Fatigue in inflammatory bowel disease beyond intestinal inflammation: A cross-sectional study

Background and aims: Fatigue is one of the most common and burdensome extraintestinal manifestations of inflammatory bowel disease (IBD) with a multifactorial aetiology that may extend beyond inflammatory activity. This study aimed to clarify the relative contribution of biological, psychological and central sensitization-related factors to fatigue in outpatients with IBD. Methods: A cross-sectional study was conducted in a sample of 106 adult consecutive outpatients with IBD. Participants completed questionnaires assessing fatigue, central sensitization, depressive and anxiety symptoms. Laboratory data including fecal calprotectin (FC), C-reactive protein (CRP), and hemoglobin (Hb) levels were retrieved from medical records. A hierarchical regression analysis assessed the contribution of biological markers (Block 1) and psychological and central sensitization-related symptoms (Block 2) to fatigue severity. Results: Clinically significant fatigue was present in 42.5% of patients. Biological markers explained a small, non-significant proportion of variance in fatigue severity. In the full model, central sensitization-related symptoms (β = 0.54, p < .001) were the strongest independent correlates of fatigue, followed by depressive symptoms (β = 0.30, p = .006) and FC (β = 0.26, p = .001). Anxiety, CRP, and hemoglobin were not independently associated with fatigue. The full model explained 55.5% of the variance in fatigue severity. In a sensitivity analysis removing fatigue-related items from the psychological scales, central sensitization-related symptoms and FC remained independently associated with fatigue, whereas depressive symptoms did not. Discussion: Although intestinal inflammation contributed independently, fatigue was more closely related to central sensitization-related symptoms than to depressive symptoms, inflammatory or hematological markers. These findings support a multidimensional assessment of fatigue, extending beyond inflammation-focused care toward an integrated, multidisciplinary approach.