Demystifying fatigue in Crohn’s disease: assessing prevalence, pathogenic and contributing factors for clinical application

Background/ Aims: Fatigue is a common symptom in patients with Crohn’s disease (CD) impairing quality of life, yet the underlying pathophysiology and effective management approaches remain unknown. Hitherto, research has been hampered by a paucity of objective measures of fatigue, definition and conceptual framework. Fatigue may be conceptualized as a multidimensional entity with physical, cognitive and psychosocial components. Hence this study aimed to utilize objective assessments of fatigue, and establish links between patients’ subjectively-reported fatigue with objectively-measured fatigue along with CD-related inflammatory and other mechanistic pathways. The primary aim was to determine the important and potentially modifiable pathogenic factors contributing to fatigue in patients with CD, thus ultimately identify potential molecular targets for clinical application. Methods: Initially, CD patients (n=181) attending a hospital clinic along with patients with ulcerative colitis (113) and healthy controls (85) as comparator groups completed surveys encompassing multidimensional fatigue questionnaires (including the Fatigue Impact Scale (FIS), anxiety/depression, sleep quality and other demographic/clinical data. Then, subgroups of these CD and healthy controls underwent clinical assessment of disease activity (Harvey-Bradshaw Index), anthropometry, pathology testing including CRP, faecal calprotectin, cytokines and micronutrients, a brief cognitive assessment (measuring cognitive fatigue) and measurement of habitual physical activity and sleep quality via accelerometry. Subsequently, participants completed muscle testing for measurement of muscle size and fatigue (representing physical fatigue), also exploring putative links between known molecular pathways of muscle atrophy/ hypertrophy and CD-related pathophysiology. Analyses focused on comparing controls and CD groups, and within the CD group examining important factors associated with physical and cognitive fatigue. Results: Literature review revealed only 17 articles had hitherto studied fatigue in IBD. In this study the prevalence and severity of fatigue in CD subjects was higher than healthy controls (57% vs 12%, median FIS 48 vs 11 respectively, each p<0.01). Furthermore in CD subjects, multivariate analyses showed factors such as active disease and poor sleep quality were independently associated with higher physical and cognitive fatigue scores. Other salient findings included the muscle analyses that revealed reduced quadriceps muscle size in CD compared to stringently matched control participants (mean difference -590mm2, p=0.03) and significantly increased muscle fatigue in CD demonstrated via dynamometer testing (mean -5.2 vs -1.3 Nm min-1, p=0.047). These differences may be explained by a reduced phosphorylated Akt: total Akt ratio and lower serum IGF1 levels in CD compared to control subjects (mean 1.09 vs 2.45, median 16.1 vs 25.4 respectively, each p<0.05). Also, performing the computerised Subtle Cognitive Impairment Test (SCIT), CD subjects demonstrated slower response times than matched controls (607 vs 551 ms, p<0.01), indicative of subtle cognitive fatigue/ dysfunction. Conclusions: This research demonstrated that fatigue is prevalent and more severe in CD and appears to relate to multiple factors including CD proinflammatory pathways, micronutrient deficiencies, neurobiological sequelae of the disease, and the cumulative effects of CD over time. Furthermore, objectively measured physical and cognitive fatigue is significantly worse in CD than controls, correlates with patients’ self-reported fatigue and provides multiple clues to the underlying pathogenesis of this disabling symptom, many of which are promising therapeutic targets for ameliorative therapies, pending further evaluation.