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1、SLE,6075 狼疮性肾炎（LN）100 病理学上改变,SLE预后因素,LN选择治疗依据,临床表现（蛋白尿、血尿、管型）肾活检（分型）肾活检+临床表现,问题,肾活检少仅凭LN临床表现:局限性,盲目性,LN病理学分型演变,1974年 WHO（I V）1982年 WHO（I VI）1995年 WHO（I VI）2003年 LN分型（I VI）Weening JJ,et al.Kidney Int 2004,65:521-530.,International Society of Nephrology/Renal Pathology Society(ISN/RPS)2003 classificat
2、ion of lupus nephritis,Class II,Class III(A),Class III(A),Class IV-G(A),Class IV-S(A),Class IV-G(A),Class IV-G(A/C),Class IV-G(A/C),Thrombotic microangiopathy,Class VI,Class IV and V(A/C),Class V,LN 治疗问题,Overtreatment!I,II,IIIUndertreatment!IV,V,LN治疗原则,Early recognitionCorrect evaluationStringent ob
3、jectivesPrompt remissionMaintain remissionAvoid renal impairmentMinimal toxicity,LN治疗,诱导治疗维持治疗,诱导、维持治疗,诱导治疗,GCCYC(NIH“high dose”,St Thomas EULAR“low dose”CellceptRituximab?GC+CYC,GC+Cellcept,GC+?,维持治疗,给药途径,药物剂量疗程,NIHGC OP and IV(1g/m2/m 12 36月）CYC 0.75 1g/m2/m6月 缓解后3月一次维持一年 Austin HA et al.N Engl J
4、Med,1986,314:614-619,Houssiau FA et al.Arthritis Rheu,2002;8:2121-2131.,药物剂量疗程,药物剂量疗程,GC 0.8mg/kg/d 10mg/d CYC 2.5mg/kg/d6月P 10mg/dAza 11.5mg/kg/dChan TM et al.Lupus 2005,14:265-272.,6月,药物剂量疗程,MMF 2g/d6m CYC 2.5g/kg/d 6m vs 1g/d 6m Aza 1.5g/kg/d 6mPred 0.8mg/kg/d 20mg/d 10mg/dRituximab 375mg/m2+GC0.
5、5mg/kg/d(IV CYC0.75g)Sfikakis PP,et al.Arthritis Rheum,2005;52:501-513,-5mg,-2.5mg,2w,4w,Chan TM,et al.N Engl J Med,2002,343:1156-1162,疗效,ELNT,HD(n=40)41.3 months followup LD(n=38)41 months followup 7/44(16%)failure(LD)9/45(20%)(HD)(P0.05)71%(LD)缓解 27(LD)复发 54%(HD)缓解 29%(HD)复发 感染发生率 HD:LD=2:1,P+MMF
6、vs.P+CYC(Aza)(诱导6月，维持6月）Chan TM et al.N Engl J Med 2000,Figure 1.Mean(SD)Serum C3 and Creatinine Concentrations in Patients with Diffuse Proliferative Lupus Nephritis Who Were Treated with Mycophenolate Mofetil and Prednisolone(Group 1)or with Cyclophosphamide and Prednisolone Followed by Azathiopri
7、ne and Prednisolone(Group 2).,Figure 2.Mean(SD)Serum Albumin Concentration and Urinary Protein Excretion in Patients with Diffuse Proliferative Lupus Nephritis Who Were Treated with Mycophenolate Mofetil and Prednisolone(Group 1)or with Cyclophosphamide and Prednisolone Followed by Azathioprine and
8、Prednisolone(Group 2).,81%CR+14%PR in MMF,15%复发，19感染76CR+14%PR in CYC,11%复发，19感染（P0.29）In CYC：23 停经 10 WBC减少 19 脱发 10 死亡,59 LN(12 Class III,46 IV,1 V)0.51g/m2 IV CYC monthly7GC 0.5mg/kg/d(13yrs),MMF0.53g/d,Aza13mg/kg/d,IV CYC0.51g/m2/3m,72months 随访,Contreras G et al.N Engl J Med 2004,350:971-980,Fig
