Efficacy and safety of belimumab in patients with lupus nephritis: a real-world retrospective observational study.

OBJECTIVES: To evaluate the differences in efficacy and safety between Lupus Nephritis (LN) patients who received belimumab plus standard therapy and those who received only standard therapy in real world practice. METHODS: Patients diagnosed with LN at the First Affiliated Hospital of Wenzhou Medical University from November 2012 to July 2023 were identified, and eligible cases were divided into two groups according to whether they received additional treatment with belimumab during the course of the disease. RESULTS: A total of 1,169 LN patients were identified from our follow-up database. 112 patients receiving add-on treatment with belimumab (BLM group) and 112 control patients matched for relevant baseline characteristics were enrolled in this study. The median duration of treatment with belimumab was 13.82 [7.24, 20.29] months. Compared with the control group, the BLM group had more significant improvement in disease activity indicators such as serum albumin and complement levels, significantly lower B cell count, immunoglobulin, and earlier first attainment of renal remission, but there was no significant improvement in renal function and kidney-related events or death during the 2-year follow-up period. In the BLM group, the treatment effect of belimumab was more prominent in patients with lower levels of proteinuria. The safety profile of belimumab treatment was favorable, with a lower incidence of respiratory tract infection in the BLM group than in the control group during the follow-up period (p= 0.015). CONCLUSIONS: This real-world study revealed that add-on treatment with belimumab provided better disease remission, and the therapeutic effect was more significant in patients with lower proteinuria levels. In addition, it had a favorable safety profile and reduced the risk of respiratory tract infection.

Transcriptional Landscape of Enhancer RNAs in Peripheral Blood Mononuclear Cells from Patients with Systemic Lupus Erythematosus.

OBJECTIVE: Enhancer RNAs (eRNAs), a class of non-coding RNAs, play indispensable roles in regulating target gene transcription and maintaining cell identity in cooperation with promoters. In this study, we investigated the transcriptional landscape and potential functions of eRNAs in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE). METHODS: PBMCs from five patients with stable SLE, five patients with active SLE, and ten healthy individuals (HCs) were subjected to RNA-sequencing. Putative regulators, differential expression, and pathways were analyzed. eRNAs that were significantly upregulated were first validated by RT-qPCR in 12 samples. Then, candidate eRNAs were confirmed in a validation cohort of 45 samples. We conducted comprehensive pathway analyses to explore the correlations between the candidate eRNAs and SLE pathology. RESULTS: By analyzing eRNA transcript data from PBMCs from SLE patients and HCs, we identified various eRNAs and functional super-enhancers potentially related with SLE. The SLE-specificity of eRNAs seemed to be largely driven by SLE-specific transcription factors (TFs). A Venn diagram of eRNAs differentially expressed in stable, active, and total SLE vs HCs revealed that 13 and 23 eRNAs were commonly upregulated and downregulated, respectively, in patients with stable SLE and those with active SLE. The commonly upregulated eRNAs participate in regulating SLE-related pathways. Only eRNA TCONS_00034326 was significantly (P < 0.05) upregulated in PBMCs of patients with SLE when compared with those of HCs as indicated by RT-qPCR. The area under the receiver-operating curve of TCONS_00034326 for distinguishing SLE patients from HCs was 0.691. Through its putative SLE-related master TF, TCONS_00034326 is involved in multiple SLE-relevant signaling pathways, especially tumor necrosis factor signaling. CONCLUSION: This study unraveled the transcriptional landscape of eRNAs, eRNA-related TFs, and super-enhancers in PBMCs from SLE patients and HCs. We identified a panel of SLE-relevant eRNAs, providing potential targets in SLE pathogenesis.

Relationship of complement activation pathway to clinical and pathological characteristics and renal outcome in patients with lupus nephritis.

BACKGROUND: Involvement of the complement system in the pathogenesis of lupus nephritis (LN) is well accepted, but its exact role remains unclear. The aim of this study was to investigate the relationship of complement activation pathway to clinical and pathological characteristics and renal outcome in patients with LN. MATERIAL AND METHODS: Patients with LN were divided into two groups: those in whom the complement system was mainly activated through the classical pathway (low serum C3 and C4 levels; CP group); and those in whom the complement system was solely activated through the alternative pathway (low serum C3 with normal C4 levels; AP group). Clinical and pathological data and renal outcomes were compared between the two groups. RESULTS: A total of 102 LN patients were enrolled in this study, 63 patients (61.8%) in the CP group and 39 patients (38.2%) in the AP group. LN patients in the CP group had significantly higher SLEDAI (p < 0.001), more anti-dsDNA (p = 0.001), higher renal activity index (p < 0.001), and more class IV LN (p = 0.008) than LN patients in the AP group. Mean length of follow-up was 50.6 ± 26.4 months. Renal outcome in the form of progression of kidney disease was significantly poorer in the CP group in the AP group (p = 0.037). CONCLUSION: Our findings suggest that evaluation of the complement activation pattern may be useful for evaluating disease activity and predicting the prognosis of LN.

microRNA-199a may be involved in the pathogenesis of lupus nephritis via modulating the activation of NF-κB by targeting Klotho.

