Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease associated with diffuse immune cell dysfunction. CD40-CD40 ligand (CD40L) interaction activates B cells, antigen-presenting cells and platelets. CD40L blockade might provide an innovative treatment for systemic autoimmune disorders. We investigated the safety and clinical activity of dapirolizumab pegol, a polyethylene glycol conjugated anti-CD40L Fab' fragment, in patients with SLE.This 32-week randomised, double-blind, multicentre study (NCT01764594) evaluated repeated intravenous administration of dapirolizumab pegol in patients with SLE who were positive for/had history of antidouble stranded DNA/antinuclear antibodies and were on stable doses of immunomodulatory therapies (if applicable). Sixteen patients were randomised to 30 mg/kg dapirolizumab pegol followed by 15 mg/kg every 2 weeks for 10 weeks; eight patients received a matched placebo regimen. Randomisation was stratified by evidence of antiphospholipid antibodies. Patients were followed for 18 weeks after the final dose.No serious treatment-emergent adverse events, thromboembolic events or deaths occurred. Adverse events were mild or moderate, transient and resolved without intervention. One patient withdrew due to infection.Efficacy assessments were conducted only in patients with high disease activity at baseline. Five of 11 (46%) dapirolizumab pegol-treated patients achieved British Isles Lupus Assessment Group-based Composite Lupus Assessment response (vs 1/7; 14% placebo) and 5/12 (42%) evaluable for SLE Responder Index-4 responded by week 12 (vs 1/7; 14% placebo). Mechanism-related gene expression changes were observed in blood RNA samples.Dapirolizumab pegol could be an effective biological treatment for SLE. Further studies are required to address efficacy and safety.NCT01764594.© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

End‐stage renal disease (ESRD) is a major consequence of lupus nephritis, but how this risk has changed over time is unknown. We conducted this systematic review to examine changes in ESRD among adults with lupus nephritis from 1971 to 2015 and to estimate risks of ESRD among contemporary patients.

Conventional treatment of systemic lupus erythematosus (SLE) and lupus nephritis (LN) is associated with damage accrual, hence increased morbidity rate. Off-label use of rituximab (RTX) has shown significant promise in this patient group; however, data are still controversial. We aimed to analyze the outcomes of RTX therapy in refractory lupus using a meta-analysis approach.Electronic search of the medical literature was conducted using a combination of relevant keywords to retrieve studies on the safety and efficacy of RTX in SLE and LN patients. Results were screened against our inclusion and exclusion criteria and two reviewers independently extracted the data for analysis. Comprehensive meta-analysis software was used to pool the data from individual studies and provide summary effect estimates.Thirty-one studies that enrolled 1112 patients were finally eligible for the meta-analysis. The overall global, complete, and partial response rates to RTX therapy were 72%, 46%, and 32%, respectively. RTX significantly decreased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and British Isles Lupus Activity Group (BILAG) scores (p<0.001). Prednisone dose was significantly reduced after RTX treatment in both SLE and LN groups (p<0.001), and proteinuria was lowered in SLE (p<0.001) than in LN patients (p=0.07). Infection and infusion-related reactions were the most common side effects.RTX therapy in refractory SLE and LN patients proved clinical efficacy and favorable safety outcomes. Larger well-designed randomized clinical trials are warranted.

Systemic lupus erythematosus (SLE) is the prototype of autoimmune disorders caused by a loss of tolerance to endogenous nuclear antigens triggering an aberrant autoimmune response targeting various tissues. Lupus nephritis (LN), a major cause of morbidity and mortality in patients with SLE, affects up to 60% of patients. The recent insights into the genetic and molecular basis of SLE and LN paved the way for newer therapies to be developed for these patients. Apart from the traditional B-cell-centered view of this disease pathogenesis, acknowledging that multiple extrarenal and intrarenal pathways contribute to kidney-specific autoimmunity and injury may help refine the individual therapeutic and prognostic characterization of such patients. Accordingly, the formerly induction-maintenance treatment strategy was recently challenged with the exciting results obtained from the trials that evaluated add-on therapy with voclosporin, belimumab, or Obinutuzumab. The scope of this review is to provide an insight into the current knowledge of LN pathogenesis and future therapeutic strategies.

