Calcineurin inhibitors in the treatment of systemic lupus erythematosus during pregnancy: A narrative review with emphasis on efficacy and safety.

Systemic lupus erythematosus (SLE) predominantly affects child-bearing women, leading to an elevated risk of maternal and fetal complications and adverse pregnancy outcomes. Since some medications can cross the placental barrier that persist a threat to both mother and fetus, the risk-benefit ratio of SLE medications should be taken into consideration during pregnancy. Calcineurin inhibitor (CNI), mainly including cyclosporin A, tacrolimus, and voclosporin, is a category of immunosuppressive agents that inhibit calcium/calmodulin-dependent phosphatase calcineurin to block T cell activation. Based on the current clinical evidence, CNI is an alternative in pregnant SLE patients with persistent disease activity (especially lupus nephritis patients) and non-responders to azathioprine. However, there is no comprehensive review that summarizes the efficacy and safety profile of CNI for SLE management during pregnancy. This review presents a summary on the utilization of CNI for SLE management during pregnancy, including the mechanism of action, gestational amelioration of lupus flare, and the balance of maternal benefit-fetal risk, which may provide more references for the management of SLE pregnancies.

Tumour necrosis factor inhibitor combined with intravenous immunoglobulin and heparin for treatment of recurrent spontaneous abortion: A two-centre, retrospective, cohort study.

WHAT IS KNOWN AND OBJECTIVE: Immune disorder is a key trigger of recurrent spontaneous abortion (RSA); meanwhile, tumour necrosis factor inhibitor (TNFi) is a fundamental therapeutic for multiple immune and inflammatory diseases. Hence, this real-world study aimed to explore the efficacy and safety of TNFi combined with intravenous immunoglobin (IVIG) and heparin therapy in RSA patients. METHODS: A total of 105 RSA patients who received TNFi+IVIG+Heparin (enoxaparin) (n = 48) or IVIG+Heparin (enoxaparin) (n = 57) were retrospectively included in this two-centre cohort study. RESULTS AND DISCUSSION: The live birth rate of RSA patients in the TNFi+IVIG+heparin group was 72.9% (95% confidence interval [CI]: 69.6%-85.9%). Besides, the live birth rate in the IVIG+heparin group was 52.6% (95% CI: 42.8%-62.4%). By comparison, the live birth rate was higher in the TNFi+IVIG+heparin group compared to the IVIG+heparin group (p = 0.033). After adjustment by the multivariate logistic regression model using the enter method, TNFi+IVIG+Heparin was also superior to IVIG+Heparin regarding increased live birth rate (odds ratio [OR] = 2.941, p = 0.015). Moreover, TNFi+IVIG+Heparin (vs. IVIG+Heparin) also served as an independent factor for increased live birth rate (OR = 2.423, p = 0.035) by the forward stepwise method in the multivariate analysis. Gestational weeks at delivery (38.3 ± 1.3 vs. 37.7 ± 2.0 weeks, p = 0.155), newborn weight (3123.9 ± 332.1 vs. 3056.6 ± 287.4 g, p = 0.390), Apgar score of newborns (9.8 ± 0.5 vs. 9.7 ± 0.7, p = 0.271) were of no difference between TNFi+IVIG+Heparin and IVIG+Heparin groups. In terms of safety profile, the adverse events were of no difference between the TNFi+IVIG+Heparin and the IVIG+Heparin groups (all p > 0.05), either. WHAT IS NEW AND CONCLUSION: TNFi combined with IVIG and heparin therapy improves the live birth rate but does not elevate the adverse events compared to IVIG and heparin therapy in RSA patients.

The myocardial infarction-associated transcript 2 inhibits lipid accumulation and promotes cholesterol efflux in oxidized low-density lipoprotein-induced THP-1-derived macrophages via inhibiting mitogen-activated protein kinase signaling and activating the nuclear factor erythroid-related factor 2 signaling pathway.

Dysregulated lipid metabolism of macrophages contributes to thrombosis and antiphospholipid syndrome (APS). The long non-coding RNAs (lncRNA) myocardial infarction-associated transcript 2 (Mirt2) has been reported to inhibit inflammation and lipid accumulation; therefore, this study intended to clarify whether Mirt2 served a role in lipid metabolism. THP-1-derived macrophages with or without Mirt2-knockdown or overexpression, were exposed to oxidized low-density lipoprotein (ox-LDL), then cell migration, lipid accumulation, cholesterol efflux and inflammation were assessed using wound healing, oil red staining, commercial kits and western blot assays. Besides, ML385 was used to treat THP-1-derived macrophages to inhibit nuclear factor erythroid-related factor 2 (NRF2) expression. The expression of proteins involved in the above processes were measured by western blot. Results demonstrated that phorbol 12-myristate 13-acetate (PMA) significantly increased Mirt2 expression in THP-1 cells. Mirt2-knockdown enhanced ox-LDL-induced macrophage migration, lipid accumulation, inflammation, and inhibited cholesterol efflux. By contrast, Mirt2 overexpression displayed the opposite effects. Furthermore, Mirt2-knockdown inhibited NRF2 signaling and enhanced mitogen-activated protein kinase (MAPK) signaling, while Mirt2 overexpression displayed the opposite effects. Finally, the NRF2 inhibitor ML385 significantly reversed the above effects of Mirt2. In summary, Mirt2 served an important role in regulating lipid metabolism in macrophages via inhibiting MAPK signaling and activating the NRF2 signaling pathway.

