Wu Z, Huang ZW, Cao ZJ, Sun Y, Zhao XX, Xu WF, Chen SL, Zhang Y, Zhao SL. Risk factors and fatigue in difficult-to-treat Crohn’s disease: A cross-sectional study of a Chinese cohort. World J Gastroenterol 2026; 32(26): 118595 [DOI: 10.3748/wjg.118595]
Corresponding Author of This Article
Shu-Liang Zhao, MD, PhD, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, No. 160 Pujian Road, Pudong New Area, Shanghai 200001, China. zhaosl@sjtu.edu.cn
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Wu Z, Huang ZW, Cao ZJ, Sun Y, Zhao XX, Xu WF, Chen SL, Zhang Y, Zhao SL. Risk factors and fatigue in difficult-to-treat Crohn’s disease: A cross-sectional study of a Chinese cohort. World J Gastroenterol 2026; 32(26): 118595 [DOI: 10.3748/wjg.118595]
Zhi Wu, Zhi-Wei Huang, Zhi-Jun Cao, Ying Sun, Xin-Xian Zhao, Wen-Fang Xu, Sheng-Liang Chen, Shu-Liang Zhao, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai 200001, China
Yue Zhang, Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
Co-corresponding authors: Yue Zhang and Shu-Liang Zhao.
Author contributions: Wu Z drafted the article; Wu Z and Huang ZW performed the data analyses and contributed to the visualization as co-first authors; Wu Z, Cao ZJ, Chen SL, Zhang Y, and Zhao SL revised the article; Cao ZJ, Chen SL, and Zhao SL designed and supervised the study; Cao ZJ, Zhang Y and Zhao SL contributed to funding acquisition; Sun Y, Zhao XX and Xu WF collected the data; Zhang Y and Zhao SL contributed to statistical and analytic support as co-corresponding authors; and all authors have read and approved the final manuscript.
Supported by “Science and Technology Innovation Action Plan” Medical Innovation Research Project of Shanghai Municipal Science and Technology Commission, No. 22Y11907900.
Institutional review board statement: The study’s protocol was reviewed and approved by the Ethics Committee of Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital (No. LY2025-003-B).
Informed consent statement: Ethical approval for this retrospective cohort study was obtained with a waiver of informed consent.
Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.
STROBE statement: The authors have read the STROBE Statement – checklist of items, and the manuscript was prepared and revised according to the STROBE Statement – checklist of items.
Data sharing statement: Data are available upon reasonable request.
Corresponding author: Shu-Liang Zhao, MD, PhD, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, No. 160 Pujian Road, Pudong New Area, Shanghai 200001, China. zhaosl@sjtu.edu.cn
Received: January 8, 2026 Revised: February 4, 2026 Accepted: April 2, 2026 Published online: July 14, 2026 Processing time: 175 Days and 9.8 Hours
Abstract
BACKGROUND
Fatigue is a prevalent and debilitating symptom in Crohn’s disease (CD). Recently, an international consensus proposed operative definitions for difficult-to-treat (DTT) inflammatory bowel disease. However, the risk factors for DTT-CD in the Chinese population and the relationship between fatigue and DTT-CD criteria remain unexplored.
AIM
To investigate the risk factors for DTT-CD in a Chinese cohort and investigate its association with fatigue.
METHODS
This single-center retrospective cohort study enrolled 175 CD patients from 2018 to 2024. DTT-CD was defined according to the consensus criteria of the International Organization for the Study of Inflammatory Bowel Diseases. Clinical characteristics, laboratory data, and fatigue assessed by the Multidimensional Fatigue Inventory were analyzed. Logistic and linear regression models were used to identify risk factors for DTT-CD and factors associated with fatigue.
