Fatigue in inflammatory bowel disease: Mechanisms, assessment, and management strategies

Abstract

Fatigue is among the most prevalent and disabling symptoms in inflammatory bowel disease (IBD), affecting a substantial proportion of patients during active disease and persisting in many despite clinical remission. It is multidimensional, spanning physical, cognitive, and emotional domains, and it is a major determinant of health-related quality of life, work disability, and healthcare use. Correlations with conventional markers of intestinal inflammation are typically modest, indicating important contributions from extraintestinal, neuroimmune, nutritional, endocrine, sleep-related, and psychological mechanisms. This article is a narrative review with a structured literature synthesis, rather than a formal scoping review. The core search covered MEDLINE/PubMed, Embase, and the Cochrane Library from January 2010 to October 31, 2024, with targeted citation updates added during revision for recently finalized publications. Compared with recent broad reviews, the present manuscript adds three specific elements: explicit differentiation of evidence derived from primary randomized trials, prespecified patient-reported outcome analyses, and post hoc fatigue analyses; an updated synthesis of fatigue data for newer advanced therapies, particularly IL-23 and JAK-pathway agents; and a pragmatic biopsychosocial assessment-and-management framework with specific discussion of Arabic-language patient-reported outcome implementation and Middle East/North Africa practice considerations. Available evidence supports a stepwise clinical approach: First assess inflammatory activity and disease control; then screen systematically for reversible contributors including iron deficiency, other micronutrient deficits, endocrine abnormalities, sleep disorders, pain, mood disturbance, sarcopenia, and deconditioning. Validated instruments such as the Inflammatory Bowel Disease-Fatigue (IBD-F) questionnaire and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale are useful for serial monitoring. A clinically meaningful FACIT-Fatigue improvement appears to be context-specific; across IBD studies, approximately 6–10 points have the strongest empirical support, while trial-specific thresholds should be reported as originally prespecified. Biologic and targeted synthetic therapies can improve fatigue, but fatigue has rarely been a primary endpoint in pivotal trials. Anti-tumor necrosis factor agents, vedolizumab, ustekinumab, JAK inhibitors, and IL-23 inhibitors have all shown beneficial effects on fatigue-related outcomes, although the evidentiary strength varies from primary trial data to exploratory post hoc analyses. Nonpharmacological strategies including intravenous iron when indicated, exercise and rehabilitation, optimization of sleep and pain, and cognitive-behavioral or mindfulness-based interventions remain essential. Fatigue should therefore be recognized as a core manifestation of IBD and incorporated into routine patient-reported outcome assessment and treat-to-target discussions.

INTRODUCTION

Fatigue in inflammatory bowel disease (IBD) is commonly defined as a persistent, overwhelming sense of tiredness or exhaustion that is disproportionate to recent activity and insufficiently relieved by rest.[1] It affects physical, cognitive, and affective domains and is consistently ranked by patients as one of the most distressing aspects of living with IBD, often exceeding the burden of pain or diarrhea.[2,3,4] Fatigue substantially reduces health-related quality of life (HRQoL), contributes to absenteeism and presenteeism, and is associated with disability, social withdrawal, and increased healthcare utilization.[2,3,4]

Historically, therapeutic targets in IBD focused predominantly on intestinal inflammation, including symptomatic remission, biomarker normalization, and mucosal healing. STRIDE-II broadened this framework by recognizing patient-reported outcomes, including fatigue and HRQoL, as important long-term treatment targets.[5] Despite this shift, routine fatigue assessment remains inconsistent, and management is often ad hoc, particularly when disease appears to be in remission.

Several recent reviews have summarized the epidemiology and pathophysiology of IBD-related fatigue, particularly the comprehensive 2024 review by Truyens and colleagues.[6] The incremental contribution of the present review is threefold: First, we distinguish more explicitly between fatigue findings derived from primary efficacy trials, prespecified secondary or patient-reported outcome analyses, and exploratory post hoc analyses; second, we integrate newer fatigue-related data for advanced therapies, including mirikizumab, risankizumab, and upadacitinib, together with their interpretive limitations; and third, we present a pragmatic clinical framework that links biopsychosocial assessment to management, while expanding the discussion of regional implementation issues relevant to Arabic-language practice environments and the Middle East/North Africa (MENA) region.

