Abstract
Background
Fatigue is common in Crohn’s disease (CD) and ulcerative colitis (UC), but the pathogenesis remains poorly understood.
Aims
This study aimed to assess changes in fatigue prevalence during the first year after diagnosis and examine the association between disease course and substantial fatigue (SF) at the 1-year follow-up.
Methods
Adults with newly diagnosed CD or UC were recruited from the population-based IBSEN III cohort. Fatigue was assessed at diagnosis and the 1-year follow-up using the Fatigue Questionnaire. Associations between SF at the 1-year follow-up and disease-related factors were quantified using multivariate logistic regression adjusted for sex, age and comorbidities.
Results
In total, 596 patients were included (CD: 196, UC: 400). SF was present at both baseline and after one year of disease for 46.9% (n = 92/196) and 40.5% (n = 162/400) of patients with CD and UC, respectively. In CD, development of endoscopically non-passable stricture and/or surgically treated stricture within first year of disease (OR = 4.52, 95%CI [1.61;12.68]), self-reported flares since diagnosis (OR = 2.55, 95%CI [1.26;5.16]), female sex (OR = 3.12, 95%CI [1.53;6.37]) and comorbidities (OR = 4.05, 95%CI [1.89;8.69]) were independently associated with SF at the 1-year follow-up. In UC, SF was associated with current biological treatment (OR = 5.14, 95%CI [1.56;16.96]), increasing Mayo endoscopic score at the 1-year follow-up (OR = 1.54, 95%CI [1.01;2.35]), self-reported flares since diagnosis (OR = 2.66, 95%CI [1.24;5.72]) and female sex (OR = 2.20, 95%CI [1.06;4.57]).
Conclusions
Fatigue frequently persists through the first year after IBD diagnosis. Clinical factors reflecting a more severe disease course were associated with SF one year after diagnosis in both CD and UC.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10620-025-09661-0.
Keywords: Inflammatory bowel disease, Ulcerative colitis, Crohn’s disease, Fatigue, Epidemiology
Introduction
Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), is an immune mediated inflammatory disorder of the gastrointestinal tract [1]. Fatigue is among the most prevalent and burdensome symptoms experienced by patients with IBD, and current evidence suggests that the aetiology is multifactorial [2–4]. While fatigue may be directly attributable to factors such malnutrition and anaemia, both potential consequences of IBD, these explain only a minority of cases in well-developed countries [5]. Numerous studies have demonstrated a consistent association between fatigue and clinical disease activity indices, where a high symptom burden may adversely impact sleep and overall health-related quality of life [5–8] However, relatively few studies have previously examined the relationship between fatigue and objective disease markers, with findings demonstrating inconsistent associations, particularly in UC, and with an even more limited evidence base in CD [2, 4, 9]. Emerging evidence suggests that fatigue in many patients with IBD may be driven by inflammatory processes and intestinal changes, including alterations in the microbiota and tryptophan metabolism [2, 5, 10, 11].
This study aimed to improve our understanding of fatigue in IBD by using clinical, biochemical, and endoscopic data from the first year following diagnosis in a population-based cohort representative of the adult IBD population in Norway. A longitudinal design was used to address limitations inherent in the more common cross-sectional studies. The primary objective was to assess the trajectory of fatigue among patients with IBD from the time of diagnosis to the 1-year follow-up and to estimate the likelihood for substantial and chronic fatigue after one year of disease based on the presence of substantial fatigue at diagnosis. A secondary objective was to identify which selected disease-related factors were associated with substantial fatigue at the 1-year follow-up, controlled for age, sex and comorbidities. All analyses were performed stratified by type of diagnosis.
Materials and Methods
Study Design and Population
The Inflammatory Bowel Disease in South-Eastern Norway III study (the IBSEN III study) is a population-based observational cohort study (Clinical Trials ID: NCT02727959). Between 2017 and 2019, patients residing in the South-Eastern Health Region with suspected IBD were invited to participate in the IBSEN III study. The cohort structure and inclusion process have been described in detail elsewhere [12]
For the present study, we included data from patients ≥ 18 years old at the time of diagnosis. Moreover, only participants with a definite diagnosis of UC or CD according to the Lennard–Jones criteria at the 1-year follow-up and available data on fatigue at both inclusion and after one year of disease were included in the analyses [13].
