Fatigue and mood disorders are highly prevalent in patients with inflammatory bowel disease: a single‐centre, cross‐sectional study using patient‐reported outcomes

Abstract

Background

Fatigue is a common and debilitating symptom in inflammatory bowel disease (IBD), yet it remains under‐recognised in clinical practice. This study aimed to quantify fatigue among Australian patients with IBD and examine associations with disease control, psychological distress and quality of life (QoL).

Methods

We conducted a cross‐sectional study of adult patients with IBD at a tertiary centre. Participants completed four validated questionnaires: Functional Assessment of Chronic Illness Therapy‐Fatigue, IBD‐Control 8, Short Inflammatory Bowel Disease Questionnaire and Hospital Anxiety and Depression Scale. Associations between fatigue and other patient‐reported outcomes were analysed, and multivariate regression identified independent predictors of fatigue.

Results

Of 1179 patients invited, 327 (28%) participated; 166 (51%) had Crohn disease, 152 (46%) ulcerative colitis and nine (3%) IBD‐unclassified. Severe fatigue was reported in 46% of participants. Depression and anxiety were present in 29% and 41% of patients respectively. Fatigue was significantly associated with poorer disease control and QoL (P < 0.0001). On multivariate analysis, independent predictors of fatigue included depressive symptoms (β = −1.03, P < 0.0001), anxiety (β = −0.41, P = 0.003), reduced disease control (β = 0.70, P < 0.0001) and lower QoL (β = 0.23, P = 0.0006). Notably, in a subgroup of 55 patients (17%) with well‐controlled disease, fatigue remained strongly linked with psychological distress and impaired QoL.

Conclusion

Fatigue is highly prevalent in IBD and persists even among patients with good disease control. Psychological distress, poor disease control and reduced QoL are independently associated with fatigue, underscoring the need for routine screening and multidisciplinary management.

Introduction

Fatigue is a highly prevalent and debilitating symptom in patients with inflammatory bowel disease (IBD) including both ulcerative colitis (UC) and Crohn disease (CD). As a chronic, relapsing, inflammatory condition, IBD presents with a range of gastrointestinal symptoms, including abdominal pain and diarrhoea, alongside significant extra‐intestinal manifestations. Among these, fatigue is frequently cited as one of the most burdensome symptoms, impacting up to 87% of patients. ¹ , ² Unlike general tiredness, fatigue is characterised by a persistent lack of energy that is disproportionate to physical activity, unrelieved by rest and often accompanied by emotional and cognitive impairments. ³

Despite its prevalence and impact, fatigue remains under‐recognised and poorly managed in clinical practice. ⁴ Fatigue is closely linked to psychological comorbidities such as depression, anxiety and sleep disturbances, which may exacerbate its severity. ⁵ , ⁶ Consequently, it can have significant impacts on a person's quality of life (QoL) and occupational and social functioning. ¹ Importantly, fatigue is not always limited to periods of active disease but persists in a significant proportion of patients even during clinical remission. ⁷

Patient‐reported outcome measures (PROMs) are vital in the holistic assessment of patients with IBD as they capture aspects of disease burden that are not evident through traditional biomarkers of inflammation. ⁸ This is especially important for subjective symptoms such as fatigue, anxiety and depression. Several validated PROMs are available and are often recommended by regulatory authorities as primary endpoints for clinical trials. ⁹ , ¹⁰ Notably, since fatigue can occur in both active and quiescent phases of disease, PROMs may provide a more patient‐centred assessment, offering insight into what truly impacts a patient's QoL.

Given the impact of fatigue, enhancing our understanding can help guide allocation of resources and improve the lives and overall outcomes for this patient population. This study aims to identify the burden of fatigue in Australian patients and the factors associated with it.

Methods

This cross‐sectional study was conducted at a single Australian metropolitan tertiary IBD centre. Inclusion criteria included any patient aged >18 years with a diagnosis of IBD. All patients with IBD who were under active care at Austin Health up to October 2024 were invited to participate in the study. For the purposes of study analysis, IBD‐unspecified patients were rolled into the UC cohort.