The review therefore aims to provide a clinically usable synthesis of the epidemiology, mechanisms, assessment, and management of fatigue in adults and children with IBD, while remaining transparent about quality of evidence and current knowledge gaps.

METHODS

This manuscript is a narrative review informed by a structured literature synthesis and should not be interpreted as a formal scoping review. A structured search was undertaken in MEDLINE (via PubMed), Embase, and the Cochrane Library for publications, from January 2010 to October 31, 2024, using combinations of the terms “inflammatory bowel disease,” “Crohn’s disease,” “ulcerative colitis,” “fatigue,” “tiredness,” “vitality,” “quality of life,” and related mechanism- or therapy-specific keywords. During peer-review revision, targeted citation updates were added for final publication details and newly available fatigue-focused papers were judged especially relevant to advanced therapy outcomes and psychometric interpretation.

Eligible publications included randomized controlled trials, prospective and retrospective cohort studies, cross-sectional studies, translational mechanistic studies, and systematic or narrative reviews that reported fatigue, vitality, or closely related patient-reported outcomes in Crohn’s disease, ulcerative colitis, or unclassified IBD. Adult and pediatric data were considered, although the evidence base remains adult-dominant. Case reports and studies in which fatigue was only mentioned without systematic assessment were not prioritized.

Since the aim of this study was to produce a clinically oriented narrative synthesis, no PRISMA-ScR flow diagram, duplicate screening workflow, protocol registration, or formal risk-of-bias instrument was undertaken. Instead, the review explicitly differentiates the type of evidence supporting each major therapeutic claim, and comments narratively on important sources of bias, including confounding in observational studies and multiplicity in post hoc analyses. Readers should therefore interpret this article as a structured narrative review rather than a comprehensive evidence map.

For practical transparency, we classified evidence qualitatively as follows: Level I, randomized interventional studies or prespecified analyses from controlled trials; Level II, prospective cohorts, controlled nonrandomized studies, and robust longitudinal observational analyses; and Level III, cross-sectional studies, retrospective cohorts, mechanistic studies without clinical endpoints, expert consensus, and post hoc exploratory analyses. Table 1 applies this framework to major management domains. Figures in this manuscript are schematic and conceptual; they are not quantitative syntheses or data-derived meta-analytic visualizations.

Table 1.

Practical management domains for IBD-related fatigue and corresponding evidence level

Management domain	Representative approach	Evidence level	Interpretation
Optimize inflammatory control	Escalate or optimize IBD therapy when objective disease activity is present.	Level I	Supported by randomized trial programs showing fatigue improvement in treatment responders, although fatigue is rarely the primary endpoint.
Iron deficiency/anemia	Prefer intravenous iron when deficiency is clinically important, particularly with active inflammation or poor oral tolerance.	Level I	One of the strongest fatigue-targeted interventions in IBD-specific trials.[7,8]
Micronutrient/endocrine correction	Replace specific deficiencies; evaluate thyroid, cortisol, or testosterone when clinically indicated.	Level II-III	Clinically important and biologically plausible, but fatigue-specific trial data are more limited.
Sleep and pain management	Treat insomnia, sleep apnea, medication-related sleep disruption, and chronic pain.	Level II-III	Evidence is mixed and often extrapolated; nevertheless these domains are highly modifiable drivers of fatigue.
Psychological therapies	CBT, mindfulness-based interventions, coping-based programs, digital or hybrid psychological care.	Level II	Benefit most likely in patients with concurrent anxiety, depression, illness distress, or maladaptive activity patterns.[9,10]
Exercise and rehabilitation	Low- to moderate-intensity aerobic exercise with progressive resistance training when feasible.	Level II	Small heterogeneous trials, but consistent signal toward improved fatigue and physical function.[11,12]
Diet/microbiome strategies	Optimize intake, address symptom triggers, and consider dietitian input.	Level III	Mechanistically plausible but currently supported by limited fatigue-specific evidence.
Routine fatigue monitoring	Measure IBD-F or FACIT-Fatigue serially to support shared decision-making and follow-up.	Level II-III	Psychometric and implementation evidence is growing, but this remains incompletely standardized across settings.

