2019年EULAR/ERA-EDTA:狼疮肾炎治疗建议的新进展

2021-09-24 从医路漫漫 MedSci原创

高达40%的系统性红斑狼疮(SLE)患者会发展成肾脏疾病,这是发病率的一个主要原因。

      高达40%的系统性红斑狼疮(SLE)患者会发展成肾脏疾病,这是发病率的一个主要原因。2012年,欧洲抗风湿病联盟-欧洲肾脏协会-欧洲透析和T移植协会(EULAR/ ERA-EDTA)制定了狼疮肾炎(LN)的联合推荐方案,涉及风湿病学家、肾病学家、肾病理学家和儿科医生。

一、推荐 

1、疑似LN患者的筛查

   有肾小球血尿和/或细胞型、蛋白尿>0.5 g/24小时(或尿蛋白/肌酸比值(UPCR) >500 mg/g)、肾小球滤过率(GFR)不明原因下降的SLE患者都可以行肾活检。轻微的临床表现(如亚肾病性蛋白尿)可能与活跃的组织学病变相关。在对1970-2016年期间进行的肾脏活检的回顾中,根据尿液异常早期使用活检(如2001 - 2016年)与预后改善相关,尽管严重组织学发生率相似。组织学评估的好处应该与某些患者(如接受抗凝治疗的患者)出血风险的增加相平衡。所有SLE患者,特别是那些怀疑肾脏受累的患者,应该进行抗磷脂抗体(APL)检测,因为抗磷脂综合征的肾脏表现,如血栓性微血管病(TMA),可能具有预后影响。疑似LN患者应考虑进行抗dsDNA和抗C1q自身抗体检测,以及补体水平(C3和C4)。

2、肾活检的病理学评价

  2003年国际肾脏学会/肾脏病理学会(ISN/RPS)的分类仍然是评估LN肾活检的金标准。TMA虽然不是病因学的病变,但应怀疑抗磷脂综合征肾病,因此,应立即进行APL检测。尽管TMA在多达25%的LN活检中被报道,但其预后意义仍不清楚。肾小管间质病变,如间质纤维化和肾小管萎缩,与不良的预后相关。

3、狼疮性肾炎免疫抑制治疗的适应证

    建议在活动性III级或IV级LN中进行免疫抑制治疗。对于单纯V级LN,尽管最佳使用肾素-血管紧张素-醛固酮系统阻滞剂,但蛋白尿>1 g/24小时的患者免疫抑制的建议适用于肾病范围蛋白尿患者,预后较差、(例如至少3个月)。II类LN通常不需要特异性免疫抑制治疗,但重复活检时可能使组织易于转变为更具侵袭性的疾病显性蛋白尿的存在应重新评估组织学以检测可能被忽略的增殖性变化。

二、成人LN的治疗

  根据治疗开始的时间进一步确定了治疗目标。来自MAINTAIN和欧洲狼疮肾炎试验的事后分析表明,12个月的蛋白尿是长期肾脏结局的最佳单项预测因子(例如,终末期肾病(ESKD)风险或10年后血清肌酸翻倍)。因此,治疗应以12个月时蛋白尿< 0.5-0.7 g/24小时为目标(达到完全临床缓解),尽管高达50%未达到这一指标的患者可能仍有长期稳定的肾功能。应在3个月时观察蛋白尿改善(GFR正常化/稳定),6个月时蛋白尿至少减少50%(部分临床反应)。对于基线时肾病范围蛋白尿的患者,由于蛋白尿恢复较慢,上述时间可能延长6-12个月。因此,考虑减少蛋白尿可以避免过早的治疗。由于SLE是一种全身性疾病,免疫抑制治疗也应以缓解或来自肾外区域的低疾病活动性为目标。

1、初始治疗

   在III- IV级LN中,一项综述显示,霉酚酸酯/霉酚酸酯(MMF/MPA)与环磷酰胺(CY)的疗效相似,但可能存在种族差异,即MMF可能在非裔美国人中更有效。10年欧洲狼疮肾炎研究数据显示,低剂量CY与高剂量CY的疗效相当,而且低剂量方案已在非欧洲人群中使用。因此,MMF/MPA和低剂量CY被推荐作为初始(诱导)治疗的一线选择。MMF的推荐目标剂量现在改为2-3 g/天(MPA 1.44 - 2.16 g/天),因为有证据表明治疗药物剂量可能在1 - 3 g/天之间。剂量可根据耐受性或不良反应、疗效和MPA血清水平进行调整。对于有不良临床症状(肾炎尿沉积和肾功能受损,GFR介于25 - 80 mL/min)或组织学(肾小球>25%的新月状或坏死)预后因素差的患者,可考虑静脉注射高剂量CY。