Data collection

Participants were asked for responses to four validated questionnaires including the Functional Assessment of Chronic Illness Therapy‐Fatigue (FACIT‐F), Short Inflammatory Bowel Disease Questionnaire (SIBDQ), the Hospital Anxiety and Depression Scale (HADS) and IBD‐Control 8 survey. ¹¹ , ¹² , ¹³ , ¹⁴ Invitations were distributed via email using RedCAP. ¹⁵ , ¹⁶ These were matched to existing records in the institutional IBD database to collate demographic and disease‐related data.

Questionnaires

• The FACIT‐F is a validated tool designed to assess fatigue in patients with chronic illnesses, including IBD. ¹¹ It measures the intensity and impact of fatigue on daily functioning and QoL. The questionnaire includes 13 items scored on a five‐point scale, addressing aspects such as ability to perform activities, energy levels and tiredness. A score of <30 indicates severe fatigue.

• The SIBDQ evaluates health‐related QoL specifically in patients with IBD. ¹³ It consists of 10 items that assess four domains: bowel symptoms, emotional health, systemic symptoms and social functioning. Responses are scored on a seven‐point scale, with higher scores indicating better QoL. A score of <60 is consistent with a reduced QoL.

• The HADS is used as a screening tool for detecting anxiety and depression in hospitalised patients but is also validated for patients with IBD. ¹⁴ It includes 14 items – with seven questions for anxiety and seven for depression, scored on a four‐point scale. It is designed to exclude physical symptoms, focusing instead on psychological distress. A score of >8 indicates anxiety or depression.

• The IBD‐Control 8 is a brief PROM assessing disease control in IBD. ¹² It comprises eight items focusing on symptom severity, impact on daily life, overall disease control and well‐being. A higher score indicates better disease control, with a score of ≥13 indicating quiescent disease. ¹⁷

Statistical analysis

Summary data are presented as n (%) for categorical variables. Mean (standard deviation) or median (interquartile range (IQR)) are used for continuous normally distributed or non‐normally distributed variables respectively. Univariate comparisons utilised the Student t ‐test or Mann–Whitney U test for continuous comparisons, and the chi‐square test was used for categorical comparisons. Pearson correlation coefficient was used to estimate the strength of correlated continuous variables. Multivariate linear and logistic regression techniques were used to identify those factors independently associated with degree of fatigue. A P value on univariate analysis of <0.2 was used to specify the multivariate model before progression with stepwise elimination. A two‐sided P value of 0.05 was considered statistically significant.

Ethics

Participation in the study was entirely voluntary, and implied consent was provided upon participants submitting their responses. Approval was obtained from the ethics committee of the Victorian Translational Research Institute. The study met the requirements of the National Statement on Ethical Conduct in Human Research.

Results

Cohort characteristics

A total of 1179 patients were invited to complete the study, of whom 327 (28%) patients responded and were included in the analysis. The median age was 49 years (IQR: 36–59 years), and 54% were female. The cohort included 166 (51%) patients with Crohn disease (CD), 152 (46%) with ulcerative colitis (UC) and nine (3%) with IBD‐unclassified (IBD‐U). The median disease duration was 11 years (IQR: 5–21 years). IBD‐related treatments varied across the cohort: 95 (29%) were receiving 5‐aminosalicylates (5‐ASA), 116 (35%) thiopurines, 39 (12%) methotrexate and 25 (7%) allopurinol; 218 (67%) were receiving advanced therapies.

When stratified by disease subtype, patients with CD were more likely to be treated with thiopurines (41% vs 30%, P = 0.04), methotrexate (18% vs 5.6%, P < 0.001) and advanced therapies (78% vs 55%, P < 0.001) compared with those with UC/IBD‐U. Conversely, patients with UC/IBD‐U were more frequently treated with 5‐ASA (55% vs 4.2%, P < 0.001).