Evidence level definitions: Level I=randomized interventional or prespecified controlled-trial evidence; Level II=prospective or controlled observational evidence; Level III=cross-sectional, retrospective, mechanistic, consensus, or post hoc exploratory evidence

EPIDEMIOLOGY AND CLINICAL BURDEN

Prevalence and patterns

Multiple population-based and clinic cohorts demonstrate that fatigue is extremely common in IBD. Approximately half of unselected adults report clinically significant fatigue, with prevalence rising during active disease and remaining substantial even in clinical or biochemical remission.[2,6,13,14,15] This persistence indicates that fatigue is not merely an epiphenomenon of overt flare activity.

The distinction between “active disease” and “remission” also depends on the definition used. Many remission cohorts are defined by symptom scores or biomarkers rather than by endoscopic or histological healing, so residual inflammatory activity may still contribute in some patients.[2,5,6,13] At the same time, the weak-to-moderate association between fatigue and standard inflammatory markers indicates that noninflammatory mechanisms are often equally important.

Risk factors and special populations

Reported risk factors include female sex, younger age at diagnosis, extraintestinal manifestations, corticosteroid exposure, sleep disturbance, iron deficiency, malnutrition, sarcopenia, endocrine dysfunction, anxiety, and depressive symptoms.[14,15,16,17,18,19,20,21] In practice, these factors frequently cluster rather than occurring in isolation. Corticosteroids, for example, may worsen sleep, contribute to metabolic dysfunction, and accentuate muscle loss, thereby amplifying fatigue through several pathways simultaneously.[19,20,21]

Pediatric data are more limited than adult data but suggest that fatigue is also common and clinically relevant in children and adolescents, with consequences for school participation, physical activity, and psychosocial development.[2,6] Older adults may face additional contributors, including frailty, multimorbidity, polypharmacy, and reduced physiological reserve. Pregnancy represents another clinically important context because fatigue may be magnified by increased iron requirements, sleep disruption, and anxiety about medication exposure and disease control.

Consequences for quality of life and function

Fatigue is strongly associated with lower HRQoL, worse IBD-specific quality-of-life scores, reduced work productivity, and greater healthcare use.[2,3,4] Importantly, fatigue often correlates more closely with mood, sleep quality, and subjective disease burden, than with C-reactive protein, fecal calprotectin, or endoscopic activity.[2,3,4,6,22] This pattern supports a multidimensional assessment strategy rather than a purely inflammatory model.

PATHOPHYSIOLOGY OF FATIGUE IN IBD

Fatigue in IBD arises from a complex interaction of inflammatory, neuroimmune, metabolic, nutritional, endocrine, sleep-related, behavioral, and psychosocial factors. Figure 1 summarizes this conceptual model. Figure 2 further organizes the pathophysiology of IBD-related fatigue into upstream drivers, central mediators, and clinical expression.

Figure 1.

Conceptual model of IBD-related fatigue. This schematic figure is not data-derived; it summarizes interacting inflammatory, neuroimmune, metabolic, nutritional, endocrine, sleep-related, and psychological pathways that can converge on physical, cognitive, and emotional fatigue

Figure 2.

Multidimensional pathophysiology of IBD-related fatigue. This schematic organizes upstream drivers, central mediators, and the physical, cognitive, and emotional expression of fatigue in IBD

Inflammatory cytokines and neuroimmune mechanisms

Proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1beta induce a stereotyped “sickness behavior” response characterized by fatigue, reduced motivation, anhedonia, and altered sleep.[20,23,24] Cytokine signaling through humoral, neural, and endothelial pathways can affect monoaminergic neurotransmission, hypothalamic-pituitary-adrenal axis regulation, and reward circuitry, thereby sustaining fatigue even after overt gastrointestinal symptoms improve.[23,24,25,26]

Gut–brain axis, autonomic dysfunction, and microbiome alterations

The bidirectional gut–brain axis integrates immune, neural, endocrine, and microbial signals. Intestinal inflammation and dysbiosis may increase epithelial permeability, drive systemic immune activation, and alter autonomic balance, while reduced short-chain fatty acid production and altered microbial metabolism may influence central nervous system signaling and resilience.[6,27,28,29] Neuroimaging studies in IBD also suggest altered activation of limbic and fatigue-related networks in symptomatic patients.[26,30]

Tryptophan-kynurenine metabolism

Inflammation upregulates indoleamine-2,3-dioxygenase pathways that divert tryptophan away from serotonin synthesis toward kynurenine metabolites with neuroactive properties.[3,23,31] This mechanism is biologically plausible in IBD and has been supported by disease-specific work showing links between tryptophan metabolism and persistent fatigue, including a randomized trial of 5-hydroxytryptophan supplementation in quiescent IBD.[32] The pathway remains promising but is not yet ready for routine clinical use as a biomarker or treatment target.

