荷兰痛风治疗目标策略与症状驱动管理（GO TEST序曲）：一项多中心、开放标签、实用、优越、随机对照试验

摘要(中文译文)

痛风管理推荐采用达标治疗（treat-to-target）策略，即通过滴定降尿酸治疗使血清尿酸达到低于0.36 mmol/L的目标，但比较达标治疗策略与症状驱动治疗策略的实用性头对头试验证据尚缺乏。我们旨在通过比较这两种策略在痛风患者中的应用来填补这一空白。我们在荷兰八家二级保健风湿病中心开展了一项多中心、开放标签、实用性、优效性、随机对照试验。年龄18岁及以上、患有痛风且伴高尿酸血症（通常定义为血清尿酸浓度>0.36 mmol/L）、且当前未使用降尿酸治疗的参与者，通过计算机生成的分配序列按1:1随机分配，接受达标治疗策略——即以结构化血清尿酸指导的口服降尿酸治疗滴定，使血清尿酸浓度达到低于0.36 mmol/L的目标（包括一线别嘌醇和二线口服非布司他或口服苯溴马隆）——或症状驱动管理，后者由医生和患者根据症状决定是否启动降尿酸治疗，药物类型和剂量由医生自行决定，不设特定的血清尿酸目标。由于采用实用性设计，参与者和研究者对治疗分配未设盲。主要结局为随访第18至24个月期间的缓解，定义为第18至24个月期间无痛风发作、第24个月时无皮下痛风石、患者报告的疼痛评分低于2分、以及患者对疾病活动度的总体评估评分高于8分。分析按意向治疗原则进行，缺失数据采用多重插补法处理，所有随机分配的参与者均纳入主要疗效和安全性分析。有痛风亲身经历者参与了研究设计和结局指标的选择。该试验已在EudraCT注册，注册号为2020-005721-82，现已停止招募。2021年3月4日至2022年11月4日期间，共308名参与者被随机分配，其中268名（87%）为男性，40名（13%）为女性；平均年龄为65.93岁（SD 15.29）。参与者被分配至达标治疗组（145名参与者）或症状驱动管理组（163名参与者）。达标治疗组在第18至24个月期间发生缓解的频率高于症状驱动管理组（39.4%[145名参与者中的57名] vs 24.0%[163名中的39名]；绝对差异为15.4个百分点[95% CI 6.4-24.4]；p=0.024）。达标治疗组有61名（42%）参与者发生不良事件，症状驱动管理组有86名（53%）参与者发生不良事件（绝对差异为-10.7个百分点[95% CI -21.8至0.4]；p=0.060）。未报告严重药物相关不良事件，也无治疗相关死亡。与症状驱动治疗相比，达标治疗策略与更好的长期疾病控制相关，且无证据表明不良事件增加。这些发现支持在痛风常规管理中使用系统性血清尿酸指导的降尿酸治疗滴定。ZonMW和Reuma Nederland资助。

Abstract

A treat-to-target approach is recommended for gout management, which involves titrating urate-lowering therapy to reach a serum urate target of less than 0·36 mmol/L, but evidence from pragmatic, head-to-head trials comparing a treat-to-target strategy with a symptom-driven approach is scarce. We aimed to address this gap by comparing these two approaches in patients with gout. We did a multicentre, open-label, pragmatic, superiority, randomised controlled trial at eight secondary care rheumatology centres in the Netherlands. Participants aged 18 years or older with gout and hyperuricaemia (typically defined as a serum urate concentration of >0·36 mmol/L), and not currently using urate-lowering therapy were randomly assigned (1:1) using a computer-generated allocation sequence to receive either a treat-to-target strategy to reach a target serum urate concentration of less than 0·36 mmol/L with structured serum urate-guided titration of oral urate-lowering therapy (including first-line allopurinol and second-line oral febuxostat or oral benzbromarone) or symptom-driven management, in which the physicians and patients decided whether to initiate urate-lowering therapy based on symptoms, and the type and dose were determined at the physician's discretion without a specific serum urate target. Because of the pragmatic design, participants and investigators were not masked to treatment allocation. The primary outcome was remission during months 18-24 of follow-up, defined as absence of gout flares during months 18-24, no subcutaneous tophi at month 24, a patient-reported pain score of less than 2, and a patient global assessment of disease activity score of more than 8. Analyses were done according to the intention-to-treat principle using multiple imputation for missing data, and all randomly assigned participants were included in the primary efficacy and safety analyses. People with lived experience of gout contributed to the study design and selection of outcome measures. The trial was registered with EudraCT, 2020-005721-82, and is closed to recruitment. Between March 4, 2021, and Nov 4, 2022, 308 participants were randomly assigned, of whom 268 (87%) were male and 40 (13%) were female; the mean age was 65·93 years (SD 15·29). Participants were allocated to the treat-to-target group (145 participants) or the symptom-driven management group (163 participants). Remission during months 18-24 occurred more often in the treat-to-target group than in the symptom-driven management group (39·4% [57 of 145 participants] vs 24·0% [39 of 163]; absolute difference 15·4 percentage points [95% CI 6·4-24·4]; p=0·024). Adverse events occurred in 61 (42%) participants in the treat-to-target group and 86 (53%) in the symptom-driven management group (absolute difference -10·7 percentage points [95% CI -21·8 to 0·4; p=0·060). No serious drug-related adverse events and no treatment-related deaths were reported. A treat-to-target strategy was associated with improved long-term disease control compared with symptom-driven care, without evidence of increased adverse events. These findings provide support for the use of systematic serum urate-guided urate-lowering therapy titration in the routine management of gout. ZonMW and Reuma Nederland.

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