Title：The Immunological Mechanisms Linking Systemic Lupus Erythematosus and Neuropsychiatric Disorders

ShiaunTzuen Su^1,2*Po Cheng Shih^3,4*James Cheng-Chung Wei^2,3*

• ¹School of Medicine, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung, Taiwan
• ²Chung Shan Medical University Hospital, Taichung, Taiwan
• ³Chung Shan Medical University, Taichung, Taiwan
• ⁴Changhua Christian Hospital, Changhua City, Taiwan

imaging biomarker is able to reliably distinguish it from other neurologic or psychiatric conditions. Diagnoses are further complicated by treatment-related effects (for example, high-dose corticosteroids and immunosuppressants could themselves induce neuropsychiatric symptoms) and by comorbidities such as antiphospholipid syndrome, infections or metabolic disturbances that might mimic or mask NPSLE. Although the precise mechanisms remain under active investigation, accumulating evidence points to a multifactorial pathogenesis in which genetic susceptibility and environmental triggers converge to drive cytokine imbalance and aberrant immune cell activation. Blood-brain barrier dysfunction permits the entry of neurotoxic mediators and autoantibodies (e.g., anti-N-methyl-D-aspartate [NMDA] receptor, anti-ribosomal P), as well as in situ immune complex formation against neuronal antigens-all of which contribute to CNS injury. 1 Current evidence indicat that an intact blood-brain barrier (BBB) ordinarily prevents inflammatory cytokines and pathogenic autoantibodies from entering the central nervous system (CNS). In SLE, compromised BBB integrity allowed autoantibodies and inflammatory cells to infiltrate the CNS, contributing to neuropsychiatric symptoms. However, as shown by Ho et al. 2 ,certain serum autoantibodies could compromise vascular integrity, cross the BBB, and bind to neural antigens, initiating in situ immune-complex formation. These immune complexes lay at the heart of SLE and NPSLE pathogenesis and often manifest clinically as elevated immunoglobulin index in cerebrospinal fluid (CSF), a potential diagnostic marker.. The deposition of immune complexes on the endothelial surface activates the complement cascade, which in turn induces endothelial cytoskeletal reorganization, disassembly of tight-junction proteins (claudin-5, occludin), and increased barrier permeability. 3 Concurrent activation of the classical complement cascade by these immune complexes correlatewith hypocomplementemia (low C3 and C4), an elevated CSF immunoglobulin index, and heightened neuropsychiatric disease activity, underscoring the pathogenic role of complement in NPSLE. Autoantibodies play a critical role in SLE, in early studies when antibodies to ribosomes were found, indicating association between anti-ribosomal P antibody and NPSLE. However, a previous study demonstrated low sensitivity and high specificity of anti-ribosomal P antibody in NPSLE, leading to a limitation in diagnosis. 4 In recent study with functional magnetic resonance imaging (fMRI), increased amplitude of lowfrequency fluctuations (ALFF) and degree centrality (DC) values were found in SLE patients with positive anti-ribosomal P antibody which suggested the early potential biomarker of brain injury. 5 Aquaporin 4-specific autoantibodies werestudied in patients with NPSLE and found to cause severe demyelination and axonal damage in patients with concurrent neuromyelitis optica spectrum disorder (NMOSD). In demyelinating NPSLE, a previous study showed 27% patients have positive AQP-4 antibodies. 6 In clinical practice, AQP4 antibodies were recommended to be investigated if SLE patients with optic neuritis.Anti-N-methyl-D-aspartate receptor (NMDAR) antibodies have been investigated in relation to neuropsychiatric SLE (NPSLE) in recent studies, with a reported prevalence of approximately 30%. These autoantibodies constituted a subset of anti-double-stranded DNA (anti-dsDNA) antibodies that cross-reacted with the NR2A and NR2B subunits of the NMDAR. 7 The correlation between anti-NR2 glutamate receptor antibodies in CSF was associated with diffuse NPSLE. 8 Despite the existing criteria for NPSLE, the unmet need in diagnostic uncertainty remained a major problem. Although cognitive impairment is categorized as one of the early diffuse manifestations of NPSLE, the symptoms remain debatable. Previous studies demonstrate no statistically significant differences in cognitive function between patients with non-NPSLE and those with NPSLE, although both groups performed worse than healthy controls. 