穿山龙在系统性红斑狼疮的临床应用

目的 评估2019欧洲抗风湿病联盟/美国风湿病学会（EULAR/ACR）、2012系统性狼疮国际合作组（SLICC）和1997ACR三个分类标准在中国西南地区儿童系统性红斑狼疮（cSLE）中的诊断效能。 方法 回顾性分析2013年1月至2022年12月四川大学华西第二医院264例cSLE及237例非cSLE结缔组织病患儿。通过对比三种分类标准的敏感性、特异性、阳性/阴性预测值及准确度，结合性别与年龄分层分析，综合评价其诊断效能。进一步采用受试者工作特征曲线（ROC）分析EULAR/ACR-2019分类标准敏感性最大化时的截断值。 结果 SLICC-2012分类标准相比较ACR-1997分类标准和EULAR/ACR-2019分类标准拥有更高的敏感性（93.9% vs. 76.5% vs. 90.2%）和准确度（95.4% vs. 87.4% vs. 93.8%），而ACR-1997分类标准特异性最高（99.5%）。分层分析显示SLICC-2012分类标准在性别及青春期前组中敏感性稳定（94%~96%）。取消EULAR/ACR-2019分类标准的抗核抗体（ANA）（≥1:80）准入限制或总分截断值调整为≥13分（原≥10分）均可提升其敏感性。 结论 SLICC-2012分类标准在中国西南地区cSLE中诊断效能最优。调整EULAR/ACR-2019分类标准截断值及准入条件可改善其儿科适用性。

朱振红，吕柳，李威，刘春平，朱华超，胡杰，王永宏，王海隆* 北京中医药大学东直门医院风湿病科，北京 摘要：近些年来随着人民生活方式的变迁，系统性红斑狼疮疾病常见之临床，因此加强其防治，对于提高人们的健康具有重大的现实意义，我们认为，毒邪在系统性红斑狼疮的发病、进展中起着不容忽视的作用，应加强毒邪对其致病作用的研究。

目的 系统性红斑狼疮(systemic lupus erythematosus，SLE)是一种以自身抗体异常生成、免疫失衡及多系统受累为主要特征的慢性自身免疫性疾病。本研究旨在探究芳香烃受体(aryl hydrocarbon receptor，AHR)激活对SLE患者滤泡调节性T(T follicular regulatory，Tfr)细胞分化和叉头框蛋白P3(forkhead box protein P3，FOXP3)表达的影响，并从表观遗传学角度阐明其内在分子机制。 方法 选取2025年6月至12月于中南大学湘雅三医院皮肤科及风湿免疫科就诊的SLE患者18例及健康体检者18例，并招募健康志愿者3例收集外周血完成机制部分研究。采用密度梯度离心法分离外周血单个核细胞，分选CD4+ T细胞。采用流式细胞术检测Tfr细胞比例(Tfr%)及FOXP3、AHR的表达水平，并分析其与疾病活动度的相关性。体外分离健康人CD4⁺ T细胞，分为Control组[二甲基亚砜(dimethyl sulfoxide，DMSO)处理]、ITE组{AHR激动剂2-(1’H-吲哚-3’-羰基)噻唑-4-羧酸甲酯[2-(1’H-Indol-3’-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester，ITE]处理}、A-485组(P300抑制剂A-485处理)及ITE+A-485组(ITE、A-485共处理)，采用细胞计数试剂盒-8(cell counting kit-8，CCK-8)法、流式细胞术、蛋白质印迹法及实时反转录聚合酶链反应(polymerase chain reaction，PCR)检测细胞增殖活性、Tfr%及相应T细胞中FOXP3、AHR蛋白与细胞毒性T淋巴细胞相关蛋白4(cytotoxic T-lymphocyte associated protein 4，CTLA-4)及白细胞介素10(interleukin-10，IL-10)的mRNA表达水平。将AHR、P300过表达质粒共转染至健康人CD4+ T细胞中，采用免疫共沉淀(co-immunoprecipitation，Co-IP)验证AHR与P300的蛋白质相互作用。采用染色质免疫共沉淀(chromatin immunoprecipitation，ChIP)-PCR验证AHR、P300在FOXP3启动子区结合位点，ChIP-定量PCR(quantitative PCR，qPCR)检测各组健康人CD4+ T细胞AHR、P300在FOXP3启动子区域的结合水平及组蛋白乙酰化水平。收集SLE患者外周血CD4+ T细胞，经CD3/CD28 T细胞激活磁珠活化后，分别给予DMSO与ITE处理。采用流式细胞术检测SLE患者CD4+ T细胞中Tfr%、FOXP3表达水平，采用ChIP-qPCR检测AHR、P300在FOXP3启动子区域的结合水平及组蛋白乙酰化水平。 结果 与健康对照组相比，SLE患者外周血CD4+ T细胞中Tfr%显著降低(P<0.001)，且与SLE疾病活动指数(systemic lupus erythematosus disease activity index，SLEDAI)呈负相关(r=-0.803，P<0.001)；Tfr细胞中FOXP3和AHR蛋白表达水平均显著下调(均P<0.01)，且二者呈正相关(r=0.596，P<0.05)。CCK-8法结果显示ITE在0~349.27 nmol/L浓度范围内、A-485在0~93.20 nmol/L浓度范围内对CD4+ T细胞增殖活性无明显影响(均P>0.05)。体外实验结果显示，与Control组相比，ITE组Tfr%、AHR、FOXP3蛋白，以及CTLA-4、IL-10的mRNA表达水平均显著上调(均P<0.05)。Co-IP实验证实，AHR与P300在CD4+ T细胞中存在蛋白质相互作用。ChIP-PCR结果显示，AHR在FOXP3启动子区域-78 bp至-263 bp及-431 bp至-596 bp区段存在结合位点，P300可结合至FOXP3启动子区域-78 bp至-263 bp区段。ChIP-qPCR结果显示，与Control组相比，ITE组FOXP3启动子区域组蛋白H3尾部赖氨酸残基(H3K9ac、H3K14ac)的乙酰化水平及AHR、P300结合水平均显著升高(均P<0.05)，A-485组FOXP3启动子区域H3K9ac、H3K14ac乙酰化水平及P300结合水平均显著降低(均P<0.05)，AHR结合水平无明显变化(P>0.05)。功能挽救实验结果显示，与ITE组相比，ITE+A-485组FOXP3蛋白表达水平及Tfr%均显著降低(均P<0.05)，FOXP3启动子区域H3K9ac、H3K14ac乙酰化水平及P300结合水平均显著降低(均P<0.05)，AHR结合水平无明显变化(P>0.05)；与A-485组相比，ITE+A-485组FOXP3启动子区AHR结合水平及FOXP3蛋白表达水平均显著上调(均P<0.05)，但低于ITE组，FOXP3启动子区H3K9ac、H3K14ac乙酰化水平及P300结合水平均无明显变化(均P>0.05)。在SLE患者CD4+ T细胞中验证发现，ITE处理后，Tfr%升高、FOXP3表达上调，FOXP3启动子区乙酰化水平、AHR及P300结合水平均升高(均P<0.05)，与上述结果一致。 结论 SLE患者外周血CD4+ T细胞中Tfr%降低及FOXP3表达下降可能与AHR表达不足有关。AHR激活可促进FOXP3表达并诱导Tfr细胞分化，其作用可能与AHR募集P300至FOXP3启动子区域并增强局部组蛋白乙酰化有关。

