Background Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious complication in SLE, and no reliable diagnostic markers for NPSLE have been identified. α-Klotho is a single-pass transmembrane protein expressed in multiple tissues, especially brain and kidneys. It is known to play an important role in the regulation of senescence in the central nervous system (CNS) through calcium homeostasis. Little is known of the significance of serum soluble α-Klotho (s-Klotho) in NPSLE.
Objectives We examined the s-Klotho levels in NPSLE and SLE patients and investigated whether s-Klotho could be a diagnostic marker of NPSLE.
Methods s-Klotho levels in NPSLE (n=21), SLE (n=22) and healthy controls (HC) (n=46) were measured by enzyme-linked immunosorbent assay. We analyzed each group's associations between s-Klotho and age, sex, disease duration, Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), anti-dsDNA antibody, anti-Sm antibody, C3, C4, anti-phospholipid antibody syndrome complication, anti-ribosomal P antibodies, presence of abnormal magnetic resonance imaging (MRI) and presence of abnormal single photon emission computed tomography (SPECT).
Results The age of onset differed significantly between the NPSLE and SLE groups (median 38 vs. 47.5 yrs: p=0.018; HC, 39.5 yrs), as did the SLEDAI-2K (median 12 vs. 6: p=0.0234), respectively. The median s-Klotho level in NPSLE (205.3 pg/mL), SLE (297.7 pg/mL) and HC (314.9 pg/mL) were compared: NPSLE vs. HC (p<0.0001) and NPSLE vs. SLE (p=0.018). A multivariate analysis showed that risk factors for NPSLE were lower s-Klotho level (odds ratio [OR], 0.98; 95% confidential interval [CI], 0.96–1.00) and earlier onset of disease (OR, 0.91; 95%CI, 0.81–1.00). A receiver operatingcharacteristic (ROC) analysis identified the optimal cut-off value for the s-Klotho level as <280.3 pg/mL, which was associated with diagnosis of NPSLE with 55% sensitivity and 86% specificity.
Conclusions Our findings provide evidence that earlier onset of disease and lower s-Klotho levels are correlated with the diagnosis of NPSLE. Considering the roles of s-Klotho as an age-regulating protein that affects oxidative stress, mineral homeostasis and insulin signaling (which are critical and basic functions in the brain), it will be important to elucidate both the mechanisms by which the expression and function of s-Klotho may vary with age and its possible role in the pathophysiology of CNS degenerative disorders. The determination of s-Klotho levels may contribute to the diagnosis of NPSLE and may help elucidate the mechanisms underlying this disease.
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Disclosure of Interest T. Ushigusa: None declared, K. Ichinose Grant/research support from: This work was supported by Japan Intractable Diseases Research Foundation and Nagao Memorial Foundation., S. Tsuji: None declared, M. Umeda: None declared, S. Fukui: None declared, A. Nishino: None declared, Y. Nakashima: None declared, T. Suzuki: None declared, Y. Horai: None declared, T. Koga: None declared, S.-Y. Kawashiri: None declared, N. Iwamoto: None declared, Y. Hirai: None declared, M. Tamai: None declared, H. Nakamura: None declared, T. Origuchi: None declared, A. Kawakami: None declared