Dysregulation of the B-cell activating factor (BAFF) system is involved in the pathogenesis of systemic lupus erythematosus (SLE). Increased serum concentrations of BAFF are related to lupus nephritis and disease activity among SLE patients. Recently, a variant of the BAFF-encoding gene, BAFF-var, was identified to be associated with autoimmune diseases, in particular SLE, and to promote the production of soluble BAFF. The present study aimed to assess the prevalence of BAFF-var in a cohort of 195 SLE patients and to analyze the association of the BAFF-var genotype (TNSF13B) with various manifestations of SLE.A cohort of 195 SLE patients from Central Europe, including 153 patients from the Swiss SLE Cohort Study and 42 patients from the University Hospital Essen, Germany, underwent genotyping for detection of BAFF-var allele.Of the 195 patients, 18 (9.2%) tested positive for BAFF-var variant according to the minor allele frequency of 4.6%. The presence of BAFF-var was associated with the occurrence of lupus nephritis (p = 0.038) (p = 0.03 and p = 0.003). Among various organ manifestations of SLE, the presence of BAFF-var was associated with the occurrence of lupus nephritis (p = 0.038; odds ratio [OR], 2.4; 95% confidence interval [CI], 0.89-6.34) and renal activity markers such as proteinuria and hematuria (p = 0.03; OR, 2.4; 95% CI, 0.9-6.4 for proteinuria; p = 0.003; OR, 3.9; 95% CI, 1.43-10.76 for hematuria). SLE patients carrying the BAFF-var allele exhibited increased disease activity at study entry, as determined by the physician's global assessment (PGA: p = 0.002; OR, 4.8; 95% CI, 1.54-14.93) and the SLE Disease Activity Index (p = 0.012; OR, 3.5; 95% CI, 1.12-11.18). Consistent with that, the percentage of patients treated with immunosuppressive agents at study entry was higher among those carrying the BAFF-var allele than among those tested negative for BAFF-var (p = 0.006; OR, 3.7; 95% CI, 1.27-10.84).Our results indicate an association between the BAFF-var genotype and increased severity of SLE. Determining the BAFF-var status of SLE patients may improve the risk stratification of patients for whom the development of lupus nephritis is more likely and thus may be helpful in the follow-up care and treatment of SLE patients.

Intravenous belimumab plus standard of care (SoC) is approved in the USA and Europe for treatment of active, autoantibody-positive systemic lupus erythematosus (SLE).This phase III, multicentre, randomised, double-blind, placebo-controlled study (BEL113750; NCT01345253) was conducted in 49 centres across China, Japan and South Korea (May 2011September 2015). Patients with SLE were randomised 2:1 to intravenous belimumab 10 mg/kg or placebo, plus SoC, every 4 weeks until Week 48. The primary endpoint was the SLE Responder Index (SRI) 4 response rate at Week 52. Secondary endpoints were the percentage of patients with ≥4 point reduction in Safety of Oestrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI), SRI7, time to first severe flare and number of days prednisone (or equivalent) dose ≤7.5 mg/day and/or reduced by 50% from baseline. Safety was assessed.The modified intent-to-treat population included 677 patients (belimumab n=451, placebo n=226). At Week 52, the SRI4 response rate was higher with belimumab versus placebo (53.8% vs 40.1%; OR: 1.99 (95% CI: 1.40, 2.82; P=0.0001)). The percentages of patients with a ≥4 point reduction in SELENA-SLEDAI and an SRI7 response were significantly greater for belimumab versus placebo. Patients in the belimumab group had a 50% lower risk of experiencing a severe flare than those receiving placebo (P=0.0004). In patients with baseline prednisone dose >7.5 mg/day, there was a significant reduction in steroid use favouring belimumab (P=0.0228). The incidence of adverse events was similar between groups.In patients with SLE from North East Asia, belimumab significantly improved disease activity, while reducing prednisone use, with no new safety issues.© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

