# Role of combination immunotherapy in restoring brain synergistic functional connectivity in patients with systemic lupus erythematosus without overt neuropsychiatric manifestations

## TL;DR

This study shows that patients with lupus have subtle brain connectivity issues even without obvious symptoms, and these can be partially reversed with combination immunotherapy.

## Contribution

The study identifies subclinical brain dysfunction in SLE and demonstrates that combination immunosuppression can partially restore disrupted interhemispheric connectivity.

## Key findings

- SLE patients showed reduced interhemispheric connectivity in multiple brain regions compared to healthy controls.
- Combination immunosuppressive therapy partially reversed disrupted connectivity in SLE patients.
- Brain connectivity changes correlated with depression and anxiety scores in SLE patients.

## Abstract

To determine whether subclinical brain dysfunction in SLE can be detected by disrupted interhemispheric connectivity and assess its modulation by immunosuppressive regimens.

234 subjects (140 patients with SLE and 94 healthy controls (HCs)) were included. Through stratified analysis, patients with SLE were divided into treatment-naïve group (n=22), glucocorticoid monotherapy group (GC group, n=30) and GC combined with cyclophosphamide (CTX) and/or hydroxychloroquine (HCQ) treatment group (n=50) to assess the differences in voxel-mirrored homotopic connectivity (VMHC) between groups.

SLE group showed lower VMHC than the HC group in bilateral superior temporal gyrus, medial superior frontal gyrus, calcarine fissure and surrounding cortex and middle occipital cortices (Gaussian random field corrected: voxel p<0.005, cluster p<0.01). The VMHC in the bilateral superior temporal gyrus (rs=−0.250, p=0.024) and medial superior frontal gyrus (rs=−0.246, p=0.026) was negatively correlated with the depression score, while the VMHC in the medial superior frontal gyrus was negatively correlated with the anxiety score (rs=−0.239, p=0.031). Three SLE subgroups and HCs had different VMHC in the postcentral/precentral gyrus (F=8.942) and anterior cingulate/paracingulate gyrus (F=9.868). Post hoc analysis found that compared with the HC group, VMHC in the treatment-naïve group was decreased in the bilateral posterior central gyrus (t=−2.953), while in the GC monotherapy group, it decreased in the posterior central gyrus (t=−2.999) and anterior cingulate/paracingulate gyrus (t=−2.999). Compared with GC combined with CTX and/or HCQ group, VMHC in GC monotherapy group was decreased in the postcentral gyrus (t=−2.999).

Even without overt neuropsychiatric symptoms, patients with SLE exhibit impaired interhemispheric functional synergy that is partially reversed by combination immunosuppression, suggesting an early targetable brain pathway.