9 The symptom was not associated with disease activity but associated with anti-NMDAR antibodies. 10 With MRI perfusion, significant reduction of cerebral blood flow was found in patients with NPSLE compared to non-NPSLE. 11 MRI might be a effective tool in evaluating early NPSLE to assist the diagnosis. Table 1 summarized neuropsychiatric syndromes in systemic lupus erythematosus. Potential of Biologic Agents in NPSLE Treatment for NPSLE remain investigational, with limited clinical trials primarily exploring agents such as memantine, corticosteroids, and cyclophosphamide. 12 "In routine clinical practice, available biologic therapies for SLE are also limited, primarily including belimumab, anifrolumab, and rituximab; however, evidence specifically addressing their efficacy in NPSLE remains limited "Belimumab has demonstrated efficacy in both non-renal SLE and lupus nephritis; however, high-level evidence supporting its use in NPSLE remains lackingA recent analysis of five clinical trials demonstrated the indeterminate nature of the protective or potentially predisposing role of belimumab. 13 There was no direct evidence in evaluation of neuropsychiatric symptoms in SLE patients treated with anifrolumab. However, a retrospective study including SLE patients who presented neuropsychiatric symptoms demonstrated that anifrolumab was effective in controlling overall disease activity. 13 Additionally, data from a retrospective analysis using the LOOPS registry in Japan indicated that anifrolumab maintained its effectiveness even among patients diagnosed with NPSLE. 14 Rituximab demonstrated its effectiveness in controlling disease activity in SLE patients, especially in refractory patients. In a study with BILAG-BR registry, the results showed that rituximab could have been an effective treatment for NPSLE. 15 In NPSLE, increased interleukin (IL) -6 was found in CSF in a previous study, and IL-6 also demonstrated the associated with incident psychosis. 16.17 Satralizumab demonstrated its effectiveness in NMOSD, which might have played a role in NPSLE via IL-6 axis. The CD40-CD40L pathway played a pivotal role in systemic and renal inflammation in lupus nephritis (LN). CD40 signaling promoted B-cell activation, IgG class switching, plasma cell differentiation, and memory B-cell survival, perpetuating autoantibody production. In LN kidneys, CD40L was expressed by T cells and activated platelets, which stimulated CD40 on mesangial and endothelial cells, leading to proliferation, monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-β1 (TGF-β1) production, and enhanced leukocyte recruitment. This drove tubulointerstitial and glomerular inflammation and fibrosis. High renal CD40 expression correlated with severe pathology and poor prognosis, making CD40-CD40L blockade a compelling therapeutic strategy. Anti-CD40 and anti-CD40L therapies showed promise in reversing proteinuria, reducing autoantibodies, and prolonging survival in LN models. 18 Dapirolizumab pegol (DZP) was an Fc-free anti-CD40L agent, showed clinical benefit in the Phase 3 PHOENYCS GO trial by reducing disease activity and enabling corticosteroid tapering in SLE patients. 19 Additionally, DZP plus standard of care improved fatigue outcomes, as measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and Patient-Reported Outcome (FATIGUE-PRO) scales. 20 However, its clinical use was limited by thrombotic risks seen with earlier anti-CD40L agents, highlighting the need for safer, targeted strategies to modulate the CD40-CD40L pathway. 18 On the other hand, alternative routes of administration beyond intravenous therapy remain unresolved but crucial, given the limitations posed by the BBB on drug efficacy in NPSLE. Intrathecal, intraventricular, and intranasal routes were proposed as potentially feasible approaches to overcome BBB challenges. NPSLE should focus on improving diagnostic tools, enhancing the understanding of its pathophysiology, and developing more effective, targeted therapies. A multidisciplinary approach is essential for accurate diagnosis, requiring collaboration among experts in neurology, psychiatry, vascular medicine, hematology, rheumatology, and neuroradiology to assess patient conditions. Future prospective studies can help optimize the management of NPSLE and improve quality of life for all patients.