Diffuse neuropsychiatric lupus: Clinical evidence, immune-mediated mechanisms, and therapeutic insights.

Neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) occur in more than half of patients with SLE, with symptoms including fatigue, anxiety, depression, pain, psychosis, and cognitive dysfunction. These symptoms are often present at the time of diagnosis of SLE and can be insidious. Patients consider these to be among their most debilitating symptoms which most diminish their quality of life, but recognition and attribution of these frequently non-acute symptoms can be difficult, resulting in underassessment, underdiagnosis, and poor understanding of the underlying pathogenic mechanisms and how to treat them. In this review, we highlight findings from neuroimaging studies which have been critical in proving the existence of structural and functional brain alterations that associate with symptomatology, and pathophysiological findings from animal models of diffuse NPSLE, focusing principally on blood brain barrier injury and brain-reactive autoantibodies. Most importantly, we demonstrate that mechanistic progress can be made with respect to these manifestations of NPSLE and that this progress leads to therapeutic strategies which can be tested in clinical trials.