高危高尿酸血症药物降尿酸治疗专家共识（2025版）

一、共识制订方法

1. 共识专家组构成:本共识专家组成员包括33名风湿免疫病学临床专家和1名方法学专家。临床专家负责提出拟纳入的临床问题、形成共识推荐意见、起草和修改共识全文以及定期对共识推荐意见进行更新。执笔专家负责相应证据收集和起草共识。

2. 共识使用者和目标人群:本共识使用者为从事HUA诊疗工作的临床医师、药师及护理人员,适用的目标人群为成人HUA患者。

3. 临床问题遴选和确定:第一次共识讨论会上专家重点围绕哪些HUA患者有预后不良风险、是否需要提出HrHUA的概念、合并哪些风险因素的HUA患者需要启动药物ULT、ULT是否有获益以及ULT的具体方案等临床问题进行了深入的讨论。经广泛采集意见,最终专家组确定18个临床问题,包括哪些HUA是HrHUA? HUA合并以下15个慢性疾病:痛风、肾结石、慢性肾脏病(CKD)、高血压、冠心病、慢性心力衰竭、2型糖尿病、卒中、关节MSU晶体沉积、肥胖、高脂体积、肥胖、高脂血症、代谢综合征(MetS)、非酒精性脂肪性肝病(NAFLD)、心肌梗死和房颤,是否推荐药物ULT?ULT的启动时机和治疗目标是什么?ULT过程中如何预防痛风急性发作?对上述18个临床问题的证据进行整理与评价,其中临床问题“HUA合并关节MSU晶体沉积、肥胖、高脂血症、MetS、NAFLD、心肌梗死或房颤患者是否推荐ULT?”,因缺乏ULT相关的循证医学证据,无法形成推荐意见。其余11个临床问题经共识专家组第二轮推荐意见投票均达成共识。

4. 证据检索、整合及分级:针对上述纳入共识研究的临床问题进行文献检索,检索的数据库包括PubMed、EMBASE、Web of science 和 Cochrane Library等,检索策略采用关键词及主题词结合自由词在数据库中的题目和摘要中进行检索,检索词采用主题词(Mesh)和自由词相结合,包括“Hyperuricemia”“Urate lowering”和关注的具体合并症等词汇,文献截止日期为2024年3月1日。优

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先检索近5年的相关系统评价和随机对照试验(RCT)研究,对未检索到系统评价和RCT的临床问题,不限定年份和研究类型进行扩充检索。除电子数据库检索外,共识专家组成员提供的关键研究以及已发表的系统评价或指南共识中纳入的研究也被作为补充资料。针对每1个临床问题制定具体的纳入和排除标准,收集相关研究证据。采用《牛津循证医学中心2011版证据等级》进行证据的等级评估(表1)[8]。此外,鉴于个别临床问题非常重要,但不适合应用常规的证据质量评级的方法来评价,共识专家组对于这类问题采用基于专家共识的推荐意见,即良好实践主张(GPS)的方式表达。

5. 推荐意见的形成:执笔专家组基于临床问题的证据总结,综合考虑医学干预的利弊平衡、证据等级、价值观念与偏好、成本与资源耗费以及可及性等因素,结合表2原则形成初步推荐意见(强/弱推荐,强/弱不推荐)。在参与共识制订的专家中,以问卷形式达成对推荐意见的共识,原则为:(1)任何1条推荐意见的等级,票数超过50%可直接确定推荐方向及强度;(2)若不能达到上述标准,但推荐方向一致的票数合计超过70%,则确定推荐方向,推荐强度为弱;(3)若上述两项均无法满足,对推荐意见进行相应的修改并进入下一阶段讨论,直至达成最终结论。

6. 共识意见的外审及批准:执笔专家就达成共识的推荐意见撰写共识全文,经所有共识专家组成员同意后交外审专家组评审。根据外审专家的反馈意见,再次对共识进行修订与完善,确定共识终稿。

7. 共识意见的实施与更新;本共识发布后,专家组将通过专业期刊、网站、学术会议等各种方式在国内组织推广和传播,确保临床医师及其他利益相关群体充分了解并正确使用本共识。未来将根据证据更新情况对本共识进行更新。

二、共识推荐意见

临床问题1:哪些HUA是HrHUA?

