Fatigue: The missing target in Crohn’s disease management

Abstract

Treat-to-target strategies have improved mucosal healing in inflammatory bowel disease; however, nearly half of patients in clinical remission still experience disabling fatigue. Morais et al published a study in the World Journal of Gastroenterology demonstrated that biologic treatment success does not necessarily improve patient-reported outcomes and fatigue cannot be explained solely by disease activity or conventional inflammatory biomarkers. A major strength of the study lies in its focus on fatigue as a primary clinical outcome. Although depression, anxiety, stress, and insomnia had limited predictive value individually, their combined assessment increased fatigue risk up to 45-fold. The composite psychological score demonstrated good discriminative performance, supporting its practical use in routine care. Fatigue was also associated with leukocyte alterations, such as relative neutrophilia and lymphopenia/eosinopenia, consistent with stress-related immune activation. No significant associations were found with anemia, nutritional deficiencies, thyroid function, or C-reactive protein, underscoring the multidimensional and largely inflammation-independent nature of fatigue in Crohn’s disease and highlighting the need for a more patient-centered management approach.

Key Words: Inflammatory bowel diseases; Fatigue; Depression; Anxiety; Crohn’s disease

Core Tip: The study by Morais et al suggested that Crohn’s disease management should move beyond controlling inflammation to addressing overall well-being and holistic healing. Fatigue emerges as a persistent, often overlooked symptom that may continue despite mucosal healing and apparent disease control. It should not be considered a nonspecific or secondary complaint but a clinically meaningful outcome with biological and psychological determinants. The use of appropriate hematologic and psychometric assessment tools enables accurate identification of fatigue and its contributors. Integrating these evaluations into routine practice may support a patient-centered approach and ultimately improve the long-term quality of life of patients with Crohn’s disease.

This editorial refers to “Psychological and hematological factors associated with fatigue in patients with Crohn's disease receiving pharmacological treatment” by Morais et al, 2026; https://doi.org/10.3748/wjg.v32.i5.115673.

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INTRODUCTION

We read with great interest the observational study by Morais et al[1] published in the World Journal of Gastroenterology, which investigated the psychological and hematological correlation of fatigue with pharmacologically treated Crohn’s disease (CD). The authors demonstrated that fatigue may persist despite clinical remission and cannot be fully explained by anemia or conventional inflammatory markers. Instead, cumulative psychological symptom burden and distinct leukocyte patterns appear to provide informative insights. These data support the recognition of fatigue as an independent, patient-centered treatment target in CD.

PSYCHOLOGICAL BURDEN: DEPRESSION AND ANXIETY AS FATIGUE DETERMINANTS

In inflammatory bowel disease (IBD), its chronicity, relapsing-remitting course, and requirement for life-long monitoring adversely affect the quality of life (QoL) of patients with these conditions, potentially leading to psychological problems such as anxiety and depression[2]. Fatigue is a common symptom not only in IBD but also in other chronic inflammatory conditions, such as rheumatoid arthritis and multiple sclerosis, and is consistently associated with QoL impairment. In patients with active IBD, approximately 70%-80% report fatigue; however, clinically significant fatigue persists in nearly 40%-50% even during remission[3]. Consistent with these observations, a 2022 systematic review and meta-analysis involving adult patients with IBD reported pooled fatigue prevalence rates of 72% and 47% in those with active disease and in remission, respectively, with an overall prevalence of 47%, highlighting the substantial burden of fatigue despite clinical disease quiescence[4]. Fatigue is more prevalent in CD than in ulcerative colitis; in recent years, it has increasingly been recognized as an extraintestinal manifestation of IBD[5-7].

These rates are markedly higher than the fatigue prevalence of approximately 7% reported in the general healthy population[8]. Despite its high prevalence and clinical effect, fatigue is often insufficiently assessed in routine clinical practice, and clear guidance for its management remains lacking.