RESULTS
Overall, 51.4% of patients met at least one DTT-CD criterion, with complex perianal disease being the most common (75.6%). Independent risk factors for DTT-CD included longer disease duration [odds ratio (OR) = 1.095, P = 0.014]; elevated interleukin (IL)-5 (OR = 2.715, P = 0.002) and IL-10 (OR = 1.234, P = 0.045); higher hemoglobin (OR = 1.025, P = 0.016); and need for partial enteral nutrition (PEN) (OR = 2.940, P = 0.017). DTT-CD patients had significantly higher mental fatigue scores than non-DTT-CD patients (P = 0.036). Among DTT-CD patients, fatigue was independently associated with partial enteral nutrition, diagnosis at age > 40 years, and surgical history. Factors related to the diagnosis of DTT-CD, such as complex perianal fistula and the number of treatment mechanisms, were not associated with fatigue across the total patient cohort.
CONCLUSION
DTT-CD, predominantly marked by complex perianal disease, is highly prevalent in these patients. Elevated IL-5 and IL-10 suggest a distinct immunophenotype in Chinese DTT-CD patients. Fatigue is associated with specific clinical features in DTT-CD patients.
Core Tip: This study applied the international difficult-to-treat (DTT) inflammatory bowel disease criteria to a Chinese cohort of Crohn’s disease (CD) patients. There was a high prevalence of DTT-CD, primarily driven by complex perianal disease. We identified elevated serum interleukin-5 and interleukin-10 as independent risk factors for DTT-CD even after adjustment for disease activity, suggesting a distinct immunophenotype. DTT-CD was associated with a significantly higher level of mental fatigue.
Citation: Wu Z, Huang ZW, Cao ZJ, Sun Y, Zhao XX, Xu WF, Chen SL, Zhang Y, Zhao SL. Risk factors and fatigue in difficult-to-treat Crohn’s disease: A cross-sectional study of a Chinese cohort. World J Gastroenterol 2026; 32(26): 118595
Crohn’s disease (CD), one of the phenotypes of inflammatory bowel disease (IBD), is a chronic and inflammatory gastroenterological disease[1,2]. Many IBD patients have symptoms that persist despite optimal treatment, a condition often termed difficult-to-treat (DTT)-IBD, which necessitates additional management approaches[3-5]. The lack of a consensus definition, however, remains a major obstacle to advancing research and comparing outcomes among studies. Parigi et al[6] convened an international consensus meeting to establish an operative definition for DTT-IBD. Through a formal voting process on 20 proposed statements (≥ 75% agreement threshold), an operative definition for DTT-IBD was established[6]. The agreed-upon definition encompasses: (1) Failure of treatment with biologics or advanced small molecules with at least two different mechanisms of action; (2) Postoperative recurrence of CD following two surgical resections in adults, or one in children; (3) Chronic antibiotic-refractory pouchitis[7]; (4) Complex perianal diseases[8]; and (5) Significant psychosocial comorbidities that directly impede effective disease management. A recent retrospective study identified the prevalence and risk factors of DTT-IBD in two tertiary centers in Italy, and found that several subtypes of the Montreal classification were risk factors for DTT-IBD[9]. However, significant knowledge gaps persist. The epidemiological, clinical and immunological profile of DTT-CD in Asian populations is poorly characterized, and it is uncertain whether the patterns observed in western cohorts can be generalized.
Fatigue is a troublesome, multidimensional and debilitating symptom that is associated with a wide variety of chronic illnesses[10]. Chronic fatigue is more prevalent in IBD patients, occurring in nearly 50% of cases. CD patients tend to experience more severe fatigue than patients with ulcerative colitis[11,12]. The relationship between DTT-IBD and fatigue remains unclear. Its pathophysiology is multifactorial, involving inflammatory activity, anemia, sleep disturbance, and psychosocial factors. Although fatigue is recognized as a core driver of impaired quality of life in IBD[13,14], its prevalence, severity and determinants within the newly defined DTT-IBD population are entirely unknown. It remains unclear whether fatigue is independently associated with the criteria that define DTT disease, such as multiple treatment failures or complex perianal disease.
To address these evidence gaps, this study aimed to: (1) Characterize the prevalence, clinical phenotype, and immunological profile of DTT-CD in a Chinese cohort; and (2) Specifically investigate the burden and correlates of fatigue within this DTT-CD patient subgroup.