Klotho is considered to have renal protective effect by prohibiting the activation of the nuclear factor (NF)-κB pathway, while the role of microRNA-199a (miR-199a)/Klotho in lupus nephritis (LN) is still unknown. A single dose of pristane (0.5 ml) was intraperitoneally injected into 8 weeks-old female mice to establish the LN model. MiR-199a mimic or miR-199a inhibitor, Klotho plasmid or Klotho siRNA, and miR-199a inhibitor plus si-Klotho were transfected into lipopolysaccharides (LPS) stimulated human embryonic kidney 293 T (HEK293 T) cells. Western Blot was adopted to measure p-P65 expression. Tumor necrosis factor (TNF)-α and interleukin (IL)-1ß in the supernatant were determined by enzyme-linked immunosorbent assay (ELISA). The expression of Klotho was suppressed by miR-199a through direct binding to the three prime untranslated regions (3'-UTR). The high miR-199a level was accompanied by low Klotho expression in the LN kidney. MiR-199a promoted LPS-induced NF-κB activation and improved the secretion of TNF-α and IL-1ß by regulation of Klotho in HEK293 T cells. If miR-199a antagomir was administrated after 48 h of pristane administration, the expression of p-P65 and the secretion of TNF-α and IL-1ß were significantly down-regulated in LN kidney. Although the direct involvement and detailed mechanism of miR-199a in LN still need further investigation, our data show that MiR-199a could regulate the activation of NF-κB by directly targeting Klotho.

Cryptococcal meningitis in adult patients with primary nephrotic syndrome
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BACKGROUND: Cryptococcal meningitis (CM) is a rare condition in patients with primary nephrotic syndrome (PNS). Here, we describe the clinical characteristics, possible risk factors, and outcomes of eleven patients with PNS and CM. MATERIALS AND METHODS: A systematic review of medical records from 11 patients with PNS and CM admitted to the First Affiliated Hospital of Wenzhou Medical University from April 2005 to April 2015 was performed. A total of 30 cases were randomly selected as controls from PNS inpatients without infection during the same period. RESULTS: The mean age at presentation was 64.6 years (range: 47.8 - 72.2 years), and the female-to-male ratio was 5 : 6. The mean duration of PNS was 14.0 months (range: 1 - 25 months); the cumulative prednisone dose over the preceding year was 3.8 ± 1.98 g; the mean albumin level was 25.8 ± 10.1 g/L; the mean serum creatinine level was 116.4 ± 64.3 µmol/L. Three patients died, 1 patient survived with sequelae, and 7 patients survived without sequelae. Unfavorable outcomes were associated with low serum albumin levels (p = 0.004) and higher cumulative prednisone dose over the preceding year (p = 0.025). Compared with PNS patients without infections, those with CM were older (p < 0.001) and usually had higher serum creatinine levels (p < 0.001). CONCLUSION: Old age and high serum creatinine levels are important risk factors for the development of CM in patients with PNS.
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Icariin alleviates murine lupus nephritis via inhibiting NF-κB activation pathway and NLRP3 inflammasome.

AIMS: Lupus nephritis (LN) is a kidney inflammatory disease caused by systemic lupus erythematosus (SLE). Both NF-κB activation and NLRP3 inflammasome activation are implicated in LN pathogenesis, suggesting they are potential targets for LN treatment. Icariin, which is isolated from Chinese medicine Horny Goat Weed (Ying Yang Huo), has been shown to have anti-inflammation activity, and inhibit activations of both NF-κB and NLRP3 inflammasome. In present study, the effects of icariin on LN were evaluated in MRL/lpr mice. MAIN METHODS: We treated MRL/lpr mice with icariin for 8 weeks and then analyzed the renal function and kidney pathology. We monitored the levels of anti-dsDNA antibody and the deposition of immune complex after icariin treatment. We also detected the macrophage infiltration, NF-κB activation, NLRP3 inflammasome activation and inflammatory cytokine TNF-α production in MRL/lpr mice after icariin treatment. KEY FINDINGS: We found that MRL/lpr mice treated with icariin displayed significantly attenuated the renal disease. Icariin-treated mice showed significantly reduced serum anti-dsDNA antibody level and immune complex deposition. Icariin inhibited NF-κB activation and TNF-α production in MRL/lpr mice. Icariin inhibited CCL2 production and macrophage infiltration in MRL/lpr mice. Finally, icariin suppressed NLRP3 inflammasome activation and IL-1ß production in MRL/lpr mice. SIGNIFICANCE: Icariin alleviated murine lupus nephritis via inhibiting NF-κB activation and NLRP3 inflammasome activation.

