatment with 5-aminosalicylate ± corticosteroid or azathioprine	Median fVAS reduced from 40 (0-94) to 22 (0-81) (P < 0.001) over 3 months, with the prevalence of significant fatigues (fVAS ≥ 50) reduced from 40.2% to 20.7%
Bączyk et al[99], 2019	Poland, prospective, n = 60 (UC: 50%, CD: 50%)	Patients with active IBD	Surgical treatment for IBD	There was a significant reduction in the fatigue score after surgery in both patients with UC and CD, with improvement in systemic and social function
Danese et al[100], 2023	Multicentric, RCT (UC: 100%)	Patients with moderate to severe active UC	UPA induction (45 mg) for 8 weeks, followed by maintenance (30 mg or 15 mg) for 52 weeks	A reduction of ≥ 5 points in the FACIT-F score was higher in the UPA group both at 8 weeks (59.1% vs 33.8% with placebo) and 52 weeks (UPA 30 mg: 58.8% vs UPA 15 mg: 55.4% vs placebo: 35.1%)
Ghosh et al[101], 2024	Multicentric, RCT, n = 1021 (CD: 100%)	Patients with moderate to severe active CD	UPA induction (45 mg) for 8 weeks, followed by maintenance (30 mg or 15 mg) for 52 weeks	FACIT-F score was higher in the UPA group both at 8 weeks (42% vs 27% with placebo in U-EXCEL and 42.3% vs 20% with placebo in U-EXCEED) and 52 weeks (UPA 30 mg: 43.3% vs UPA 15 mg: 28.4% vs placebo: 16.9%)
Regueiro et al[102], 2024	Multicentric, RCT, n = 191 (CD: 100%)	Patients with moderate to severe active CD	Mirikizumab	At 12 weeks, mirikizumab groups reported improved FACIT-F scores compared with placebo, and improvement was maintained through week 52 and week 104
Other pharmacotherapies
Costantini and Pala[103], 2013	Italy, prospective, single-arm, n = 12 (UC: 75%, CD: 25%)	Patients in remission with moderate to severe fatigue as per CFS scale	Thiamine started at 600 mg/day and increased by 300 mg every two days if no improvement	In 10/12 (83.3%) patients, the values of the CFS scale after therapy were equal to zero, suggesting complete improvement. Two other patients had 50% and 66.6% regression from baseline score
Scholten et al[104], 2018	The Netherlands, RCT, n = 39 (UC: 49%, CD: 51%)	Fatigue duration > 3 months with a high score (≥ 35) on the fatigue subscale of CIS score and not on corticosteroids	8-weeks period treatment with 1000 μg vitamin B12	Scores on the CIS subscale ‘motivation’ improved, but no significant improvement was observed in the overall score and subscale ‘subjective fatigue’
Bager et al[105], 2021	Denmark, RCT, n = 40 (UC: 50%, CD: 50%)	Patients in remission with chronic fatigue (IBD-Fatigue score > 12 and duration > 6 months)	Weight and gender-based high-dose oral thiamine ranging from 600-1800 mg/d for 4 weeks	Significant decrease in fatigue score and health-related quality of life from baseline, and a significantly higher proportion of patients showed improvement with thiamine compared to placebo
Moradi et al[106], 2021	Iran, RCT, n = 80 (UC: 100%)	Active mild-to-moderate UC	500 mg capsule of Spirulina, twice daily for eight weeks	There was no difference between the two groups in terms of fatigue score, nor there was any improvement from the baseline score
Bager et al[107], 2022	Denmark, RCT, n = 40 (UC: 50%, CD: 50%)	Patients in remission with chronic fatigue (IBD-Fatigue score > 12 & duration > 6 months) recruited from the previous trial	Maintenance dose oral thiamine 300 mg/d for 12 weeks followed by self-treatment with over-the-counter thiamine × 6 m	No beneficial effect of thiamine for 12 weeks on fatigue. Patients who took OTC thiamine had lower level of fatigue at 52 weeks (7.8; 5.5–10.1) compared to no thiamine (11.0; 9.2–12.8) (P = 0.02)