In terms of advanced therapies, the CD subgroup had 129 (78%) advanced therapies recorded, with the most used being infliximab (57 (44%)), ustekinumab (35 (27%)) and adalimumab (24 (19%)). Among the 89 (55%) patients with UC/IBD‐U taking advanced therapies, 30 (34%) were taking infliximab and 24 (27%) were taking vedolizumab, followed by upadacitinib (13 (15%)) and tofacitinib (four (4.5%)). Age and sex distribution were similar between groups.

Among 161 (49%) patients with UC/IBD‐U, disease extent based on the Montreal classification was predominantly extensive colitis E3 with 75 (47%) patients, followed by left‐sided colitis E2 with 51 (32%) and proctitis E1 with 18 (11%) patients. For patients with CD, 103 (62%) were diagnosed between the ages of 17 and 40 years. Disease location was similar, with ileal (L1), colonic (L2) and ileocolonic (L3) present in 52 (31%), 54 (33%) and 52 (31%) patients respectively. Nonstricturing/nonpenetrating (B1) phenotype predominated with 115 (69%) patients. Perianal disease was reported in 65 (39%) patients. Table 1 gives an overview of the cohort.

Table 1.

Cohort overview

Characteristic	Overall (N = 327†)	CD (n = 166†)	UC/IBD‐U (n = 161†)	P value‡
Demographics
Age	49 (36, 59)	51 (36, 59)	47 (35, 58)	0.2
Female	176 (54)	90 (54)	86 (53)	0.9
Male	151 (46)	76 (46)	75 (47)	0.9
IBD type
CD	166 (51)	166
UC/IBD‐U	161 (49)		161
Disease duration in years	11 (5, 21)	12 (5, 22)	9 (5, 19)	0.5
Duration unknown	54	30	24
Medication use
5‐ASA	95 (29)	7 (4)	88 (55)	<0.001
Thiopurines	116 (35)	68 (41)	48 (30)	0.035
Allopurinol	25 (7)	15 (9)	10 (6)	0.3
Methotrexate	39 (12)	30 (18)	9 (5)	<0.001
Advanced therapy use	218 (67)	129 (78)	89 (55)	<0.001
Adalimumab		24 (19)	2 (2)
Etrasimod		0 (0)	1 (1)
Infliximab		57 (44)	30 (34)
Tofacitinib		0 (0)	4 (4)
Upadacitinib		9 (7)	13 (15)
Ustekinumab		35 (27)	15 (17)
Vedolizumab		4 (3)	24 (27)
CD montreal classification
Age at diagnosis
A1 (≤16 years)		16 (10)
A2 (17–40 years)		103 (62)
A3 (>40 years)		47 (28)
Location
L1 (ileum)		52 (31)
L2 (colon)		54 (33)
L3 (ileocolon)		52 (31)
L2/L3/L4 + L4 only		8 (5)
Behaviour
B1 (non‐stricturing)		115 (69)
B2 (stricturing)		30 (18)
B3 (penetrating)		21 (13)
Perianal disease		65 (39)
UC/IBD‐U montreal classification
Extent
E1 (proctitis)			18 (11)
E2 (left‐sided colitis)			51 (32)
E3 (extensive colitis)			75 (47)
Unknown			17§ (10)

^†Median (interquartile range); n (%).

^‡Wilcoxon rank sum test; Pearson chi‐squared test.

^§Due to patients with prior diagnoses who transferred care without accompanying documentation. 5‐ASA, 5‐aminosalicylates; CD, Crohn disease; IBD, inflammatory bowel disease; IBD‐U, inflammatory bowel disease‐unclassified; UC, ulcerative colitis.

Patient‐reported disease control

In terms of disease control, the median IBD‐8 score was 14 (IQR: 10–17), with scores ranging from 2 to 18. An IBD‐8 score of ≥13 indicates patients with quiescent disease. ¹⁷ A total of 203 (62%) patients had good control, suggesting that, overall, the majority of patients felt that their disease was well controlled (Fig. 1). When stratified by subgroups, UC/IBD‐U and CD groups had similar median scores (14 vs 14, P = 0.6). Patients with UC/IBD‐U (n = 97, 60%) and CD (n = 106, 64%) reported well‐controlled disease, indicating that perceived disease control was generally comparable between these two subgroups.

