Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies.

OBJECTIVES: We explored the impact of circulating anti-N-methyl-D-aspartate receptor (NMDAR) antibodies on the severity of fatigue in patients with systemic lupus erythematosus (SLE). METHODS: Serum samples of 426 patients with SLE were analysed for the presence of antibodies to the NR2 subunit of the NMDAR. In parallel, the severity of fatigue was determined according to the Fatigue Scale for Motor and Cognitive functions questionnaire. In a subgroup of patients with SLE, the hippocampal volume was correlated with the levels of anti-NR2 antibodies. Isolated immunoglobulin G from patients with anti-NR2 antibodies were used for murine immunohistochemical experiments and functional assays on neuronal cell lines. Treatment effects were studied in 86 patients with lupus under belimumab therapy. RESULTS: We found a close correlation between the titre of anti-NR2 antibodies, the severity of fatigue, the clinical disease activity index (Systemic Lupus Erythematosus Disease Activity Index 2000) and anti-double stranded DNA antibodies-independently of the presence of neuropsychiatric lupus manifestations. Pathogenic effects could be demonstrated by (1) detection of anti-NR2 antibodies in the cerebrospinal fluid, (2) in situ binding of anti-NR2 antibodies to NMDAR of the hippocampus area and (3) distinct functional effects in vitro: downregulating the energy metabolism of neuronal cells without enhanced cytotoxicity. Treatment with belimumab for at least 6 months affected both the severity of fatigue and the levels of anti-NR2 antibodies. CONCLUSION: The presence of anti-NR2 antibodies in patients with SLE with fatigue is a helpful diagnostic tool and may offer a major approach in the therapeutic management of this important disabling symptom in patients with SLE.

High cardiovascular risk in mixed connective tissue disease: evaluation of macrovascular involvement and its predictors by aortic pulse wave velocity.

OBJECTIVES: Macrovascular involvement and cardiovascular (CV) risk has not been sufficiently studied in mixed connective tissue disease (MCTD). In particular, the gold standard assessment method of aortic stiffness carotid-femoral pulse wave velocity (cfPWV) has never been evaluated in patients with this disease. The aims of the present study were therefore to examine cfPWV in MCTD and to evaluate its associations with MCTD-associated markers and traditional CV risk factors. METHODS: Measurements of cfPWV were performed in 43 MCTD patients and 107 healthy controls. The difference between cfPWV in the two groups was statistically examined and subsequently controlled for the effect of possible confounding factors. The association of cfPWV with MCTD-associated organ involvement, routine laboratory parameters and immunoserological markers was also evaluated. Finally, the relationship of cfPWV with medications and traditional CV risk factors was examined. RESULTS: Adjusted statistical analyses for confounding factors showed significantly higher cfPWV values in MCTD patients in comparison to controls (padj<0.001). cfPWV correlated in both the patients and the control group significantly with age (rho=0.69, p<0.001 and rho=0.67, p<0.001 respectively) and diastolic arterial pressure (padj=0.024 and padj=0.032 respectively). Moreover, cfPWV correlated in the control group with systolic and mean arterial pressure (padj<0.001 and p=0.002 respectively). Finally, higher cfPWV values could be documented in the subset of MCTD patients without lung involvement (padj=0.007). CONCLUSIONS: Patients with MCTD have significantly higher aortic stiffness and thus CV risk in comparison to controls. Except for the disease itself, age and blood pressure were the main predictors of cfPWV.