Data Collection and Handling
At inclusion and the 1-year follow-up, study participants were invited to their local hospitals for a clinical interview, examination and blood samples, while the patient-reported outcome measures were collected electronically. Faecal calprotectin was analysed at a single study specific laboratory (Enzyme-linked immunoassay: Bühlmann Calprotectin ELISA EK-CAL; Bühlmann Laboratories AG, Switzerland) after collection of faecal samples at baseline and after 3, 6 and 12 months using a home-based sampling kit. At baseline, all patients underwent a colonoscopy with biopsy, and in patients with CD additional upper endoscopy, capsule endoscopy, and radiology (Intestinal Magnetic Resonance Imaging (MRI)/Computed Tomography (CT)) were performed when clinically indicated. For the 1-year follow-up, endoscopy and radiology were performed if clinically indicated. Due to the covid-19 pandemic, the window for conducting the 1-year follow-up for patients diagnosed in 2019 was extended from 1 year − / + 3 months to 1 year − 3/ + 12 months.
Disease Activity
The Montreal Classification system was used to classify disease location and behaviour for CD [14, 15]. A surgically treated stricture and/or endoscopically non-passable stricture (simple endoscopic score for CD (SES-CD)) were defined as a severe intestinal stricture [16] In UC, Montreal Classification system was used to classify extension of disease, while endoscopic activity was graded using the Mayo endoscopic sub-score and analysed as a continuous variable (scale: 0–3) [14, 17]. C-reactive protein ≥ 5 mg/L and faecal calprotectin > 250 µg/g were considered elevated and indicative of active inflammation [18, 19] At the 1-year follow-up, patients were asked to categorize their disease course since diagnosis according to one out of four different pre-defined curve patterns reflecting the subjective symptom burden, as shown in Fig. 3.
Fig. 3.
Subjective disease course through the first year after diagnosis. The clinical course of disease from diagnosis to the 1-year follow-up was illustrated by four different pre-defined graphs reflecting different disease patterns based on the symptom burden. The result was presented separately for patients with Crohn’s disease (CD) or ulcerative colitis (UC). The proportion of patients for each category was stratified by patients with or without substantial fatigue (SF) at the 1-year follow-up, presented with number of patients and percentages (n (%))
Comorbidities
Comorbidities were patient reported and for the purpose of this study defined in the same manner as the Trøndelag Health Study (HUNT) database, [20] including professionally treated psychological problems, migraine, atopic eczema, chronic obstructive pulmonary disease (COPD), asthma, hyper- or hypothyroidism, heart disease, atrial fibrillation, previous cerebral insult, psoriasis, kidney disease, rheumatoid arthritis, ankylosing spondylitis and/or podagra.
The Fatigue Questionnaire (FQ)
Fatigue was evaluated using the Fatigue Questionnaire (FQ), a generic patient reported outcome measurement (PROM) developed by Chalder et al. in 1993 [21]. The questionnaire has been translated and validated in Norwegian [22]. The FQ is divided into two dimensions, physical fatigue (question 1–7) and mental fatigue (question 8–11). Responses are scored on a Likert scale ranging from 0 to 3. The total fatigue score is obtained when summarising these responses, where a higher score implies a greater level of fatigue (maximum total score of 33). Further, the scale may be dichotomized into 0 (score 0–1) and 1 (score 2–3). Substantial fatigue (SF) is defined as a dichotomized score ≥ 4. Chronic fatigue (CF) is defined as substantial fatigue lasting ≥ 6 months [21]
Statistical Analysis
Patient characteristics were presented stratified by type of diagnosis and subdivided into patients with and without substantial fatigue at the 1-year follow-up. Categorical data were presented as counts and percentages. Continuous variables were described with median and interquartile range (IQR) or ranges for consistency due to skewed distribution for the majority of variables in the subgroups. The proportions of missing data are not displayed in the patient characteristics table for variables with < 5% missing data for all subcategories. Crude differences between patients with and without substantial fatigue at the 1-year follow-up stratified by diagnosis were assessed using chi-square test (χ2) for pairs of categorical variables and Mann–Whitney-U test for pairs of continuous variables that were not normally distributed. The normality assumption was assessed using graphical presentations of the variables (histograms) combined with the Shapiro–Wilk’s test.
Univariate binary logistic regression analysis was used to assess the associated odds between substantial fatigue at the time of diagnosis and substantial or chronic fatigue at the 1-year follow-up compared to those without fatigue at baseline. SankeyMATIC was used to create the figures to illustrate the fatigue trajectory with changes in the proportions of chronic, substantial and no fatigue from baseline to the 1-year follow-up stratified by diagnosis. Chi-square test (χ2) was used to compare the distribution of fatigue (chronic fatigue, substantial fatigue and absence of fatigue) between diagnoses (CD or UC) at baseline and the 1-year follow-up.
Associations between substantial fatigue at the 1-year follow-up and disease-related factors collected from baseline to the 1-year follow-up, were assessed using a multivariate binary logistic regression model with backward elimination mode (Wald). The analyses were stratified by diagnosis (CD or UC) and adjusted for sex, age and the presence of comorbidities. The results were expressed as odds ratios (OR) with 95% confidence interval (CI). Only variables with p-values ≤ 0.1 in the univariate regression analyses were included in the multivariate regression model.