Truyens et al[108], 2022	Belgium, RCT, n = 166 (UC: 28%, CD: 72%)	Patients in remission for > 3 months with fVAS score ≥ 5	8-week treatment of HTP orally 100 mg twice daily	The proportion of patients achieving ≥ 20% reduction and a mean reduction in fVAS was comparable between 5-HTP and placebo
Bager et al[109], 2023	Denmark, RCT, n = 40 (UC: 50%, CD: 50%)	Adult patients with quiescent, IBD and chronic fatigue (IBD-F score > 12)	Weight and gender-based high-dose oral thiamine ranging from 600-1800 mg/day for 4 weeks	Reduction in the fatigue score by ≥ 3 points was observed in 65% (26/40) patients
Moulton et al[110], 2024	United Kingdom, prospective case series, n = 10 (UC: 20% CD: 80%)	Patients with quiescent or mildly active disease and severe fatigue (IBD fatigue assessment scale score ≥ 11)	Modafinil 100 mg twice a day and gradually increased to 200 mg twice a day based on response	There was an improvement in the mean score by 58.1% from the baseline, with 60% reporting ≥ 50% improvement from the baseline score
Psychological interventions
Vogelaar et al[111], 2011	The Netherlands, RCT, n = 29	A high score on the fatigue scale (CIS score ≥ 35) and in clinical remission	Psychological interventions, including PST and SFT	Improvement in fatigue score was observed in 85.7% and 60% of SFT and PST groups, respectively, compared to 45.5% in controls. Medical costs lowered in 57.1% of the patients in the SFT group, 45.5% in the control group and 20% in the PST group
Vogelaar et al[112], 2014	The Netherlands, RCT, n = 98 (UC: 41%, CD: 59%)	A high score on the fatigue scale (CIS score ≥ 35) and in clinical remission	SFT vs CAU	39% of patients in the SFT group achieved a CIS-fatigue score < 35 after treatment, compared to 18% in the CAU group (P = 0.03). Although SFT significantly reduced fatigue and improved QoL at 3 and 6 months, these benefits diminished by 9 months
Artom et al[113], 2019	United Kingdom, RCT, n = 31 (UC: 22.6%, CD: 67.7%)	Patients in remission with self-reported fatigue	CBT: One 60-minute & seven 30-minute sessions over 8-weeks	There was more reduction in the impact of fatigue than the severity of fatigue at 6 months with CBT, with improvement in quality-of-life scores
O’Connor et al[114], 2019	United Kingdom, RCT, n = 29 (UC: 13% CD: 87%)	Patients in remission with score ≥ 1 on Section I of the Crohn’s and Colitis. United Kingdom IBD fatigue self-assessment scale	Psychoeducational intervention: Delivered in small groups for 1 hour every 8 weeks over a period of 6 months	Mean fatigue severity and impact scores improved for patients in the intervention group and worsened in the control group
Hashash et al[115], 2022	United States, RCT, n = 52 (100% CD)	Biopsy-proven, young (15-30 years) CD patients with PSQI ≥ 7 and Multidimensional Fatigue Inventory (MFI) ≥ 4	Sequential brief behavioral therapy for sleep followed by bupropion for those not improving	There was a significant improvement in fatigue following 4 weeks of behavioral therapy. Adding bupropion improved fatigue further, but was not statistically significant
Strobel et al[116], 2022	United States, retrospective, n = 19 (UC: 21%, CD: 79%)	Patients with controlled, but persistent, symptoms	Functional medicine program, including dietary advice: 2-hour sessions alternate weeks for 10 weeks	There was a significant improvement in the median score of the FSS from 43 (27-53.5) to 27 (18-45). 73% (11) of the 15 patients who completed the follow-up had improvement in FSS score
Regev et al[117], 2023	Israel, RCT, n = 120 (CD: 100%)	Confirmed diagnosis of CD for ≥ 1 year, with mild-to-moderate disease activity	Cognitive-behavioral and mindfulness based stress reduction with daily exercise	The intervention group demonstrated significantly lower levels of fatigue and the change in fatigue was independent of the changes in disease activity