维生素D是维持机体正常生理活动的必需维生素。大量研究表明，维生素D作为脂溶性维生素，除钙磷代谢经典效应外，在机体的免疫调节、抗炎症反应、细胞增殖等方面的作用日受到研究者的关注。系统性红斑狼疮（systemic lupus erythematosus,SLE）是一种是受环境、遗传等多种因素共同作用下导致多组织、多器官损害的特异性自身免疫性结缔组织病。在诸多因素中，维生素D代谢通路基因对于其发生发展起十分重要的调控作用。遗传多态性是个体差异和疾病发生发展的遗传基础，单核苷酸多态性是最常见的遗传变异。多篇文献表明，维生素D代谢通路基因单核苷酸多态性与SLE有相关联性。于是论文通过查阅相关文献，从基因层面出发，对维生素代谢通路基因单核苷酸多态性与SLE发生发展相关的研究进展进行归纳总结，为未来治疗提供新思路

目的 通过研究细胞色素P450（CYP）3A5基因多态性对狼疮肾炎（lupus nephritis, LN）患者他克莫司（tacrolimus, TAC）血药浓度的影响，探索不同基因型LN患者适宜的起始剂量及达到临床缓解的时间差异，并分析影响LN预后的相关因素。 方法 招募四川大学华西医院风湿免疫科门诊就诊的狼疮肾炎活动期患者，测定患者CYP3A5基因型。根据基因型的不同分为AA+GA（快代谢组，基因型为CYP3A5*1/*1，即AA+CYP3A5*1/*3）、GG（慢代谢组，基因型为CYP3A5*3/*3）两组，收集每组患者的基本信息、临床表现、有无其他疾病史及用药史。每种基因型组内按照简单随机分组的原则分为两个起始剂量组，分别给予TAC 0.05 mg/（kg·d）或0.075 mg/（kg·d）起始剂量治疗。每月收集各组包括TAC血药浓度在内的实验室检查指标，血压等相关临床随访指标。每月评估患者是否达到临床缓解，若0.05 mg/（kg·d）起始组治疗2个月后未达到临床缓解者，则增加剂量至0.075 mg/（kg·d）继续观察至第6个月；0.075 mg/（kg·d）起始组治疗期间无论是否达到临床缓解，均持续随访6个月。 结果 在同一TAC起始剂量组中，GG基因型LN患者的累积缓解率均高于AA+GA基因型患者，但只有0.05 mg/（kg·d）起始剂量组中，两基因型累积缓解率差异有统计性学意义（P<0.05）；对比同一基因型的不同TAC起始剂量，0.075 mg/（kg·d）患者缓解率均高于0.05 mg/（kg·d）起始组，但只有AA+GA基因型患者中两起始剂量组缓解率差异具有统计学意义（P<0.05）。无论是同一TAC起始剂量组中不同基因型，还是同一基因型的不同TAC起始剂量，患者达到完全缓解时间差异均无统计学意义（P>0.05）。无论TAC起始剂量如何，在整个治疗过程中，GG基因型患者TAC血药浓度高于AA+GA基因型。治疗期间的TAC血药浓度（OR=1.941，95%CI 1.47～2.563, P<0.001），CYP3A5*1基因型（OR=0.161，95%CI 0.053～0.492，P=0.001），TAC起始剂量（OR=0.205，95%CI 0.113～0.371, P<0.001）均能影响患者疗效， TAC血药浓度越大，GG基因型和起始剂量为0.075 mg/（kg·d）的患者达到临床缓解的概率更大。同一基因型不同起始剂量组的不良反应发生率差异均无统计学意义（P>0.05）。 结论 TAC治疗LN患者的疗效与CYP3A5基因型、TAC血药浓度、TAC起始剂量相关。TAC的血药浓度受CYP3A5基因型的影响，慢代谢组TAC血药浓度高于快代谢组，在TAC血药浓度达到6~10 ng/mL时，LN患者更易达到临床缓解。

