SAN FRANCISCO – The announcement of a first-ever multicenter randomized trial of ACE inhibitors for the treatment of cognitive impairment in systemic lupus erythematosus patients generated some of the biggest buzz at LUPUS 2019.
Bruce Jancin/MDedge News
Dr. Betty Diamond
“The time has come to implement clinical trials in lupus to see if we can address what is one of the most distressing aspects of the disease to patients,” Betty Diamond, MD, said in announcing the planned trial at an international congress on systemic lupus erythematosus (SLE).
Neuropsychiatric lupus, characterized most often by cognitive impairment, affects 40%-90% of SLE patients, according to various epidemiologic studies. This confusion and memory loss has been shown to be independent of systemic disease activity.
“Cognitive impairment is a very common problem and a very insidious problem in lupus patients,” emphasized Dr. Diamond, professor and head of the Center for Autoimmune Musculoskeletal and Hematopoietic Diseases at the Feinstein Institute for Medical Research in Manhasset, New York.
Dr. Diamond was the recipient of the 2018 Lupus Insight Prize awarded by the Lupus Research Alliance, which is funding the multicenter randomized trial. For the study, roughly 70 SLE patients with cognitive impairment not associated with a focal brain lesion will be randomized to receive a centrally acting ACE inhibitor – captopril was the one she and her coinvestigators have used in their mouse model and preliminary clinical studies – or to a non–centrally acting ACE inhibitor, such as enalapril.
“The clinical trial compares an ACE inhibitor that crosses the blood-brain barrier with one that doesn’t. They both have the same renal protection and systemic anti-inflammatory effects,” explained Dr. Diamond, who is also professor of molecular medicine and of medicine at the Zucker School of Medicine at Hofstra/Northwell, East Garden City, N.Y.
In a recent publication (J Exp Med. 2018 Oct 1;215[10]:2554-66), Dr. Diamond and her coinvestigators presented much of the background work that underpins the upcoming randomized trial. Sixteen years ago, they discovered two anti-DNA antibodies that cross-react with the N-methyl-D-aspartate receptor (NMDAR) and enhance NMDAR signaling. They showed that while the NMDARs are critical in learning and memory, their prolonged stimulation results in a high degree of calcium influx, causing neuronal death. These anti-DNA/anti-NMDAR antibodies, known as DNRAbs, are present at elevated titers in 30%-40% of SLE patients, and in a higher proportion of those with neuropsychiatric lupus.
“Most importantly, DNRAbs are present in the cerebrospinal fluid of patients who have nonfocal CNS manifestations of lupus,” Dr. Diamond said.
She and her coworkers developed a mouse model of cognitive impairment in lupus and utilized it to identify a two-stage model of the pathogenesis of DNRAb-mediated neuropsychiatric lupus. First, a traumatic event such as an infection causes a temporary opening in the blood-brain barrier, allowing the DNRAbs to reach the brain. This results in acute excitotoxic neuronal death. This is followed by a second stage, which entails activation of microglia – known as the macrophages of the CNS – with resultant loss of neuronal dendritic arborization and complexity. In the mouse model, this causes a selective impairment in spatial memory that corresponds well to the spatial memory deficit the investigators documented in DNRAb-positive SLE patients, compared with healthy controls and DNRAb-negative lupus patients.
A key finding in this project, Dr. Diamond continued, was that activated microglia turn out to be critical for dendritic loss. If the microglia are deactivated, regrowth of the dendritic processes occurs. This raises a possibility that attendees at LUPUS 2019 found thrilling: Perhaps the cognitive impairment of neuropsychiatric SLE can be prevented and even reversed by suppressing microglial activation.
Promising work in the field of Alzheimer’s disease suggests that centrally acting ACE inhibitors can indeed suppress microglial activation and actually improve cognition. Dr. Diamond and her colleagues showed this also was the case in their mouse model. Moreover, in a small clinical study they used PET brain imaging to show that captopril reduced the increased glucose uptake and hippocampal hypermetabolism associated with DNRAb-positive neuropsychiatric lupus, an effect maintained through 18 months of follow-up.
“We think DNRAbs contribute to cognitive impairment in SLE patients, but we certainly wouldn’t say that antibodies are the only mechanism. Other investigators have shown that interferon can also do this, and that, like the antibodies, interferon acts through microglial activation. We think that this microglial activation is going to be a general paradigm in cognitive impairment in lupus and in other diseases, so microglia are a very good therapeutic target,” Dr. Diamond said.
The primary outcomes in the forthcoming randomized trial involve PET neuronal imaging. They investigators are hoping to see reduced hippocampal hypermetabolism and suppression of activated microglial cells.
“We’ll see if we’re actually hitting our target. We’re doing neuropsychologic testing, too, but we’re really concentrating on imaging outcomes, because those are objective and have many fewer variables to confound them,” according to Dr. Diamond.
Microglial activation is a current topic of intense research interest within the pharmaceutical industry, she added. If the imaging study is positive, she anticipates drug companies will quickly ramp up and conduct large clinical trials powered to show significant results in terms of neuropsychologic test scores and clinical outcomes.
Dr. Diamond reported having no financial conflicts regarding her work, which has been supported largely by the National Institutes of Health.