To assess generalizability of our results to the original IBD patient population in IBSEN III, Mann–Whitney-U and Chi-square test (χ2) were performed to compare the selected sociodemographic and clinical data for those with and without available FQ data. P-values ≤ 0.05 were considered statistically significant. All analyses were considered exploratory so no correction for multiple testing was done. Statistical analyses were performed using IBM SPSS Statistics version 28 and STATA/SE 16.0, both for Windows.
Results
Study Population
A total of 596 out of 1370 (43.5%) patients with a definite diagnosis of CD or UC at the 1-year follow-up were included in the study (CD: 196 (32.9%), UC: 400 (67.1%)). The inclusion process is illustrated in Fig. 1. Compared to patients without available FQ data, those with complete FQ data were significantly younger (median age difference of 6 years) and had fewer IBD-related hospitalisations prior to the 1-year follow-up (7.4% vs. 11.1%). No other significant differences in sociodemographic or disease-related characteristics were observed between the two groups.
Fig. 1.
Inclusion process. Flow chart illustrating the inclusion process from the Inflammatory Bowel Disease in South-Eastern Norway III study (the IBSEN III study). Only patients ≥ 18 years old at the time of diagnosis with a definite diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC) at the 1-year follow-up were eligible for inclusion. Patients without available data on the Fatigue Questionnaire (FQ) at both inclusion and after one year of disease were excluded from the analyses. IBD Inflammatory bowel disease. IBD-U Unclassified IBD
Patient characteristics at the 1-year follow-up, stratified by diagnosis and presence of substantial fatigue, are presented in Table 1. The most frequently reported comorbidities at the 1-year follow-up were professionally treated psychological problems, migraine, atopic eczema, psoriasis and/or asthma, each with a proportion between 10 and 20%, where substantial fatigue were significantly more often present for patients with psychological comorbidity, migraine (UC) and/or atopic eczema (CD).
Table 1.
Patient characteristics
| CD (n = 196) | UC (n = 400) | |||||
|---|---|---|---|---|---|---|
| SF 1y | No SF 1y | p-value | SF 1y | No SF 1y | p-value | |
| Age, years (median (range)) | 37 (18–76) | 44 (18–72) | 0.25 | 40 (18–82) | 42 (18–80) | 0.27 |
| Sex (n (%)) | < 0.001 | < 0.001 | ||||
| Female | 77 (65.3) | 41 (34.7) | 112 (60.2) | 74 (39.8) | ||
| Male | 30 (38.5) | 48 (61.5) | 88 (41.1) | 126 (58.9) | ||
| Comorbidity 1y* (n (%)) | 81 (65.3) | 43 (34.7) | < 0.001 | 129 (57.3) | 96 (42.7) | < 0.001 |
| Psychological comorbidity | 27 (79.4) | 7 (20.6) | 0.001 | 47 (77.0) | 14 (23.0) | < 0.001 |
| Atopic eczema | 21 (80.8) | 5 (19.2) | 0.004 | 28 (57.1) | 21 (42.9) | 0.29 |
| Migraine | 24 (64.9) | 13 (35.1) | 0.14 | 36 (63.2) | 21 (36.8) | 0.03 |
| Subjective disease flares within 1. year (n (%)) | 57 (68.7) | 26 (31.3) | < 0.001 | 120 (60.9) | 77 (39.1) | < 0.001 |
| IBD-related hospitalisation within 1. year (n (%)) | 14 (82.4) | 3 (17.6) | 0.016 | 18 (66.7) | 9 (33.3) | 0.08 |
|
IBD-related surgery (including perianal) within 1. year (n (%)) |
11 (68.8) | 5 (31.3) | 0.24 | 1 (50.0) | 1 (50.0) | 1.0 |
| Montreal location of disease 1y (n (%)) | 0.74 | |||||
| L1: Ileal | 51 (56.0) | 40 (44.0) | ||||
| L2: Colonic | 17 (58.6) | 12 (41.4) | ||||
| L3: Ileocolonic | 39 (51.3) | 37 (48.7) | ||||