No abstract available

No abstract available

No abstract available

No abstract available

No abstract available

No abstract available

No abstract available

No abstract available

No abstract available

No abstract available

No abstract available

No abstract available

No abstract available

No abstract available

No abstract available

No abstract available

No abstract available

No abstract available

No abstract available

ETHNOPHARMACOLOGICAL RELEVANCE Autoimmune diseases (ADs) are characterized by high prevalence, severity, and a significant impact on quality of life. Conventional treatments, such as corticosteroids and biologics, often lead to adverse reactions. Traditional Chinese medicine, with its multi-component and multi-target characteristics, demonstrates potential as an alternative therapy for ADs. In traditional Chinese medicine, Dioscorea nipponica Makino (DnM) is often used in the treatment of rheumatic diseases and type 1 diabetes, among other autoimmune conditions. Therefore, we delve into the association of this herb with ADs. AIM OF THE STUDY We investigate the therapeutic potential and multi-target mechanisms of DnM (a traditional Chinese medicine with anti-inflammatory and immunomodulatory properties) in the treatment of ADs, elucidating its regulatory effects on immune cells and key signaling pathways. This work aims to provide a comprehensive phytopharmacological perspective for advancing ADs therapy and research. MATERIALS AND METHODS A systematic search was conducted across seven databases to analyze, compare, and review relevant studies. A comprehensive literature review was performed on the chemical components, quality control, clinical observations, pharmacological mechanisms, and toxicology of DnM, and DnM was compared to popular drug treatment strategies. RESULTS DnM and its bioactive constituents (notably dioscin, Diosgenin and Total Saponins of Rhizoma Dioscorea Nipponica (TSDN)) modulate T lymphocyte proliferation, regulate the TLR4/NF-κB pathway, suppress the release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and bidirectionally regulate apoptosis through Fas/FasL and Bcl-2/Bax pathways (depending on disease-specific microenvironments in ADs). DnM demonstrates significant therapeutic efficacy in rheumatoid arthritis, autoimmune thyroiditis, psoriasis, and systemic lupus erythematosus, alleviating symptoms, delaying disease progression, and exhibiting a favorable safety profile. CONCLUSION DnM exerts multi-target effects by modulating key inflammatory and apoptotic pathways in ADs. The NF-κB, STAT3, and TGF-β/Smad signaling pathways may serve as key targets for DnM in modulating inflammatory states in ADs, while Fas/FasL and Bax/Bcl-2 are potential mediators of its apoptosis-regulating effects. Clinical evidence supports its efficacy in rheumatoid arthritis (RA) and Hashimoto's thyroiditis (HT), highlighting its multi-faceted therapeutic potential. This review systematically summarizes DnM's clinical outcomes, mechanisms, and toxicological profile, however, large-scale randomized controlled trials are required to validate its therapeutic potential across diverse ADs. Collectively, this work underscores DnM's promise as a candidate for AD therapeutics.

Rheumatoid arthritis (RA) is a systemic autoimmune disease, and TL1A and its receptor DR3 play important roles in its pathogenesis. Th9 cells are involved in RA development. Dioscin from Dioscorea nipponica (DDN) has a therapeutic effect on RA, but its effect on TL1A/DR3 and Th9 cells remains unclear. A collagen-induced arthritis (CIA) model was established in DBA/1 mice, and the therapeutic effects of DDN were determined using pathological sections and arthritis index scores. Western blotting and PCR were used to detect TL1A, DR3, PU.1, TGF-β and IRF-4. Enzyme-linked immunosorbent assay was used to detect the expression of TL1A and IL-9 in the serum. Immunofluorescence was used to detect the localization and expression of TL1A, DR3, and PU.1 in synovial tissue. Flow cytometry was used to detect TL1A and DR3 expression in different immune cells and Th9 cells. DDN ameliorated bone destruction, inflammatory cell infiltration, synovial inflammation, cartilage tissue destruction, and proteoglycan loss. DDN downregulated TL1A, DR3, and PU.1 in the synovium of the lymph nodes and spleen and TL1A and IL-9 in the serum. DDN decreased the number of TL1A-expressing APCs and macrophages, DR3-expressing CD4 + T cells, and Th9 cells. Th9 cell differentiation-related factors TGF-β and IRF-4 were also inhibited by DDN. We conclude that DNN inhibited the expression of TL1A/DR3 in CIA mice and suppressed the expression of the Th9 cell-specific transcription factor PU.1, Th9 cell number, and IL-9 secretion. DDN inhibited the function of Th9 cells by targeting TGF-β and IRF-4 in the TL1A/DR3 pathway, thereby reducing inflammation.

A group of previously undescribed diarylheptanoids with mono/di-glucose substitution, diodiarylheptosides A-F (1-6), together with six known diarylheptanoids (7-12) were isolated from the rhizomes of Dioscorea nipponica. Their structures were established by comprehensive UV, IR, HR-ESI-MS and NMR analyses, and their absolute configurations were determined by a comparison of calculated and experimental ECD, some with optical rotations, after acid-hydrolysis. Moreover, bioassay results showed that compounds 3 and 11 exhibited stronger NO inhibitions on lipopolysaccharides-induced RAW 264.7 cells, with the IC50 values of 14.91 ± 0.62 and 12.78 ± 1.12 μM.

Chronic kidney disease (CKD) is a widespread ailment that significantly impacts global health. It is characterized by high prevalence, poor prognosis, and substantial healthcare costs, making it a major public health concern. The current clinical treatments for CKD are not entirely satisfactory, leading to a high demand for alternative therapeutic options. Chinese herbal medicine, with its long history, diverse varieties, and proven efficacy, offers a promising avenue for exploration. One such Chinese herbal medicine, Dioscorea nipponica Makino (DNM), is frequently used to treat kidney diseases. In this review, we have compiled studies examining the mechanisms of action of DNM in the context of CKD, focusing on five primary areas: improvement of oxidative stress, inhibition of renal fibrosis, regulation of metabolism, reduction of inflammatory response, and regulation of autophagy.