目的 分析血清B细胞活化因子（sBAFF）水平与狼疮肾炎（LN）患儿临床与病理特征的关系，探讨其在儿童LN中的意义。 方法 纳入2014年10月1日至2016年12月31日在中山大学附属第一医院小儿肾病中心确诊LN且有完整临床资料的患儿54例，按初入院时的治疗情况分为经治组（已接受激素和/或免疫抑制剂治疗，44例）和初发组（既往未接受激素和/或免疫抑制剂治疗，10例）；按诱导治疗6个月后是否肾脏缓解分为缓解组（20例）和非缓解组（34例）；按是否出现肾脏复发分为复发组（6例）和非复发组（48例）；按入院后肾活检病理结果分为病理III型组（5例）、IV型组（28例）和V型组（10例）。15名体检健康儿童为对照组。以酶联免疫吸附测定法（ELISA）检测sBAFF水平，分析其与临床资料、检验指标、肾活检病理及随访预后的相关性。 结果 （1）LN患儿sBAFF水平高于对照组（t=3.821，P＜0.001）；合并神经精神性狼疮（NPSLE）者sBAFF水平高于未合并者（t=2.202，P=0.032）。（2）初发组sBAFF水平高于经治组（LSD-t=2.309，P=0.025）。肾脏非缓解组sBAFF水平高于缓解组（LSD-t=2.035，P=0.046）。（3）病理Ⅲ型、Ⅳ型及Ⅴ型组间sBAFF水平差异无统计学意义（F=1.080，P=0.459）。LN患儿sBAFF水平与Austin肾脏病理评分中急性病变指数（AI）或慢性病变指数（CI）均无相关性（r=-0.273，P=0.063；r=0.150，P=0.314）。（4）单因素分析提示LN患儿sBAFF水平与血白细胞水平呈负相关（r=-0.337，P=0.013），与血沉及血IgG水平呈正相关（r=0.289，P=0.036；r=0.340，P=0.017）。多重线性回归分析示肾脏缓解情况（β'=-0.271，P=0.037）与血清IgG水平（β'=0.517，P=0.001）为sBAFF水平的独立影响因素。 结论 LN患儿肾脏缓解情况及血清IgG水平是sBAFF水平的影响因素。sBAFF水平有助于临床评估LN患儿的肾脏缓解情况。

Renal involvement in systemic lupus erythematosus (SLE) carries substantial morbidity and mortality. Conventional immunosuppressive agents (cyclophosphamide and azathioprine) have suboptimal efficacy and substantial toxicity. Mycophenolate mofetil has emerged as an alternative agent for both induction and maintenance therapy in lupus nephritis because of its reduced gonadal toxicity, despite its failure to demonstrate superiority over cyclophosphamide in pivotal studies. The calcineurin inhibitor tacrolimus has equivalent efficacy to cyclophosphamide and mycophenolate mofetil for inducing remission of lupus nephritis. Although rituximab has shown promise in refractory lupus nephritis, combining rituximab with mycophenolate mofetil as initial therapy offers no additional benefit. Considerable interethnic variation is evident in the efficacy and tolerability of the various immunosuppressive regimens, which necessitates individualized treatment and comparison of the efficacy of new regimens across different ethnic groups. For example, low-dose combinations of tacrolimus and mycophenolate mofetil seem to be more effective than pulse cyclophosphamide as induction therapy in Chinese patients. The same regimen has also been used successfully to treat refractory proliferative and membranous lupus nephritis in patients of various ethnic groups. Finally, novel serum and urinary biomarkers are being validated for diagnosis, prognostic stratification and early recognition of flares in lupus nephritis.

Lupus nephritis (LN) is associated with significant morbidity and mortality. Current treatment outcomes remain suboptimal. No disease modifying medications are licensed for the treatment of LN. Voclosporin, a novel calcineurin inhibitor, has been investigated as induction therapy in LN in combination with myocophenolate mofetil (MMF) and a glucocorticoid (GC). Two phase II trials of voclosporin were the first trials of a potential treatment of active LN that met their primary endpoints. Areas covered: This article reviews the pharmacology of voclosporin and the efficacy and safety data from the two existing phase II trials. In the phase IIb randomized controlled trial AURA-LV, voclosporin was shown to be superior to placebo, when used in combination with MMF (1-2 g/day) and GC, in achieving remission in active LN. Expert opinion: While the positive outcome of existing trials is promising, further data confirming its efficacy and evaluating its safety are required. A phase III trial is currently recruiting. Importantly, the positive results were achieved despite a novel and rapid GC taper regime, suggesting that rapid taper of GC may be a viable treatment option in active LN which merits further investigation.

