Prevalence, risk factors, and prognosis of central nervous system manifestations in antiphospholipid syndrome.

The central nervous system (CNS) is considered as one of the most frequently affected organs in antiphospholipid syndrome (APS). This study investigated the prevalence of CNS manifestations in APS and associated risk factors and evaluated stroke recurrence. We carried out this retrospective study from 2009 to 2021 at Peking University People's Hospital, which enrolled 342 APS patients, and 174 neurologic events were suffered by 119 patients (34.8%). Patients with and without CNS involvement were compared regarding demographics and laboratory parameters. The analysis showed that older age, livedo reticularis, and dyslipidaemia were significant related factors for CNS manifestations (P = 0.047, 0.038, and 0.030 respectively). The use of anticoagulants (P = 0.004), and/or hydroxychloroquine (P = 0.016) appeared to associated with a lower incidence of CNS manifestations. During a median follow-up of 4.1 years, 10 individuals developed new episodes of stroke in APS patients with previous ischemic strokes. Livedo reticularis, smoking and male gender may predict the risk of recurrent stroke (P = 0.020, 0.006, and 0.026 respectively). Collectively, our results indicated the protective and risk factors for CNS manifestations, as well as demonstrated that APS patients appeared at high risk of stroke recurrence despite current therapy.

Low dose versus standard dose rituximab for the treatment of antiphospholipid syndrome: A pilot study from a tertiary medical center.

Background: To investigate the therapeutic effects and safety of low-dose and standard-dose rituximab (RTX) in the treatment of antiphospholipid syndrome (APS). Methods: In this real-world study, we included 22 consecutive patients with APS who received RTX. Standard dose (SD) was defined as an overall dosage of RTX ≥ 1000mg in the induction period, and low dose (LD) was defined as an overall dosage of RTX <1000mg. Results: Of included patients, 1 patients died, 2 patients withdrew and 19 patients completed 6-month follow-up. Nine patients received SD-RTX and 13 patients received LD-RTX, and elder patients [LD-RTX vs. SD-RTX: (49.1 ± 15.5) vs. (35.8 ± 12.3) years, p = 0.044] and patients with later-onset [LD-RTX vs. SD-RTX: (46.8 ± 16.3) vs. (31.3 ± 13.6) years, p = 0.029] were more frequently included in LD-RTX than SD-RTX. Following 6 month RTX treatment, 8 patients (42.1%) achieved complete remission, 8 patients (42.1%) achieved partial remission and 3 patients (15.8%) showed no remission. The titers of anticardiolipin antibodies [baseline vs. 6 months: 30.8 (10.7, 90) vs. 19.5 (2.45, 69.10) U/L, p = 0.023] and the levels of erythrocyte sedimentation rate [baseline vs. 6 months: 29 (6, 63) vs. '6 (3, 14) mm/h, p = 0.021] exhibited a significantly decrease in all APS patients. Remission rate and titers of anti-ß2-glycoprotein I and lupus anticoagulant did not differ significantly between two groups. Conclusion: RTX might be a safe and effective option for patients with APS, and low dose confers equal efficacy as standard dose. Further cohort studies are needed to confirm our findings.

A novel aGAPSS-based nomogram for the prediction of ischemic stroke in patients with antiphospholipid syndrome.

Background: Ischemic stroke (IS) is the most common and life-threatening arterial manifestation of antiphospholipid syndrome (APS). It is related to high mortality and severe permanent disability in survivors. Thus, it is essential to identify patients with APS at high risk of IS and adopt individual-level preventive measures. This study was conducted to identify risk factors for IS in patients with APS and to develop a nomogram specifically for IS prediction in these patients by combining the adjusted Global Anti-Phospholipid Syndrome Score (aGAPSS) with additional clinical and laboratory data. Methods: A total of 478 consecutive patients with APS were enrolled retrospectively. All patients were randomly assigned to the training and validation cohorts. Univariate and multivariate binary logistic analyses were conducted to identify predictors of IS in the training cohort. Then, a nomogram was developed based on these predictors. The predictive performance of the nomogram for the training and validation cohorts was evaluated by determining areas under the receiver operating characteristic curve (AUROC) and creating calibration plots. A decision curve analysis (DCA) was conducted to compare the potential net benefits of the nomogram with those of the aGAPSS. Results: During a mean follow-up period of 2.7 years, 26.9% (129/478) of the patients were diagnosed with IS. Binary logistic regression analysis revealed that five risk factors were independent clinical predictors of IS: age (P < 0.001), diabetes (P = 0.030), hyperuricemia (P < 0.001), the platelet count (P = 0.001), and the aGAPSS (P = 0.001). These predictors were incorporated into the nomogram, named the aGAPSS-IS. The nomogram showed satisfactory performance in the training [AUROC = 0.853 (95% CI, 0.802-0.896] and validation [AUROC = 0.793 (95% CI, 0.737-0.843)] cohorts. Calibration curves showed good concordance between observed and nomogram-predicted probability in the training and validation cohorts. The DCA confirmed that the aGAPSS-IS provided more net benefits than the aGAPSS in both cohorts. Conclusion: Age, diabetes, hyperuricemia, the platelet count, and the aGAPSS were risk factors for IS in patients with APS. The aGAPSS-IS may be a good tool for IS risk stratification for patients with APS based on routinely available data.