INTRODUCTION . Dioscin, a natural steroid saponin, has anticancer, anti-inflammatory, anti-hyperlipidemic, and glycemic capabilities. This study focused on dioscin roles and its related mechanisms in experimental lupus nephritis. MATERIALS AND METHODS . Lupus-prone NZB/W F1 mice were intragastrically administered with dioscin, prednisone or vehicle, and kidney, urine and blood samples were harvested after the mice were sacrificed. Proteinuria, blood urea nitrogen (BUN), creatinine, anti-dsDNA, IL-1β, and IL-18 levels in serum as well as IFN-γ, IL-6, IL-17 and TNF-α levels in kidney tissues were assessed. Renal histopathology was examined through hematoxylin-eosin staining. IgG and C3 expression in kidney was evaluated using immunofluorescence staining. The number of glomerular F4/80-positive cells and NLRP3-positive cells was determined by immunohistochemical staining. The protein expression was examined by western blotting. RESULTS . Dioscin alleviated lupus nephritis in NZB/W F1 mice. Dioscin declined serum anti-dsDNA level, prevented deposition of immune complexes in renal glomeruli, and inhibited the inflammatory response and infiltration of macrophages into mouse kidneys. Dioscin inhibited NF-κB and NLRP3 inflammasome in NZB/W F1 mice. CONCLUSIONS . Dioscin ameliorates lupus nephritis through inhibition of NLRP3 inflammasome and NF-κB signaling.

The objective is to provide evidence‐based and expert guidance for the screening, treatment, and management of lupus nephritis.

No abstract available

Introduction It remains unclear how the presence of renal involvement will affect the cardiovascular (CV) risk factors and complications in patients with SLE. Methods We conducted a systematic review and meta-analysis using PubMed, EMBASE, MEDLINE and Scopus to identify studies published between 1947 and 2022 that evaluate the CV risk factors and complications in patients with SLE with or without lupus nephritis (LN). Results 58 studies were evaluated, with 22 two-arm studies (n=8675) included in two-arm meta-analysis and 45 studies (n=385 315) included in proportional meta-analysis. Patients with SLE with LN showed significantly higher risk of hypertension (HT) (OR=4.93, 95% CI=3.17 to 7.65, p<0.00001, I2=56%), hyperlipidaemia (OR=11.03, 95% CI=4.20 to 28.95, p<0.00001, I2=0%) and diabetes mellitus (DM) (OR=1.88, 95% CI=1.09 to 3.25, p=0.02, I2=32%) compared with those without LN. Patients with LN showed numerically higher prevalence of myocardial infarction (OR=1.35, 95% CI=0.53 to 3.45, p=0.52, I2=78%) and cerebrovascular accident (OR=1.64, 95% CI=0.79 to 3.39, p=0.27, I2=23%) than general patients with SLE. The incidence rates of CV mortality are also increased in patients with SLE with LN compared with those without LN (11.7/1000 patient-years vs 3.6/1000 patient-years). Conclusion Patients with SLE with LN show increased risk of CV risk factors including DM, HT and hyperlipidaemia. Early identification and optimal control of these CV risk factors may reduce the risk of CV disease and other non-CV complications. PROSPERO registration number CRD42022314682.

Background Pathogenic mutations in genes encoding components of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway cause RASopathy. Here, we describe five unrelated patients with SLE carrying mutations associated with RASopathy and investigate the activity of the Ras-MAPK pathway. Methods Pathogenic variants were identified by whole-exome/whole-genome sequencing. The activity of the Ras-MAPK pathway in peripheral blood mononuclear cells (PBMC) and kidneys was evaluated using RNA sequencing and datasets from the nephroseq database, respectively. Results Five (likely) pathogenic variants in four Ras-MAPK genes were identified, including NRAS: c.G38A: p.G13D; ARAF: c.C1435T: p.R479C; KRAS: c.T341C: p.V114A; PTPN11: c.G455A: p.R152H and NRAS: c.G34A: p.G12S. Kidney injury is the main feature, presenting with nephrotic syndrome (2/5), proteinuria and haematuria (2/5). Acute kidney injury and rapidly progressive nephritic syndrome were noted in one patient each. Other clinical features included mucocutaneous lesions (5/5), cardiac involvement (4/5) and arthralgia (3/5). Laboratory abnormalities included hypocomplementaemia (5/5), presence of antiphospholipid antibodies (4/5), decreased regulatory T cells (3/3), pancytopenia (3/5) and persistent monocytosis (2/5). Kidney biopsy revealed lupus nephritis. Most patients responded well to standard therapy, with the exception of the patient with the NRAS p.G13D mutation who died. The Ras-MAPK pathway was activated in both PBMC and kidney of patients with LN as indicated by increased expression of NRAS, KRAS, RIT1, MRAS, PPP1CB, SHOC2, SOS2 and MAP2K1, as well as decreased expression of negative regulators of the Ras-MAPK pathway, CBL, LZTR1 and NF1. Conclusion Kidney involvement may be the main feature of the clinical spectrum of RASopathy. Genetic screening should be considered for patients with early onset lupus.