To evaluate the efficacy and safety of ustekinumab through 1 year in a phase II trial in patients with systemic lupus erythematosus (SLE).

To evaluate the safety of sifalimumab in Japanese patients with systemic lupus erythematosus (SLE). This phase 2, open-label study consisted of a 52-week initial stage (Stage I) and a long-term extension (Stage II). In Stage I, sequential cohorts of patients received ascending doses of sifalimumab (intravenous [IV] 1.0, 3.0, and 10.0 mg/kg or subcutaneous 100 mg every 2 weeks; IV 600 and 1200 mg every 6 weeks). In Stage II, patients enrolled before June 2012 received the same dose of sifalimumab as during Stage I for up to 157 weeks or sifalimumab 600 mg IV every 4 weeks if they enrolled later. The safety of sifalimumab was assessed by adverse events (AEs). Thirty patients enrolled in Stage I and 21 patients entered Stage II. The majority of patients experienced AEs (96.7% in Stage I and 100% in Stage II); most were mild or moderate in severity. Serious AEs occurred in 30.0% and 57.1% of patients in Stage I and II, respectively; most were instances of SLE flares. The proportion of patients in Stage I and II who had AEs leading to discontinuation was 10.0% and 28.6%, respectively. Sifalimumab was well tolerated in Japanese patients with SLE.

Lupus nephritis depends on autoantibody deposition and activation of multiple immune cell types that promote kidney inflammation, including lymphocytes and monocyte/macrophages. Laquinimod, currently in clinical trials for multiple sclerosis and lupus nephritis, reduces infiltration of inflammatory cells into the spinal cord in experimental autoimmune encephalomyelitis. Activated monocyte/macrophages infiltrate the kidneys during nephritis in systemic lupus erythematosus (SLE). We undertook this study to determine whether using laquinimod to reduce monocyte/macrophage‐driven tissue damage as well as to alter lymphocytes in SLE nephritis could have greater therapeutic benefit than current treatments that primarily affect lymphocytes, such as mycophenolate mofetil (MMF).

Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5‐eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5‐eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5‐eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.

In this study, we aimed to systematically review available literature on the efficacy of eculizumab for the treatment of renal involvement in patients with systemic lupus erythematosus (SLE). We conducted a literature search developed a priori, to identify articles reporting clinical experience with the use of eculizumab in SLE patients, focusing on renal involvement. The search strategy was applied to Ovid MEDLINE, EMBASE, In-Process and Other Non-Indexed Citation, Cochrane Central Register of Controlled Trials and Scopus from 2006 to present. Abstracts from EULAR and ACR congresses were also screened. We included six publications describing the renal outcome in SLE patients receiving eculizumab. Five out of six cases described the occurrence of thrombotic microangiopathy (TMA) in renal biopsies of patients with known SLE; three cases with biopsy-proven lupus nephritis (LN) and two patients with SLE-related antiphospholipid syndrome without histologic evidence of LN. One study reported the outcome of a patient with severe refractory LN successfully treated with eculizumab. All patients, regardless of the presence of concomitant LN, presented with severe hypocomplementemia and renal function impairment. All patients showed a sustained improvement of renal function and normalization of complement parameters after treatment with eculizumab[median follow-up 9 months (1-17)]. Despite the limitations of the currently available evidence, existing data are promising and provide preliminary support for the use of eculizumab in selected cases of SLE with renal involvement, especially in the presence of TMA, or in patients with refractory LN.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a considerable impact on patients' quality of life. Despite the plethora of clinical trials for SLE since the turn of the millennium, only one new treatment has been approved for the condition, and the overall pace of successful drug development remains slow. Nevertheless, the myriad of clinical studies has yielded insights that have informed and refined our understanding of eligibility criteria, outcome measures and trial design in SLE. In this review, we highlight the achievements of clinical trials as well as the major pitfalls that have been identified in drug development for SLE and, in doing so, identify areas where collaboration and consensus will be important to facilitate progress.© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Objective The treatment of refractory lupus nephritis (LN) remains challenging for clinicians because these patients either do not respond to conventional therapy or relapse during the maintenance treatment period. The aim of this study was to investigate the efficacy and safety of bortezomib combined with glucocorticoids in refractory lupus patients. Methodology Five refractory LN patients aged 21 to 43 years (four females and one male) with biopsy-proven diagnosis (four with type IV and one with type V+IV) were recruited. These patients received bortezomib therapy for four cycles (1.3 mg per square meter of body surface area as an intravenous bolus on days 1, 4, 8, and 11 of 21-day cycles) and glucocorticoids (methylprednisolone 0.5 g/d intravenously for three days, followed by prednisone 0.6 mg/kg/d orally for four weeks, with gradual tapering to 10 mg/d). Proteinuria, serum albumin and creatinine, and immunological parameters were assessed, and adverse effects were also evaluated. Results After two to four bortezomib treatment cycles, four patients achieved partial remission with decreases in SLE disease activity index scores from the range of 12-16 to that of 4-8. The patients also exhibited a decline in proteinuria and an elevation of albumin level after treatment. SCr level was decreased in three of five patients with elevated SCr at baseline. The anti-autoantibodies and complements were also improved. Adverse events were of grades 1-2 and included transient thrombocytopenia, gastrointestinal symptoms and acroesthesia. During a 6- to 24-month follow-up period, three patients achieved complete remission, and one had partial remission. However, one patient received renal replacement therapy. Conclusion Bortezomib combined with glucocorticoids reduces proteinuria, improves renal function and decreases anti-autoantibodies, with good tolerance and mild adverse events, thus representing an alternative therapy for refractory LN and warranting further study.