Risk Factors and Outcomes of Acute Myocardial Infarction in a Cohort of Antiphospholipid Syndrome.

Background: Antiphospholipid syndrome (APS) is a disorder associated with thromboembolic diseases, including acute myocardial infarction (AMI). Given that AMI is a relatively common condition with poor prognostic features, identification of risk factors for AMI in APS is important. Methods: A retrospective cohort study was performed consisting of 332 patients with APS, and 239 patients with thrombotic APS were finally included. Patients were followed up in the outpatient department for 5 years. Clinical data and laboratory parameters were analyzed to identify the risk factors for AMI in APS. The primary and secondary clinical outcomes were all-cause mortality and recurrence of thrombosis, respectively. Results: AMI was observed in 12.1% (29/239) of patients with APS. Compared to patients without AMI, patients with AMI had multiple organ thrombosis (55.1 vs. 34.3%, p = 0.029), recurrent thrombosis (58.6 vs. 34.3%, p = 0.011), a higher incidence of atherosclerosis (62.1 vs. 23.8%, p < 0.001), higher neutrophil count (×109/L) [4.68 (3.25, 8.17) vs. 3.71 (2.64, 5.80), p = 0.036], longer QT interval (ms) [438 ms (423, 454) vs. 425 ms (410, 446), p = 0.016], and fewer venous thrombosis events (27.6 vs. 63.3%, p < 0.001). Multivariate logistic regression analysis (adjusted for age and gender) identified several factors that were positively associated with AMI, including multiple organ thrombosis [odds ratio (OR) 8.862, 95% confidence interval (CI): 1.817-43.212, p = 0.007), atherosclerosis (OR 5.397, 95%CI: 1.943-14.994, p = 0.001), and elevated neutrophil count (>6.3 ×109/L) (OR 3.271, 95%CI: 1.268-8.440, p = 0.014). The venous thrombosis was negatively associated with AMI (OR 0.106, 95%CI: 0.036-0.314, p < 0.001). Kaplan-Meier analysis revealed that the recurrence rates of arterial thrombosis differed significantly between patients with AMI and those without AMI [hazard ratio (HR) = 3.307, p = 0.038]. Conclusion: Atherosclerosis, multiple organ thrombosis, an increased number of neutrophils are variables positively associated with AMI in APS, and venous thrombosis had a negative association with AMI. AMI only predicts the subsequent recurrence of arterial thrombosis. These findings suggest that distinct pathophysiological mechanisms may exist and contribute to the development of venous or arterial thrombotic APS.

Synthesis of oxadiazole-2-oxide derivatives as potential drug candidates for schistosomiasis targeting SjTGR.

BACKGROUND: Schistosomiasis is a chronic parasitic disease that affects millions of people's health worldwide. Because of the increasing drug resistance to praziquantel (PZQ), which is the primary drug for schistosomiasis, developing new drugs to treat schistosomiasis is crucial. Oxadiazole-2-oxides have been identified as potential anti-schistosomiasis reagents targeting thioredoxin glutathione reductase (TGR). METHODS: In this work, one of the oxadiazole-2-oxides derivatives furoxan was used as the lead compound to exploit a series of novel furoxan derivatives for studying inhibitory activity against both recombinant Schistosoma japonicum TGR containing selenium (rSjTGR-Sec) and soluble worm antigen protein (SWAP) containing wild-type Schistosoma japonicum TGR (wtSjTGR), in order to develop a new leading compound for schistosomiasis. Thirty-nine novel derivatives were prepared to test their activity toward both enzymes. The docking method was used to detect the binding site between the active molecule and SjTGR. The structure-activity relationship (SAR) of these novel furoxan derivatives was preliminarily analyzed. RESULTS: It was found that several new derivatives, including compounds 6a-6d, 9ab, 9bd and 9be, demonstrated greater activity toward rSjTGR-Sec or SWAP containing wtSjTGR than did furoxan. Interestingly, all intermediates bearing hydroxy (6a-6d) showed excellent inhibitory activity against both enzymes. In particular, compound 6d with trifluoromethyl on a pyridine ring was found to have much higher inhibition toward both rSjTGR-Sec (half-maximal inhibitory concentration, IC50,7.5nM) and SWAP containing wtSjTGR (IC50 55.8nM) than furoxan. Additionally, the docking method identified the possible matching sites between 6d and Schistosoma japonicum TGR (SjTGR), which theoretically lends support to the inhibitory activity of 6d. CONCLUSION: The data obtained herein showed that 6d with trifluoromethyl on a pyridine ring could be a valuable leading compound for further study.

Design, synthesis and biological evaluation of artemisinin derivatives containing fluorine atoms as anticancer agents.

Ten novel artemisinin derivatives containing fluorine atoms were synthesized and their structures were confirmed by 1H NMR, 13C NMR and HRMS technologies in this study. The in vitro cytotoxicity against U87MG, SH-SY5Y, MCF-7, MDA-MB-231, A549 and A375 cancer cell lines was evaluated by MTT assay. Compound 9j was the most potent anti-proliferative agent against the human breast cancer MCF-7 cells (IC50 = 2.1 µM). The mechanism of action of compound 9j was further investigated by analysis of cell apoptosis and cell cycle. Compound 9j induced cell apoptosis and arrested cell cycle at G1 phase in MCF-7 cells. Our promising findings indicated that the compound 9j could stand as potential lead compound for further investigation.