Recent advances in the management of lupus nephritis, together with earlier renal biopsy and selective use of aggressive immunosuppressive therapy, have contribut-ed to a favorable outcome in children and adolescents ...Recent advances in the management of lupus nephritis, together with earlier renal biopsy and selective use of aggressive immunosuppressive therapy, have contribut-ed to a favorable outcome in children and adolescents with systemic lupus erythematosus （SLE）. Neverthe-less, we believe that a more effective and less toxic treatment is needed to attain an optimal control of the activity of lupus nephritis. Recent published papers and our experiences regarding treatment of young patients with lupus nephritis using calcineurin inhibitors are re-viewed. Although it has been reported that intermittent monthly pulses of intravenous cyclophosphamide （IVCY） are effective for preserving renal function in adult pa-tients, CPA is a potent immunosuppressive agent thatinduces severe toxicity, including myelo- and gonadal toxicity, and increases the risk of secondary malig-nancy. Thus, treatment for controlling lupus nephritis activity, especially in children and adolescents, remains challenging. Cyclosporine A （CsA） and tacrolimus （Tac） are T-cell-specific calcineurin inhibitors that prevent the activation of helper T cells, thereby inhibiting thetranscription of the early activation genes of interleu-kin （IL）-2 and suppressing T cell-induced activation of tumor necrosis factor-α, IL-1β and IL-6. Therefore, both drugs, which we believe may be less cytotoxic, are attractive therapeutic options for young patients with lupus nephritis. Recently, a multidrug regimen of prednisolone （PDN）, Tac, and mycophenolate mofetile （MMF） has been found effective and relatively safe in adult lupus nephritis. Since the mechanisms of action of MMF and Tac are probably complementary, multidrug therapy for lupus nephritis may be useful. We propose as an alternative to IVCY, a multidrug therapy with mizoribine, which acts very similarly to MMF, and Tac, which has a different mode of action, combined with PDN for pediatric-onset lupus nephritis. We also believe that a multidrug therapy including CsA and Tac may bean attractive option for young patients with SLE and lupus nephritis展开更多
Lupus nephritis(LN),a severe manifestation of systemic lupus erythematosus,poses a substantial risk of progression to end-stage renal disease,with increased mortality.Conventional therapy for LN relies on broad-spectr...Lupus nephritis(LN),a severe manifestation of systemic lupus erythematosus,poses a substantial risk of progression to end-stage renal disease,with increased mortality.Conventional therapy for LN relies on broad-spectrum immunosuppressants such as glucocorticoids,mycophenolate mofetil,and calcineurin inhibitors.Although therapeutic regimens have evolved over the years,they have inherent limitations,including non-specific targeting,substantial adverse effects,high relapse rates,and prolonged maintenance and remission courses.These drawbacks underscore the need for targeted therapeutic strategies for LN.Recent advancements in our understanding of LN pathogenesis have led to the identification of novel therapeutic targets and the emergence of biological agents and small-molecule inhibitors with improved specificity and reduced toxicity.This review provides an overview of the current evidence on targeted therapies for LN,elucidates the biological mechanisms of responses and failure,highlights the challenges ahead,and outlines strategies for subsequent clinical trials and integrated immunomodulatory approaches.展开更多
Lupus nephritis leads to significant morbidity and mortality in patients with systemic lupus erythematous. Immunosuppressive agents are recommended in management of Class III, IV and V lupus nephritis. The goals of th...Lupus nephritis leads to significant morbidity and mortality in patients with systemic lupus erythematous. Immunosuppressive agents are recommended in management of Class III, IV and V lupus nephritis. The goals of therapy are to control the disease and to prevent relapse while minimizing side-effects of therapy. Most of the evidences in managements of Class III and IV lupus nephritis comes from randomized controlled trials using intravenous cyclophosphamides, oral mycophenolate mofetil and oral azathioprine. In Class V lupus nephritis, there are few studies available and they have assessed the use of intravenous cyclophsophamide, oral mycophenolates mofetil and oral cyclosporine. In this review article, we have summarized the major randomized controlled trials in managements of Class III, IV and V lupus nephritis and offer an interpretation of the evidence to date.展开更多