| Montreal disease behaviour 1y (n (%)) | ||||||
| B1: Non-stricturing, non-penetrating | 77 (55.4) | 62 (44.6) | 0.88 | |||
| B2: Stricturing | 20 (51.3) | 19 (48.7) | 0.53 | |||
| B3: Penetrating (intra-abdominal) | 1 (100) | 0 (0) | 0.37 | |||
| B3p: Penetrating (perianal) | 10 (71.4) | 4 (28.6) | 0.19 | 1 (50.0) | 1 (50.0) | 1.0 |
| Severe intestinal stricture** with or without abscess/fistula formation within 1. year (n (%)) | 23 (69.7) | 10 (30.3) | 0.08 | |||
| Montreal extent of disease 1y (n (%)) | 0.32 | |||||
| Normal | 48 (47.5) | 53 (52.5) | ||||
| Proctitis | 32 (58.2) | 23 (41.8) | ||||
| Left sided colitis | 20 (64.5) | 11 (35.5) | ||||
| Extensive colitis | 23 (51.1) | 22 (48.9) | ||||
| Mayo endoscopic score 1y (n (%)) | 0.24 | |||||
| 0: Normal | 50 (47.6) | 55 (52.4) | ||||
| 1: Mild | 28 (50.9) | 27 (49.1) | ||||
| 2: Moderate | 38 (61.3) | 24 (38.7) | ||||
| 3: Severe | 7 (70.0) | 3 (30.0) | ||||
| Mayo endoscopic score 3 + extensive colitis 1y (n (%)) | 2 (50.0) | 2 (50.0) | 0.9 | |||
| Missing (n (%)) | 77 (38.5) | 91 (45.5) | ||||
| Mayo endoscopic score 3 + extensive colitis 0y (n (%)) | 17 (44.7) | 21 (55.3) | 0.51 | |||
| Medical treatment at the 1-year follow-up: | ||||||
| Missing (n (%)) | 6 (5.6) | 8 (9.0) | 2 (1.0) | 4 (2.0) | ||
| 5-ASA (n (%)) | 10 (52.6) | 9 (47.4) | 0.79 | 153 (48.9) | 160 (51.1) | 0.28 |
| Budesonide (oral/local) (n (%)) | 12 (63.2) | 7 (36.8) | 0.48 | 4 (40.0) | 6 (60.0) | 0.51 |
| Azathioprine (n (%)) | 28 (56.0) | 22 (44.0) | 0.93 | 24 (72.7) | 9 (27.3) | 0.007 |
| Methotrexate (n (%)) | 7 (70.0) | 3 (30.0) | 0.34 | 3 (75.0) | 1 (25.0) | 0.32 |
| Biologic (n (%)) | 51 (58.0) | 37 (42.0) | 0.52 | 41 (74.5) | 14 (25.5) | < 0.001 |
| Infliximab (n (%)) | 30 (60.0) | 20 (40.0) | 0.45 | 17 (73.9) | 6 (26.1) | 0.019 |
| Adalimumab (n (%)) | 19 (59.4) | 13 (40.6) | 0.63 | 16 (72.7) | 6 (27.3) | 0.03 |
| Vedolizumab (n (%)) | 2 (40.0) | 3 (60.0) | 0.48 | 6 (75.0) | 2 (25.0) | 0.16 |
| ≥ 2 different biologics within 1. year | 2 (40.0) | 3 (60.0) | 0.48 | 10 (83.3) | 2 (16.7) | 0.02 |
| Steroid treatment (IV/oral/local) during 1. year | 40 (58.8) | 28 (41.2) | 0.49 | 78 (63.9) | 44 (36.1) | < 0.001 |
| Faecal calprotectin 1y (µg/g) (median/IQR) | 192/327 | 200/335 | 0.94 | 126/499 | 71/107 | 0.015 |
| Faecal calprotectin ≤ 250 µg/g at 3 m/6 m and 1y (n (%)) | 32 (58.2) | 23 (41.8) | 0.22 | 60 (42.3) | 82 (57.7) | < 0.001 |
| Missing (n (%)) | 35 (32.7) | 22 (24.7) | 59 (29.5) | 69 (34.5) | ||
| C-reactive protein 1y (mg/L) (median/IQR) | 3.8/7.9 | 2.2/3.7 | 0.04 | 2.0/4.0 | 1.7/3.0 | 0.29 |
| C-reactive protein ≥ 5 mg/L 1y (n (%)) | 29 (67.4) | 14 (32.6) | 0.04 | 36 (57.1) | 27 (42.9) | 0.31 |
| Missing (n (%)) | 12 (11.2) | 8 (9.0) | 21 (10.5) | 30 (15.0) | ||
| Anaemia 1y*** (n (%)) | 3 (50.0) | 3 (50.0) | 0.80 | 11 (61.1) | 7 (38.9) | 0.39 |
| Iron deficiency**** (n (%)) | 20 (66.7) | 10 (33.3) | 0.07 | 27 (60.0) | 18 (40.0) | 0.14 |
| Missing (n (%)) | 7 (6.5) | 7 (7.9) | 19 (9.5) | 28 (14.0) | ||
| Vitamin B12 deficiency***** (n (%)) | 7 (43.8) | 9 (56.3) | 0.40 | 12 (57.1) | 9 (42.9) | 0.47 |
| Missing (n (%)) | 22 (20.6) | 16 (18.0) | 54 (27.0) | 47 (23.5) | ||
| Vitamin D deficiency****** (n (%)) | 19 (63.3) | 11 (36.7) | 0.19 | 25 (47.2) | 28 (52.8) | 0.77 |
| Missing (n (%)) | 22 (20.6) | 16 (18.0) | 54 (27.0) | 47 (23.5) | ||
CD Crohn’s disease, UC Ulcerative colitis, SF Substantial fatigue, 0y At diagnosis/baseline, 1y At 1-year follow-up, L1-3 Location, B1-3 Behaviour
