The presence of brain-reacting autoantibodies may explain the prevalence of fatigue in patients with systemic lupus erythematosus (SLE), according to research published in Annals of the Rheumatic Diseases.

Researchers examined the relevance of circulating anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in patients with SLE experiencing fatigue. Serum samples from these patients, who met at least 4 American College of Rheumatology criteria for SLE, were retrospectively analyzed for the presence of NR2 subunit antibodies. Lupus disease activity was assessed via the SLE Disease Activity Index (SLEDAI-2K), while standard serologic measures and fatigue were assessed by the Fatigue Scale for Motor and Cognitive Functions (FSMC) questionnaire.

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A subgroup of the Mainz Lupus Cohort (n=426) ranging from 18 to 76 years in age completed the FSMC questionnaire and was eligible for inclusion in the current analysis. Fatigue was present in 75% of this cohort, with more than 50% classified with severe fatigue. Four grades of fatigue severity were used to correlate the clinical extent of patient’s fatigue and anti-NR2 antibodies titre. A significant difference between anti-NR2 antibody level and fatigue severity was noted.

When examining the relationship between anti-NR2 antibodies and other SLE disease activity parameters, researchers found that these titres also correlated with SLEDAI-2K and anti-double stranded DNA antibodies. No correlation with complement factors, erythrocyte sedimentation rate, C-reactive protein, or renal function was found.

In 22 patients with SLE, researchers analyzed the level of anti-NR2 antibodies present in cerebrospinal fluid samples; low levels of antibodies were found in the cerebrospinal fluid, but high titres were found in the sera.

Researchers also sought to assess the long-term effect of anti-NR2 antibodies on hippocampus volume and did this by forming a magnetic resonance imaging cohort that consisted of 33 SLE patients with severe fatigue. Over a 2-year period of observation, researchers noted a reduction in hippocampal volume that was linked with high titres of anti-NR2 antibodies, SLEDAI-2K score, and low C3c complement levels.

Finally, a subgroup of patients treated with belimumab therapy (n=86) was analyzed. These patients completed a clinical fatigue score at baseline and after therapy while researchers analyzed anti-NR2 antibody titres. The mean time of belimumab therapy was 12±8.5 months (range 6 to 36 months). Researchers noted a significant decline in anti-NR2 antibody levels, while a “clinically significant” reduction in the total fatigue score and motoric and cognitive components.

“The results of our study offer a sustained clinical advantage: to add an objective measurement of fatigue in lupus patients to a subjective questionnaire,” the researchers of the study concluded. “Anti-NMDAR antibodies should be identified routinely for patients with lupus suffering from fatigue.”

They added that additional studies are needed to “clearly define the diagnostic and therapeutic impact of the growing number of brain-reactive autoantibodies in patients with SLE.”

Disclosures: The investigator-initiated-study was in part supported by GSK. Dr Andreas Schwarting has received speaker fees and grant/research support from AbbVie, Novartis, Roche, and GSK. Dr Konstantinos Triantafyllias has received speaker fees and research support from Pfizer.

Reference

Schwarting A, Möckel T, Lütgendorft F, et al. Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies [published online June 11, 2019]. Ann Rheum Dis. doi:10.1136/annrheumdis-2019-215098