In CD, “fatigue” is often perceived by clinicians as a secondary complaint during outpatient visits; however, for patients, it represents one of the most disabling symptoms, profoundly limiting daily functioning and QoL. Patients often assume that symptom relief will follow once abdominal pain, diarrhea, or bleeding resolved, and clinicians may similarly expect QoL improvement once inflammation is suppressed. However, this expectation is frequently unmet in practice. Even in clinical remission, fatigue may persist and become the primary factor that prevents patients from feeling fully well. Therefore, fatigue should not be viewed merely as a reflection of disease activity but as a multidimensional component of disease burden positioned at the intersection of systemic, behavioral, and psychological aspects of CD.

A recent large-scale analysis demonstrated that patients with IBD and concomitant fatigue had nearly twice the hospitalization rates and emergency department visits with those without fatigue. Moreover, the annual healthcare expenditures, including IBD-related direct costs, were considerably higher among patients experiencing fatigue[9].

A comprehensive review indicated the multifactorial etiopathogenesis of fatigue in IBD, which cannot be explained solely by disease activity. Proinflammatory cytokine responses during active inflammation, anemia of chronic disease, micronutrient deficiencies (e.g., iron, vitamin B12, and folate), and malabsorption constitute key biological mechanisms contributing to fatigue. Nevertheless, clinically significant fatigue was reported to persist in a substantial subgroup of patients even after inflammation is controlled and hematinic or micronutrient deficiencies are corrected[10]. This observation presents that non-inflammatory determinants, such as sleep disturbances, pain, psychiatric comorbidities, and physical deconditioning, also play an important role.

One of the most striking findings of Morais et al[1] is the lack of association between fatigue and traditional biochemical explanations. In this study, fatigue in patients with CD persisted independently of anemia, iron deficiency, or inflammatory activity, indicating that fatigue represents a multidimensional symptom linked to psychological and immunological mechanisms, even during clinical remission. Therefore, beyond classical biological explanations, fatigue should be considered a complex process involving intertwined psychological, behavioral, and immune pathways. This study provides original and valuable support for such a multidimensional conceptual framework. Although the study demonstrated that classical explanatory factors (e.g., anemia, iron or vitamin deficiencies, thyroid dysfunction, and routine inflammatory markers) are not always decisive, they also open the following two clinically accessible and highly relevant windows: (1) A composite index capturing cumulative psychological symptom burden; and (2) Leukocyte subpopulation patterns derived from routine complete blood counts.

The study evaluated factors associated with fatigue in 100 outpatients with CD receiving pharmacological treatment. Fatigue was assessed using the IBD-specific IBD fatigue (IBD-F) scale and a visual analog scale, whereas symptoms of depression, anxiety, and stress were evaluated using the 21-tem Depression, Anxiety, and Stress Scale. Insomnia was evaluated separately. The IBD-F captures fatigue’s severity, duration, and effect on daily functioning, enabling a multidimensional and clinically meaningful assessment of fatigue in patients with IBD[11,12].

Laboratory parameters, such as complete blood count, C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), iron indices, vitamin B1 and B12 levels, and thyroid function, were measured shortly after questionnaire administration[13].

Some studies have demonstrated a strong association between fatigue severity and psychological status in patients with CD[13,14]. Depression and anxiety disorders are more prevalent in patients with IBD than in the general population, and these psychiatric conditions can substantially exacerbate patients’ experience of fatigue. For instance, a study found clinically significant fatigue in > 90% of patients with IBD experiencing depressive symptoms[15].

In a large cohort study conducted in Eastern China involving 311 patients, depression was identified as the strongest risk factor for fatigue, in which patients with IBD diagnosed with depression having nearly an eight-fold higher likelihood of experiencing fatigue than those without depression [odds ratio (OR) = 8.1]. In this study, anxiety disorder was also identified as an independent risk factor, which increased the risk of fatigue by approximately 2.4-fold[2].

