Objective We sought to determine the effect of hydroxychloroquine therapy on the levels proinflammatory/prothrombotic markers and disease activity scores in patients with systemic lupus erythematosus (SLE) in a multiethnic, multi-center cohort (LUMINA). Methods Plasma/serum samples from SLE patients (n=35) were evaluated at baseline and after hydroxychloroquine treatment. Disease activity was assessed using SLAM-R scores. Interferon (IFN)-α2, interleukin (IL)-1β, IL-6, IL-8, inducible protein (IP)-10, monocyte chemotactic protein-1, tumor necrosis factor (TNF)-α and soluble CD40 ligand (sCD40L) levels were determined by a multiplex immunoassay. Anticardiolipin antibodies were evaluated using ELISA assays. Thirty-two frequency-matched plasma/serum samples from healthy donors were used as controls. Results Levels of IL-6, IP-10, sCD40L, IFN-α and TNF-α were significantly elevated in SLE patients versus controls. There was a positive but moderate correlation between SLAM-R scores at baseline and levels of IFN-α (p=0.0546). Hydroxychloroquine therapy resulted in a significant decrease in SLAM-R scores (p=0.0157), and the decrease in SLAM-R after hydroxychloroquine therapy strongly correlated with decreases in IFN-α (p=0.0087). Conclusions Hydroxychloroquine therapy resulted in significant clinical improvement in SLE patients, which strongly correlated with reductions in IFN-α levels. This indicates an important role for the inhibition of endogenous TLR activation in the action of hydroxychloroquine in SLE and provides additional evidence for the importance of type I interferons in the pathogenesis of SLE. This study underscores the use of hydroxychloroquine in the treatment of SLE.
Purpose To examine the prevalence of isolated IgA anti-β2Glycoprotein I (anti-β2GPI) positivity and the association of these antibodies, and a subgroup that bind specifically to domain IV/V of β2GPI, with clinical manifestations of the Antiphospholipid Syndrome (APS) in three patients groups. The pathogenicity of IgA anti-β2GPI was also evaluated in a mouse model of thrombosis. Methods Patients with systemic lupus erythematosus (SLE) from a multiethnic, multicenter cohort (LUpus in MInorities, NAture versus nurture [LUMINA]) (n=558), patients with SLE from the Hopkins Lupus Cohort (n=215), and serum samples referred to the Antiphospholipid Standardization Laboratory (APLS) (n=5,098) were evaluated. IgA anti-β2GPI titers and binding to domain IV/V of β2GPI were examined by enzyme-linked immunosorbent assay (ELISA). CD1 mice were inoculated with purified IgA anti- β2GPI antibodies, and surgical procedures and ELISAs were performed to evaluate thrombus development and tissue factor (TF) activity. Results A total of 198 patients were found to be positive for IgA anti-β2GPI isotype, and 57 patients were positive exclusively for IgA anti-β2GPI antibodies. Of these, 13 of 23 patients (56.5%) in the LUMINA cohort, 17 of 17 patients (100%) in the Hopkins cohort, and 10 of 17 patients (58.9%) referred to APLS had at least one APS-related clinical manifestation. Fifty-four percent of all the IgA anti-β2GPI positive serum samples reacted with domain IV/V of anti-β2GPI, and 77% of those had clinical features of APS. Isolated IgA anti-β2GPI positivity was associated with an increased risk for arterial thrombosis (p<0.001), venous thrombosis (p=0.015) and all thrombosis (p<0.001). The association between isolated IgA anti-β2GPI and arterial thrombosis (p=0.0003) and all thrombosis (p=0.0003) remained significant after adjusting for other risk factors for thrombosis. In vivo mouse studies demonstrated that IgA anti-β2GPI antibodies induced significantly larger thrombi and higher TF levels compared to controls. Conclusion Isolated IgA anti-β2GPI positive titers may identify additional patients with clinical features of APS. Testing for these antibodies when other antiphospholipid (aPL) tests are negative and APS is suspected is recommended. IgA anti-β2GPI antibodies directed to domain IV/V of β2GPI represent an important subgroup of clinically relevant antiphospholipids.
5062 Purpose Systemic Lupus Erythematosus (SLE) and Antiphospholipid Syndrome (APS) are two closely related diseases. APL antibodies are present in 30-40% of SLE patients. Studies have indicated that certain cytokines, chemokines, tissue factor (TF), vascular endothelial growth factor (VEGF), soluble (s) E-selectin (sE-sel), tumor necrosis (TNF)-a, may be associated with APS and/or SLE. However, whether those biomarkers are elevated in plasma of APS patients with or without SLE is uncertain. Here we examined whether the levels of cytokines/chemokines in aPL antibody-positive patients positive are different from controls. Methods Twenty-two sera/plasma of patients with significantly and persistently elevated levels aPL antibodies (IgG and/or IgM aCL, and/or IgG and/or IgM anti-β2glycoprotein I (β2GPI) and/or positive lupus anticoagulant (LAC), demographic and clinical data were obtained from an on-going pilot clinical study (clinical trials.gov#NCT00674297). Patients that were on more than 10 mg prednisone/day, or on other immunosuppressive therapy, or on hydroxychloroquine or on statins were excluded. Thirty-two healthy donors with no evidence of autoimmune, infectious or inflammatory diseases were used as controls. .Levels of IL1b, IL6, IL8, TNF-a, VEGF, IP-10, sCD40L were measured in serum using a Millipore Millliplex” Multiplex Assay; titers of sE-sel, and sTF were detected by ELISA. The Kruskal-Wallis test was used to compare levels of biomarkers in aPL positive subjects vs. controls and Spearman tests to correlate levels of the biomarkers in the different subgroups of patients. Results Significant number of aPL-positive samples had elevated levels of IL1b, IL6, TNF-a, VEGF, IP-10, sCD40L, sTF, sCD40L and sE-sel and their titers were significantly different when compared to controls. APS /SLE patients (n=8) showed significantly higher levels of TNF-a compared to APS without SLE (n=6), to “asymptomatic” aPL positive (n=4), to “asymptomatic” aPL positive with SLE (n=2) or with “catastrophic” APS (n=2) patients (p=0.00630). Conclusions This study underscores the importance of identifying biomarkers of disease that may help to better understand pathogenic mechanisms, predict disease activity and possibly to better address treatment of patients with aPL antibodies. Disclosures No relevant conflicts of interest to declare.
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