MATERIALS AND METHODS
Patients
The single-center study was conducted at Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital. Patients diagnosed with CD and aged > 14 years were enrolled from 2018 to 2024.
Perianal disease was classified as simple or complex based on the American Gastroenterological Association criteria[8]. A fistula is considered simple if it meets all of the following criteria: (1) It is low (superficial, or low intersphincteric, or low trans-sphincteric); (2) It has a single external opening; (3) It presents without pain or fluctuance indicating a perianal abscess; and (4) There is no evidence of a rectovaginal fistula or an anorectal stricture. A fistula is classified as complex if it exhibits a high origin (high inter-asphincteric, trans-asphincteric, extra-asphincteric, or supr-asphincteric) or has multiple external openings. It may also be associated with one or more of the following: (1) Pain or fluctuance indicative of a perianal abscess; (2) Rectovaginal fistula; (3) Anorectal stricture; and (4) Active rectal disease observed on endoscopy. Pelvic magnetic resonance imaging fistula and endoscopy reports were used to determine whether a patient had complex perianal disease.
Clinical characteristics such as disease duration, Montreal classification, anal fistula, previous CD-related surgery, enteral nutrition, and type of medication were investigated. Social demographic data such as marital status were recorded. Laboratory data such as hemoglobin, interleukin (IL), C-reactive protein, vitamins, folate, ferritin, tumor necrosis factor (TNF) and trace elements were also determined. Disease activity was measured by CD Activity Index (CDAI). The clinical remission criterion used in this study was CDAI < 150. Mild, moderate and severe disease activity were equivalent to CDAI 150-220, 220-450 and > 450, respectively[15]. Patients with these levels of disease activity were consolidated into the active disease group.
Multidimensional Fatigue Inventory
The Multidimensional Fatigue Inventory (MFI) is a self-report questionnaire to evaluate fatigue that consists of five dimensions: (1) General fatigue (GF); (2) Physical fatigue (PF); (3) Mental fatigue (MF); (4) Reduced activity (RA); and (5) Reduced motivation (RM). Each subscale contains four items. The total MFI score ranges from 20 to 100. A higher score indicates higher fatigue level[16]. A Chinese version of MFI has been validated. MFI-20 demonstrated good internal consistency, with a Cronbach’s alpha of 0.84[17]. Patients who were unable to complete the questionnaire and whose diagnosis was uncertain were excluded.
Statistical analysis
Descriptive statistics were used to present demographic data. Categorial variables were presented as n (%) and were compared using the χ2 test. The normality of all continuous variables was assessed using the Shapiro-Wilk test. For normally distributed data, results are presented as mean ± SD, and comparisons between groups were performed using Student’s t-test or analysis of variance. The mean difference was derived from the t-test or analysis of variance results. For nonnormally distributed data, results are presented as median with interquartile range, and comparisons were performed using the nonparametric Mann-Whitney U test or Kruskal-Wallis test. Logistic regression analysis was conducted to calculate odds ratios (ORs). Univariate and multivariable linear regression analyses were conducted to calculate coefficients and evaluate the factors independently associated with fatigue. All analyses were performed using SPSS version 27.0. A two-sided P < 0.05 was considered statistically significant.
RESULTS
Demographic data
The study included 175 CD patients, and 90 (51.4%) met at least one criterion for DTT-IBD (Table 1)[18]. Most of them were in accordance with the 2003 American Gastroenterological Association criteria for complex perianal disease (n = 68; 75.6%). Forty-three patients (47.8%) met the criteria for failure of treatment with biologics or small molecules with at least two different mechanisms of action. One patient (1.1%) experienced disease recurrence following two CD-related intestinal resections. No cases of chronic antibiotic-refractory pouchitis or coexisting psychosocial issues were identified. Although the difference in disease course between DTT-CD and non-DTT-CD patients did not reach significance (mean difference = 1.62, P = 0.057), it suggested a trend toward a longer duration in the DTT-CD group. DTT-IBD patients had a significantly higher MF score than non-DTT-CD patients (mean difference = 1.00, P = 0.032). The complete demographic and disease characteristics are provided in Supplementary Table 1[18].