Background: Increasing studies in the last decade have led to the widespread understanding that C4d, a split product of complement component 4 (C4), is a potential biomarker for systemic lupus erythematosus (SLE) and lupus nephritis (LN). Purpose: The aim of this review is to summarize the highlights of studies investigating the use of C4d as a biomarker for diagnosing and monitoring SLE and LN patients. Data collection: we searched PubMed/Medline and Wanfang databases using the terms “C4d and systemic lupus erythematosus”, “C4d and lupus nephritis”, and “Complement C4d”. Results: The deposition of C4d on circulating blood cells has been shown in several clinical studies to be a potential diagnostic marker that can be used to monitor patients with SLE. In addition, C4d deposits on circulating blood cells may be a helpful diagnostic marker for LN, one of the most severe complications of SLE. Meanwhile, studies utilizing renal biopsy specimens have indicated that C4d deposition in the renal peritubular capillaries of LN patients may predict more severe LN or a worse patient prognosis. Generally, a high plasma C4d level and a high plasma C4d/C4 ratio may also be promising indicators that can be used to monitor patients with SLE and LN. Conclusions: C4d detection may be a novel strategy for further clinical prediction and therapy.

Objective To explore the efficacy of initial treatment of newly diagnosed childhood-onset lupus nephritis (cLN) with combination of belimumab and either cyclophosphamide, mycophenolate mofetil, tacrolimus or multitargeted therapy. Methods A historical control study was conducted on children aged 5–17 years with newly diagnosed cLN. All patients recruited met the 2012 Systemic Lupus International Collaborating Clinics and/or 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for SLE, and the 2003 International Society of Nephrology/Renal Pathology Society histopathological criteria for LN. The primary endpoint was primary efficacy renal response (PERR) at 12 months, and secondary endpoints included complete renal response (CRR), lupus low disease activity state (LLDAS) and remission (Definitions of Remission in Systemic Lupus Erythematosus (DORIS)) at 12 months, changes of SLE Disease Activity Index (SLEDAI) and dose of glucocorticoid (GC). Results A total of 101 patients were included with 38 patients in the belimumab group and 63 patients in the standard immunotherapy group. There were no statistically significant differences between the two groups at baseline. At 12 months, compared with the standard immunotherapy group, more patients in the belimumab group had a higher PERR (97.1% vs 80.0%, χ2=3.965, p=0.046), CRR (94.1% vs 76.6%, χ2=4.679, p=0.031), LLDAS (75.0% vs 18.6%, χ2=27.84, p<0.001) and DORIS (34.4% vs 11.9%, χ2=6.626, p=0.01). The belimumab group had faster and greater reductions in SLEDAI and dose of GC (p<0.05), with a significantly higher proportion of patients with dose of GC ≤7.5 mg/day (82.9% vs 30.4%, χ2=19.737, p<0.001). In the standard immunotherapy group, 4 patients (6.3%) experienced a decline in estimated glomerular filtration rate of 30% or more at 12 months, while no patients in the belimumab group experienced worsening of renal function. There were no serious adverse events reported in two groups, and there was no significant difference in the occurrence of infection between the two groups. Conclusion This study reported for the first time the effectiveness of combined belimumab therapy in a Chinese cohort of patients with cLN. The strategy of initial combination with belimumab helps achieve treatment targets earlier and faster GC tapering. And initial combination therapy in children with cLN with high disease activity may yield more significant benefits.

Objective To determine if the serum levels of neutrophil extracellular trap (NET) remnants (Elastase-DNA and HMGB1-DNA complexes) at the time of a lupus nephritis (LN) flare predict renal outcomes in the following 24 months. Methods This was a retrospective study performed in prospectively followed cohorts. The study included two cohorts: an exploratory cohort to assess the association between NET remnant levels and the presence of active LN, and a separate LN cohort to determine the utility of NET remnants to predict renal outcomes over the subsequent 24 months. Results Ninety-two individuals were included in the exploratory cohort (49 active systemic lupus erythematosus (SLE), 23 inactive SLE and 20 healthy controls (HC)). NET remnants were significantly higher in patients with SLE patients compared with HC (p<0.0001 for both complexes) and those with active LN (36%) had significantly higher levels of NET remnants compared with active SLE without LN (Elastase-DNA: p=0.03; HMGB1-DNA: p=0.02). The LN cohort included 109 active LN patients. Patients with proliferative LN had significantly higher levels of NET remnants than non-proliferative LN (Elastase-DNA: p<0.0001; HMGB1-DNA: p=0.0003). Patients with higher baseline levels of NET remnants had higher odds of not achieving complete remission (Elastase-DNA: OR 2.34, p=0.007; HMGB1-DNA: OR 2.61, p=0.009) and of progressing to severe renal impairment (Elastase-DNA: OR 2.84, p=0.006; HMGB1-DNA: OR 2.04, p=0.02) at 24 months after the flare. Conclusions Elastase-DNA and HMGB1-DNA complexes predict renal outcomes, suggesting they could be used to identify patients requiring more aggressive therapy at flare onset.

Major reason for mortality among systemic lupus erythematosus patients is renal failure due to the deposition of immune complexes in the glomeruli. Being a chronic disease with multiple relapses and remissions across the lifespan, it’s important to know the degree of nephritis for diagnosis as well as the long-term clinical management of the patients. Currently, renal biopsy is being used as the gold standard to diagnose and define the stages of the disease. However, renal biopsy being invasive only provides a localized picture of nephritis, and has the risk of bleeding. Additionally, it is also cost-intensive. Hence, a reliable, non-invasive biomarker is required for lupus nephritis. This study has evaluated extracellular mitochondrial components, including cell-free mitochondria, and cell-free mitochondrial DNA as probable biomarkers of the degree of nephritis. Both showed a significant correlation with proteinuria and protein-creatinine ratio. Our study substantiates their usage as clinical biomarkers of nephritis upon their validation in a larger cohort of lupus nephritis patients and other forms of nephritis. Although the current data suggest using cell-free mitochondria as a biomarker of lupus nephritis is better than the cell-free mitochondrial DNA.