Hematologic, nutritional, and endocrine factors

Iron deficiency, with or without overt anemia, is one of the most clinically actionable biological drivers of fatigue in IBD.[7,8] Iron is essential for mitochondrial energy production, muscle oxygen handling, and neurotransmitter synthesis. Other micronutrient deficiencies, including vitamin D, vitamin B12, folate, zinc, and thiamine deficiency, may contribute, while hypothyroidism, adrenal suppression, and hypogonadism can further worsen fatigue and reduced physical capacity.[14,25,33]

Sleep disorders, sarcopenia, and deconditioning

Poor sleep is highly prevalent in IBD and may both reflect and worsen disease burden.[21,34] Insomnia, sleep fragmentation, restless legs symptoms, and obstructive sleep apnea can amplify daytime exhaustion, pain sensitivity, and low mood. Chronic inflammation, inadequate nutrition, reduced activity, and corticosteroid exposure also contribute to sarcopenia and deconditioning, which worsen physical fatigue and may reinforce central fatigue through inflammatory and metabolic mechanisms.[20,21]

Evidence directly linking resistance training to reversal of IBD-specific sarcopenia-associated fatigue remains limited. Existing exercise studies support benefit for fatigue and physical function more broadly, but targeted interventional data in sarcopenic IBD subgroups are still an evidence gap that deserves prospective study.

Psychological and behavioral factors

Depression, anxiety, illness uncertainty, catastrophising, and low self-efficacy can strongly amplify fatigue and often explain more variance in fatigue severity than inflammatory markers alone.[16,23,35] Behavioral patterns such as overexertion on good days followed by prolonged inactivity may perpetuate deconditioning and symptom vigilance. These interactions make fatigue an archetypal biopsychosocial symptom.

Integrated pathways

No single mechanism explains fatigue in all patients with IBD. Rather, individual patients typically have several partially overlapping drivers, which is why a systematic and multimodal clinical approach is needed.

ASSESSMENT OF FATIGUE

Fatigue assessment should be deliberate, repeated over time, and incorporated into routine review rather than relying on casual questioning. Figure 3 outlines a practical clinical algorithm. A stepwise clinical assessment-and-management workflow is provided in Figure 4.

Figure 3.

Practical assessment and management algorithm for fatigue in IBD. This schematic figure is intended as a clinical workflow, not a quantitative evidence map. It emphasizes parallel assessment of inflammatory activity, reversible biological factors, sleep and mood, physical deconditioning, and follow-up fatigue measurement

Figure 4.

Stepwise clinical assessment-and-management workflow for fatigue in IBD. The algorithm emphasizes parallel screening, integration of findings, and a four-pillar management bundle with repeated fatigue measurement

Step 1: Evaluate disease activity

Clinicians should first assess whether fatigue is occurring in the context of active intestinal inflammation or apparent remission. This usually includes symptom indices, inflammatory biomarkers, and when indicated in endoscopy or imaging.[5,6] Although fatigue may improve when inflammation is controlled, persistence after apparent remission should prompt investigation of additional contributors.

Step 2: Screen for reversible biological contributors

A focused workup commonly includes full blood count, ferritin, iron studies, vitamin B12, folate, vitamin D, thyroid-stimulating hormone, and other tests guided by symptoms or treatment history. Medication review is essential, particularly for opioids, sedating agents, or corticosteroids. Depending on the clinical picture, targeted endocrine assessment, sleep evaluation, or nutritional review may be warranted.[7,8,33,21]

Step 3: Screen for psychological and sleep comorbidity

Brief tools such as PHQ-9 and GAD-7 can help identify depression and anxiety, while directed questioning about insomnia, snoring, nonrestorative sleep, restless legs, pain, and activity limitation can uncover modifiable comorbidity.[9,16,21,23,35]