Table 1 Characteristics of patients with difficult-to-treat Crohn’s disease and non difficult-to-treat Crohn’s disease, n (%)/mean ± SD/ median (interquartile range).
Multiple regression analysis revealed only one subtype of Montreal classification that was significantly associated with DTT-CD. Combined invasion of the terminal ileum and upper gastrointestinal (GI) tract (L1 + L4) was a significant risk factor for developing DTT-CD (OR = 6.443; 95%CI: 1.011-41.081; P = 0.049). No other Montreal classification subtypes showed a significant association. Multiple regression analysis identified other independent risk factors for DTT-CD. Longer disease duration was significantly associated with increased risk (OR = 1.095, 95%CI: 1.018-1.178; P = 0.014). Higher serum levels of IL-5 (OR = 2.715, 95%CI: 1.457-5.058; P = 0.002) and IL-10 (OR = 1.234, 95%CI: 1.005-1.515; P = 0.045) were also independent risk factors. Elevated serum hemoglobin (OR = 1.025, 95%CI: 1.005-1.047; P = 0.016) and partial enteral nutrition (PEN) (OR = 2.940, 95%CI: 1.209-7.153; P = 0.017) were significantly associated with a higher risk of DTT-CD (Table 2).
Table 2 Multivariable logistic regression analysis of risk factors for difficult-to-treat Crohn’s disease.
Given the association of IL and hemoglobin with disease activity, disease activity was adjusted for in the model to isolate the independent association of these biomarkers with the outcome (Table 3). IL-5, IL-10 and hemoglobin remained independently associated with DTT-CD, even after adjustment for disease activity in the regression model [adjusted OR (aOR) = 2.656; 95%CI: 1.421-4.964; P = 0.002; aOR = 1.255; 95%CI: 1.011-1.558, P = 0.040 and aOR = 1.023; 95%CI: 1.002-1.045, P = 0.035, respectively]. Even after controlling for disease activity, disease duration and PEN remained independently associated with DTT-CD (aOR = 1.096; 95%CI: 1.016-1.182, P = 0.018 and aOR = 2.858; 95%CI: 1.165-7.014, P = 0.022, respectively). However, the association for combined terminal ileum and upper GI involvement (L1 + L4) did not retain statistical significance in the adjusted analysis (aOR = 6.032, 95%CI: 0.954-38.135; P = 0.056).
Table 3 Results of a multivariable logistic regression analysis examining risk factors for difficult-to-treat Crohn’s disease.
Multiplevariable linear regression analysis of MFI and its subscales in DTT-CD patients
Multiplevariable linear regression analysis was conducted to identify factors independently associated with fatigue in DTT-CD (Table 4). PEN was independently associated with higher total MFI, GF, PF and RM scores (b = 7.023, 95%CI: 0.240-13.806, P = 0.043; b = 2.286, 95%CI: 0.534-4.038, P = 0.011; b = 2.087, 95%CI: 0.296-3.877, P = 0.023; b = 1.955, 95%CI: 0.358-3.552, P = 0.017). Diagnosis of CD at age > 40 years was significantly associated with higher MFI, PF and RM scores (b = 14.328, 95%CI: 1.552-27.103, P = 0.029; b = 3.806, 95%CI: 0.407-7.206, P = 0.029; b = 3.385, 95%CI: 0.451-6.320, P = 0.024). Patients with GI tract stenosis or penetration (B2 or B3) had significantly lower RM scores (b = -1.816, 95%CI: -3.342 to -0.289, P = 0.020; b = -2.810, 95%CI: -5.099 to -0.520, P = 0.017). Patients with both GI tract stenosis and penetration showed a trend toward lower RM scores compared with those with isolated B2 or B3 disease, although the difference did not reach statistical significance (P = 0.064). No subscale of location was significantly associated with MFI total score or its subscales. Surgical history was significantly positively associated with RA score (b = 1.621, 95%CI: 0.210-3.033, P = 0.025). Disease activity was independently associated with PF score (b = 2.540, 95%CI: 0.531-4.549, P = 0.014). MF score was not significantly associated with the specific clinical characteristics or serum factors listed in this Table 4.