Figure 1.

IBD‐Control 8 scores (disease control) for all patients.

Fatigue, anxiety and depression were highly prevalent in the cohort

The median FACIT‐Fatigue score was 32.0 (IQR: 23.0–43.3), with 46% of participants classified as experiencing severe fatigue (FACIT‐F <30). The median scores for HADS‐Depression (HADS‐D) and HADS‐Anxiety (HADS‐A) were 5.0 (IQR: 2.0–8.0) and 7.0 (IQR: 3.0–10.0) respectively. Based on threshold scores, 29% screened positive for depression and 41% for anxiety. The SIBDQ score, which reflects IBD‐specific QoL, had a median of 50.0 (IQR: 42.0–58.0). Using the identified cut‐off of SIBDQ <60, 82% of patients were classified as having impaired QoL.

Fatigue, anxiety and depression were (strongly) correlated with patient‐reported clinical disease control

IBD‐Control 8 scores were significantly associated with patient‐reported fatigue, QoL and symptoms of anxiety/depression across the cohort (Fig. 2). Higher IBD‐Control 8 scores had a moderately strong association with reduced fatigue, as measured by the FACIT‐F score (P < 0.0001, r = 0.5). Similarly, better disease control correlated with improved QoL, with a robust relationship observed between IBD‐Control 8 and SIBDQ scores (P < 0.0001, r = 0.6). In terms of psychological well‐being, greater disease control was associated with lower levels of both depression and anxiety. There were moderately strong negative correlations between IBD‐Control 8 scores and both HADS‐D (P < 0.0001, r = 0.3) and HADS‐A (P < 0.0001, r = 0.3) scores.

Figure 2.

IBD‐Control 8 scores (disease control) compared with FACIT‐F, SIBDQ and HADS scores for all patients. FACIT‐F, Functional Assessment of Chronic Illness Therapy‐Fatigue; HADS, Hospital Anxiety and Depression Scale; SIBDQ, Short Inflammatory Bowel Disease Questionnaire.

Together, these findings highlight that better reported disease control is significantly linked to lower fatigue, improved QoL and lower rates of anxiety and depression in patients with IBD.

Depression, anxiety, disease control and QoL are independently associated with worsening fatigue severity

A multiple linear regression model was specified to identify independent predictors of fatigue, as measured by the FACIT‐F score (Table 2). The final model included psychological symptoms (HADS‐D and HADS‐A scores), disease control (IBD‐Control 8) and health‐related QoL (SIBDQ).

Table 2.

FACIT‐F as a continuous variable – multivariate linear regression

Parameter	Variable	Estimate	95% CI	P value
β1	HADS D score	−1.03	−1.34 to −0.72	<0.0001
β2	HADS A score	−0.41	−0.67 to −0.14	0.003
β3	IBD‐Control 8 Score	0.70	0.38–1.01	<0.0001
Β4	SIBDQ score	0.23	0.098–0.35	0.0006

CI, confidence interval; FACIT‐F, Functional Assessment of Chronic Illness Therapy‐Fatigue; HADS, Hospital Anxiety and Depression Scale; SIBDQ, Short Inflammatory Bowel Disease Questionnaire.

Higher depressive symptom burden by the HADS‐D score was significantly associated with greater fatigue (β = −1.03, P < 0.0001), indicating a positive relationship between depression and fatigue severity. Anxiety (HADS‐A) also showed a significant association (β = −0.41, P = 0.003). Better disease control (IBD‐Control 8 score) was significantly associated with less fatigue (β = 0.70, P < 0.0001), as was better QoL (SIBDQ) (β = 0.23, P = 0.0006).

