Advances in Attribution and Management of NPSLE Manifestations of Lupus: Current Paradigms and Emerging Evidence

Neuropsychiatric involvement in systemic lupus erythematosus remains a significant clinical challenge, encompassing a broad spectrum of manifestations affecting both the central and peripheral nervous systems. Accurate diagnosis and attribution require a structured approach, ideally supported by a multidisciplinary team evaluation and the application of validated attribution models. Recent evidence has reinforced the utility of existing algorithms in improving the attribution of neuropsychiatric events to systemic lupus erythematosus, with advances in laboratory testing and neuroimaging enhancing the ability to establish a causal link between the disease and its clinical manifestations. In parallel, emerging insights into disease pathogenesis are helping to clarify the role of targeted therapeutic strategies, closely tied to attribution processes. High-dose glucocorticoids plus cyclophosphamide remain the cornerstone for severe, inflammatory, neuropsychiatric systemic lupus erythematosus, while rituximab has shown the most consistent signal in refractory disease, albeit mainly in uncontrolled studies. Therapeutic development is progressively expanding along the B-cell lineage, from enhanced CD20 targeting (e.g., obinutuzumab) to profound B-cell depletion via chimeric antigen-T-cell-based strategies, and further toward upstream and parallel pathway modulation, including dual BAFF/APRIL blockade with telitacicept and type I interferon receptor inhibition with anifrolumab, both currently supported by case-based evidence. This narrative review summarizes recent developments in the diagnosis, attribution, pathogenesis, and treatment of neuropsychiatric systemic lupus erythematosus, with the aim of providing clinicians with an updated framework to better recognize and manage this complex and often underappreciated manifestation, ultimately improving patient outcomes.