Rigshospitalet Glostrup, Glostrup, Denmark, and University of Copenhagen, Copenhagen, Denmark.
Aarhus University Hospital, Aarhus, Denmark.
Arthritis Rheumatol. 2019 Dec;71(12):1997-2004. doi: 10.1002/art.41031.
Nationwide Danish guidelines regarding rheumatoid arthritis (RA) patients initiating biologic treatment (i.e., biologic disease-modifying antirheumatic drugs [DMARDs]) are issued on an approximately annual basis. For biologics-naive patients treated with concomitant methotrexate, mandatory medications included certolizumab pegol (CZP; year 2013-2014, recommended compliance 80%), abatacept (ABA; 2014-2015, 80%), and biosimilar infliximab (CT-P13; 2015-2016, 50%). We hypothesized that these guidelines could be perceived as a surrogate randomization tool in which calendar period rather than patient-specific factors defined the choice of the biologic DMARD. We undertook this study to assess compliance with guidelines (supporting the assumption of surrogate randomization) and to compare the effectiveness of CZP, ABA, and CT-P13 in patients treated according to guidelines.
This was an observational cohort study emulating a randomized trial (using intent-to-treat analyses). RA patients compliant with the treatment guidelines were identified in DANBIO, and information on prior comorbidities was obtained by linking to national registries. Outcome measures included remission rates according to the Disease Activity Score in 28 joints (DAS28) (at 6 and 12 months) and treatment retention at 1 year, compared across treatment regimens. Comorbidity/confounder-adjusted multivariable logistic and Cox regression analyses were used.
Seven hundred seventy-six patients were included in the study (336 receiving CZP, 215 receiving ABA, 225 receiving CT-P13). Compliance with treatment guidelines was high: 70%, 65%, and 59%, respectively. Six-month DAS28 remission rates were 35%, 33%, and 42%, and 12-month rates were 35%, 31%, and 35%, respectively. Compared to CZP, adjusted odds ratios for 6- and 12-month DAS28 remission rates were 0.96 (95% confidence interval [95% CI] 0.63-1.47) and 0.74 (95% CI 0.47-1.15) for ABA and 1.38 (95% CI 0.91-2.09) and 0.96 (95% CI 0.62-1.49) for CT-P13, respectively. Adjusted hazard ratios for withdrawal (during days 0-90 and days 91-365) were 0.70 (95% CI 0.39-1.27) and 1.16 (95% CI 0.84-1.60) for ABA and 0.58 (95% CI 0.33-1.10) and 0.83 (95% CI 0.59-1.17) for CT-P13, respectively, compared to CZP.
The surrogate randomization procedure enabled head-to-head comparisons of CZP, ABA, and CT-P13. Although some differences in estimated effectiveness were observed across drugs, confidence intervals were wide and statistical significance was not reached.
丹麦全国范围内针对类风湿关节炎（RA）患者开始使用生物制剂治疗（即生物改善病情抗风湿药[DMARDs]）的指南每年发布一次。对于同时接受甲氨蝶呤治疗的生物制剂初治患者，强制性药物包括培塞利珠单抗（CZP；2013-2014 年，推荐遵医率 80%）、阿巴西普（ABA；2014-2015 年，80%）和生物类似物英夫利昔单抗（CT-P13；2015-2016 年，50%）。我们假设这些指南可以被视为一种替代随机化工具，其中日历时期而不是患者特定因素决定了生物 DMARD 的选择。我们进行了这项研究，以评估对指南的遵守情况（支持替代随机化的假设），并比较 CZP、ABA 和 CT-P13 在根据指南治疗的患者中的有效性。
这是一项模仿随机试验的观察性队列研究（使用意向治疗分析）。在 DANBIO 中确定符合治疗指南的 RA 患者，并通过与国家登记册链接获取先前合并症的信息。结局指标包括根据 28 个关节疾病活动度评分（DAS28）（6 个月和 12 个月）评估的缓解率，以及 1 年时的治疗保留率，比较不同治疗方案的结果。采用合并症/混杂因素调整的多变量逻辑和 Cox 回归分析。
研究纳入了 776 名患者（336 名接受 CZP 治疗，215 名接受 ABA 治疗，225 名接受 CT-P13 治疗）。对治疗指南的遵守率很高：分别为 70%、65%和 59%。6 个月时 DAS28 缓解率分别为 35%、33%和 42%，12 个月时的缓解率分别为 35%、31%和 35%。与 CZP 相比，ABA 在 6 个月和 12 个月时的 DAS28 缓解率的调整后比值比分别为 0.96（95%置信区间[95%CI]0.63-1.47）和 0.74（95%CI 0.47-1.15），CT-P13 的比值比分别为 1.38（95%CI 0.91-2.09）和 0.96（95%CI 0.62-1.49）。ABA 在 0-90 天和 91-365 天期间停药（退出）的调整后危险比分别为 0.70（95%CI 0.39-1.27）和 1.16（95%CI 0.84-1.60），CT-P13 分别为 0.58（95%CI 0.33-1.10）和 0.83（95%CI 0.59-1.17），与 CZP 相比。
替代随机化程序使 CZP、ABA 和 CT-P13 之间能够进行头对头比较。尽管在药物的估计效果方面观察到了一些差异，但置信区间较宽，未达到统计学意义。