推荐意见1:存在预后不良风险,若不进行综

合管理可能会导致不良结局的HUA称为HrHUA, 如HUA合并痛风或关节MSU晶体沉积、合并肾脏疾病(肾结石、CKD)、合并心血管疾病(高血压、慢性心力衰竭、冠心病、心肌梗死、房颤)、合并代谢性疾病(2型糖尿病、肥胖、MetS、高脂血症、NAFLD)以及合并神经系统疾病(卒中)等。(证据等级II~III,强推荐)

操作要点:对所有HUA患者,应根据临床病史、体格检查以及实验室、影像学等辅助检查结果,明确有无HUA相关损害的预后不良危险因素,评估HrHUA及病情严重程度。

证据总结: HUA 不仅可导致痛风,还可导致肾结石、CKD、心力衰竭等并发症的发生,这些并发症以及相关合并症的共存将进一步影响 HUA 的预后,具体研究证据见表3。

临床问题2: HUA合并痛风患者是否推荐 ULT?

推荐意见2:对于HUA合并痛风的患者,若痛风发作每年≥2次,推荐启动ULT(证据等级II,强推荐);若既往痛风发作≥2次,但每年≤1次,可考虑启动ULT(证据等级II,弱推荐);若仅有1次痛风发作且CKD≥3期、血尿酸水平>540 µmol/L或肾结石患者可考虑启动ULT(证据等级II~V,弱推荐);若出现痛风石或影像学显示有痛风引起的关节损伤患者,推荐启动ULT。(证据等级II,强推荐)

操作要点:ULT药物主要包括抑制尿酸生成药如别嘌醇和非布司他,促进尿酸排泄药如苯溴马隆和选择性尿酸盐转运蛋白1(URAT1)抑制剂多替诺雷,以及尿酸酶如普瑞凯希等[63]。别嘌醇治疗前应尽可能筛查HLA-B*5801基因,阳性者禁用。促尿酸排泄药治疗时应适当增加水分摄入,必要时碱化尿液,维持尿pH值在6.2~6.9。重度肾功能不全患者不推荐使用促尿酸排泄药。若单药治疗不能使血尿酸达标,可考虑不同作用机制的降尿酸药物联合治疗。痛风间歇期可考虑启动ULT,但急性发

表1 2011版牛津大学循证医学中心证据分级标准

|(临床)问题|若不给予这个治疗会发生什么?(预后风险问题)|这个治疗有用吗?(疗效收益问题)| |---|---|---| |证据等级 I*|起始队列研究的系统评价|RCT或单病例RCT的系统评价| |证据等级 II*|起始队列研究|RCT或具有显著效果的观察性研究| |证据等级 III*|队列研究或随机研究的对照组*|非随机对照队列/随访研究$^{b}$| |证据等级 IV*|病例列或病例对照研究,或低质量预后队列研究$^{b}$|病例系列,病例对照研究,或历史对照研究$^{b}$| |证据等级 V*|N/A|基于机制的推理|

注:“因研究间不一致性或绝对效应量非常小,证据级别可考虑研究质量、精确度、间接性而降级,也可考虑效应量显著或非常显著而升级,$^{b}$系统评价普遍地优于单项研究;RCT为随机对照研究;N/A为不适用

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表2 本共识采用推荐等级标准

|定义|具体描述| |---|---| |支持使用某项干预措施的强推荐|评价者确信干预措施利大于弊| |支持使用某项干预措施的弱推荐|利弊不确定或无论高低质量的证据均显示利弊相当| |反对使用某项干预措施的强推荐|评价者确信干预措施弊大于利| |基于共识的推荐意见|缺乏试验性研究证据,但属于GPS|