SLE is a severe autoimmune disease characterized by autoreactive B cells and IC formation, which causes systemic inflammation. B cell-targeted therapy could be a promising treatment strategy in SLE patients; nevertheless, randomized clinical trials have not always been successful. However, some groups have demonstrated beneficial effects in severe SLE patients with off-label rituximab (RTX) with belimumab (BLM), or bortezomib (BTZ), which targeted different B cells subsets. This study assembled sera from SLE cohorts treated with RTX+BLM (n = 15), BTZ (n = 11) and RTX (n = 16) to get an in-depth insight into the immunological effects of these therapies on autoantibodies and IC formation.Autoantibodies relevant for IC formation and the avidity of anti-dsDNA were determined by ELISA. IC-mediated inflammation was studied by complement levels and ex vivo serum-induced neutrophil extracellular trap formation.Reductions in autoantibodies were observed after all approaches, but the spectrum differed depending upon the treatment. Specifically, only RTX+BLM significantly decreased anti-C1q. Achieving seronegativity of ≥1 autoantibody, specifically anti-C1q, was associated with lower disease activity. In all SLE patients, the majority of anti-dsDNA autoantibodies had low avidity. RTX+BLM significantly reduced low-, medium- and high-avidity anti-dsDNA, while RTX and BTZ only significantly reduced medium avidity. IC-mediated inflammation, measured by C3 levels and neutrophil extracellular trap formation, improved after RTX+BLM and RTX but less after BTZ.This study demonstrated the impact of different B cell-targeted strategies on autoantibodies and IC formation and their potential clinical relevance in SLE.© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.

To understand the status of mizoribine use in patients with lupus nephritis (LN) and to collect safety- and efficacy-related data on 2-year treatment with mizoribine.A continuous survey was conducted between March 2010 and July 2015.The analysis set included 559 patients (mean age 39.5 years, females 82.6%, mean duration of systemic lupus erythematosus (SLE) 8.4 years, mean duration of LN 5.9 years). Renal function was satisfactory for 6 months, but worsened from 12 months, with significant worsening at 24 months. By the ACR 2006 remission criteria (eGFR >60), at 24 months, 26.5% of patients achieved complete remission, and 63.3% achieved complete or partial remission. The urine protein to creatinine ratio decreased significantly. The SLE Disease Activity Index 2000 score decreased significantly at 12 and 24 months. Overall, 98 (17.5%) patients experienced 124 adverse drug reactions (ADRs); 3.6% experienced serious ADRs. Mizoribine was used with a steroid in 99.3% and an immunosuppressant in 51.2%; tacrolimus was used in 43.8%. The oral steroid dosage decreased from baseline to 24 months. The incidence of ADRs was not significantly different with concomitant tacrolimus use.The results suggest that long-term mizoribine is safe and effective, even when used with tacrolimus.

