Cognitive Dysfunction in Systemic Lupus Erythematosus: A Case for Initiating Trials

Abstract

Cognitive dysfunction (CD) is an insidious and underdiagnosed manifestation of systemic lupus erythematosus (SLE) that has a considerable impact on quality of life, which can be devastating. Given the inconsistencies in the modes of assessment and the difficulties in attribution to SLE, the reported prevalence of CD ranges from 5% to 80%. Although clinical studies of SLE‐related CD have been hampered by heterogeneous subject populations and a lack of sensitive and standardized cognitive tests or other validated objective biomarkers for CD, there are, nonetheless, strong data from mouse models and from the clinical arena that show CD is related to known disease mechanisms. Several cytokines, inflammatory molecules, and antibodies have been associated with CD. Proposed mechanisms for antibody‐ and cytokine‐mediated neuronal injury include the abrogation of blood–brain barrier integrity with direct access of soluble molecules in the circulation to the brain and ensuing neurotoxicity and microglial activation. No treatments for SLE‐mediated CD exist, but potential candidates include agents that inhibit microglial activation, such as angiotensin‐converting enzyme inhibitors, or that protect blood–brain barrier integrity, such as C5a receptor blockers. Structural and functional neuroimaging data have shown a range of regional abnormalities in metabolism and white matter microstructural integrity in SLE patients that correlate with CD and could in the future become diagnostic tools and outcome measures in clinical trials aimed at preserving cognitive function in SLE.

Neuronal surface P antigen (NSPA) modulates postsynaptic NMDAR stability through ubiquitination of tyrosine phosphatase PTPMEG

“…Until now, empiric immunomodulatory therapy remains the main treatment for antibody-related neuropsychiatric disorders [ 2 , 73 ]. However, improvements in understanding the pathogenic pathways of different antibodies are opening possibilities for evidence-based personalized and targeted therapies that are so far unavailable [ 73 , 79 ]. For instance, recent evidence in animal models suggests increasing the availability of NMDAR at the cell surface through Ephrin-B2 receptor activation in certain anti-NMDAR autoimmune encephalitis [ 73 ], while selective inhibition of GluN2A subunits [ 25 ] and microglia [ 78 ] would be more adequate in SLE patients bearing dsDNA/NMDAR antibodies.…”

Prevalence, involved domains, and predictor of cognitive dysfunction in systemic lupus erythematosus

“…9 The pathogenesis of SLE-related CD involves comprehensive factors such as autoantibodies, an inflammatory protein, cytokines and BBB destruction, which lead to cerebrovascular diseases and neurotoxicity. 14–19 To our knowledge, little is known about the prevalence, involved domains, and possible predictors in China.…”

Cognitive dysfunction in autoimmune rheumatic diseases

“…Additional hurdles in the diagnosis of neuropsychiatric manifestations are that they often develop insidiously, can present and progress independently of other signs of SLE activity and often do not respond to standard immunosuppression. Thus, there is growing recognition that CD in lupus patients remains underdiagnosed and under-addressed in the clinical setting [18].…”