Step 4: Measure fatigue with a validated instrument

The IBD-F questionnaire is disease-specific and captures both fatigue severity and impact on daily life.[36] FACIT-Fatigue is widely used in clinical trials and increasingly in practice; higher scores indicate less fatigue. One important clarification, raised by peer review, is that there is no single universally applicable threshold for a “clinically meaningful” FACIT-Fatigue improvement across all IBD settings. In mixed CD/UC psychometric work, meaningful within-person change has ranged approximately from 4 to 9 points in UC and 7 to 10 points in CD,[37] whereas VIVID-1 analyses in active CD support a 6–9 point threshold.[22] For practical interpretation in this review, we therefore describe clinically meaningful change as context-specific and report the trial-specific threshold when available rather than imposing one universal cutoff.

Arabic-language versions of FACIT-Fatigue are available, and the instrument has demonstrated good psychometric performance in Arabic-speaking oncologic populations.[38] However, formal validation specifically in Arabic-speaking IBD populations remains limited. A dedicated Arabic-language validation study for IBD-related fatigue should therefore be considered a research priority and a prerequisite for broader regional implementation.

MANAGEMENT STRATEGIES

Management of IBD-related fatigue requires a multidimensional, biopsychosocial approach. In most patients, successful management combines optimization of intestinal disease control with targeted treatment of reversible extraintestinal contributors and structured self-management support.

Optimizing inflammatory disease control

When fatigue accompanies active inflammation, optimization or escalation of IBD therapy is the first priority. This recommendation is supported by Level I evidence because fatigue often improves in responders across biologic and small-molecule trials, even though fatigue is rarely the primary endpoint.[5,39,40,41,42,43,44,45,46,47]

Correction of iron deficiency and other biological factors

Iron deficiency and anemia should be addressed proactively. Intravenous iron is generally preferred for patients with active inflammation, moderate-to-severe deficiency, poor tolerance of oral iron, or when rapid repletion is desired. This is among the strongest fatigue-directed interventions in IBD and is supported by Level I trial evidence.[7,8] Correction of other micronutrient deficits and endocrine abnormalities is also clinically important, although the supporting fatigue-specific evidence is more often Level II-III than Level I.[14,25,33]

Sleep, pain, and psychological interventions

Sleep optimization, treatment of sleep apnea or insomnia where present, medication timing adjustment, and multimodal pain management can meaningfully improve fatigue burden. The evidence base here is mixed: It includes observational IBD data, extrapolation from other chronic conditions, and smaller intervention studies, corresponding mainly to Level II-III evidence.[9,21]

Psychological interventions deserve particular attention because fatigue clusters strongly with distress and coping burden. Cognitive-behavioral therapy, mindfulness-based interventions, and combined programs such as COBMINDEX can improve fatigue, coping, and quality of life, particularly in selected patients with high baseline psychological burden.[9,10] Although access remains variable, digital and hybrid delivery models may improve feasibility.

Exercise and rehabilitation

Structured low- to moderate-intensity aerobic activity, with or without resistance training, appears safe in most patients with stable IBD and can improve fatigue, conditioning, and HRQoL.[11,12] The evidence is best characterized as Level II because trials are generally small and heterogeneous, but the consistency of benefit supports routine recommendation with appropriate individualization.

Diet and microbiome-directed strategies

Dietary management should aim to ensure adequate energy, protein, and micronutrient intake and to reduce symptom triggers that impair sleep, mood, or daily functioning. Microbiome-directed strategies remain mechanistically attractive, but robust fatigue-specific trial evidence is limited; this domain currently remains Level III.[27,29,48]

Special biological populations

Children and adolescents may require earlier integration of school support, family-centered counseling, dietetics, and mental health care. In pregnancy, proactive screening for iron deficiency, sleep disturbance, and anxiety is important, alongside maintenance of disease control. In older adults, fatigue frequently intersects with frailty, sarcopenia, cardiopulmonary comorbidity, and polypharmacy, therefore interventions should be individualized to preserve function and minimize adverse events.

Regional implementation considerations in the Middle East and North Africa

The MENA region is experiencing a rising IBD burden, yet structured fatigue assessment remains underdescribed in regional practice.[49,50] Expanding fatigue-focused care in this setting is likely to require more than instrument translation alone. Pragmatic barriers may include variable clinic time, limited multidisciplinary staffing, uneven access to psychologists or sleep services, stigma around discussing fatigue and mental health, differing levels of health literacy, and variable digital access among older or socioeconomically disadvantaged patients.