Epratuzumab, a monoclonal antibody that targets CD22, modulates B cell signaling without substantial reductions in the number of B cells. The aim of this study was to report the results of 2 phase III multicenter randomized, double‐blind, placebo‐controlled trials, the EMBODY 1 and EMBODY 2 trials, assessing the efficacy and safety of epratuzumab in patients with moderately to severely active systemic lupus erythematosus (SLE).

The association between treatment-related lymphopenia in multiple sclerosis, drug efficacy and the risk of infections is not yet fully understood.The objective of this study was to assess whether lymphopenia is associated with short-term treatment response and infection rate in a real-life multiple sclerosis population treated with fingolimod and dimethyl-fumarate. We assessed the associations between baseline absolute lymphocyte count and the lymphocyte mean percentage decrease at 6 and 12 months with treatment response and the occurrence of adverse events over 12 months in the entire cohort of patients and in the two treatment groups separately.This is a retrospective observational real-world study of patients with multiple sclerosis treated with fingolimod and dimethyl-fumarate at the MS Center of the University of Genoa between 2011 and 2018. Patients with at least 12 months of follow-up were eligible if [1] they had an Expanded Disability Status Scale assessment at baseline and 12 months after treatment onset, [2] they had undergone brain magnetic resonance imaging at baseline and after 12 months, and [3] absolute lymphocyte counts were available at baseline, 6 and 12 months. Patients shifting from dimethyl-fumarate to fingolimod or vice versa were excluded from the analysis.In total, 137 and 75 patients treated with fingolimod and dimethyl-fumarate, respectively, were included in the analysis. At 12 months, fingolimod-treated patients were more likely to experience grade II and grade III lymphopenia compared with dimethyl-fumarate patients (p < 0.001, χ2 = 94) and had a higher lymphocyte mean percentage decrease (p < 0.001, U = 540). A higher number of previous therapies and a lower baseline absolute lymphocyte count were predictors of lymphopenia at 6 months (p = 0.047, odds ratio = 1.60 and p = 0.014, odds ratio = 1.1) and 12 months (p = 0.003, odds ratio = 1.97 and p = 0.023, odds ratio = 1.1). In fingolimod-treated patients only, female sex and a higher Expanded Disability Status Scale score were predictors of lymphopenia at 12 months (p = 0.006, odds ratio = 7.58 and p = 0.03, odds ratio = 1.56). Neither absolute lymphocyte count at 6 and 12 months nor the mean percentage decrease at 6 and 12 months predicted No Evidence of Disease Activity (NEDA-3) status at 1 year, the occurrence of relapses, disease activity on MRI or disability progression.Our findings suggest that peripheral blood lymphocyte changes are not associated with short-term treatment response and with the rate of infections during fingolimod and dimethyl-fumarate treatment in real-world patients. Higher treatment exposure and a lower baseline absolute lymphocyte count are risk factors for lymphopenia development during fingolimod and dimethyl-fumarate therapy.

Neuropsychiatric (NP) involvement in systemic lupus erythematosus (SLE) severely impacts patients' quality of life and leads to a poor prognosis. The current therapeutic protocol, corticosteroid administration, can also induce neuropsychiatric disorders. FTY720 is an immunomodulator that selectively confines lymphocytes in lymph nodes and reduces autoreactive T cell recruitment to the central nervous system (CNS). This study aimed to identify a novel therapeutic strategy for NPSLE. B6.MRL-lpr mice were treated with oral administration of FTY720 (2 mg/kg) three times per week for 12 weeks, to evaluate its efficacy in a model of NPSLE. FTY720 significantly attenuated the impulsive and depression-like behavior of B6.MRL-lpr mice. Neuronal damage was reduced in the cortex, hippocampus, and amygdala of the FTY720-treated B6.MRL-lpr mice, as well as in TNF-α-treated HT22 cells. Additionally, FTY720 downregulated levels of inflammatory cytokines, and reduced the infiltration of T cells and neutrophils in the brain parenchyma. FTY720 also acted directly on cerebral endothelial cells and reduced the permeability of the blood-brain barrier (BBB) in B6.MRL-lpr mice, as evidenced by reduced central IgG and albumin levels. Finally, FTY720 significantly inhibited activation of PI3K/Akt/GSK3β/p65 signaling, which further reduced the expression levels of adhesion molecules in bEND.3 cells treated with B6.MRL-lpr mouse serum. Collectively, our data indicate that oral administration of FTY720 at an early stage has beneficial effects in NPSLE-model B6.MRL-lpr mice, suggesting that it may represent an effective new therapeutic strategy for NPSLE.Copyright © 2018 Elsevier Inc. All rights reserved.