These findings underscore the profound effect of mental health on fatigue in patients with CD and indicate that nearly all patients with depression experience fatigue. Morais et al[1] not only corroborated the associations between depression, anxiety, and fatigue described in the large cohort investigation by Gong et al[3] but also demonstrated that these relationships persist even in patients with CD in clinical remission. Moreover, by developing a composite psychological symptom index that incorporates depression, anxiety, stress, and insomnia, the authors showed that cumulative psychological burden is a stronger and more clinically meaningful predictor of fatigue than individual symptoms alone. Although clinical practice often focuses on screening for depression or anxiety in isolation, these findings highlight the importance of addressing psychological vulnerability more holistically.

Psychological distress and sleep disturbances consistently emerge as key correlates of fatigue in CD. Using the IBD-F scale, the prevalence of fatigue in the study population was 77%[1]. Notably, 79% of the patients were in clinical remission; however, no significant differences in disease activity were observed between patients with and without fatigue. Given the collinearity among depression, anxiety, stress, and insomnia when entered separately into regression models, a composite symptom score ranging from 0 to 4 was constructed based on the presence of each symptom. This composite score demonstrated a strong association with fatigue, with an OR of 2.60 per additional symptom (95% confidence interval: 1.61-4.83). The model demonstrated good discriminative ability (area under the curve value of 0.775); using a threshold of ≥ 2 symptoms yielded 91.3% specificity and 54.6% sensitivity[1].

Data from the IBD in South-Eastern Norway III cohort, reinforcing the dissociation between disease activity and fatigue, indicated that among patients in endoscopic and/or radiologic remission at 1 year after diagnosis, increasingly stringent remission definitions did not correspond to reduced fatigue levels[16]. Complementing these findings, a large multicenter prospective study from Spain involving > 500 patients reported a fatigue prevalence of approximately 40%, with anxiety and depression emerging as strong independent predictors of fatigue (OR = 2.5). Moreover, fatigue severity demonstrated a close association with psychological distress, sleep disturbance, and presence of extraintestinal manifestations[17]. Notably, sleep disturbance emerged as one of the strongest independent predictors of chronic fatigue in this patient subgroup (OR = 10.40), underscoring the prominent role of non-inflammatory and potentially modifiable factors in fatigue persistence despite objective disease quiescence.

A key methodological strength of this study lies in its use of a composite measure to capture the cumulative burden of depression, anxiety, stress, and insomnia, which often coexist and reinforce one another in clinical practice. This approach effectively addresses collinearity, which often obscures the independent effects of individual symptoms in regression analyses. The finding that a composite score ranging from 0 to 4 robustly predicted fatigue (OR = 2.60; P < 0.001) demonstrates that the presence of multiple concurrent psychological symptoms substantially increases the risk for fatigue in patients with CD. Together, these findings support collective screening and management of psychological symptoms when addressing fatigue. Recent cross-sectional data further demonstrate independent associations between anxiety, depressive symptoms, active disease activity, and fatigue severity, which reinforce the central role of psychological burden in symptom persistence[18].

HEMATOLOGICAL AND IMMUNOLOGICAL MARKERS: REFLECTIONS OF INFLAMMATION

Inflammation is crucially involved in the pathophysiology of fatigue. During active disease, increased proinflammatory cytokine levels may affect the central nervous system, which constitutes the biological basis of fatigue. However, the persistence of significant fatigue even in patients with CD and well-controlled disease suggests that the complexity of this symptom cannot be explained solely by biochemical or inflammatory parameters and that persistent immune activation not captured by conventional markers may be involved.

Morais et al[1] support this concept by demonstrating that fatigue was not associated with anemia, iron deficiency, vitamin B1 or B12 levels, thyroid function, CRP level, or ESR. This finding proposes that fatigue in patients with CD is not merely a consequence of “correctable biological deficiencies” but may involve deeper and more complex mechanisms.

Nevertheless, the finding that patients with higher clinical activity scores report severe fatigue levels, along with positive correlations between fatigue and inflammatory markers such as CRP, ESR, and fecal calprotectin, highlights the relevance of the inflammation-fatigue relationship[9]. Furthermore, patients exposed to chronic high disease activity experience persistently high fatigue levels. Collectively, these findings indicate the crucial role of inflammation in fatigue development; however, it is insufficient as a sole explanatory factor.

