Chronic Fatigue Mechanisms in Autoimmune Diseases: Lessons from Primary Biliary Cholangitis and Systemic Sclerosis

Systemic sclerosis (SSc) is an autoimmune disease affecting the body's connective tissues, resulting in progressive fibrosis and vasculopathy. In some cases, individuals with SSc may also develop primary biliary cholangitis (PBC), another autoimmune disease characterized by damage to their liver’s bile ducts. Chronic fatigue frequently affects SSc and PBC patients, significantly impacting their cognitive abilities and quality of life. To date, there are no reliable treatments for these patients’ fatigue. Research on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) - a type of chronic fatigue characterized by post-exertional malaise - has uncovered potential connections between chronic fatigue and abnormalities in the metabolic dysfunction, atypical hypoxia responses, problems with oxygen delivery, and the immune system. The shared disease characteristics among PBC, SSc, and ME/CFS patients suggest that chronic fatigue has a physical basis and is not just a psychological phenomenon. This thesis provides an overview of the roles of metabolic dysfunctions, hypoxia responses, oxygen delivery problems, and immune system abnormalities in PBC and SSc individuals, as well as the similarities to findings in those with ME/CFS. A deeper understanding of the commonalities between SSc and PBC will serve as a catalyst for designing more effective therapies for chronic fatigue, ultimately enhancing the patients' quality of life

Severe fatigue is associated with diminished lung function and elevated Galectin-9 levels in early systemic sclerosis

IntroductionSymptoms resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) frequently affect patients with rheumatic diseases, but little is known about their frequency and disease manifestations, particularly in systemic sclerosis (SSc) patients. We sought to determine if severe fatigue in SSc patients with early disease (< 7 years) is associated with increased disability, inflammation and fibrosis.MethodsIn this exploratory cross-sectional study, 51 SSc patients were recruited locally (UofA cohort). Disability, disease damage accrual, inflammatory markers and, indicators of fibrotic and vascular complications (e.g. lung function, nailfold capillaroscopy) were compared between patients with and without severe fatigue. Fatigue was assessed using validated questionnaires (e.g. FACIT, MFI) and ME/CFS criteria. Findings were further corroborated in the national CSRG (Canadian Scleroderma Research Group) SSc cohort (n=126).ResultsSSc patients with severe fatigue had significantly increased disability, reduced lung function capacity, and elevated Galectin-9 levels when compared to patients without fatigue. Galectin-9 levels correlated with reduced pulmonary function, and increased disease damage accrual. Further analysis in the UofA cohort suggested that indictors associated with disease progression such as reduced nailfold capillary density, and elevated VEGF, LTα and IL-16 were present in severely fatigued patients.DiscussionSevere fatigue in SSc patients is associated with increased disability, reduced pulmonary function and increased vascular remodeling. We propose that ME/CFS-like symptoms in patients with SSc may be indicative of sub-clinical inflammation and fibrosis. Further studies are required to determine whether Gal-9,may be a useful tool for the stratification of SSc patients - particularly those with severe fatigue resembling ME/CFS