Table 4 Multiplevariable linear regression analysis of factors associated with fatigue in difficult-to-treat Crohn’s disease patients.
Multiple linear regression analysis of the association between DTT-related diagnostic factors and fatigue in CD patients
We investigated fatigue-associated factors in all CD patients (Table 5)[18]. Disease activity was significantly associated with higher MFI, GF, PF, RA and RM scores. Complex perianal disease and number of biologics with different mechanisms of action were not significantly associated with fatigue. Patients diagnosed at 17-40 years and > 40 years were significantly and positively associated with GF score (b = 2.677, 95%CI: 0.393-4.962, P = 0.022; b = 3.119, 95%CI: 0.557-5.681, P = 0.017). A3 subtype was significantly associated with RM score (b = 2.131, 95%CI: 0.022-4.241, P = 0.048). Patients with combined ileocolonic and upper gastroenterological tract involvement (L3 + L4) were significantly associated with higher GF score (b = 2.094, 95%CI: 0.083-4.105, P = 0.041).
Table 5 Association between difficult-to-treat characteristics at diagnosis and fatigue in a cohort of patients with Crohn’s disease: A multiple linear regression analysis.
This study applied the recently proposed International Organization for the Study of Inflammatory Bowel Diseases criteria for DTT-IBD in a Chinese CD population, assessing their risk factors and exploring the association between fatigue and the criteria of DTT-CD.
Our data show that over half (51.4%) of CD patients met at least one DTT-IBD criterion, which was significantly higher than the approximately 25% previously reported in an Italian population[9]. The high proportion (75.6%) of our cohort meeting the complex perianal disease criterion – a reflection of the prevalence of perianal involvement in Chinese CD patients – may be a key contributor to the observed difference in DTT-CD prevalence. Parigi et al[9] found that only 5.3% of CD patients met the criterion of complex perianal disease, while the majority (77%) of them failed at least two methods of treatment. This direct comparison indicates that complex perianal lesions represent a more prominent feature in Chinese patients meeting DTT-CD criteria than reported in the Italian population. This observation is further supported by a prior American study that found a higher prevalence of perianal disease among Asian CD patients (including both United States-born and immigrants) compared to white American patients[19]. Based on these findings, ethnicity or genetic ancestry may be the key factor influencing CD phenotype. The mechanisms underlying these ethnic and phenotypic differences warrant further investigation.
Beyond this phenotypic driver, methodological and systemic factors must also be considered. These include potential subtle variations in the clinical application of the International Organization for the Study of Inflammatory Bowel Diseases criteria among centers, as well as the referral bias, which attracted more severe and complex cases in this study. Therefore, the compound effect of assessment and referral patterns cannot be ruled out. The epidemiological differences warrant future investigation in prospectively designed multicenter studies.
In classic CD, a Th1-dominant profile is often described, whereas ulcerative colitis tends toward a Th2 response involving cytokines such as IL-5[20-22]. Our DTT-CD cohort revealed elevated serum IL-5 as an independent risk factor. The magnitude of this OR, despite a modest absolute difference in mean serum levels, may be interpreted from the perspective of a nonlinear or threshold biological effect. Research has established that early recurrent mucosal lesions are characterized by marked elevation of IL-5 and eosinophil infiltration following radical surgery[23]. Studies in a murine model of Crohn’s-like ileitis have demonstrated that IL-5 production in gut-associated lymphoid tissues is significantly correlated with severity of intestinal inflammation, and that CD4+ T cells from these sites can transfer severe disease[24]. Clinically, IL-5 is specifically upregulated within the fistulous tracts of CD patients[25]. Considering the predominance of complex perianal fistula in our DTT-CD cohort, we hypothesize that elevated serum IL-5 reflects heightened and pathogenic mucosal IL-5 activity, positioning it as a potential immunological driver of sustained severe intestinal damage, such as complex perianal fistula formation. Future studies should directly measure IL-5 in the intestinal mucosa and fistulous tracts of DTT-CD patients to validate its local pathogenic role and cellular source, moving beyond the systemic assessment presented here.
