New Biomarker for Neuropsychiatric Events in Lupus?

TAKE HOME POINTS

A new study in the journal Arthritis Research Therapy has identified DNA elements called nitrated nucleosomes (NNs) as a promising new biomarker for distinguishing neuropsychiatric events due to systemic lupus erythematosus (SLE) from those from other causes.¹

“In this multi-centre study we found that serum NN levels rise at the time of a neuropsychiatric event in a proportion of patients with SLE, including some cases of headache,” wrote lead author Anisur Rahman, PhD, of University College London, and colleagues.
Research suggests that about 40% of patients with SLE may experience a neuropsychiatric event over 2 years.² Yet most of these events are not due to SLE itself. Because neuropsychiatric events caused by SLE may resolve more quickly than those from other causes, determining the cause is important for decisions about management and prognosis.

Blood biomarkers hold promise for improving the diagnosis of neuropsychiatric events in SLE. Yet identifying them has proven challenging, mainly because these events are so rare. Over the past 30 years, researchers have tested autoantibodies, cytokines, and chemokines, but none have yielded robust results. 

In the current study, researchers were tipped off to NNs by results from past studies showing that both nitration and nucleosome levels increase in active SLE. Nucleosomes are ways that human cells package DNA, and consist of segments of DNA with proteins wrapped around them. They are released when cells die, and their clearance is slowed in SLE.

A previous study by this group found that NN levels increase in some patients with SLE around the time of neuropsychiatric flares, but the study was too small to draw definite conclusions.³

To test their findings in a larger group, researchers analyzed blood samples before, during, and after neuropsychiatric events from a subset of participants in the Systemic Lupus International Collaborative Clinics (SLICC) study-one of largest studies of SLE, which includes patients from 31 centers in North America, Europe, and Asia. The study included 216 patients with SLE and neuropsychiatric events experienced during the study, who were matched to 2 controls with SLE but without neuropsychiatric events.  Neuropsychiatric events included headache, mild depression, anxiety, mild cognitive impairment, polyneuropathy, seizures, psychosis, aseptic meningitis, and cognitive dysfunction.

Key results
• Higher mean serum NN during neuropsychiatric event onset for SLE compared to controls (p<0.001)
• 26 neuropsychiatric events due to SLE
o No link between event onset and increased blood NN
• 190 neuropsychiatric events not due to SLE
o Median serum NN level increased at event onset and fell after the event (p=0.006)
o Mean serum NN levels at onset were significantly higher vs controls (p<0.001)
o Predominant clinical symptoms: headache, mood disorder, anxiety

Those with neuropsychiatric events not caused by SLE were originally included as a control group. The authors did not expect NN levels to rise and fall before and after neuropsychiatric events in this group. Rather, they expected NN levels to rise and fall in the group with neuropsychiatric events due to SLE. Indeed, in their earlier study, about one-third of patients with SLE and neuropsychiatric events had persistently negative NN levels. But that study did not distinguish between neuropsychiatric events due to SLE and those from other causes.

While the new study adds a finer level of detail and points to NNs as a promising biomarker for distinguishing neuropsychiatric events due to SLE, the test is not yet ready for prime time. Further studies are needed to determine whether testing for NN has clinical value, and whether the assay that measures NN levels needs further validation and standardization.

References:

1. Ferreira I, Croca S, Raimondo MG, et al. Nitrated nucleosome levels and neuropsychiatric events in systemic lupus erythematosus; a multi-center retrospective case-control study. Arthritis Res Ther.2017;22;19:287.
2. Hanly JG, Urowitz MB, Su L, Bae SC, et al. Prospective analysis of neuropsychiatric events in an international disease inception cohort of patients with systemic lupus erythematosus. Ann Rheum Dis. 2010;69: 529–35
3. Croca S, Bassett P, Pericleous C, et al. Serum nitrated nucleosome levels in patients with systemic lupus erythematosus: a retrospective longitudinal cohort study. Arthritis Res Ther. 2014;16(1):R48