*Psychological problems, migraine, atopic eczema, COPD, asthma, hyper- and hypothyroidism, heart disease, atrial fibrillation, previous cerebral insult, psoriasis, kidney disease, rheumatoid arthritis, ankylosing spondylitis and/or podagra
**Severe intestinal stricture: Endoscopically non-passable stricture and/or surgically treated stricture
***Haemoglobin level of < 13 g/dL for males and < 12 g/dL[18]
****Transferrin saturation < 20%[40]
*****Vitamin B12 level < 148 ymol/L [41]
******Vitamin D level < 50 nmol/L[42]
Fatigue Trajectory Through the First Year of Disease
The proportion of patients with substantial fatigue at the time of diagnosis declined from 66.3% (n = 130/196) and 60.0% (n = 240/400), to 54.6% (n = 107/196) and 50.0% (n = 200/200) at the 1-year follow-up in CD and UC patients, respectively. Substantial fatigue was present at both baseline and after one year of disease for 46.9% (n = 92/196) and 40.5% (n = 162/400) of patients with CD and UC, respectively. Among patients with substantial fatigue at baseline, 19.4% (n = 38/196) of those with CD and 19.5% (n = 78/400) of those with UC, no longer reported substantial fatigue after one year. Conversely, only 7.7% (n = 15/196) of patients with CD and 9.5% (n = 38/400) of patients with UC developed substantial fatigue during the follow-up period. Fatigue trajectories stratified by diagnosis are illustrated in Fig. 2 and did not significantly differ between CD and UC (p > 0.1). Regardless of diagnosis, patients with substantial fatigue at diagnosis had significantly higher odds for both substantial and chronic fatigue at the 1-year follow-up compared to those without substantial fatigue at baseline (Supplementary Table 1).
Fig. 2.
Fatigue trajectory throughout the first year of disease stratified by diagnosis. Flow diagram showing the evolution of fatigue from the time of diagnosis (year 0) to the 1-year follow-up (year 1), presented with percentages. Fatigue was divided into chronic fatigue (substantial fatigue with duration ≥ 6 months), presented at the top, substantial fatigue (duration of fatigue symptoms < 6 months), presented in the middle and absence of fatigue (no substantial fatigue) presented at the bottom. The numbers presented as circles are the percentage of patients who changed fatigue category from year 0 to year 1, while the rounded squares are those who retained the same category
Associations Between Selected Disease-Related Factors and Substantial Fatigue One Year After Diagnosis
After one year of disease, the development of a severe intestinal stricture (endoscopically non-passable stricture and/or surgically treated stricture) during the first year (OR = 4.52, 95% CI [1.61;12.68]), self-reported disease flare since diagnosis (OR = 2.55, 95% CI [1.26; 5.16]), female sex (OR = 3.12, 95% CI [1.53; 6.37]) and the presence of one or more comorbidities at the 1-year follow-up (OR = 4.05, 95% CI [1.89; 8.69]) were all independently associated with substantial fatigue at the 1-year follow-up in patients with CD (Table 2). Among patients with UC, current biological treatment (OR = 5.14, 95% CI [1.56; 16.96]), increasing Mayo endoscopic score (scale: 0–3) at the 1-year follow-up (OR = 1.54, 95% CI [1.01; 2.35]), self-reported disease flare since diagnosis (OR = 2.66, 95% CI [1.24; 5.72]) and female sex (OR = 2.20, 95% CI [1.06; 4.57]) were all independently associated with substantial fatigue at the 1-year follow-up (Table 3).
Table 2.