Elevated serum IL-10 emerged as an independent risk factor in our cohort. It is noteworthy that patients with monogenic defects in the IL-10 signaling pathway (e.g., IL-10 or IL-10 receptor deficiency) present with a severe, very early-onset IBD phenotype[26] that is consistently characterized by severe perianal complications[27-31]. While our study did not investigate genetic mutations or IL-10 pathway activity, the association between elevated serum IL-10 and complex perianal fistula in DTT-CD prompts a hypothesis. Could chronic, severe inflammation in DTT-CD lead to a state of acquired IL-10 pathway dysfunction or functional resistance, distinct from the genetic defects seen in very early-onset IBD? In this scenario, elevated IL-10 might represent a compensatory yet insufficient anti-inflammatory response, or even a marker of a specific disease endotype (e.g., the complex fistula phenotype). This remains speculative and necessitates direct investigation. Therefore, future studies are needed to directly assess the functional activity of the IL-10/JAK–STAT pathway in immune cells from DTT-CD patients, particularly in those with complex perianal disease, to validate or refute this hypothesis.
Multivariate logistic regression analysis identified several independent risk factors for DTT-CD. Longer disease duration was independently associated with increased risk. A previous study noted a numerical trend toward longer disease duration in DTT-CD patients compared to their non-DTT counterparts, although this difference was not significant. The DTT-IBD definition indirectly incorporates the element of time through its multidrug failure criterion, which necessitates the sequential trial of multiple therapies[9]. In the study by Parigi et al[9], most patients met one of the DTT-IBD; namely, multidrug failure pathway. In contrast, within our cohort, a smaller proportion fulfilled the criterion based on multidrug failure. This distinction suggests that disease duration itself may have been an independent risk factor for developing DTT-IBD in our population, distinct from the pathway of cumulative treatment attempts.
In our cohort, higher hemoglobin level was associated with DTT-CD status, which contrasts with the typical association of anemia with active inflammation[32,33]. Given the lack of data on prior anemia-correcting interventions (e.g., iron supplementation or transfusion) and the tertiary-center nature of our study, this association was likely confounded by clinical management rather than representing direct pathophysiology. Therefore, we interpret this finding not as a causative risk factor, but as an indicator of the complex clinical profile in DTT-CD, where aggressive supportive care may normalize hematological parameters. This underscores the necessity in future studies to rigorously account for treatment history when evaluating laboratory biomarkers in similar populations.
The need for PEN was a strong and independent predictor for DTT status and was associated with higher fatigue levels among DTT-CD patients. This possibly suggests that PEN requirement and fatigue share an underlying pathophysiology, possibly reflecting a severe, systemic disease state characterized by intestinal dysfunction and heightened symptom burden.