注:GPS为良好实践主张

作期启动ULT必须在充分抗炎治疗的基础上。

证据总结:两项RCTs共纳入225例HUA合并严重痛风的患者(过去18个月痛风发作次数≥3,或≥1个痛风石,或影像学显示有痛风引起的关节损伤),分为3组(普瑞凯希每2周1次,普瑞凯希每4周1次,安慰剂),维持治疗6个月,普瑞凯希治疗组血尿酸水平降低至360 µmol/L以下的患者比例更高[分别为42%(95%CI:32%~54%)和35%(95%CI:24%~46%)比0(95%CI:0~8%),均P<0.001[64];痛风发作频次在ULT组表现出先升高(治疗1~3个月)后下降的趋势(治疗4~6个月);痛风石完全缓解率更高(40%和21%比7%);接受ULT组疼痛和肿胀关节数更少(压痛关节数变化:-7.4±11.9和-6.1±10.6比-1.2±12.3;肿胀关节数变化:-5.5±10.5和-5.1±7.8比-2.6±11.6),同时生活质量较高[36项简明健康调查表评分变化:(4.4±9.4)和(4.9±8.5)比(-0.3±9.0)分]。另一项RCT研究纳入314例HUA合并痛风发作频率低的患者(既往痛风发作≤2次,且前一年内痛风发作不超过1次),随访24个月后,与安慰剂组(n=157)相比,ULT组(n=157)血尿酸得到控制(62.8%比5.7%,P<0.001),痛风发作的总发生率降低(29.3%比41.1%,P<0.05),ULT组与安慰剂组治疗期间出现不良事件无差异(89/157比76/157)[65]。此外,2020年美国风湿病学会(ACR)痛风管理指南推荐,对于痛风首次发作后CKD≥3期、血尿酸水平>540 µmol/L或肾结石患者有条件地建议启动ULT[6]。

一项2021年发表的荟萃分析[66], 6项RCTs纳入557例急性痛风发作患者,所有患者基线接受低嘌呤饮食和(或)秋水仙碱和(或)非甾体抗炎药(NSAIDs)治疗,结果显示:与未使用ULT药物的患者相比,ULT药物治疗的患者尿酸水平显著下降[标准化化均值差(SMD)=-0.73、95%CI: -0.92~-0.54, P<0.00001],用药依从性较好[危险度比

(RR)=1.40, 95%CI: 1.18~1.65, P<0.0001],但在疼痛视觉模拟评分(VAS)[均值差(MD)=0.06,95%CI:-0.13~0.25, P=0.55]以及急性痛风复发率方面(RR=0.84,95%CI: 0.59~1.19, P=0.33),两组患者无显著差异。另一项荟萃分析纳入445例急性痛风发作患者,所有患者均接受秋水仙碱或NSAIDs治疗,结果显示,与未使用ULT药物的患者相比,ULT组在自评疼痛评分(基线:SMD=0.08,95%CI:-0.11~0.27, P=0.42;第3~4天:SMD=-0.01,95%CI:-0.21~0.18, P=0.88;第7~8天:SMD=0.07,95%CI:-0.13~0.27, P=0.50;第10天:SMD=-0.11,95%CI:-0.49~0.28, P=0.59;第14~15天:SMD=-0.08,95%CI:-0.36~0.20, P=0.57)、痛风发作的缓解时间(SMD=0.77 d, 95%CI:-0.26~1.79 d, P=0.14)以及复发风险(RR=1.06, 95%CI: 0.59~1.92, P=0.84)方面均无差异[67]。这一结果也得到了另外两项荟萃分析的支持[68-69]。

我国台湾省的一项病例匹配队列研究显示, 随访6.5年后, 与接受ULT的患者(n=764)相比, 未接受ULT的痛风患者(n=764)心血管死亡风险[风险比(HR)=2.43, 95%CI: 1.33~4.45]和全因死亡风险(HR=1.45, 95%CI: 1.05~2.00)显著升高[20]。另一项病例匹配队列研究纳入5218例患者, 与未使用ULT组(n=2609)相比, ULT(n=2609)可降低住院痛风患者的卒中风险(aHR=0.52, 95%CI: 0.39~0.70, P<0.001)和全因死亡风险(aHR=0.60, 95%CI: 0.39~0.92, P=0.02)[71]。

临床问题3: HUA 合并肾结石患者是否推荐 ULT?

推荐意见3:对于无症状HUA合并肾结石的患者,可考虑启动ULT以减少肾结石复发。(证据等级II,弱推荐)

操作要点:对于无症状HUA合并肾结石者,推荐使用抑制尿酸生成药物,如别嘌醇或非布司他。

证据总结:一项RCT研究表明,ULT可显著降低HUA合并草酸钙肾结石病史患者肾结石的复发率,并延长复发时间[72]。另一项RCT纳入了99例HUA合并含肾结石病石患者,随机分为非布司他组(n=33)、别嘌醇组(n=33)和安慰剂组(n=33),治疗6个月后,降尿酸药物可降低尿尿酸排泄量(非布司他组24h尿尿酸下降百分比(-58.6%)显著高于别嘌醇组(-36.4%, P=0.003)和安慰剂组(-12.7%, P<0.001),但对改善结石大小和数量没有影响(结石大小:非布司他-6.50%±28.4%,别嘌醇

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