Treatment of class V+IV lupus nephritis remains unsatisfactory despite the progress made in the treatment of diffuse proliferative lupus nephritis. In this prospective study, 40 patients with class V+IV lupus nephritis were randomly assigned to induction therapy with mycophenolate mofetil, tacrolimus, and steroids (multitarget therapy) or intravenous cyclophosphamide (IVCY). Patients were treated for 6 mo unless complete remission was not achieved, in which case treatment was extended to 9 mo. An intention-to-treat analysis revealed a higher rate of complete remission with multitarget therapy at both 6 and 9 mo (50 and 65%, respectively) than with IVCY (5 and 15%, respectively). At 6 mo, eight (40%) patients in each group experienced partial remission, and at 9 mo, six (30%) patients receiving multitarget therapy and eight (40%) patients receiving IVCY experienced partial remission. There were no deaths during this study. Most adverse events were less frequent in the multitarget therapy group. Calcineurin inhibitor nephrotoxicity was not observed, but three patients developed new-onset hypertension with multitarget therapy. In conclusion, multitarget therapy is superior to IVCY for inducing complete remission of class V+IV lupus nephritis and is well tolerated.

Our previous studies showed that multitarget therapy is superior in efficacy to intravenous cyclophosphamide as an induction treatment for lupus nephritis in Asian populations. We conducted an open label, multicenter study for 18 months as an extension of the prior induction therapy trial in 19 renal centers in China to assess the efficacy and safety of multitarget maintenance therapy in patients who had responded at 24 weeks during the induction phase. Patients who had undergone multitarget induction therapy continued to receive multitarget therapy (tacrolimus, 2-3 mg/d; mycophenolate mofetil, 0.50-0.75 g/d; prednisone, 10 mg/d), and patients who had received intravenous cyclophosphamide induction treatment received azathioprine (2 mg/kg per day) plus prednisone (10 mg/d). We assessed the renal relapse rate during maintenance therapy as the primary outcome. We recruited 116 patients in the multitarget group and 90 patients in the azathioprine group. The multitarget and azathioprine groups had similar cumulative renal relapse rates (5.47% versus 7.62%, respectively; adjusted hazard ratio, 0.82; 95% confidence interval, 0.25 to 2.67; 0.74), and serum creatinine levels and eGFR remained stable in both groups. The azathioprine group had more adverse events (44.4% versus 16.4% for multitarget therapy; <0.01), and the multitarget group had a lower withdrawal rate due to adverse events (1.7% versus 8.9% for azathioprine; =0.02). In conclusion, multitarget therapy as a maintenance treatment for lupus nephritis resulted in a low renal relapse rate and fewer adverse events, suggesting that multitarget therapy is an effective and safe maintenance treatment for patients with lupus nephritis.Copyright © 2017 by the American Society of Nephrology.

本文综述了狼疮肾炎患者的妊娠结局及其影响因素，并评估妊娠狼疮肾炎患者的妊娠时机，为构建本土化的狼疮肾炎患者妊娠时机评估体系，优化狼疮肾炎患者的妊娠管理提供参考。

Systemic lupus erythematosus is a multisystem autoimmune disease that commonly affects the kidneys. Lupus nephritis (LN) is the most common cause of kidney injury in systemic lupus erythematosus and a major risk factor for morbidity and mortality. The pathophysiology of LN is heterogeneous. Genetic and environmental factors likely contribute to this heterogeneity. Despite improved understanding of the pathogenesis of LN, treatment advances have been few and risk for kidney failure remains unacceptably high. This installment in the Core Curriculum of Nephrology provides an up-to-date review of the current understanding of LN epidemiology, pathogenesis, diagnosis, and treatment. Challenging issues such as the management of LN in pregnancy, timing of transplantation, and the evolving role of corticosteroid use in the management of LN are discussed. We review the currently accepted approach to care for patients with LN and highlight deficiencies that need to be addressed to better preserve long-term kidney health and improve outcomes in LN.Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.