Introduction Mycophenolic acid (MPA) is a primary immunosuppressive agent used in the treatment of lupus nephritis (LN). While therapeutic drug monitoring (TDM) of MPA is well established in organ transplantation, its role in LN treatment remains uncertain. Our objective was to review and summarise current knowledge on TDM of MPA in the LN treatment. Methods A systematic search was conducted in the online databases, specifically targeted patients diagnosed with LN receiving MPA treatment. The included studies had to report both MPA pharmacokinetic parameters and renal outcomes. A random-effects model meta-analysis was conducted to assess the relationship between clinical responses and MPA pharmacokinetics. Results A total of 1507 studies were initially screened, resulting in the inclusion of 16 studies for meta-analysis, encompassing 433 patients. The response group exhibited significantly higher MPA area under the concentration-time curve (AUC) compared with the non-response group (51.44±21.73 mg·h/L vs 30.30±16.24 mg·h/L). The weighted mean difference (WMD) of MPA-AUC between responders and non-responders was 16.83 mg·h/L (95% CI 10.59 to 23.06; p<0.001). Similarly, trough concentration (C0) of MPA showed a strong association with renal response, evidenced by C0 values of 2.50±1.73 mg/L in the response group vs 1.51±1.33 mg/L in the non-response group (WMD 1.37 mg/L; 95% CI 0.77 to 1.97; p<0.001). There was no significant relationship identified between MPA-AUC and adverse events. Conclusion This meta-analysis emphasised the meaningful correlation between MPA AUC and C0 with renal response in LN treatment. Randomised controlled trials are necessary to validate this approach and determine its superiority over fixed dosing in the context of LN treatment.

Objectives In SLE, deregulation of haematopoiesis is characterised by inflammatory priming and myeloid skewing of haematopoietic stem and progenitor cells (HSPCs). We sought to investigate the role of extramedullary haematopoiesis (EMH) as a key player for tissue injury in systemic autoimmune disorders. Methods Transcriptomic analysis of bone marrow (BM)-derived HSPCs from patients with SLE and NZBW/F1 lupus-prone mice was performed in combination with DNA methylation profile. Trained immunity (TI) was induced through β-glucan administration to the NZBW/F1 lupus-prone model. Disease activity was assessed through lupus nephritis (LN) histological grading. Colony-forming unit assay and adoptive cell transfer were used to assess HSPCs functionalities. Results Transcriptomic analysis shows that splenic HSPCs carry a higher inflammatory potential compared with their BM counterparts. Further induction of TI, through β-glucan administration, exacerbates splenic EMH, accentuates myeloid skewing and worsens LN. Methylomic analysis of BM-derived HSPCs demonstrates myeloid skewing which is in part driven by epigenetic tinkering. Importantly, transcriptomic analysis of human SLE BM-derived HSPCs demonstrates similar findings to those observed in diseased mice. Conclusions These data support a key role of granulocytes derived from primed HSPCs both at medullary and extramedullary sites in the pathogenesis of LN. EMH and TI contribute to SLE by sustaining the systemic inflammatory response and increasing the risk for flare.

Objective To determine if serum interferon (IFN)-α levels at the time of a lupus nephritis (LN) flare are associated with renal outcomes. Methods Patients with an LN flare who had a preflare estimated glomerular filtration rate (eGFR) ≥60 mL/min were included in the study. The following outcomes were ascertained: (1) Time to first and second LN flares during follow-up, (2) Time to a sustained decline in eGFR by 30% and 50%, and progression to end-stage renal disease (ESRD, <15 mL/min), and (3) Time to an adverse renal event (≥2 renal flares and/or at least a 30% sustained decline in eGFR during follow-up). Serum IFN-α was measured by Simoa. Results 92 patients with active LN were included in the study. Elevated serum baseline levels of IFN-α predicted poor renal outcomes. Patients with higher baseline IFN-α had a greater risk of having two or more subsequent LN flares (HR: 1.31 (1.08–1.59), p=0.006), sustained 30% decline in eGFR (HR: 1.27 (1.14–1.40), p<0.001), 50% decline in eGFR (HR: 1.27 (1.12–1.33), p<0.001) and progressing to ESRD (HR: 1.29 (1.14–1.47), p<0.001). Receiver operating characteristic analysis identified an IFN-α cut-off, 0.6 pg/ml, for predicting an adverse renal event. Conclusions Elevated serum IFN-α levels measured at the time of an LN flare are associated with poor renal outcomes, including the development of ≥2 LN flares, and a clinically meaningful decline in kidney function.