Univariate and multivariate logistic regression of selected clinical factors on substantial fatigue at the 1-year follow-up for patients with CD
| CD | |||||||
|---|---|---|---|---|---|---|---|
| Univariate | Multivariate | ||||||
| n | OR | 95% CI | p-value | OR | 95% CI | p-value | |
| Sex (ref. male) | 196 | 3.01 |
1.66; 5.44 |
< 0.001 | 3.12 |
1.53; 6.37 |
0.002 |
| Age ≤ 40 years at diagnosis (ref. > 40 years) | 196 | 1.45 |
0.82; 2.55 |
0.20 | |||
| Comorbidity 1y (ref. no comorbidity 1y) | 196 | 3.33 |
1.82; 6.11 |
< 0.001 | 4.05 |
1.89; 8.69 |
< 0.001 |
|
Self-reported flare within 1. Year (ref. no flare) |
195 | 2.82 |
1.55; 5.11 |
< 0.001 | 2.55 |
1.26; 5.16 |
0.009 |
|
Faecal calprotectin ≤ 250 µg/g at 3 m/6 m and 1y (ref. > 250 µg/g at 3 m/6 m and/or 1y) |
139 | 1.53 |
0.77; 3.04 |
0.22 | |||
| C-reactive protein ≥ 5 mg/L 1y (ref. < 5 mg/L) | 176 | 2.10 |
1.02; 4.33 |
0.044 | 1.76 |
0.76; 4.12 |
0.19 |
| Non-stricturing, non-penetrating disease through the 1. Year (B1) (ref. B2 or B3 within 1. year) | 192 | 0.95 |
0.50; 1.80 |
0.88 | |||
|
Stricturing disease within 1. Year (B2) (ref. B1 or B3 within 1. year) |
192 | 0.80 |
0.40; 1.62 |
0.53 | |||
|
Penetrating disease within 1. Year (B3) (ref. B1 or B2 within 1. year) |
194 | 2.24 |
0.68; 7.40 |
0.19 | |||
|
Severe intestinal stricture with or without abscess/fistula formation within 1. year (ref. absence of severe intestinal stricture) |
186 | 2.04 |
0.91; 4.58 |
0.08 | 4.52 |
1.61; 12.68 |
0.004 |
|
IBD-related hospitalisation within 1. year (ref. no hospitalisation) |
196 | 4.32 |
1.20; 15.54 |
0.025 | 2.94 |
0.64; 13.53 |
0.17 |
|
Steroid treatment within 1. year (ref. no steroid treatment after diagnosis) |
182 | 1.24 |
0.68; 2.28 |
0.49 | |||
|
Biologic treatment 1y (ref. no biological treatment at 1y) |
182 | 1.21 |
0.68; 2.18 |
0.52 | |||
|
Multivariate: 167 |
|||||||
CD Crohn’s disease, UC Ulcerative colitis, n number of patients included in analysis, 1y At 1-year follow-up, *Severe intestinal stricture: Endoscopically non-passable stricture and/or surgically treated stricture
Table 3.
Univariate and multivariate logistic regression of selected clinical factors on substantial fatigue at the 1-year follow-up for patients with UC
| UC | |||||||
|---|---|---|---|---|---|---|---|
| Univariate | Multivariate | ||||||
| n | OR | 95% CI | p-value | OR | 95% CI | p-value | |
| Sex (ref. male) | 400 | 2.17 |
1.45; 3.23 |
< 0.001 | 2.20 |
1.06; 4.57 |
0.034 |
| Age ≤ 40 years at diagnosis (ref. > 40 years) | 400 | 1.27 |
0.86; 1.88 |
0.23 | |||
| Comorbidity 1y (ref. no comorbidity 1y) | 399 | 2.00 |
1.34; 2.98 |
< 0.001 | 0.97 |
0.46; 2.03 |
0.97 |
|
Self-reported flare within 1. Year (ref. no flare) |
394 | 2.33 |
1.55; 3.49 |
< 0.001 | 2.66 |
1.24; 5.72 |
0.012 |
|
Faecal calprotectin ≤ 250 µg/g at 3 m/6 m and 1y (ref. > 250 µg/g at 3 m/6 m and/or 1y) |
272 | 0.44 |
0.27; 0.72 |
0.001 | 1.51 |
0.66; 3.48 |
0.33 |
| C-reactive protein ≥ 5 mg/L 1y (ref. < 5 mg/L) | 349 | 1.33 |
0.77; 2.31 |
0.31 | |||
|
Montreal extent of disease 1y (scale: normal-extensive colitis (0–3)) |
232 | 1.10 |
0.88; 1.38 |
0.40 | |||
|
Mayo endoscopic score 1y (scale: 0–3) |
232 | 1.33 |
1.002; 1.76 |
0.048 | 1.54 |
1.01; 2.35 |
0.048 |
|
IBD-related hospitalisation within 1. year (ref. no hospitalisation) |
395 | 2.07 |
0.91; 4.72 |
0.085 | 0.83 |
0.16; 4.17 |
0.82 |
|
Steroid treatment within 1. year (ref. no steroid treatment after diagnosis) |
394 | 2.25 |
1.45; 3.49 |
< 0.001 | 1.12 |
0.48; 2.64 |
0.79 |
|
Biologic treatment 1y (ref. no biological treatment at 1y) |
394 | 3.40 |
1.78; 6.46 |
< 0.001 | 5.14 |
1.56: 16.96 |
0.007 |
|
Multivariate: 152 |
|||||||
CD Crohn’s disease, UC Ulcerative colitis, N number of patients included in analysis, 0y At diagnosis/baseline, 1y At 1-year follow-up
The patient-reported clinical disease course during the first year after diagnosis differed significantly between those with and without substantial fatigue at the 1-year follow-up (CD: p < 0.001/UC: p < 0.001) (Fig. 3). The proportion of patients with chronic continuous or intermittent symptoms was notably higher among patients with substantial fatigue at the 1-year follow-up (CD: n = 47/185 (25.4%), UC: n = 75/365 (20.3%)) compared to those without substantial fatigue (CD: n = 17/185 (9.2%), UC: n = 29/369 (7.9%)).