Tumor necrosis factor inhibitors as therapeutic agents for recurrent spontaneous abortion (Review).

Recurrent spontaneous abortion (RSA) is a troublesome pregnancy disorder that manifests as sequential early pregnancy losses; its causes are diverse and complex. Among the known possible causes of RSA, the development of an immune disorder in response to the embryo appears to be the most pronounced. The imbalance between immune rejection and immune tolerance contributes to pregnancy loss in females with RSA, wherein the abnormal ratio of T helper (Th)1 cell­related cytokines [predominantly tumor necrosis factor (TNF)­α] and Th2 cell­related cytokines is a strong risk factor for RSA. TNF­α is a pro­inflammatory cytokine and TNF inhibitors have been effective in the treatment of various autoimmune diseases, such as ankylosing spondylitis, and inflammatory diseases, such as ulcerative colitis. Based on their immunomodulatory properties, TNF inhibitors have been used in the treatment of RSA to reduce the immune rejection rate and improvement in pregnancy outcomes has been observed in females suffering from RSA who were treated with TNF inhibitors. The aim of the present review was to interpret the involvement of TNF­α in the immunological disorder underlying RSA and summarize the clinical outcomes of TNF inhibitor treatment in patients with RSA.

RapaLink-1 plays an antithrombotic role in antiphospholipid syndrome by improving autophagy both in vivo and vitro.

BACKGROUND: RapaLink-1 is a third generation mammalian target of rapamycin (mTOR) inhibitor and displays superior inhibitory effect on mTOR complex 1 (mTORC1). mTOR pathway is known to block autophagy and inhibition of it can protect thrombosis-related diseases including atherosclerosis, antiphospholipid syndrome (APS) and stroke. The objective of this study was to investigate whether RapaLink-1 could exert anti-thrombotic effects on APS via improving autophagy. METHODS: BALB/c mice were injected with monoclonal anti-beta-2-GPI (ß2GPI) antibodies to induce APS in vivo, and anti-ß2GPI antibodies together with anticardiolipin (aCL) antibodies in mice serum were assessed. The aortas of mice were isolated, and oil red and haematoxylin and eosin (HE) staining were used for thrombus morphology. The levels of LC3B and CD68 were quantified. Human monocyte cell line THP-1 was stimulated with oxidized low-density lipoprotein (ox-LDL) and treated with RapaLink-1 in vitro. The cell viability, LDH activity, apoptosis rate and rate of fate-positive cells were detected. LC3 expression was quantified by immunofluorescence. Western blot was utilized to assess the protein expression of LC3-І, LC3-П, Beclin-1 and p62. RESULTS: The size of arterial thrombus plaque together with the level of anti-ß2GPI antibodies and aCL was reduced by RapaLink-1. Immunostaining protocols confirmed that the application of RapaLink-1 inhibited plaque initiation and progression while decreased the extent of macrophage infiltration and enhanced the autophagy process. In vitro cultured THP-1 macrophages exposed to ox-LDL study showed that RapaLink-1 prevented cell apoptosis and enhanced autophagy of macrophages, indicated by the increasing expression of autophagy-related protein and morphological character under electron microscopy. CONCLUSION: Our results revealed that Rapalink-1 has a potential to inhibit the formation of thrombus plaque in APS and these effects were dependent on facilitating cell autophagy both in vivo and in vitro.

Gentiopicrin exerts anti-rheumatic effect in human fibroblast-like synoviocytes via inhibition of p38MAPK/NF-κB pathway.

To investigate the effect of gentiopicrin on the expressions of inflammatory factors in human fibroblast-like synoviocytes (HFLS) and the underlying mechanism. Human fibroblast-like synoviocytes (HFLS) were cultured in vitro at 37 °C in Dulbecco's modified Eagle's medium (DMEM) supplemented with 5 % fetal bovine serum (FBS) in a humidified incubator containing 5 % CO2. Cell viability was determined using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-tetrazolium bromide (MTT) assay, while real-time quantitative polymerase chain reaction (qRT-PCR) was used to determine the expressions of interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) mRNAs. The expressions of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor kappa light chain enhancer of activated B cells (NF-κB) were determined using Western blotting. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of IL-1ß and IL-6 in cell lysate. Treatment with 5-25 µM gentiopicrin did not significantly affect the number of viable cells, when compared with control group (p > 0.05). However, at 50 and 100 µM gentiopicrin, the number of viable cells were significantly increased, relative to control group (p < 0.05). Results of qRT-PCR showed that the expression levels of IL-1ß and IL-6 mRNAs were significantly higher in TNF-α group than in control group (p < 0.05). However, treatment with gentiopicrin significantly and dose-dependently decreased their expression levels compared with TNF-α group (p < 0.05). Western blotting results showed that the expressions of p-p38MAPK and NF-κB-p65 proteins were significantly upregulated in TNF-α group, when compared with control group (p < 0.05). However, treatment with gentiopicrin significantly and dose-dependently down-regulated the expression of these proteins compared with TNF-α group (p < 0.05). The levels of IL-1ß and IL-6 in cell lysate were significantly higher in TNF-α group than in control group (p < 0.05). However, treatment with gentiopicrin, and p38MAPK/NF-κB pathway inhibitors (SB203580 and BAY11-7082) significantly reduced the levels of these inflammatory factors compared with TNF-α group (p < 0.05).  Gentiopicrin has therapeutic potential for Rheumatoid arthritis (RA  ) through a mechanism involving the inhibition of p38MAPK/NF-κB pathway.