Document resource
Introduction Severe fatigue frequently affects patients with rheumatic diseases. We have previously shown that mitochondrial dysregulation, elevated inflammatory markers (e.g. Galectin-9), and reduced lung function are associated with severe fatigue in systemic sclerosis (SSc) patients. The oxygen-transport-cascade, which encompasses the heart/lungs, hemoglobin/oxygen carrying capacity, microvasculature and finally the mitochondria, plays an important role in promoting fatigue. Importantly, interferon signaling has been linked to both mitochondrial dysregulation and fatigue. We sought to determine whether oxygen-transport-cascade defects and elevated interferon signals are evident in SSc patients with severe fatigue.Material and Methods In this exploratory cross-sectional study, 58 lcSSc patients were recruited, 29 with severe fatigue (meeting ME/CFS and FACIT criteria), and 29 without. Plasma samples were subject to unbiased metabolomics analysis and a four gene interferon score (Mx1, Siglec1, IF144L, CXCL10) generated through qPCR from whole blood RNA. Disability, disease-associated damage accrual (via the SCTC-damage index), inflammatory changes, indicators of lung fibrosis (via lung functions) and microvascular changes were assessed.Results Metabolomics analysis indicated changes in the citric acid cycle (pathway influence (Impact) 0.19, p=0.002)), alanine, aspartate and glutamate (Impact 0.53, p=0.041), and vitamin B6 (Impact 0.568, p=0.0424) pathways. Interferon scores were elevated in SSc patients with severe fatigue (0.008), compared to patients without fatigue (0.003) (p=0.037). The interferon score correlated negatively with fatigue and inflammatory measures, as well as capillary density (p=0.027). There was a positive correlation between red blood cell distribution width and the interferon score (p=0.010). CXCL10, a marker of both type I and type II interferon, was found to negatively correlate with the expression of mitochondrial gene ND4 (p=0.021) and DLCO lung function (p=0.006). CXCL10 correlated positively with measures of fatigue, disability and pain (p<0.04), IL-7, TNFalpha, VEGF (p<0.009), with trends evident for the expression of mitochondrial gene Cox7C and Galectin-9.Conclusions We have found that lcSSc patients with severe fatigue display evidence of dysfunction at nearly every level within the intersections of the oxygen-transport-cascade. This is highlighted by reduced lung functions; dysregulated RDW and vitamin B6 (which play a role in hemoglobin oxygen carrying capacity); reduced capillary density; and mitochondrial dysregulation. Importantly, interferon signals (e.g. CXCL10) are associated with microvasculopathy, mitochondrial dysfunction and reduced lung function - suggesting that they may be linked with the mechanisms promoting fatigue in SSc. Future mechanistic studies are needed to better understand these associations, which may lead to novel insights, and potential therapeutic advances for fatigue in SSc patients.Funding Kaye Grant/Arthritis Society