Discussion
In this study we observed, consistent with the findings of prior non-inception cohorts, that the proportion of patients with CD and UC with and without substantial fatigue were relatively stable during the first year after diagnosis [23–25]. Among patients with substantial fatigue at baseline, approximately 20% experienced symptom resolution within the 1-year follow-up. Conversely, fewer than 10% of patients without substantial fatigue at baseline developed such symptoms within the first year. These patterns were supported by the significantly increased odds for both substantial and chronic fatigue at one year in those who had substantial fatigue at diagnosis.
Of the selected possible predictive factors for substantial fatigue analysed in this study, clinical indicators of severe disease, such as severe stricturing disease in CD and biological therapy in UC, were independently associated with the highest odds for substantial fatigue at the 1-year follow-up. Other factors independently associated with substantial fatigue at the 1-year follow-up included self-reported disease flare and female sex (in both UC and CD), a higher mayo endoscopic score (UC) and comorbidities (CD).
The revealed association between substantial fatigue and self-reported disease flares and the predominance of chronic continuous or intermittent symptoms in patients with substantial fatigue after one year of disease, aligns with previous longitudinal studies linking persistent symptom burden to ongoing fatigue [8, 25]. This reinforces the well-established relation between clinical disease activity and fatigue, commonly reported in cross-sectional studies [4, 9]. Notably, in patients with UC, a higher Mayo endoscopic score was independently associated with fatigue, both at diagnosis and the 1-year follow-up, underscoring the role of intestinal inflammation in fatigue [26].
In CD, severe intestinal strictures were independently associated with substantial fatigue. Interestingly, unspecified strictures, neither in our study or previous studies, have shown an association with fatigue [2, 8] The role of stricturing disease behaviour for fatigue remains to be clarified. As expected, the proportion of patients with penetrating disease behaviour was low during the first year after diagnosis but was more frequent among fatigued patients, consistent with prior observational findings [8, 15].
In the IBSEN III study, among patients with IBD in endoscopic remission, chronic fatigue was previously found to be independently associated with infliximab treatment and sleep disturbances [27]. In the current analysis, however, biological therapy was associated with substantial fatigue only in patients with UC. For patients with CD, no such association was observed. In our cohort and in line with treatment guidelines, almost 50% of the patients with CD were currently treated with biologics, while this was only the case for 14% of patients with UC [28, 29]. Hence, the association between fatigue and biological treatment in UC likely reflects a preceding severe disease course. Current evidence suggests that biological therapy may reduce fatigue indirectly by mitigating IBD-related inflammation [2, 30–33].
Approximately 60% of patients with at least one comorbidity reported substantial fatigue at the 1-year follow-up. In CD, comorbidities were independently associated with substantial fatigue regardless of IBD activity and severity. Particularly co-existing psychological problems were of relevance, with almost 80% of these patients experiencing substantial fatigue regardless of IBD subtype. This is consistent with established evidence that depression and anxiety, whether or not comorbid with IBD, are associated with elevated fatigue levels [2, 34, 35].
Consistent with prior studies, female sex was independently associated with substantial fatigue at the 1-year follow-up, regardless of diagnosis [34, 36] As shown in prior IBSEN III publications, sex was no longer significant when analysed alongside self-reported symptoms of anxiety and depression [26, 27]. This may reflect on the sex-related difference in both prevalence and reporting of such symptoms [34, 37, 38].