Importantly, fatigue often remains unresolved even when CD is in remission. This has led to the hypothesis that subclinical inflammation or ongoing immune dysregulation could play a contributory role in fatigue among a subset of patients in remission. However, several studies evaluating specific inflammatory markers in remissive IBD cohorts did not show consistent associations; for example, some analyses did not detect significant relationships between circulating markers, such as CRP, interleukin-5 (IL-5), IL-8, and IL-12, and fatigue severity in patients with clinically quiescent disease, indicating that simple elevations of proinflammatory cytokine levels alone may not fully explain the presence of persistent fatigue in these settings[17].

The inconsistent evidence regarding circulating cytokines in remissive cohorts may reflect differences in cohort composition (e.g., disease phenotype, treatment exposures, and comorbid sleep or mood disorders), definitions of remission (clinical vs biomarker vs endoscopic), and analytical variability across assay platforms. Such heterogeneity may contribute to discrepant findings and suggests that single-marker approaches may fail to adequately capture the immune-neural pathways underlying fatigue[19].

Additionally, proteomic profiling in large cohorts of patients with quiescent IBD has not revealed a clear subclinical proinflammatory protein signature that distinguishes individuals with and without fatigue, indicating that inflammatory proteins studied to date may not be directly associated with fatigue.

Independent evidence supports the hypothesis that fatigue in remissive IBD may be linked to subtle immune activation. In a well-characterized cohort study by Vogelaar et al[20], patients with IBD in clinical remission experiencing fatigue exhibited significantly high circulating levels of proinflammatory cytokines, such as tumor necrosis factor-α and interferon gamma, along with a Th1-dominant immune profile compared with non-fatigued controls. These findings suggest that fatigue may reflect ongoing immune dysregulation not captured by routine markers such as CRP or ESR in at least a subset of patients. Importantly, this independent cohort demonstrates that fatigue-associated immune alterations are not confined to a single study population, supporting a broader and biologically plausible framework for understanding fatigue in CD.

Nevertheless, the overall evidence remains heterogeneous. Although some studies support the immune activation hypothesis, others have failed to demonstrate significant associations between selected cytokines and fatigue in patients in remission[21]. This inconsistency suggests that fatigue may arise from a sustained, low-grade “alarm state” of the immune system in certain individuals, whereas non-inflammatory mechanisms may predominate in others. Together, these findings underscore the multifactorial and potentially patient-specific nature of fatigue in CD.

In contrast to cytokine-based hypotheses, classical hematological abnormalities remain clinically relevant contributors to fatigue. Among these, anemia remains the most widely recognized and extensively examined factor. Anemia of chronic disease and iron deficiency anemia are common CD complications, and anemia is considered a leading contributor to fatigue[2,22]. In the study by Gong et al[3], patients with IBD and anemia had approximately a 2.5-fold higher risk of experiencing fatigue than those with normal hemoglobin levels (OR = 2.50). Accordingly, occult blood loss and iron deficiency must be evaluated as a first step in the clinical assessment of patients with CD presenting with fatigue.

However, more recent evidence presents that fatigue may be associated not only with classical hematological deficiencies but also with more subtle alterations in immune cell profiles. In the study by Morais et al[1], patients with CD presenting with fatigue exhibited considerably high total leukocyte and neutrophil counts, along with reduced lymphocyte and eosinophil levels. This pattern characterized by relative neutrophilia and lymphopenia was associated with moderate-to-high effect sizes (Cohen’s d = 0.4-0.6), indicating potential clinical and statistical significance.

The identified leukocyte profile is consistent with immune response patterns associated with chronic stress and potential activation of the hypothalamic-pituitary-adrenal axis. Under chronic stress, cortisol-mediated mechanisms may reduce lymphocyte counts while increasing neutrophil proportions, a phenomenon commonly referred to as “stress-related immune activation”. In this context, the observed leukocyte pattern may reflect a sustained systemic stress response or inflammatory burden.

