ObjectiveThis study investigated differences in cardiorespiratory fitness, muscular function, perceived exertion, and anxiety/depression between patients and healthy controls (HCs) and assessed which of these variables may account for the fatigue experienced by patients.MethodsFatigue was measured in 48 antineutrophil cytoplasmic antibody–associated vasculitis patients and 41 healthy controls using the Multidimensional Fatigue Inventory (MFI-20), focusing on the physical component. Quality of life, anxiety/depression, and sleep quality were assessed by validated questionnaires. Muscle mass was measured by dual-energy x-ray absorptiometry scan, strength as the maximal voluntary contraction (MVC) force, and endurance as sustained isometric contraction at 50% MVC of the quadriceps. Voluntary activation was assessed by superimposed electrical stimulation. Cardiorespiratory fitness ( and oxygen pulse [O2 pulse]) and perceived exertion (Borg scale) were measured during progressive submaximal exercise.ResultsPatients reported elevated physical fatigue scores compared to HCs (patients MFI-20 physical 13 [interquartile range (IQR) 8–16], HCs MFI-20 physical 5.5 [IQR 4–8]; P < 0.001). Muscle mass was the same in both groups, but MVC and time to failure in the endurance test were lower due to reduced voluntary activation in patients. Estimated and O2 pulse were the same in both groups. For the same relative workload, patients reported higher ratings of perceived exertion, which correlated with reports of MFI-20 physical fatigue (R2 = 0.2). Depression (R2 = 0.6), anxiety (R2 = 0.3), and sleep disturbance (R2 = 0.3) were all correlated with MFI-20 physical fatigue.ConclusionThese observations suggest that fatigue in patients is of a central rather than peripheral origin, supported by associations of fatigue with heightened perception of exertion, depression, anxiety, and sleep disturbance but normal muscle and cardiorespiratory function.