Our study is not without limitations. A response rate of 43.5% for the Fatigue Questionnaire at both baseline and follow-up introduces the possibility of selection bias. However, the study population was generally representative for the broader IBSEN III cohort, except for age and a higher frequency of hospitalisations, indicating a greater frequency of a more severe disease course among the excluded patients. Further, the missing data on faecal samples and endoscopic examinations for the 1-year follow-up might have led to selection bias. Additionally, because of limitations in the Montreal classification, a non-standardised definition of stricturing disease in CD was used [14, 39] The evaluation of comorbidities in this study is subject to certain limitations, including the reliance on patient-reported data and the consideration of only a restricted number of potential comorbid conditions. Additionally, the classification of professionally treated psychological disorders encompasses a broad array of diagnoses, resulting in an unspecific and less rigorous categorisation.
In conclusion, fatigue may be expected to persevere after one year of disease if present at the time of diagnosis. A more severe disease course and higher symptom burden throughout the first year after diagnosis were associated with substantial fatigue at the 1-year follow-up. Female sex and comorbidities (in CD) were also associated with substantial fatigue, reflecting the relevance of a co-existing burden for the presence of fatigue in patients living with IBD.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgments
The authors would like to thank all members of the IBSEN III study group, including the study nurses, local study personnel and the local principal investigators: A. Sagosen, A. Haslund, C.M. Ystrøm, J. Pallenschat, O. Høie, T. Tønnessen and Ø. Asak who have contributed to the enrolment of patients and collection of patient data in the IBSEN III study. The authors also thank the Unger-Vetlesen Institute for analysing the faecal samples.
Abbreviations
- CF
Chronic fatigue
- CD
Crohn’s disease
- COPD
Chronic obstructive pulmonary disease
- FQ
Fatigue questionnaire
- IBD
Inflammatory bowel disease
- IBSEN III
Inflammatory bowel disease in South-Eastern Norway III
- PROMs
Patient-reported outcome measures
- SF
Substantial Fatigue
- UC
Ulcerative Colitis
Author Contributions
M.L.H, G.H.H, R.O, S.O.F, T.E.D, V.A.K, T.B, L.P.J.J, and K.A.H. conceived and designed the study. M.L.H, G.H.H, R.O, B.C.O, I.J, T.E.D, V.S, M.B.B, T.B.A, R.T, Ø.H, R.B, S.O.F, V.A.K, M.He. and K.A.H. participated in patient data collection. M.Ha., L.P.J.J. and K.A.H. analysed and interpreted the results. T.B, M.He, G.H.H, L.P.J.J. and K.A.H. drafted the manuscript. All authors commented on previous versions of the manuscript and critically reviewed the final version for important intellectual content and provided consent for its publication.
Funding
Open access funding provided by University of Oslo (incl Oslo University Hospital). This work was supported by funding from the Østfold Hospital Trust (Project number AB3526). In addition, the IBSEN III study was supported by an investigator-initiated research grant from Takeda Pharmaceuticals and non-restricted research grants from Ferring Pharmaceuticals, Pfizer, Tillotts Pharma, the Dam Foundation, and the Southeastern Health Authorities in Norway. The funding bodies played no role in the design of the study; collection, analysis, and interpretation of data; or writing of the manuscript.
Data Availability
The data underlying this article cannot be shared publicly due to the privacy of individuals that participated in the study. The data will be shared on reasonable request to the corresponding author.
Declarations
Conflict of interest
T.B, R.O, B.C.O, I.J, M.B.B, T.B.A, R.T, M.Ha, Ø.H, R.B, M.He, G.H.H, L.P.J.J and K.A.H. declare that they have no conflicts of interest. T.E.D: Served as a speaker, consultant or advisory board member for AbbVie, Ferring, Johnson&Johnsen, Pfizer, Pharmacosmos, Takeda, Tillotts, and Vifor Pharma. He has received unrestricted research grants from AbbVie, and Pharmacosmos. S.O.F: Personal fees from Takeda, Galapagos, Jansen-Cilag, Abbvie, Pharmacosmos and Bristol-Myers-Squibb. V.S: Sponsored by funds from Takeda. V.A.K: Consultant for Janssen-Cilag, scientific advisory board and consultant for Takeda, speaker for Thermo Fischer, advisory board for Tillotts Pharma. M.L.H: Investigator-initiated research grants from Takeda, Pfizer, Tilllotts, Ferring and Janssen. Speaker honoraria from Takeda, Tillotts, Ferring, AbbVie, Galapagos, MSD and Meda. Advisory board for Takeda, Galapagos, MSD, Lilly, Janssen, Pfizer and AbbVie.
Ethical approval
The IBSEN III study was approved by the Southeast Regional Committee for Medical and Health Research Ethics (Ref 2015/946–3). Signed informed consent was obtained from all patients before study inclusion, with the possibility to withdraw consent at any point during the observational period.
Footnotes
Publisher's Note
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Associated Data
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Supplementary Materials
Data Availability Statement
The data underlying this article cannot be shared publicly due to the privacy of individuals that participated in the study. The data will be shared on reasonable request to the corresponding author.