Tripterygium wilfordii Hook F(TWHF)is a traditional Chinese medicine widely used in the treatment of systemic lupus erythematosus(SLE),with triptolide(TP)as its main active ingredient.However,its side effects also ind...Tripterygium wilfordii Hook F(TWHF)is a traditional Chinese medicine widely used in the treatment of systemic lupus erythematosus(SLE),with triptolide(TP)as its main active ingredient.However,its side effects also induced by TP,especially hepatotoxicity and reproductive toxicity,largely limit its application in a subset of patients.Monoclonal antibodies(mAbs)developed for the treatment of SLE that deplete B cells by targeting B cell-expressing antigens,such as CD19,have failed in clinical trials,partly due to their poor efficacy in consuming B cells.Here,we report the development of a rationally designed antibody‒drug conjugate(ADC),CD19 mAb-TP conjugate,to alleviate the side effects of TWHF and simultaneously improve the therapeutic efficacy of CD19 mAb.The CD19 mAb-TP conjugate,which was named ADC-TP,selectively depleted B cell subsets both in vitro and in vivo and effectively alleviated disease symptoms in mouse lupus models with enhanced therapeutic efficacy than CD19 mAb and fewer side effects than TP.Our present study proposes a CD19 mAb‒TP conjugate strategy to mitigate the toxicity of TWHF while also enhancing the therapeutical efficacy of CD19 mAbs for the treatment of SLE,providing a feasible method for improving the current agents used for treating SLE.展开更多
Objective：To investigate the therapeutic effects and mechanisms of using artemisinin（Art） combined with glucocorticoid（GC） to treat lupus nephritis（LN） mice.Methods：Forty hybrid female mice were randomly and e...Objective：To investigate the therapeutic effects and mechanisms of using artemisinin（Art） combined with glucocorticoid（GC） to treat lupus nephritis（LN） mice.Methods：Forty hybrid female mice were randomly and equally divided into four groups with the method of random number table：control group,model group,prednisone group administrated with 6.45 mg/（kg·d） prednisone suspension,and Art＋prednisone group administrated with 150 mg/（kg·d） Art suspension and 3.225 mg/（kg·d） prednisone suspension.A mice model of LN was established by injection with living lymph cell suspension.The changes of urine protein/24h,the expressions of GC receptorα（GRα） mRNA,GC receptorβ（GRβ） mRNA in peripheral blood mononuclear cells（PBMCs）,and transcriptional coactivator P300/CBP protein in renal tissue were measured.Results： Compared with the model group,the treatment groups had significant decrease in urine protein/24 h,and renal pathological lesion（P0.01）.In the same groups,the expression of transcriptional coactivator P300/CBP protein in renal tissue and GRαmRNA were significantly increased,and GRβmRNA expression was significantly decreased（P0.01）.And the Art＋prednisone group has a better therapeutic effect than the prednisone group （P0.01）.Conclusions：Art has therapeutic sensitization effects on GC in the LN mice.The underlying mechanism could be correlated with the effect of Art on the increase of the expressions of GRαmRNA and transcriptional coactivator P300/CBP protein in renal tissue and on the decrease of the expression of GRβmRNA in PBMCs.展开更多
This study aimed to evaluate the efficacy and safety of mycophenolate mofetil(MMF)or tacrolimus(TAC)compared with azathioprine(AZA)as maintenance therapy for active lupus nephritis(ALN).Patients with ALN who responded...This study aimed to evaluate the efficacy and safety of mycophenolate mofetil(MMF)or tacrolimus(TAC)compared with azathioprine(AZA)as maintenance therapy for active lupus nephritis(ALN).Patients with ALN who responded to 24 weeks of induction treatment were enrolled.Patients who received MMF or TAC as induction therapy continued MMF or TAC treatment during the maintenance period,whereas those who received intravenous cyclophosphamide were subjected to AZA treatment.The primary endpoint was the incidence of renal relapse.Secondary endpoints included extrarenal flares and composite endpoints(deaths,end-stage renal disease,or doubling of serum creatinine levels).A total of 123 ALN patients(47 in the MMF group,37 in the TAC group,and 39 in the AZA group)were enrolled.The median follow-up time was 60 months.Ten MMF-treated patients,ten TAC-treated patients,and eight AZA-treated patients experienced renal relapses(P=0.844).The cumulative renal relapse rates in the MMF group(P=0.934)and TAC group(P=0.673)were similar to the renal relapse rate in the AZA group.No significant difference in the incidence of severe adverse event was observed among the groups.Long-term maintenance therapies with MMF or TAC might have similarly low rates of renal relapse and similar safety profiles compared with AZA.展开更多