A multivariate logistic regression model was also performed to identify independent predictors of severe fatigue (Table 3). In keeping with the previous analysis, greater depressive symptoms were strongly associated with greater odds of severe fatigue (odds ratio (OR): 1.52 (95% confidence interval (CI): 1.36–1.71); P < 0.001). Better perceived disease control was independently associated with reduced odds of severe fatigue (OR: 0.77 (95% CI: 0.70–0.85); P < 0.001). Gender also emerged as an independent predictor, with males having significantly lower odds of severe fatigue compared with females (OR: 0.39 (95% CI: 0.20–0.75); P = 0.005).

Table 3.

FACIT‐F dichotomised as severe fatigue or not – logistic regression model (entire cohort)

Characteristic	OR	95% CI	P value
HADS‐D	1.52	1.36–1.71	<0.001
IBD‐Control 8	0.77	0.70–0.85	<0.001
Sex
Female	2.53	1.34–4.92	0.005
Male	0.39	0.20–0.75	0.005

CI, confidence interval; FACIT‐F, Functional Assessment of Chronic Illness Therapy‐Fatigue; HADS, Hospital Anxiety and Depression Scale; OR, odds ratio.

Fatigue burden remains high despite good reported disease control

A total of 203 (62%) patients reported adequate disease control, as defined by an IBD‐8 score of ≥13. ¹⁷ Compared with patients with poor disease control (n = 124, 38%), those with good control had significantly better scores across all patient‐reported outcomes.

Among patients with good disease control, severe fatigue was reported by 55 (27%) individuals. This group of patients had significantly worse psychological outcomes and QoL compared with those without severe fatigue (Table 4). Specifically, patients with severe fatigue had higher anxiety (HADS‐A: 9 vs 3, P < 0.0001) and depression scores (HADS‐D: 7 vs 2, P < 0.0001) and lower SIBDQ scores (49 vs 58, P < 0.0001).

Table 4.

Good disease control: Severe fatigue versus no severe fatigue

	Severe fatigue (n = 55†)	No severe fatigue (n = 148†)	P value‡
HADS‐A	9 (6–12)	3 (1–6)	<0.0001
HADS‐D	7 (5–10)	2 (1–4)	<0.0001
SIBDQ	49 (43–54)	58 (53–62)	<0.0001

^†Median (interquartile range); n (%).

^‡Wilcoxon rank‐sum test; Pearson chi‐squared test. HADS, Hospital Anxiety and Depression Scale; SIBDQ, Short Inflammatory Bowel Disease Questionnaire.

A multivariable logistic regression model was used to identify factors independently associated with severe fatigue among patients with good disease control (Table 5). Higher HADS‐D scores (OR: 1.52 (95% CI: 1.26–1.85), P < 0.0001) and HADS‐A scores (OR: 1.16 (95% CI: 1.01–1.34), P = 0.03) were associated with increased odds of severe fatigue. In contrast, higher SIBDQ scores were seen to have lower odds of fatigue (OR: 0.89 (95% CI: 0.82–0.96), P = 0.003).

Table 5.

FACIT‐F as a dichotomous variable – logistic regression model (good disease control cohort)

Characteristic	OR	95% CI	P value
HADS‐D	1.515	1.26–1.85	<0.0001
HADS‐A	1.16	1.01–1.335	0.03
SIBDQ	0.89	0.82–0.96	0.003

CI, confidence interval; FACIT‐F, Functional Assessment of Chronic Illness Therapy‐Fatigue; HADS, Hospital Anxiety and Depression Scale; OR; odds ratio; SIBDQ, Short Inflammatory Bowel Disease Questionnaire.

Discussion

Fatigue is increasingly recognised as one of the most burdensome symptoms experienced by patients with inflammatory bowel disease irrespective of clinical disease control. ¹⁸ In our Australian IBD cohort, nearly half (46%) of the participants reported severe fatigue, a finding which aligns with similar studies where fatigue rates are reported from 24% to 87%. ¹ , ⁵ , ¹⁹ , ²⁰ , ²¹ Specifically, an Australian study showed that 57% of CD and 47% of UC patients self‐reported excessive fatigue. ²¹ Importantly, our results demonstrate that fatigue is prevalent even in individuals with self‐reported, well‐controlled disease.