Objective To assess the effect of tubulointerstitial inflammation (TII) and interstitial fibrosis and tubular atrophy (IFTA) on kidney survival in lupus nephritis (LN). Methods Two hundred eighty five patients with biopsy-proven LN were retrospectively studied. Kidney survival was defined as the time from initial biopsy to end-stage kidney disease (ESKD), dialysis, or transplant. Kidney survival analysis was performed by the Kaplan–Meier method and the statistical difference between survival curves compared by the log-rank test. Cumulative incidence functions with competing risk of death for kidney survival were also graphed. Multivariable Cox proportional hazards regression and competing-risk analyses were performed to identify independent predictors of ESKD. Results Fifty-seven patients (20%) progressed to ESKD during a median time of 4.2 (2.0–55.2) months after biopsy. TII was present in 206 (72.3%) biopsies, while IFTA in 99 (34.7%) biopsies. Patients with moderate-to-severe IFTA had worse kidney survival than those with none or mild IFTA in both the Kaplan–Meier (p = 0.018) and the competing-risk analyses (p = 0.017). Patients with class IV ± V LN had worse kidney survival than those with non-class IV LN by the Kaplan–Meier method (p = 0.050), but not in the competing-risk analysis (p = 0.154). Worse kidney survival was also found among those with fibrous crescents than those without, in both the Kaplan–Meier (p = 0.010) and the competing-risk (p = 0.011) analyses. By multivariable Cox regression analysis, older age (HR 1.04, 95% CI 1.01–1.07) and class IV ± V LN (HR 5.06, 95% CI 1.82–14.09) were associated with higher risk of ESKD after adjusting for sex, ethnicity, TII, and IFTA. By competing-risk analyses, class IV ± V LN (SHR 3.32, 95% CI 1.25–8.83) and no response to immunosuppressive therapy (SHR 4.55, 95% CI 1.54–13.41) were associated with a higher risk of ESKD, while eGFR >90 mL/min/1.73 m2 (SHR 0.98 for each ml/min/1.73 m 2 , 95% 0.97–0.99) with a lower risk. Conclusions Patients with moderate-to-severe IFTA had worse kidney survival than those with none or mild IFTA. Worse kidney survival was also found among those with class IV LN and fibrous crescents versus those without IV LN and fibrous crescents, respectively.

The relationship between viral infection and onset of autoimmune diseases such as systemic lupus erythematosus remains uncertain. During the COVID-19 pandemic, organ-specific and multisystemic autoimmune phenomena temporally related to the viral infection have been described. Immune dysregulation triggered by the SARS-CoV-2 virus leading to hyperactivation of both the innate and adaptive immune systems contributes to the excessive production of pro-inflammatory cytokines, autoantibodies, and subsequent autoimmune manifestations. We report two patients without known autoimmune diseases who developed lupus nephritis shortly after a documented mild SARS-CoV-2 infection. Together with other similar cases in the literature, the observation supports a viral trigger of the development of systemic lupus erythematosus in susceptible individuals.

No abstract available

No abstract available

Treatment-refractory lupus nephritis (LN) has a high risk of a poor outcome and is often life-threatening. Here we report a case series of six patients (one male and five females) with a median age of 41.3 years (range, 20–61 years) with refractory LN who received renal biopsies and were subsequently treated with intravenous daratumumab, an anti-CD38 monoclonal antibody (weekly for 8 weeks, followed by eight biweekly infusions and up to eight monthly infusions). One patient did not show any improvement after 6 months of therapy, and daratumumab was discontinued. In five patients, the mean disease activity, as assessed by the Systemic Lupus Erythematosus Disease Activity 2000 index, decreased from 10.8 before treatment to 3.6 at 12 months after treatment. Mean proteinuria (5.6 g per 24 h to 0.8 g per 24 h) and mean serum creatinine (2.3 mg dl^−1 to 1.5 mg dl^−1) also decreased after 12 months. Improvement of clinical symptoms was accompanied by seroconversion of anti-double-stranded DNA antibodies; decreases in median interferon-gamma levels, B cell maturation antigen and soluble CD163 levels; and increases in C4 and interleukin-10 levels. These data suggest that daratumumab monotherapy warrants further exploration as a potential treatment for refractory LN. In a case series of six patients with refractory lupus nephritis who were treated off-label with an anti-CD38 monoclonal antibody, five patients achieved complete or partial renal responses by 12 months of follow-up.

Objective To characterise the safety and efficacy of anifrolumab in active lupus nephritis (LN) through year 2 of the phase II randomised, double-blind Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP)-LN trial (NCT02547922) of 2 anifrolumab dosing regimens versus placebo. Methods Patients received intravenous anifrolumab 900 mg for the first 3 doses followed by 300 mg anifrolumab (intensified regimen (IR)), 300 mg anifrolumab (basic regimen (BR)) or placebo every 4 weeks throughout. To continue into Year 2, patients must have achieved at least partial renal response and a glucocorticoid tapering target. Results Of 147 randomised patients, 101 completed Year 1 study treatment; of these, 75 (74%) continued into Year 2 (anifrolumab IR: n=29, BR: n=23 and placebo: n=23). During Year 2, 72% of patients reported ≥1 adverse event (AE); serious AEs were reported in 6.9%, 8.7% and 8.7% of patients (anifrolumab IR, BR and placebo, respectively); 3 patients discontinued treatment due to an AE (anifrolumab IR: n=2 and placebo: n=1) and herpes zoster was reported in 2 patients (anifrolumab IR: n=1 and BR: n=1). The study was ongoing at the start of the pandemic, but no COVID-19 cases were reported. Of the 145 patients receiving treatment, more patients on the IR attained complete renal response at Week 104 compared with those on BR or placebo (27.3% vs 18.6% and 17.8%) and simultaneously achieved sustained glucocorticoid tapering (IR: 25.0%; BR: 18.6% and placebo: 17.8%). The improvements in estimated glomerular filtration rate were numerically larger in both anifrolumab groups versus placebo. Conclusions The safety and tolerability profile through Year 2 of TULIP-LN was generally consistent with Year 1, with promising efficacy results for the anifrolumab IR regimen. Collectively, the results support further investigation of an anifrolumab intensified dosing regimen in larger populations of patients with active proliferative LN. Trial registration number NCT02547922.