Simple hematological indices, such as the neutrophil-to-lymphocyte ratio, are associated with prognostic outcomes in several chronic diseases and may be indirect markers of inflammatory activity and stress responses. Similarly, high neutrophil-to-lymphocyte ratios in CD may be linked to fatigue. Reduced eosinophil levels may also indicate distinct fatigue-related immune response patterns, such as a Th1-dominant response accompanied by Th2-associated cell suppression. Although data in this context remain limited, the integrated evaluation of hematological and immunological parameters alongside psychological factors may contribute to a more comprehensive understanding of the mechanisms underlying fatigue.

Additionally, these immune alterations do not correspond with classical inflammatory markers, such as CRP or ESR, suggesting the potential association of fatigue in CD with a “silent” or subclinical immune stress state that is not readily detected by standard laboratory tests.

MANAGEMENT OF FATIGUE AND FUTURE RESEARCH DIRECTIONS

Management of fatigue in CD remains an evolving field and should be prioritized in clinical practice and research. The current guidelines recommend that potentially reversible causes should be addressed first in patients with IBD presenting with fatigue[23,24].

From an implementation standpoint, a brief stepwise workflow may help in translating these recommendations into routine care: (1) Systematically screen and quantify fatigue (severity, duration, and functional effect) using a validated tool; (2) Reassess inflammatory control and address reversible contributors (anemia/iron deficiency, micronutrient deficiencies, sleep disorders, medication-related adverse effects, and pain); (3) Evaluate cumulative psychological burden and coping resources and initiate or refer for targeted psychosocial and sleep interventions if fatigue persists in remission; and (4) Support gradual reconditioning with individualized, symptom-contingent physical activity plans.

Specifically, anemia, deficiencies in iron and vitamins B12 and D, active inflammation, medication-related adverse effects (e.g., corticosteroid use), and considerable sleep disturbances should be systematically screened for and treated appropriately. Indeed, corticosteroid discontinuation or immunomodulator dose reduction can alleviate fatigue in some patients, whereas effective disease control with anti-tumor necrosis factor biologic therapies (e.g., infliximab and adalimumab) has been associated with reductions in fatigue symptoms[25,26].

Despite associations of biologic therapies with improvements in patient-reported outcomes, including fatigue, the overall effect size remains modest and heterogeneous across studies in a recent systematic review. This suggests that while reduction in inflammatory burden contributes to symptom improvement, additional psychological, behavioral, and neuroimmune mechanisms likely play a role in persistent fatigue[27]. This reinforces the need to broaden therapeutic targets beyond inflammation alone.

These observations underscore the importance of optimal disease control and avoidance of unnecessary medication burden in mitigating fatigue. Nevertheless, conventional approaches alone are insufficient for all patients, as some continue to experience severe fatigue despite the absence of active inflammation, anemia correction, and management of other apparent contributing factors.

Accordingly, novel strategies are needed for managing fatigue in CD. Psychosocial support is paramount, as psychological status and coping mechanisms strongly influenced fatigue. Patients with depression or anxiety should be referred for psychiatric evaluation, and appropriate interventions, such as cognitive behavioral therapy, should be considered. Similarly, encouraging regular physical activity and implementing graded exercise programs may be beneficial, as physical inactivity can perpetuate a vicious cycle that exacerbates fatigue.

Evidence for non-inflammatory interventions in IBD-related fatigue remains heterogeneous; however, a recent systematic review and meta-analysis including 11 studies reported a small-to-moderate but significant reduction in fatigue with non-pharmacological approaches (standardized mean difference approximately 0.33) compared with usual care[28]. These interventions included cognitive behavioral strategies, psychoeducation, problem-solving therapy, and structured exercise programs. Despite the modest effect sizes, the findings support the clinical relevance of integrating behavioral and rehabilitative strategies alongside inflammatory control.

