Cause of Neuropsychiatric Ills Common to Lupus Seen in Study, Potential Treatment Raised

Neuropsychiatric symptoms in people with systemic lupus erythematosus may be caused by increased levels of the inflammatory molecule interferon-alpha in their brains, according to a study published in the journal Nature. But a treatment now in clinical trials may be able to arrest the processes that lead to those symptoms.

The inflammatory molecule appears to activate microglial cells in the brain, and these cells, in turn, destroy synapses (structures that support communication between neurons) — at least, that was the process seen in a mouse model of lupus. But the research team from Boston Children’s Hospital also found increased interferon activity in patients’ brains, suggesting the same process might be going on in people lupus.

“In general, lupus patients commonly have a broad range of neuropsychiatric symptoms, including anxiety, depression, headaches, seizures, even psychosis,” Allison Bialas, PhD, the study’s first author, said in a press release. “But their cause has not been clear for a long time; it wasn’t even appreciated that these were symptoms of the disease.”

To study the impact of autoimmune processes on neuropsychiatric lupus, the team used a mouse model of the disease in which the immune processes depend on signaling through the interferon-alpha receptor 1 (IFNAR). Researchers know that this type of immune signaling is found in 50% to 80% of all lupus patients.

Like many lupus patients, the mice showed signs of psychiatric disease. They were anxious, had a poor cognition, and were aggressive in social settings.

Injecting mice with labeled interferon — so it could be tracked — the researchers discovered that it entered the brain in sufficient quantities to elicit a response. Their report, “Microglia-dependent synapse loss in type I interferon-mediated lupus,” describes how the team used advanced microscopic techniques to catch the activated microglia in action.

Microglia are the brain’s main immune cell. They can release inflammatory factors of their own, but also clear the brain of pathogens or cell debris. The team could see how the microglia engulfed synapses, causing the animals to lose a significant amount of synapses in the frontal cortex part of their brains.

But treating the mice with an anti-IFNAR drug, called anifrolumab, prevented synapse loss. Researchers also noted that the treatment reduced their behavioral abnormalities.

Anifrolumab is currently in Phase 3 clinical trials in lupus, and the team’s data suggest that the drug might have the potential to prevent neuropsychiatric symptoms in lupus. Patients with severe, active neuropsychiatric lupus are, however, excluded from these trials, so future studies will be needed to evaluate the drug’s effectiveness in these people.

The researchers believe the findings likely will affect research into lupus and other diseases, particularly since inflammation is present in numerous other conditions.

“We’ve found a mechanism that directly links inflammation to mental illness. This discovery has huge implications for a range of central nervous system diseases,” said Michael Carroll, PhD, the study’s senior author.

“We’ve seen microglia dysfunction in other diseases like schizophrenia, and so now this allows us to connect lupus to other CNS [central nervous system] diseases,” Bialas added. “CNS lupus is not just an undefined cluster of neuropsychiatric symptoms, it’s a real disease of the brain and it’s something that we can potentially treat.”