Lupus nephritis (LN) is a major course of morbidity and mortality in patients with systemic lupus erythematosus (SLE), best managed by a multidisciplinary group. To this end, we gathered a group of rheumatologists, nephrologists and a nephropathologist to review current evidence regarding diagnosis and management of LN. In this consensus paper, we summarize the key points from this meeting and provide practice guidelines for the management of kidney involvement in SLE, in view of emerging new data concerning novel agents approved recently. Renal biopsy is indispensable for the management of LN. Yet, important pearls and pitfalls need to be considered regarding indications and interpretation, which are summarized in informative tables. In new-onset LN, experts agreed that, although belimumab may be added from disease onset, patients with moderate to severe proliferative nephritis (defined as: NIH activity index > 5 plus ≥ 1 of the following: (i) NIH chronicity index > 2, (ii) proteinuria > 3 g/24 h, and (iii) increase in serum creatinine > 20%) may be more likely to benefit the most. In all other patients who have already started standard-of-care treatment with either mycophenolate mofetil (MMF) or cyclophosphamide (CY), belimumab could be considered in cases with an inadequate clinical response by 3 months, or in cases that experience a nephritic flare following initial response, or have an inability to reduce the dose of glucocorticoids. In all circumstances, the drug should be given as add-on therapy, that is, in combination with a standard-of-care therapy (MMF or CY). Voclosporin could be considered for up to 3 years, in combination with MMF, in patients with heavy proteinuria (well above the nephrotic range), wherein a quick reduction of protein loss in urine is desirable to avoid the complications of the nephrotic syndrome, either as part of the initial regimen, or in cases of inadequate reduction of proteinuria with MMF. In view of the potential scarring effects, long-term administration beyond the first year requires further documentation.

Autoimmune diseases are typically characterized by aberrant activation of immune system that leads to excessive inflammatory reactions and tissue damage. Nevertheless, precise targeted and efficient therapies are limited. Thus, studies into novel therapeutic targets for the management of autoimmune diseases are urgently needed. Radical S-adenosyl methionine domain-containing 2 (RSAD2) is an interferon-stimulated gene (ISG) renowned for the antiviral properties of the protein it encodes, named viperin. An increasing number of studies have underscored the new roles of RSAD2/viperin in immunomodulation and mitochondrial metabolism. Previous studies have shown that there is a complex interplay between RSAD2/vipeirn and mitochondria and that binding of the iron-sulfur (Fe-S) cluster is necessary for the involvement of viperin in mitochondrial metabolism. Viperin influences the proliferation and development of immune cells as well as inflammation via different signaling pathways. However, the function of RSAD2/viperin varies in different studies and a comprehensive overview of this emerging theme is lacking. This review will describe the characteristics of RSAD2/viperin, decipher its function in immunometabolic processes, and clarify the crosstalk between RSAD2/viperin and mitochondria. Furthermore, we emphasize the crucial roles of RSAD2 in autoimmune diseases and its potential application value.

Alpha-fetoprotein (AFP) has long been associated with regulation and modulation of the immune system in a variety of mammals. In the last several decades, AFP has been linked to autoimmune diseases (ADs) during both pregnancy and in non-gestational disorders via an immunomodulatory function. The course of ADs are highly influenced by soluble factors such as cytokines, chemokines, interleukins, hormones, kinins, growth factors, proteins such as AFP, and various T-cells generated from the immune response. Such factors appear to serve as protective or ameliorating agents during the induction effector stages of the immune response. Immunomodulatory activities of AFP are known to affect: 1) induction of T-cell suppressor activity; 2) down-regulating dendritic-like cell antigen expression; and 3) impairing the function of macrophages and T-cells. Some factors may even be involved in blocking the rejection of the embryo/fetus as an allograft in the mother at the initiation of pregnancy. Thus, the present report reviews the immunomodulation function of AFP during the course of autoimmune disease utilizing AD disorders such as: myasthenia gravis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, autoimmune liver disorders, diabetes, thyroiditis, and others.

Introduction: Cannabinoids such as ▵-9-THC and CBD can downregulate the immune response by modulating the endocannabinoid system. This modulation is relevant for the treatment of prevalent autoimmune diseases (ADs), such as multiple sclerosis (MS), systemic lupus erythematosus (SLE), diabetes mellitus type 1 (DMT1), and rheumatoid arthritis (RA). These conditions require new therapeutic options with fewer side effects for the control of the autoimmune response. Objective: to conduct a literature review of preclinical scientific evidence that supports further clinical investigations for the use of cannabinoids (natural or synthetic) as potential immunomodulators of the immune response in ADs. Methodology: A systematic search was carried out in different databases using different MeSH terms, such as Cannabis sativa L., cannabinoids, immunomodulation, and ADs. Initially, 677 journal articles were found. After filtering by publication date (from 2000 to 2020 for SLE, DMT1, and RA; and 2010 to 2020 for MS) and removing the duplicate items, 200 articles were selected and analyzed by title and summary associated with the use of cannabinoids as immunomodulatory treatment for those diseases. Results: Evidence of the immunomodulatory effect of cannabinoids in the diseases previously mentioned, but SLE that did not meet the search criteria, was summarized from 24 journal articles. CBD was found to be one of the main modulators of the immune response. This molecule decreased the number of Th1 and Th17 proinflammatory cells and the production of the proinflammatory cytokines, interleukin (IL)-1, IL-12, IL-17, interferon (IFN)-γ, and tumor necrosis factor alpha, in mouse models of MS and DMT1. Additionally, new synthetic cannabinoid-like molecules, with agonist or antagonist activity on CB1, CB2, TRPV1, PPAR-α, and PPAR-γ receptors, have shown anti-inflammatory properties in MS, DMT1, and RA. Conclusion: Data from experimental animal models of AD showed that natural and synthetic cannabinoids downregulate inflammatory responses mediated by immune cells responsible for AD chronicity and progression. Although synthetic cannabinoid-like molecules were evaluated in just two clinical trials, they corroborated the potential use of cannabinoids to treat some ADs. Notwithstanding, new cannabinoid-based approaches are required to provide alternative treatments to patients affected by the large group of ADs.