基于ORAL监测计划的初步结果，这是一个风险丰富患者的事件驱动临床试验，要求鉴定接受托珀替尼与肿瘤坏死因子抑制剂（TNFi）的不同相对风险（即“高风险”和“低风险”的亚种群）。对年龄≥50岁且存在≥ 1项额外心血管风险因素的类风湿关节炎患者进行托珀替尼5或10毫克两次/日或TNFi治疗。根据安全性结果的先前分析，已确认年龄和吸烟是特别感兴趣的风险因素。按独立或组合评估年龄和吸烟危险比（HRs）和发生率。结果在托珀替尼开发计划范围内得到证实。将年龄≥65岁或曾经吸烟定义为一组（“高风险”）患者，这组患者在接受托珀替尼（合并剂量）与TNFi相比增加了恶性肿瘤（非黑色素皮肤癌除外）、主要不良心血管事件、心肌梗死、静脉血栓栓塞和全因死亡的风险（HRs介于1.41-5.19之间）。对于“年龄<65岁且从未吸烟”的患者（“低风险”），在6年跟踪期内未发现托珀替尼与TNFi相比的风险增加（HRs ≈1.0），绝对风险仍然很低，并在托珀替尼类风湿性关节炎、银屑病性关节炎和溃疡性结肠炎计划中予以证实，观察期长达10年。 ORAL监测计划的这个事后分析确定了两个不同于TNFi的托珀替尼亚种群相对风险的亚种群。高危仅限于由不同风险因素（年龄≥65岁或吸烟）定义的患者，这些不同风险因素解释了在托珀替尼与TNFi比较中观察到的过度风险。这些发现可以指导托珀替尼的个体效益/风险评估和临床决策。NCT02092467、NCT01262118、NCT01484561、NCT00147498、NCT00413660、NCT00550446、NCT00603512、NCT00687193、NCT01164579、NCT00976599、NCT01059864、NCT01359150、NCT02147587、NCT00960440、NCT00847613、NCT00814307、NCT00856544、NCT00853385、NCT01039688、NCT02281552、NCT02187055、NCT02831855、NCT00413699、NCT00661661、NCT00787202、NCT01465763、NCT01458951、NCT01458574、NCT01470612、NCT01877668、NCT01882439、NCT01976364。© 作者（或其雇主）2023年。CC BY-NC下允许再利用。不得进行商业再利用。由BMJ出版。

Based on primary results from ORAL Surveillance, an event-driven clinical trial of risk-enriched patients, identify subpopulations with different relative risk (ie, 'high-risk' and 'low-risk') with tofacitinib versus tumour necrosis factor inhibitors (TNFi).Patients with rheumatoid arthritis aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 or 10 mg two times a day or TNFi. Prior analyses had identified age and smoking as risk factors of particular interest across safety outcomes. Hazard ratios (HRs) and incidence rates were evaluated by age and smoking individually and in combination. Results were validated across tofacitinib development programmes.'Age ≥65 years or ever smoker' defined a group ('high-risk') with increased risk of malignancies (excluding non-melanoma skin cancer), major adverse cardiovascular events, myocardial infarction, venous thromboembolism and all-cause death with tofacitinib (combined doses) versus TNFi (HRs 1.41-5.19). In patients 'aged <65 years and never smokers' ('low-risk'), there was no detectable risk increase with tofacitinib versus TNFi (HRs ≈1.0) up to 6 years of follow-up, and absolute risk remained low and was corroborated across tofacitinib rheumatoid arthritis, psoriatic arthritis and ulcerative colitis programmes with up to 10 years of observation.This posthoc analysis of ORAL Surveillance identified two tofacitinib subpopulations with different relative risk versus TNFi. High risk was confined to patients defined by distinct risk factors age ≥65 years or smoking, and these differentiating risk factors accounted for the excess risk observed with tofacitinib versus TNFi. These findings can guide individualised benefit/risk assessment and clinical decision-making on treatment with tofacitinib.NCT02092467, NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661, NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612, NCT01877668, NCT01882439, NCT01976364.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.