Regional registries and electronic patient-reported outcome platforms may help close this gap, and recent work describing the IBD Middle East Registry illustrates both the opportunities and the governance, infrastructure, and data-quality challenges involved in building multicountry systems.[50] In practical terms, a regional research agenda should prioritize validation of Arabic-language fatigue instruments in IBD, implementation studies of brief clinic-based screening workflows, and integration of fatigue outcomes into existing registry and quality-improvement initiatives.

BIOLOGIC AND TARGETED SYNTHETIC THERAPIES AND FATIGUE

Biologic and targeted synthetic therapies are central to modern IBD management and can improve fatigue in parallel with disease control. However, a key methodological point is that fatigue has seldom served as the primary endpoint in pivotal IBD trials. As a result, fatigue literature spans a spectrum from prespecified patient-reported outcome analyses within randomized trials to exploratory post hoc analyses and real-world observational data. These evidence types should not be interpreted as equivalent.

Anti-TNF agents such as infliximab and adalimumab have the longest clinical track record and improve fatigue in many responders, although residual fatigue commonly persists after inflammatory control.[39] Vedolizumab and ustekinumab also improve patient-reported wellbeing and quality-of-life domains, with fatigue-related benefit most often inferred from HRQoL or vitality measures rather than fatigue-specific primary analyses.[40,41,42]

JAK-pathway inhibition has yielded particularly clear fatigue-related signals in ulcerative colitis and Crohn’s disease, but the evidentiary context differs by study. In ulcerative colitis, upadacitinib fatigue data derive from a post hoc analysis of phase 3 trials, which showed statistically significant and clinically meaningful FACIT-Fatigue improvement versus placebo.[43] In Crohn’s disease, upadacitinib fatigue and work-productivity findings were reported in a dedicated analysis of phase 3 induction and maintenance trials, supporting early and sustained benefits.[47] Tofacitinib also improves HRQoL in ulcerative colitis, although fatigue-specific evidence is less direct and often based on vitality or related patient-reported domains rather than dedicated fatigue endpoints.[44]

Among IL-23 inhibitors, mirikizumab and risankizumab have strengthened the evidence base for fatigue outcomes in Crohn’s disease. In VIVID-1, mirikizumab improved fatigue-related outcomes versus placebo, and a subsequent dedicated fatigue analysis showed higher rates of clinically meaningful FACIT-Fatigue improvement at Weeks 12 and 52, together with stronger correlations between fatigue improvement and patient-reported quality-of-life measures than with endoscopic or laboratory indices.[22,45,51] Across the ADVANCE, MOTIVATE, and FORTIFY programs, risankizumab likewise improved HRQoL and fatigue-related outcomes during induction and maintenance.[46]

These findings are clinically important, but they also require interpretive caution. Post hoc analyses are vulnerable to multiplicity, selective emphasis, and the absence of fatigue-specific randomization or powering. Even prespecified patient-reported outcome analyses remain secondary to the main efficacy objectives of most trials. Accordingly, the appropriate conclusion is that advanced therapies can meaningfully improve fatigue, but comparative claims between classes remain uncertain and should not be overstated. Table 2 summarizes this evidence and explicitly identifies the evidentiary status of each fatigue signal. Figure 5 provides a complementary visual summary of advanced-therapy fatigue evidence and its evidentiary status.

Table 2.

Selected fatigue-related evidence for advanced therapies in IBD, with explicit distinction between primary trial evidence, prespecified patient-reported outcomes, and post hoc analyses