文摘Recent advances in the management of lupus nephritis, together with earlier renal biopsy and selective use of aggressive immunosuppressive therapy, have contribut-ed to a favorable outcome in children and adolescents with systemic lupus erythematosus （SLE）. Neverthe-less, we believe that a more effective and less toxic treatment is needed to attain an optimal control of the activity of lupus nephritis. Recent published papers and our experiences regarding treatment of young patients with lupus nephritis using calcineurin inhibitors are re-viewed. Although it has been reported that intermittent monthly pulses of intravenous cyclophosphamide （IVCY） are effective for preserving renal function in adult pa-tients, CPA is a potent immunosuppressive agent thatinduces severe toxicity, including myelo- and gonadal toxicity, and increases the risk of secondary malig-nancy. Thus, treatment for controlling lupus nephritis activity, especially in children and adolescents, remains challenging. Cyclosporine A （CsA） and tacrolimus （Tac） are T-cell-specific calcineurin inhibitors that prevent the activation of helper T cells, thereby inhibiting thetranscription of the early activation genes of interleu-kin （IL）-2 and suppressing T cell-induced activation of tumor necrosis factor-α, IL-1β and IL-6. Therefore, both drugs, which we believe may be less cytotoxic, are attractive therapeutic options for young patients with lupus nephritis. Recently, a multidrug regimen of prednisolone （PDN）, Tac, and mycophenolate mofetile （MMF） has been found effective and relatively safe in adult lupus nephritis. Since the mechanisms of action of MMF and Tac are probably complementary, multidrug therapy for lupus nephritis may be useful. We propose as an alternative to IVCY, a multidrug therapy with mizoribine, which acts very similarly to MMF, and Tac, which has a different mode of action, combined with PDN for pediatric-onset lupus nephritis. We also believe that a multidrug therapy including CsA and Tac may bean attractive option for young patients with SLE and lupus nephritis
基金supported by grants from the National Natural Science Foundation of China(Nos.81970599 and 82170737)Key Laboratory of National Health Commission,and Key Laboratory of Nephrology,Guangdong Province,Guangzhou,China(Nos.2002B60118 and 2020B1212060028)Guangdong Medical Science and Technology Research Fund Project of China(No.A2020085)
文摘Lupus nephritis(LN),a severe manifestation of systemic lupus erythematosus,poses a substantial risk of progression to end-stage renal disease,with increased mortality.Conventional therapy for LN relies on broad-spectrum immunosuppressants such as glucocorticoids,mycophenolate mofetil,and calcineurin inhibitors.Although therapeutic regimens have evolved over the years,they have inherent limitations,including non-specific targeting,substantial adverse effects,high relapse rates,and prolonged maintenance and remission courses.These drawbacks underscore the need for targeted therapeutic strategies for LN.Recent advancements in our understanding of LN pathogenesis have led to the identification of novel therapeutic targets and the emergence of biological agents and small-molecule inhibitors with improved specificity and reduced toxicity.This review provides an overview of the current evidence on targeted therapies for LN,elucidates the biological mechanisms of responses and failure,highlights the challenges ahead,and outlines strategies for subsequent clinical trials and integrated immunomodulatory approaches.
文摘Lupus nephritis leads to significant morbidity and mortality in patients with systemic lupus erythematous. Immunosuppressive agents are recommended in management of Class III, IV and V lupus nephritis. The goals of therapy are to control the disease and to prevent relapse while minimizing side-effects of therapy. Most of the evidences in managements of Class III and IV lupus nephritis comes from randomized controlled trials using intravenous cyclophosphamides, oral mycophenolate mofetil and oral azathioprine. In Class V lupus nephritis, there are few studies available and they have assessed the use of intravenous cyclophsophamide, oral mycophenolates mofetil and oral cyclosporine. In this review article, we have summarized the major randomized controlled trials in managements of Class III, IV and V lupus nephritis and offer an interpretation of the evidence to date.
基金supported by the National Key R&D Program of China(2022YFC3601800 to Qianjin Lu)the National Natural Science Foundation of China(No.82304509 to Lai Wang)+3 种基金the Natural Science Foundation of Jiangsu Province(BK20230131 to Lai Wang)the Special Program of National Natural Science Foundation of China(No.32141004 to Qianjin Lu)the CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1-059 to Qianjin Lu,China)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2020-RC320-003 to Qianjin Lu).