Our study found that fatigue was associated with some subtypes and clinical characteristics in DTT-CD patients. It revealed that diagnosis at age > 40 years was independently associated with higher total MFI scores and several subscales (GF, PF and RM). Furthermore, patients with surgery experienced higher RA score than those without surgery. The relationship between surgery and IBD has been discussed. Gong et al[32] found that IBD-related surgery was a risk factor for fatigue in Chinese IBD patients. Furthermore, Lee et al[33] revealed that IBD patients with a history of surgery were significantly associated with MFI scores. However, a prospective study from Poland indicated that surgical treatment significantly decreased fatigue in IBD patients, contrasting with our results[34]. This discrepancy can be critically evaluated by recognizing the distinct relationships captured by each study design. The prospective design measures the change in fatigue following surgery as an intervention, likely reflecting short-term symptomatic relief. Conversely, our cross-sectional design in a refractory cohort identified history of surgery as a marker of long-term disease severity and complexity, which is intrinsically associated with a higher burden of fatigue. Bączyk et al[35] indicated that high fatigue levels in postoperative patients potentially resulted from complications, postoperative pain, fear of stoma care, and acceptance of the new situation. While stenotic or penetrating disease behavior (B2/B3) was negatively associated with RM scores, it was independently linked to DTT-CD[9]. Given the scarce discussion on Montreal classification and fatigue, future studies should aim to confirm these intriguing findings. Disease activity was positively correlated with elevated levels of PF, which aligns with previous findings[32,33,36,37]. Fatigue is linked to anxiety, depression, and diminished quality of life in IBD patients, irrespective of disease activity[38-40]. Standardizing the assessment of psychosocial status in DTT-IBD remains a challenge due to its multidimensional nature. It is therefore significant that the expert consensus deliberately retains this difficult but crucial criterion, aiming to highlight the often-neglected role of mental health in disease management[9]. This emphasis is strongly supported by a key finding of our study: DTT-CD patients exhibited significantly higher MF scores compared to their non-DTT CD counterparts. The lack of correlation with standard biomarkers within the DTT-CD group suggests that their fatigue may have arisen from the multifaceted clinical and psychosocial burden inherent to the DTT condition, rather than from a single biological parameter. This result, showing significantly higher MF in DTT-CD patients, provides direct evidence that DTT-CD status is linked to greater fatigue burden. This finding suggests that DTT-CD is associated with a more complex psychosocial profile, which warrants formal assessment in future studies. In line with the STRIDE-II consensus that advocates inclusion of psychological and quality-of-life outcomes in assessing treatment response[41], this study sought to identify specific patient subtypes and clinical characteristics associated with fatigue. It enables clinicians to better recognize these patients and develop tailored management strategies, ultimately aiming to improve patient quality of life.
This study had some limitations. Firstly, its single-center, tertiary-hospital design may have overestimated DTT-CD prevalence due to referral bias. Secondly, we did not assess psychosocial comorbidities, a core DTT criterion; thus, our DTT phenotyping was incomplete. Thirdly, the cross-sectional data preclude causal inference for the observed biomarker-fatigue associations. Furthermore, potential confounding by concomitant medications that affect cytokines and fatigue was not addressed. Finally, the exclusion of patients due to incomplete data might have introduced selection bias. Despite these limitations, our findings provide novel insights into DTT-CD within a Chinese cohort.
CONCLUSION
This study applied the international DTT-IBD criteria in a Chinese CD population, revealing a high prevalence of DTT-CD, largely attributable to complex perianal disease – a phenotype more common in the Chinese cohort. We identified several independent risk factors for DTT-CD, including longer disease duration, elevated serum IL-5 and IL-10, higher hemoglobin, and the need for PEN, with IL-5 and IL-10 persisting as biomarkers even after adjusting for disease activity. These cytokines may reflect distinct immune dysregulation, particularly in fistulizing disease. Importantly, DTT-CD patients experienced higher levels of MF. Fatigue of DTT-CD patients was further associated with PEN, older age at diagnosis, and surgical history. Disease activity remained linked to PF in the broader CD group, but the DTT criteria themselves, such as multi-mechanism biologic failure or complex perianal disease, were not directly correlated with fatigue scores across the total patient cohort. Future studies are needed to validate biomarkers, clarify causal pathways, and develop tailored strategies to manage both disease activity and fatigue in this challenging patient population.
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Footnotes
Peer review: Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific quality: Grade B, Grade B, Grade B, Grade C
Novelty: Grade B, Grade B, Grade B, Grade C
Creativity or innovation: Grade B, Grade B, Grade B, Grade C
Scientific significance: Grade B, Grade B, Grade B, Grade C
P-Reviewer: Jeong T, PhD, Adjunct Professor, Researcher, South Korea; Li F, MD, Associate Chief Physician, Associate Professor, China; Xiao Y, MD, PhD, Assistant Professor, China S-Editor: Luo ML L-Editor: A P-Editor: Lei YY