Therapy/class	Population	Evidence status	Main fatigue message	Key limitation
Anti-TNF agents	CD/UC	Randomized trials and post hoc analyses (Level I/III)	Consistent improvement in fatigue, vitality, and HRQoL among treatment responders.[39]	Fatigue usually secondary/exploratory; residual fatigue remains common after inflammatory response.
Vedolizumab	UC	Prespecified HRQoL analyses from phase 3 trials; some real-world PRO data (Level I/II)	Improves HRQoL and related vitality/energy domains, supporting likely fatigue benefit.[40,41]	Fatigue often inferred from HRQoL/vitality rather than dedicated fatigue endpoints or FACIT-Fatigue.
Ustekinumab	CD	Prespecified PRO analyses within randomized and long-term studies (Level I/II)	Meaningful improvement in patient-reported well-being and HRQoL accompanies clinical response.[42]	Dedicated fatigue-specific endpoints remain limited.
Tofacitinib	UC	Phase 3 HRQoL analyses; fatigue evidence largely indirect or exploratory (Level I/III)	Improves HRQoL and vitality-related domains during induction and maintenance.[44]	Less direct fatigue evidence than for upadacitinib; fatigue often not measured as a standalone endpoint.
Upadacitinib	UC	Post hoc analysis of phase 3 program (Level III exploratory within RCT dataset)	Clinically meaningful FACIT-Fatigue improvement versus placebo during induction and maintenance.[43]	Fatigue analysis was post hoc and vulnerable to multiplicity.
Upadacitinib	CD	Dedicated phase 3 PRO/fatigue analysis from induction and maintenance trials (Level I/II)	Improved fatigue as early as Week 4, with sustained benefit through maintenance.[47]	Still secondary to primary efficacy objectives; not powered around fatigue alone.
Mirikizumab	CD	Phase 3 trial plus dedicated fatigue analysis and psychometric follow-up (Level I/II)	Higher proportions achieved clinically meaningful FACIT-Fatigue improvement at Weeks 12 and 52 versus placebo.[22,45,51]	Fatigue was important but not the primary efficacy endpoint of VIVID-1.
Risankizumab	CD	Prespecified HRQoL/fatigue-related analyses from phase 3 program (Level I/II)	Improved HRQoL and fatigue-related outcomes across induction and maintenance studies.[46]	Interpretation depends on patient-reported secondary endpoints rather than a fatigue-primary design.

CD, Crohn’s disease; UC, ulcerative colitis; HRQoL, health-related quality of life; PRO, patient-reported outcome. Fatigue was not the primary efficacy endpoint in the studies summarized above

Figure 5.

Visual summary of advanced-therapy fatigue evidence in IBD, organized by therapy/class, population, and evidentiary status. This figure is intended as a structured evidence overview rather than a comparative effectiveness analysis

FUTURE DIRECTIONS

Key priorities include better phenotyping of fatigue, identification of biomarkers that track fatigue burden more closely than conventional inflammatory indices, and development of trials in which fatigue is a prespecified and clinically meaningful endpoint rather than an optional exploratory outcome.[3,6,22,31,37] Mechanistic targets of interest include kynurenine-pathway metabolites, autonomic measures, sleep metrics, and wearable-derived behavioral phenotypes.

Future work should also address understudied groups and settings: pediatric populations, pregnancy, postsurgical patients, sarcopenic patients, and populations from the MENA region and other historically under-represented settings. Persistent fatigue after colectomy, stoma formation, or other major IBD surgery is particularly understudied and may involve distinct physiological and psychological mechanisms deserving separate investigation.

Digital health tools offer opportunities for repeated fatigue assessment and remote delivery of behavioral support, but implementation must account for alert fatigue, clinic workflow burden, digital exclusion, and uneven access to smartphones or reliable internet. Any future application of artificial intelligence or machine-learning approaches should also recognize that training data from MENA populations remain limited, raising concerns about representativeness and transportability of predictive models.

CONCLUSION

Fatigue is a pervasive, multidimensional, and clinically important manifestation of IBD that cannot be understood solely through conventional inflammatory disease activity measures. It emerges from interacting inflammatory, neuroimmune, metabolic, nutritional, endocrine, sleep-related, and psychosocial pathways, and it remains common even when bowel disease appears quiescent.

Effective care therefore requires systematic assessment, transparent evidence grading, and a structured biopsychosocial management strategy. Optimization of disease control, correction of iron deficiency and other biological abnormalities, screening for sleep and mood disorders, rehabilitation, and targeted psychological support are all relevant. Advanced therapies can improve fatigue, but the fatigue evidence they generate must be interpreted according to whether it comes from primary trial endpoints, prespecified patient-reported outcome analyses, or post hoc exploratory work.

Recognizing fatigue as a core outcome – and measuring it routinely with validated tools such as IBD-F or FACIT-Fatigue – will bring IBD care closer to the outcomes patients identify as most meaningful: the ability to function, work, participate socially, and live well despite chronic disease.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.