2、后续治疗

   MMF/MPA和硫唑嘌呤(AZA)仍然是后续免疫抑制治疗的首选药物,在初始阶段有足够的治疗反应。与Aspreva狼疮管理研究(ALMS)相比,在维持治疗的10年随访中,两种方案在肾脏恶化方面没有差异,后者显示MMF的优越性。基于有证据表明在MMF/MPA治疗后服用AZA会增加复发,我们推荐MMF/MPA诱导治疗后继续进行MMF/MPA维持治疗。CY诱导后可用MMF/MPA或AZA诱导;如果考虑怀孕或MMF的成本较高,则首选后者。由于慢性使用这些药物可能增加肾脏副作用的风险,CNI可以以最低的有效剂量用于V级LN。

3、治疗无反应/难治性疾病

   所有一线治疗,包括MMF/MPA(2-3g/d),CY和CNI(特别是TAC),作为单一疗法或多靶点疗法,推荐用于治疗无反应疾病。B细胞耗竭疗法,如RTX,虽然不在以上范围内,但也被认为是MMF/MPA或CY的单一疗法或附加疗法;循环中B细胞的完全耗尽预示着几周的临床缓解。最近,一项成功的阿托珠单抗试验证实了这一点。在对RTX有反应之后,复发并不少见,但会在不同的时间后发生。重复剂量可以被认为是预防或治疗复发的方法。虽然贝利木单抗没有正式用于治疗LN,但随机对照试验和观察性研究的非正式分析表明,当加入标准护理(包括MMF)时,它可能会逐渐减少蛋白尿和肾脏红斑的风险。重要的是,贝利木单抗作为LN补充疗法的III期RCT的积极结果已经公布,这项研究的结果还在等待中。RTX贝利木单抗联合应用于难治性疾病,当有糖皮质激素或免疫抑制药物的禁忌症(如感染)时,可以考虑大剂量静脉注射免疫球蛋白(2g/kg),但很少需要血浆置换。

4、狼疮性肾炎患者的辅助治疗

    推荐肾素-血管紧张素-醛固酮系统阻滞剂(在非妊娠患者中),因为它具有抗蛋白尿和降压作用;对于肾功能受损的患者,应慎重使用。高血压应控制在130/80mmHg以下。一般肾脏保护措施(如避免服用非甾体抗炎药)怎么强调都不为过。应调查疫苗接种状况,并相应地为患者接种减毒疫苗。强烈建议接种针对流感和肺炎链球菌的V型疫苗;关于针对带状疱疹的疫苗接种,现有数据表明,狼疮患者使用减毒活疫苗(在大多数国家均可获得)具有安全性。这个决定应该是个体化的,考虑到患者的年龄和免疫抑制的状态。免疫抑制程度较轻的患者可能更适合接种疫苗。

   他汀类药物的治疗应该根据血脂水平和是否存在其他心血管危险因素来决定。建议使用系统性冠状动脉风险评估QRisk3或其他验证评分来计算10年心血管疾病风险,以帮助做出这一决定,考虑到这些评分可能低估了实际风险,特别是在年轻的SLE患者中。建议在存在高危APL特征的情况下使用小剂量阿司匹林一级预防血栓形成,平衡血栓形成和出血的风险。根据骨折风险,骨保护和骨质疏松症的预防应遵循非药理学(运动摄取、维持正常体重指数)和药理学措施。

5、狼疮性肾炎的监测和预后

   中心应定期对患者进行评估,由经验丰富的临床医生检查尿液镜检、血清学和组织学。前6-12个月内蛋白尿和血肌酐的动态变化比血尿更敏感。蛋白尿的定量可以通过UPCR来完成,因为在大多数研究中,它与24小时尿蛋白的相关性很高(尽管当尿蛋白<1000 mg/24小时时相关性较低)。在治疗之前,24小时尿蛋白可能是首选的。每次就诊时应包括尿检肾小球血尿或细胞管型的再次出现可预测即将发生的肾炎。应监测血清C3/C4和抗dsDNA,虽然抗dsDNA滴度的升高与肾炎的发生有关,但特异性不高。抗C1q抗体与活动期LN的相关性最高,也可预测复发。