Bredero et al[118], 2024	The Netherlands, RCT, n = 108 (UC: 47%, CD: 53%)	Patients in remission with elevated levels of fatigue (CIS – subjective fatigue ≥ 27)	Mindfulness-based cognitive therapy (MBCT) for 8 weeks	Improvements in IBD-related fatigue following MBCT are maintained during a 9-month follow-up period, with about one-third of patients reporting clinically significant enhancement from pretreatment to follow-up
Physical intervention
Horta et al[119], 2020	Spain, RCT, n = 52 (UC: 11.5%, CD: 88.5%)	Patients in clinical remission with persistent fatigue (Two consecutive Functional FACIT-FS scores < 40)	Electroacupuncture: 2 sessions in the first week and then 1 per week for 7 weeks (Total 8 weeks) vs acupuncture vs none	Significant improvement in fatigue in both electroacupuncture and acupuncture groups from baseline. Fatigue improvement (≥ 3-point increase in FACIT-FS) seen in 86.6%, 66.6%, & 8.3% of electroacupuncture, acupuncture, & none group fatigue remission (FACIT-FS > 40) observed in 27.7%, 11.1%, & 0% of electroacupuncture, acupuncture, & none group
van Erp et al[120], 2021	The Netherlands, prospective, n = 25 (UC: 16%, CD: 84%)	Fatigue duration > 3 months with a high score (≥ 35) on the fatigue subscale of CIS score and in clinical remission	Personalized exercise program (aerobic + resistance based on cardiopulmonary exercise test) of three training sessions per week for 12 consecutive weeks	There was a significant reduction in the total CIS score and severity of fatigue (CIS-F score), with the scores remaining unchanged in only one patient. There was a significant improvement in the health-related quality of life as assessed by IBD questionnaire
Lamers et al[121], 2022	The Netherlands, prospective, n = 25 (UC: 54%, CD: 46%)	Patients with a diagnosis of IBD for > 2 years with mild active disease or in remission	Personalized dietary and physical activity advice in 6 consults	Significant decrease in mean IBD-F from baseline at 3 months (P = 0.002) and 6 months (P = 0.008), but not at 1 month (P = 0.07)
You et al[122], 2022	China, RCT, n = 70 (UC: 63%, CD: 37%)	Patients with fatigue and quiescent or mildly active disease and receiving stable medication	Aromatherapy through the skin and by inhalation: 30 minutes × 3 times a week	There was no difference between the two groups based on the Multidimensional Fatigue Inventory score, but there was significant improvement in sub-dimensions of physical and mental fatigue
Scheffers et al[95], 2023	The Netherlands, RCT, n = 15 (UC: 33.3%, CD: 66.7%)	Pediatric patients aged 6-8 years with a diagnosis of IBD	12-week lifestyle program (3 physical training sessions per week plus personalized healthy dietary advice)	Significant reduction in disease activity, fecal calprotectin and fatigue and improvement in quality of life

CD: Crohn’s disease; IBD: Inflammatory bowel disease; RCT: Randomized controlled trial; UC: Ulcerative colitis; CIS: Checklist individual strengths; FACIT-FS: Functional assessment of chronic illness therapy-fatigue scale; MBCT: Mindfulness-based cognitive therapy; FSS: Fatigue severity scale; PSQI: Pittsburgh sleep quality index; CBT: Cognitive-behavioral therapy; QoL: Quality of life; SFT: Solution-focused therapy; PST: Problem-solving therapy; IBD-F: Inflammatory bowel disease fatigue; 5-HTP: 5-hydroxytryptophan; OTC: Over-the-counter; CFS: Chronic fatigue syndrome; FACIT-F: Functional assessment of chronic illness therapy–fatigue; UPA: Upadacitinib; fVAS: Fatigue visual analog scale; CAU: Care as usual.