Anti-NR2 glutamate receptor antibodies and cognitive function in systemic lupus erythematosus

To determine the prevalence of circulating anti-NR2 antibodies and their association with neuropsychiatric systemic lupus erythematosus (NP-SLE), particularly cognitive function, in women with SLE.

Cognitive function was assessed in 65 consecutive women with SLE from a single referral center using standardized neuropsychological tests. These were selected subtests of the Wechsler Adult Intelligence Scale-Revised, the Wechsler Memory Scale-Revised, and the California Verbal Learning Test, which provided information on 8 areas of cognitive function. After a mean followup of 64 (range 52-71) months, cognitive assessments were repeated. Global and domain-specific cognitive impairment was examined using predetermined decision rules, and the change in individual tests of cognitive performance over time was also examined. Overt NP-SLE was identified by clinical assessment and classified using the American College of Rheumatology nomenclature. Circulating IgG anti-NR2 and anti-dsDNA antibodies were determined by ELISA on up to 4 occasions over the study period. A positive result was defined as at least 3 standard deviations above the mean of healthy controls.

At enrollment, 15/65 (23%) patients had cognitive impairment. This fell to 7/54 (13%) at followup. In addition 15/65 (23%) patients had a history of clinically overt NP-SLE. Twenty-three of 65 (35%) patients had anti-NR2 antibodies and 48/65 (74%) had anti-dsDNA antibodies. Anti-NR2 antibodies were present in 18/48 (38%) patients with anti-DNA antibodies, and 18/23 patients (78%) with anti-NR2 antibodies also had anti-dsDNA antibodies. There was no association between global cognitive impairment, domain-specific cognitive impairment, or a history of clinically overt NP-SLE and either the presence or amount of anti-NR2 or anti-dsDNA antibodies (p > 0.05). When change in cognitive performance or the occurrence of new NP-SLE events over the 5-year followup period was examined, there was no significant association with persistent elevation of either antibody (p > 0.05). Similarly there was no association between a rise in autoantibodies over time and the development of overt NP events or cognitive decline (p > 0.05).

These results indicate that anti-NR2 antibodies occur in 35% of women with SLE and are infrequent in the absence of detectable anti-dsDNA antibodies. Their presence in the circulation is not associated with cognitive dysfunction at a single timepoint, and an increase in or persistently elevated antibody levels are not associated with a change in cognitive performance over time. There was no association with clinically overt NP-SLE. However, as our study did not examine cerebrospinal fluid samples, these results do not exclude a potential pathogenic role in selected patients for this group of autoantibodies should they penetrate the blood-brain barrier and thereby gain direct access to neuronal tissues.