Clinical characteristics and risk factors of severe infections in hospitalized adult patients with primary nephrotic syndrome.

Objective Infection is a common condition in patients with nephrotic syndrome. The objective of the present study is to investigate the clinical characteristics and risk factors of infections in adult patients with primary nephrotic syndrome (PNS). Methods Medical charts of 138 consecutive patients with PNS and infections who were admitted to hospital from April 2013 to April 2016 were systematically reviewed. Results Patients were divided into three groups according to the degree of infections: mild infection group (n = 45), moderate infection group (n = 60), and severe infection group (n = 33). In the severe infection group, most patients (96.9%) had pulmonary infections with opportunistic pathogens. There were significant differences in cumulative prednisone dose, immunosuppressor use, and CD4+ T cell count among the three groups. A lower CD4+ T cell count (<300 cells/mm3) (odds ratio = 4.25 [95% confidence interval 1.680-10.98]) and higher cumulative dose of prednisone (odds ratio = 1.38 [95% confidence interval 1.05-3.26]) were risk factors for severe infections in adult patients with PNS. Conclusions CD4+ T cell count (<300 cells/mm3) and a higher cumulative dose of prednisone are important risk factors for severe infections in adult patients with PNS.

Plasma levels of the tissue inhibitor matrix metalloproteinase-3 as a potential biomarker in oral cancer progression.

Oral cancer is the most common malignancy with poor prognosis and is the fourth most common cancer in men in Taiwan. The tissue inhibitor of metalloproteinase-3 (TIMP3) acts as a tumor suppressor gene by inhibiting the growth, angiogenesis, migration, and invasion of cancer cells. However, few studies have examined the association of plasma TIMP3 levels with oral squamous cell carcinoma (OSCC), and the role of plasma TIMP3 levels in OSCC progression is still unclear. We measured the plasma TIMP3 levels of 450 OSCC patients and 64 healthy controls by using a commercial enzyme-linked immunosorbent assay. We also analyzed TIMP3 mRNA levels of 328 OSCC patients and 32 normal tissues from The Cancer Genome Atlas (TCGA) dataset. Our results revealed that plasma TIMP3 levels were significantly lower in patients with OSCC than in healthy controls (p < 0.001). Moreover, plasma TIMP3 levels in patients with OSCC were significantly associated with the tumor stage and tumor status but not with the lymph node status, metastasis, and cell differentiation. To verify our findings, we also examined TCGA bioinformatics database and discovered similar results for the association with the pathological stage of OSCC. In conclusion, our results suggest that plasma TIMP3 is a potential biomarker for predicting the tumor stage and T status in patients with OSCC.

Functional variants inPXRare associated with colorectal cancer susceptibility in Chinese populations.

BACKGROUND: As an important member of the steroid nuclear receptor family, recent research has suggested that PXR may play important roles in the development of multiple cancers. However, no well-designed studies has been conducted to investigate the associations between genetic polymorphisms of PXR and colorectal cancer (CRC) risk in Chinese populations. MATERIALS AND METHODS: We performed a hospital-based case-control analysis to assess two genetic polymorphisms in the 3'-untranslated regions (3'-UTR) via allele-specific MALDI-TOF mass spectrometry assay and evaluated the associations between two polymorphisms and risk of CRC. RESULTS: The PXR rs3814058C>T polymorphism was significantly associated with a higher risk of CRC (P<10-3), and the CT/TT variant genotypes had an increased CRC risk (adjusted odds ratio=1.54, 95% confidence interval=1.27-1.83) comparing CC genotype. In stratified analyses, rs3814058CT+TT genotypes was associated with increased risk among alcohol consumers (P=0.002). In vitro experiments indicated that the rs3814058C to rs3814058T transition gained a new binding of the microRNA hsa-miR-129-5p and decreased the PXR expression. CONCLUSIONS: Our data suggest that the functional polymorphism rs3814058C>T in 3'-UTR of PXR may be a functional biomarker to predict risk of CRC.