Importantly, fatigue assessment and access to multidisciplinary management (including psychology, sleep medicine, physiotherapy, and social support) vary across patient populations. In real-world practice, fatigue evaluation and management are shaped by not only biological factors but also social determinants of health, such as access to care, health literacy, socioeconomic conditions, and psychosocial support. Inequities in specialist access and care delivery may influence the systematic measurement of patient-reported outcomes and prompt referral to multidisciplinary interventions, potentially widening QoL gaps despite achieving inflammatory targets. Therefore, implementing standardized fatigue screening and scalable, low-resource care pathways, such as structured sleep and psychological screening, graded activity guidance, and remote or hybrid psychoeducational programs, may help promote equity and ensure meaningful translation of research findings into clinical practice[29-31].

Although psychosocial and behavioral strategies remain central to fatigue management, emerging biological interventions have also been explored in selected CD phenotypes. For instance, hyperbaric oxygen therapy (HBOT) has shown sustained clinical and radiologic benefits in patients with therapy-refractory perianal fistulizing disease in the HOT-TOPIC trial, where 40 treatment sessions were associated with improvement at 1-year follow-up[32]. Experimental and translational data further suggest that HBOT ameliorates intestinal and systemic inflammation by modulating gut microbiota dysbiosis and immune signaling pathways[33]. Although HBOT is not currently included in routine clinical guidelines and its direct effect on fatigue has not been established, its immunomodulatory and metabolic rationale warrants further controlled studies evaluating both fistula healing and systemic and patient-reported outcomes, including fatigue.

Future research should focus on identifying reliable biomarkers of fatigue in CD. The combined approach proposed in this study may represent a practical tool for identifying patients at a high risk of fatigue. Such composite risk scores should be validated in independent cohorts and refined for clinical application. Further investigation into the gut-brain axis mechanisms is also warranted. Emerging evidence presents that gut microbiota alterations, chronic low-grade inflammation, autonomic nervous system dysregulation, and structural or functional changes in the central nervous system may contribute to the pathogenesis of fatigue.

In patients with persistent fatigue despite clinical remission, advanced approaches, such as neuroimaging and microbiome analyses, may help uncover the underlying hidden triggers of fatigue. Ultimately, these efforts may guide the development of treatments that target both symptoms and underlying mechanisms of fatigue.

In recent literature, fatigue has increasingly been highlighted as an underrecognized issue. Ananthakrishnan et al[9] emphasized that fatigue affects up to 60% of patients with IBD, characterizing it as an unmet need in clinical care. Similarly, a 2024 review study[10] proposed a new paradigm for understanding the pathogenesis of fatigue by advocating for the investigation of the gut-brain axis mechanisms and neuroimmune interactions in addition to the classical risk factors.

Such perspectives underscore that fatigue affects not only the daily lives of patients with CD but also the long-term disease trajectories, making it a critical area of focus for both clinicians and researchers.

CONCLUSION

Fatigue in CD is not merely an extension of inflammation but represents an independent disease burden that may persist even during remission, substantially impairing patients’ QoL and functional capacity. The high prevalence of fatigue (77%) observed in the cohort studied by Morais et al[1], together with its lack of consistent association with classical markers, such as disease activity indices, CRP, ESR, or anemia and iron deficiencies, compels clinicians to adopt a broader evaluative perspective. The most practical implication of this work is that integrating an assessment of cumulative psychological symptom burden (depression, anxiety, stress, and insomnia) with routine hematological findings may represent a low-cost and clinically feasible approach for identifying patients at an increased risk of fatigue.

Accordingly, fatigue should be systematically incorporated into longitudinal disease monitoring within a patient-centered “treat-to-impact” framework that aligns therapeutic success with not only inflammatory control but also patients’ lived experience and functional well-being. Effective management extends beyond inflammation suppression and requires structured evaluation of psychological distress, sleep disturbances, and physical deconditioning within a multidisciplinary care model.

Future work should prioritize multicenter validation of composite psychological-hematological risk models, longitudinal studies clarifying causal mechanisms, and pragmatic intervention trials integrating behavioral and immunomodulatory approaches.

Importantly, disparities in access to multidisciplinary care, mental health services, and structured rehabilitation programs may influence the assessment and management of fatigue in real-world practice. Ensuring equitable implementation of fatigue screening and supportive interventions is essential to translate emerging evidence into meaningful clinical benefit.