Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, USA
Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Sagamihara, Japan.
Ann Rheum Dis. 2023 Mar;82(3):331-343. doi: 10.1136/ard-2022-222543. Epub 2022 Dec 5.
To evaluate malignancies and their associations with baseline risk factors and cardiovascular risk scores with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA).
In an open-label, randomised controlled trial (ORAL Surveillance; NCT02092467), 4362 patients with RA aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 (N=1455) or 10 mg two times per day (N=1456) or TNFi (N=1451). Incidence rates (IRs; patients with first events/100 patient-years) and HRs were calculated for adjudicated malignancies excluding non-melanoma skin cancer (NMSC), NMSC and subtypes. Post hoc analyses for malignancies excluding NMSC, lung cancer and NMSC included risk factors identified via simple/multivariable Cox models and IRs/HRs categorised by baseline risk factors, history of atherosclerotic cardiovascular disease (HxASCVD) and cardiovascular risk scores.
IRs for malignancies excluding NMSC and NMSC were higher with tofacitinib (combined and individual doses) versus TNFi. Risk of lung cancer (most common subtype with tofacitinib) was higher with tofacitinib 10 mg two times per day versus TNFi. In the overall study population, the risk of malignancies excluding NMSC was similar between both tofacitinib doses and TNFi until month 18 and diverged from month 18 onwards (HR (95% CIs) for combined tofacitinib doses: 0.93 (0.53 to 1.62) from baseline to month 18 vs 1.93 (1.22 to 3.06) from month 18 onwards, interaction p=0.0469). Cox analyses identified baseline risk factors across treatment groups for malignancies excluding NMSC, lung cancer and NMSC; interaction analyses generally did not show statistical evidence of interaction between treatment groups and risk factors. HxASCVD or increasing cardiovascular risk scores were associated with higher malignancy IRs across treatments.
Risk of malignancies was increased with tofacitinib versus TNFi, and incidence was highest in patients with HxASCVD or increasing cardiovascular risk. This may be due to shared risk factors for cardiovascular risk and cancer.
NCT02092467, NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661.
评估托法替布与肿瘤坏死因子抑制剂（TNFi）相比在类风湿关节炎（RA）患者中的恶性肿瘤及其与基线风险因素和心血管风险评分的相关性。
在一项开放性标签、随机对照试验（ORAL Surveillance；NCT02092467）中，4362 名年龄≥50 岁且有≥1 个额外心血管风险因素的 RA 患者接受托法替布 5 mg（N=1455）或 10 mg 每日 2 次（N=1456）或 TNFi（N=1451）治疗。通过协变量校正后计算恶性肿瘤（排除非黑色素瘤皮肤癌[NMSC]）、NMSC 和亚型的发生率（IR；每 100 患者-年发生的首次事件患者数）和 HR。对排除 NMSC、肺癌和 NMSC 的恶性肿瘤的事后分析包括通过简单/多变量 Cox 模型识别的风险因素，以及根据基线风险因素、动脉粥样硬化性心血管疾病（ASCVD）病史和心血管风险评分进行分类的 IR 和 HR。
与 TNFi 相比，托法替布（联合和单剂量）的 NMSC 排除和 NMSC 的 IR 更高。与 TNFi 相比，托法替布 10 mg 每日 2 次的肺癌（最常见的托法替布亚型）风险更高。在整个研究人群中，在第 18 个月之前，托法替布两种剂量和 TNFi 的 NMSC 排除风险相似，从第 18 个月开始，两种药物的风险开始出现差异（联合托法替布剂量的 HR（95%CI）：从基线至第 18 个月为 0.93（0.53 至 1.62），从第 18 个月开始为 1.93（1.22 至 3.06），交互作用 p=0.0469）。Cox 分析确定了不同治疗组中排除 NMSC、肺癌和 NMSC 的基线风险因素；交互作用分析通常没有显示出治疗组和风险因素之间的统计学证据。ASCVD 或心血管风险评分增加与所有治疗方法的恶性肿瘤 IR 升高相关。
与 TNFi 相比，托法替布的恶性肿瘤风险增加，在有 ASCVD 病史或心血管风险增加的患者中发病率最高。这可能是由于心血管风险和癌症的共同风险因素所致。
NCT02092467、NCT01262118、NCT01484561、NCT00147498、NCT00413660、NCT00550446、NCT00603512、NCT00687193、NCT01164579、NCT00976599、NCT01059864、NCT01359150、NCT02147587、NCT00960440、NCT00847613、NCT00814307、NCT00856544、NCT00853385、NCT01039688、NCT02281552、NCT02187055、NCT02831855、NCT00413699、NCT00661661。