文摘Tripterygium wilfordii Hook F(TWHF)is a traditional Chinese medicine widely used in the treatment of systemic lupus erythematosus(SLE),with triptolide(TP)as its main active ingredient.However,its side effects also induced by TP,especially hepatotoxicity and reproductive toxicity,largely limit its application in a subset of patients.Monoclonal antibodies(mAbs)developed for the treatment of SLE that deplete B cells by targeting B cell-expressing antigens,such as CD19,have failed in clinical trials,partly due to their poor efficacy in consuming B cells.Here,we report the development of a rationally designed antibody‒drug conjugate(ADC),CD19 mAb-TP conjugate,to alleviate the side effects of TWHF and simultaneously improve the therapeutic efficacy of CD19 mAb.The CD19 mAb-TP conjugate,which was named ADC-TP,selectively depleted B cell subsets both in vitro and in vivo and effectively alleviated disease symptoms in mouse lupus models with enhanced therapeutic efficacy than CD19 mAb and fewer side effects than TP.Our present study proposes a CD19 mAb‒TP conjugate strategy to mitigate the toxicity of TWHF while also enhancing the therapeutical efficacy of CD19 mAbs for the treatment of SLE,providing a feasible method for improving the current agents used for treating SLE.
基金Supported by the Sci-tech Project of Shaanxi Province[No. 2006K14-G2(5)]
文摘Objective：To investigate the therapeutic effects and mechanisms of using artemisinin（Art） combined with glucocorticoid（GC） to treat lupus nephritis（LN） mice.Methods：Forty hybrid female mice were randomly and equally divided into four groups with the method of random number table：control group,model group,prednisone group administrated with 6.45 mg/（kg·d） prednisone suspension,and Art＋prednisone group administrated with 150 mg/（kg·d） Art suspension and 3.225 mg/（kg·d） prednisone suspension.A mice model of LN was established by injection with living lymph cell suspension.The changes of urine protein/24h,the expressions of GC receptorα（GRα） mRNA,GC receptorβ（GRβ） mRNA in peripheral blood mononuclear cells（PBMCs）,and transcriptional coactivator P300/CBP protein in renal tissue were measured.Results： Compared with the model group,the treatment groups had significant decrease in urine protein/24 h,and renal pathological lesion（P0.01）.In the same groups,the expression of transcriptional coactivator P300/CBP protein in renal tissue and GRαmRNA were significantly increased,and GRβmRNA expression was significantly decreased（P0.01）.And the Art＋prednisone group has a better therapeutic effect than the prednisone group （P0.01）.Conclusions：Art has therapeutic sensitization effects on GC in the LN mice.The underlying mechanism could be correlated with the effect of Art on the increase of the expressions of GRαmRNA and transcriptional coactivator P300/CBP protein in renal tissue and on the decrease of the expression of GRβmRNA in PBMCs.
基金The present study was supported by the National Natural Science Foundation of China(No.81170671)Shanghai Health and Family Planning Committee Hundred Talents Program(No.2018BR37).
文摘This study aimed to evaluate the efficacy and safety of mycophenolate mofetil(MMF)or tacrolimus(TAC)compared with azathioprine(AZA)as maintenance therapy for active lupus nephritis(ALN).Patients with ALN who responded to 24 weeks of induction treatment were enrolled.Patients who received MMF or TAC as induction therapy continued MMF or TAC treatment during the maintenance period,whereas those who received intravenous cyclophosphamide were subjected to AZA treatment.The primary endpoint was the incidence of renal relapse.Secondary endpoints included extrarenal flares and composite endpoints(deaths,end-stage renal disease,or doubling of serum creatinine levels).A total of 123 ALN patients(47 in the MMF group,37 in the TAC group,and 39 in the AZA group)were enrolled.The median follow-up time was 60 months.Ten MMF-treated patients,ten TAC-treated patients,and eight AZA-treated patients experienced renal relapses(P=0.844).The cumulative renal relapse rates in the MMF group(P=0.934)and TAC group(P=0.673)were similar to the renal relapse rate in the AZA group.No significant difference in the incidence of severe adverse event was observed among the groups.Long-term maintenance therapies with MMF or TAC might have similarly low rates of renal relapse and similar safety profiles compared with AZA.
