Background: Rheumatoid arthritis (RA) is an inflammatory joint disease that leads to significant impairment in hand function. Chronic systemic inflammation in RA has been shown to change the activity of specific brain structures [1]. The relationship between brain structure and hand dysfunction in RA is underexplored.

Objectives: We investigated structural changes in the brain of RA patients in relation to grip strength (GS), aiming to identify peripheral and brain immune responses associated with these changes.

Methods: Based on GS measurement using a dynamometer, we analysed 60 RA patients with an mean age 60 years (range 23-73), disease duration 14 years (range 0-45), and mean GS 197 N (range 29-400). Patients were dichotomized by the median GS to compare the groups with weak GS versus strong GS. A subset of 12 patients underwent hand training consisting of 5 simple exercises performed separately for each hand for 10 minutes daily during 6 months. Instructions were given on an individual basis. Each patient wrote a training diary. Patients reported their functional disability using the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire, the Health Assessment Questionnaire (HAQ) and the Fibromyalgia Impact Questionnaire (FIQ). Brain tissue was assessed by T1-weighted magnetic resonance imaging (MRI) at the baseline and after 6 months of hand training for the subset of 12 patients. Volumes of 121 brain regions were analysed using MAPER software with respect to grey matter (GM), white matter (WM), and cerebrospinal fluid (CSF) compartments. Levels of IFNγ in serum and supernatants of CD4+ T cells were determined by ELISA. RNA sequencing was used to analyse the transcriptional profile of peripheral blood CD4+ T cells.

Results: RA patients with weak GS had significantly higher functional disability according to DASH and HAQ, and experienced more pain according to FIQ scores (all, p<0.001). There was no significant difference in age, disease duration or disease activity by DAS28 between the weak GS and strong GS patients. We found that the weak-GS patients had significantly increased WM volume in the putamen (L, p=0.002; R, p=0.0046) and caudate nucleus (L, p=0.0082; R, p=0.067) and decreased GM volume in the thalamus (L, p=0.038; R, p=0.028), regions which play a role in planning the execution of movement. Weak-GS patients also had significantly smaller WM volumes of the sensorimotor network, including the precentral gyrus (PG) (L, p=0.025; R, p=0.083), middle frontal gyrus (MFG) (L, p=0.0023; R, p=0.0099) and superior temporal gyrus anterior part (STGAP) (R, p=0.0051). Interestingly, after 6 months of hand training, some of the sensorimotor regions were increased in 12 patients who completed the training (MFG: 0.75% increase, p=0.0024; STGAP: 2.7% increase, p=0.033). Furthermore, weak-GS patients had lower levels of IFNγ in both serum (p=0.0006) and CD4+ T cell supernatants (p=0.0018). In the CD4+ T cells of the weak-GS patients, the downregulated genes were involved in T-cell activation and migration, and IFNγ production and response, while the upregulated genes were related to ribosome biogenesis. Further correlation analysis showed that the IFNγ sensitive genes were significantly correlated with the WM volume of the PG and putamen, and genes involved in ribosome biogenesis were correlated with WM volume of the PG and MFG.

Conclusion: Hand GS loss in RA patients is associated with measurable changes in the brain volume of motor cortex and the dorsal striatum. These changes can be mitigated by daily hand training. Regional brain changes were associated with dysregulated immune system and impaired IFNγ production and signalling in CD4+ T cells. This study provides new clues for understanding the interaction between the immune and nervous systems in RA, which should be taken into account during treatment of RA patients.

REFERENCES: [1] Schrepf et al. Nature Communications. 2018.

Acknowledgements: NIL.

Disclosure of Interests: None declared.