9、.3.Kaplan-Meier Estimates of Patient Survival,Fig.4.KaplanMeier Estimates of Event-free Survival,Fig.5.KaplanMeier Estimates of Relapse-free Survival,P0.05 P0.01 P0.01 P0.01,10 LN pts(4 class III,6 IV)Rituximab(375mg/m2/month)+GC(0.5mg/kg/d)4(III)+4(IV)缓解5例 CR(28month)12month followup Arthritis Rheu
10、m 2005,52:501-513.,LN治疗面临的挑战,CYC相关的性腺抑制,年龄 NIH方案 停经 25岁 发生率17累积量 2630岁 43 31岁 100Boumpas DT,et al.Ann Intern Med,1993;119:366-369,LN治疗复发,LN复发的危险因素,对LN治疗的再认识,PIV CYC仍常用 PMMF等效，毒性低 诱导缓解时间短？维持治疗 Aza或MMF疗效高于IV CYC 口服CYC累积量提高，性腺抑制 维持治疗时间长？,重症难治性LN治疗策略,血浆置换或免疫吸附联合诱导治疗非清髓性化疗干细胞移植（清髓性）,非清髓性诱导治疗,朱。女，25岁。SLE病
11、程3年。肾活检 IV LNBP160、105mmHgCTX累积用量4.8g骁悉 2g/d+P(1年）诱导治疗 P(20mg/d)+CTX 2.2g,诱导治疗后血细胞的变化,24小时尿蛋白的变化,血清Cr,BUN的变化,SPECT检测GFR,SLE与干细胞移植,T,B细胞高度活化HSC transfer ADCD34+apoptosis,Papadaki HA,et al.(2001)Br J Haematol 115:167-174.,SLE(CD34+),SLE-HSCs,Sun Lingyun et al Clin Rheumatol,Comparison of BM CD34+cells
12、 surface markers between SLE patients and normal control,*P0.05 vs normal,SLE-CD34+,The expression percentage of CD166 on BM CD34+cells correlated with SLEDAI score,r=0.480，P=0.026,SLE-HSCs,The expression percentage of CD123 on BM CD34+cells correlated with WBC count,r=0.700 P=0.03,SLE-HSCs,SLE-Mese
13、nchymal Stem Cells，MSCs,生物学特性来源广泛自我更新、多向分化潜能易扩增传代能力,MSCs,IL-6,IL-7,IL-10,IL-11,SCF,SDF-1GM-CSF,M-CSF.,adipocyteosteocytechondrocytemyoblast,cardiocyteNerve cellhepatocyte,可来源于骨髓、胰腺、皮肤、肺脏等多处器官组织,体外能够传40代，并保持稳定的表型和多向分化的潜能,SLE 骨髓MSC 异常,原代生长缓慢细胞因子分泌异常:IL-6,IL-7凋亡增加传代减少 Sun Lingyun,et al Lupus,2007,16:12
14、1-128,MSCs的免疫调节作用,MSC-mediated modulation of cells involved in the immune response:the bidirectional interaction between MSC,T cells,B cells andNK cells is described.In the case of DC,the influence of DC on MSC has not yet been proven.The effects ofimmune cells on MSC are depicted in black while tho
15、se of MSC on immune cells are in red.,MSC移植后24小时尿蛋白变化,未治疗对照组,MSC移植组,MSC移植对MRL/lpr鼠肾组织病理改变的影响A:对照组，B:CTX组，C:MSC组，D:MSC+CTX组,MSC移植对MRL/lpr鼠肾小球补体C3沉积的影响,异基因骨髓MSC移植治疗SLE,女，21岁，SLE13年，尿蛋白3+，血Cr477umol/L，P20mg/d,CTX 2年(20克),Cellcept 6months,BP160-180/100-120mmgHb 60g/L,异基因骨髓MSC移植治疗SLE,LN治疗,IndividualMornitoringFellowupEducationAim at good quality of life!,Thank you!,