In line with a recent systematic review, our findings indicate that psychological distress is a strong independent predictor of fatigue. ¹ Both depression and anxiety were significantly associated with higher fatigue scores, a relationship consistently demonstrated across multiple studies. ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ Furthermore, our identification of female sex as an independent predictor of severe fatigue concurs with findings highlighted by Uhlir et al. ²⁵ Improved disease control was also linked to lower fatigue levels, reflecting observations from Huppertz‐Hauss et al. and Bager et al., who found that perceived symptom burden correlates closely with fatigue severity. ²⁴ , ²⁶ Similarly, we observed a strong association between fatigue severity and impaired QoL, consistent with findings by Chavarria et al. ²⁷

It is important to recognise that fatigue in IBD may arise from a variety of possible mechanisms. One possible explanation is that these patients have subclinical disease activity that is not evident on routine clinical assessment, but possibly detectable via biochemical or endoscopic evaluation. Another is that fatigue may represent a manifestation that is independent from the disease itself. Apart from psychological comorbidities and inflammation, Borren et al. highlight that the mechanism of fatigue is not uniform in all patients, and other contributing factors such as nutritional deficiency and altered metabolism can play a role. ⁵ In order to address fatigue in this setting, different interventions should be utilised to target the varying factors. ⁵

In our cohort, a notable proportion (17%) of patients with well‐controlled disease still reported significant fatigue. This subgroup of patients and their fatigue scores were significantly associated with psychological distress, perceived disease control and QoL. Patients with severe fatigue had significantly higher depression and anxiety scores, as well as markedly lower QoL when compared with their non‐fatigued counterparts. This reinforces the concept that fatigue is not solely driven by IBD‐related symptoms but has a complex, multifactorial pathophysiology. Even in the absence of clinically active inflammatory symptoms, psychosocial factors appear to play a central role in fatigue severity, highlighting that mental health is a hidden burden in IBD. Unsurprisingly, psychological distress was identified in 50% of Australian patients with IBD from a cross‐sectional study, with many not having access to the appropriate mental health care. ²⁸ However, these findings are only associations and do not establish causation. While psychological distress may contribute to fatigue, the reverse may also be true. Fatigue itself can negatively affect mood, anxiety levels and perceived QoL. As such, addressing fatigue directly, regardless of disease activity, may have the potential to positively impact psychological well‐being and QoL.

Several limitations of this study should be acknowledged. First, the study relied on self‐reported data collected through online surveys, which introduces the potential for response bias. Response to the surveys was optional and the results may differ from those who did not respond. This may lead to a possible over‐representation of individuals who are more engaged with their care or more symptomatic, thereby limiting the generalisability of our findings. Additionally, the response rate was relatively low (28%), raising the risk of non‐response bias. However, within the IBD cohort, other large studies report response rates between 31% and 59%, with one of the main barriers being digital literacy. ²⁹ , ³⁰ , ³¹ Our response rates were consistent with these. Finally, the FACIT‐F survey is a validated tool to assess fatigue in patients with IBD. However, direct comparison with previous studies using different fatigue‐specific tools may be limited.

Conclusion

Fatigue remains a highly prevalent and debilitating symptom among patients with inflammatory bowel disease, even in those with well‐controlled disease. Our findings highlight its significant association with psychological distress, QoL and disease activity. Fatigue is complex and multifactorial, and recognising the different contributors is essential for clinicians to develop tailored management strategies. This is particularly important in those with quiescent disease, as severe fatigue can still be present. Addressing fatigue directly, regardless of disease activity, may have a meaningful impact on patients' psychological well‐being and QoL. Future studies should focus on developing evidence‐based, targeted interventions to better support patients experiencing this burdensome symptom.

Data availability statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.