6、抗磷脂综合征与狼疮性肾炎

   抗磷脂综合征相关肾病是一种罕见而独特的急性早幼粒细胞白血病诱导的血管性肾病。尽管TMA被认为是抗磷脂综合征相关性肾病的标志,但TMA并不是病因学上的,因为类似的病变在血栓性血小板减少性紫癜/溶血性尿毒症综合征、恶性高血压或补体介导的TMA中也有发现。目前还没有对照研究来指导抗磷脂综合征相关性肾病的治疗。除HCQ外,还推荐使用抗血小板药物或抗凝剂(如果符合抗磷脂综合征的标准)。阻断肾素-血管紧张素-醛固酮系统可能延缓疾病进展

原文出处

Fanouriakis A,  Kostopoulou M,  Cheema K,et al,2019 Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis.Ann Rheum Dis 2020 06;79(6)

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    学习

    0

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    2021-09-29 13f0c37dm61暂无昵称

    值得学习和反复研究判读。

    0

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  6. [GetPortalCommentsPageByObjectIdResponse(id=1196018, encodeId=81c6119601828, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3c31528806, createdName=gqylhd, createdTime=Tue Feb 22 11:47:31 CST 2022, time=2022-02-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1739056, encodeId=c4571e3905605, content=<a href='/topic/show?id=6e566913df' target=_blank style='color:#2F92EE;'>#ERA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=6913, encryptionId=6e566913df, topicName=ERA)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=e36234488643, createdName=124988c7m106暂无昵称, createdTime=Thu Oct 07 07:11:30 CST 2021, time=2021-10-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1056074, encodeId=d52410560e426, content=值得学习和反复研究判读。, beContent=null, objectType=article, channel=null, level=null, likeNumber=62, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=cfc84293490, createdName=13f0c37dm61暂无昵称, createdTime=Wed Sep 29 13:10:29 CST 2021, time=2021-09-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1332955, encodeId=1278133295531, content=<a href='/topic/show?id=d17c68153ab' target=_blank style='color:#2F92EE;'>#狼疮肾炎#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=68153, encryptionId=d17c68153ab, topicName=狼疮肾炎)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d4902500082, createdName=1249883fm12暂无昵称, createdTime=Sun Sep 26 14:11:30 CST 2021, time=2021-09-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1387463, encodeId=906d138e46373, content=<a href='/topic/show?id=8a3a6814425' target=_blank style='color:#2F92EE;'>#狼疮#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=68144, encryptionId=8a3a6814425, topicName=狼疮)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7a6e2500005, createdName=sunrural_42825357, createdTime=Sun Sep 26 14:11:30 CST 2021, time=2021-09-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1455360, encodeId=1829145536086, content=<a href='/topic/show?id=4272e0771a' target=_blank style='color:#2F92EE;'>#EULAR#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=7077, encryptionId=4272e0771a, topicName=EULAR)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=7f855654200, createdName=muzishouyi, createdTime=Sun Sep 26 14:11:30 CST 2021, time=2021-09-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1532306, encodeId=a2aa1532306d2, content=<a href='/topic/show?id=10b5825e4aa' target=_blank style='color:#2F92EE;'>#肾炎#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=82574, encryptionId=10b5825e4aa, topicName=肾炎)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=84df12331144, createdName=villahu, createdTime=Sun Sep 26 14:11:30 CST 2021, time=2021-09-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1537071, encodeId=cc75153e071af, content=<a href='/topic/show?id=aaaf653e44' target=_blank style='color:#2F92EE;'>#EDTA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=6537, encryptionId=aaaf653e44, topicName=EDTA)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=328c12785299, createdName=ycmayy, createdTime=Sun Sep 26 14:11:30 CST 2021, time=2021-09-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1054655, encodeId=c6811054655bf, content=色咯喔VIP会员吗密子君威忑1回去, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTIrrxxDxnLic8t6EAs38Qfwo6H2h6JMleIgb9OSYf6LMnVDkQEqUXWoSDWboibjhOBI9SJDTXweqQIA/132, createdBy=50aa5321359, createdName=查查佳佳, createdTime=Sat Sep 25 10:03:45 CST 2021, time=2021-09-25, status=1, ipAttribution=)]
    2021-09-26 muzishouyi
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    2021-09-26 villahu
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    2021-09-26 ycmayy
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    2021-09-25 查查佳佳

    色咯喔VIP会员吗密子君威忑1回去

    0

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