Fatigue is a major disabling symptom in patients with rheumatic disorders such as RA and GPA. This work was carried out to investigate whether macro/microstructural changes are associated with the presence and severity of fatigue in patients with RA. We obtained T1, diffusion tensor and magnetisation transfer magnetic resonance scans from a group of 60 patients with RA (30 with active disease and 30 with inactive disease) at baseline and follow-up scans in addition to 14 patients with GPA, 14 matched fatigue controls FC and 20 healthy controls HC. No significant differences in a range of volumetric qMRI, DTI or MTI measures were found between RA active and non-active patients. Volumetric data analysis revealed that subcortical GM change in volume is related to fatigue irrespective of whether patients had RA or GPA. Moreover, longitudinal findings in patients with RA whose fatigue levels improved between the two scanning sessions indicate that, firstly, white matter microstructural abnormalities occur in the neuronal circuitry connecting bilaterally the striatal and cortical regions. Secondly, there is an imbalance in limbic-thalamic-cortical circuit connecting basal ganglia with limbic system of the improver group. Finally, demyelination of either neural circuit to the facilitator afferent vagus nerve could contribute to fatigue in this patient cohort. Fatigue-related RA does not appear to be related to disease activity or sleep disturbance and might therefore be related to other factors such as pain or depression status. Reductions in the myelin integrity as detected by the MTR in RA fatigue patients overlapped with those detected with the DTI analysis, especially in the cerebellar connections, corona radiata, corpus callosum, fornix, corticospinal tract and right cingulum suggesting that brain volumes, FA and MTR measures might be potential biomarkers of fatigue-related RA.