Eli Lilly and Company, Indianapolis, Indiana, USA.
Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria.
Ann Rheum Dis. 2022 May;81(5):622-631. doi: 10.1136/annrheumdis-2021-221323. Epub 2022 Feb 22.
To evaluate if baricitinib, a Janus kinase inhibitor, further enhances disease-modifying effects by uncoupling the link between disease activity and structural damage progression in patients with rheumatoid arthritis (RA) using two phase III randomised, double-blinded trials.
In RA-BEAM, patients with established RA and inadequate response to methotrexate (MTX-IR) received placebo (PBO), baricitinib 4 mg or adalimumab 40 mg on background MTX. In RA-BEGIN, conventional synthetic disease-modifying antirheumatic drug (csDMARD)-naïve patients received MTX, baricitinib 4 mg or baricitinib 4 mg plus MTX. Using linear regression analyses, joint damage progression (assessed by change from baseline in van der Heijde modification of the Total Sharp Score) was compared between treatment groups for patients achieving certain disease activity states by the Clinical Disease Activity Index. Time-averaged postbaseline responses were used to week 24 (RA-BEAM) and week 52 (RA-BEGIN).
For MTX-IR patients, structural damage progression was reduced regardless of disease activity states in baricitinib-treated patients (p=0.6), whereas in PBO patients there was a clear dependence on disease activity states, being significantly lower in those who achieved remission/low disease activity (REM/LDA) compared with moderate/high disease activity (MDA/HDA) (p=0.02). Furthermore, the baricitinib MDA/HDA group had less damage progression than the PBO MDA/HDA group (p<0.001). For csDMARD-naïve patients, progression was lower in REM/LDA versus MDA/HDA within the MTX group (p<0.001). However, for baricitinib+MTX (p=0.5) or baricitinib monotherapy (p=0.07), progression was similar regardless of disease activity. In MDA/HDA groups, progression was lower with baricitinib+MTX (p<0.001) and numerically lower with baricitinib monotherapy (p=0.07) versus MTX. C reactive protein (≤5 mg/L and >5 mg/L) sensitivity analyses supported the primary findings.
Baricitinib reduces structural damage progression versus PBO with background MTX and/or MTX, even in patients with MDA/HDA, showing a disease-modifying effect across all disease activity states.
通过两项 III 期随机、双盲试验，评估 Janus 激酶抑制剂巴利昔替尼是否通过解除疾病活动与结构损伤进展之间的关联，从而增强类风湿关节炎（RA）患者的疾病改善作用。
在 RA-BEAM 中，对接受甲氨蝶呤（MTX）治疗但疗效不佳的 RA 患者（MTX-IR）给予安慰剂（PBO）、巴利昔替尼 4 mg 或阿达木单抗 40 mg 联合 MTX 治疗。在 RA-BEGIN 中，对初治常规合成改善病情抗风湿药（csDMARD）的患者给予 MTX、巴利昔替尼 4 mg 或巴利昔替尼 4 mg 联合 MTX 治疗。采用线性回归分析，比较在临床疾病活动指数（CDAI）评估的特定疾病活动状态下，各治疗组患者的关节损伤进展（以基线时 van der Heijde 总Sharp 评分修订版的变化评估）。采用时间平均基线后应答，评估 RA-BEAM 至 24 周和 RA-BEGIN 至 52 周的结果。
对于 MTX-IR 患者，无论疾病活动状态如何，巴利昔替尼治疗组的结构损伤进展均减少（p=0.6），而 PBO 组的结构损伤进展与疾病活动状态密切相关，与中重度疾病活动（MDA/HDA）相比，处于缓解/低疾病活动（REM/LDA）的患者明显减少（p=0.02）。此外，巴利昔替尼 MDA/HDA 组的损伤进展少于 PBO MDA/HDA 组（p<0.001）。对于初治 csDMARD 的患者，MTX 组的 REM/LDA 患者的损伤进展低于 MDA/HDA 患者（p<0.001）。然而，巴利昔替尼+MTX（p=0.5）或巴利昔替尼单药治疗（p=0.07），无论疾病活动如何，进展均相似。在 MDA/HDA 组中，与 MTX 相比，巴利昔替尼+MTX（p<0.001）和巴利昔替尼单药治疗（p=0.07）的进展减少。C 反应蛋白（≤5 mg/L 和>5 mg/L）的敏感性分析支持主要发现。
与 MTX 联合 PBO 和/或 MTX 相比，巴利昔替尼可减少结构损伤进展，甚至在 MDA/HDA 患者中也具有疾病改善作用，在所有疾病活动状态下均表现出疾病改善作用。
