Hashimoto Teppei, Tsuboi Kazuyuki, Abe Takeo, Yoshikawa Takahiro, Noguchi Kazuteru, Furukawa Tetsuya, Tateishi Koji, Terashima Yasuhiro, Sibanuma Nao, Azuma Naoto, Yamane Takashi, Matsui Kiyoshi, Hashiramoto Akira
Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan.
Department of Rheumatology, Kobe City Medical Center West Hospital, Kobe, Japan.
Arthritis Res Ther. 2025 Apr 17;27(1):91. doi: 10.1186/s13075-025-03555-2.
Inflammatory cytokine levels exhibit a circadian rhythm in sera, peaking from late night to early morning in patients with rheumatoid arthritis (RA). This cytokine kinetics is a recognized therapeutic target. This clinical study aimed to evaluate the effectiveness of night-time baricitinib administration based on cytokine secretion.
In this 52-week multicenter non-randomized controlled study, 122 patients with RA were assigned to four groups: baricitinib 2 mg morning (BAR2MORN), 2 mg evening (BAR2EVE), 4 mg morning (BAR4MORN), or 4 mg evening (BAR4EVE). The primary endpoint was assessed using the 20% improvement in the American College of Rheumatology criteria (ACR20) at week 12. The secondary endpoints were ACR20/50/70 and changes in the clinical disease activity index (CDAI) through 52 weeks. The results were evaluated using the propensity score inverse probability of treatment weighted to reduce selection bias in patient background.
BAR4EVE resulted in better primary endpoint improvement than BAR4MORN (78.2 vs. 43.3%; p < 0.001). No difference in improvement was observed in the primary endpoint between BAR2EVE and BAR2MORN (75.5 vs. 60.6%; p = 0.10). However, BAR2EVE demonstrated higher ACR20 at weeks 4, 24, and 52 and ACR50 at weeks 4 and 12 than BAR2MORN. BAR4EVE demonstrated higher ACR20/50 at weeks 4, 8, and 12 and ACR70 at weeks 8, 12, and 24 than BAR4MORN. CDAI changes were significantly reduced in BAR4EVE than in BAR4MORN at weeks 4 and 8.
Chronotherapy targeting cytokine secretion resulted in rapid drug response, proposing a new potential application for JAK inhibitors.
UMIN000040094, July 1, 2020.
炎症细胞因子水平在血清中呈现昼夜节律，类风湿关节炎（RA）患者从深夜到清晨达到峰值。这种细胞因子动力学是一个公认的治疗靶点。这项临床研究旨在评估基于细胞因子分泌的夜间巴瑞替尼给药的有效性。
在这项为期52周的多中心非随机对照研究中，122例RA患者被分为四组：巴瑞替尼2毫克早晨服用（BAR2MORN）、2毫克晚上服用（BAR2EVE）、4毫克早晨服用（BAR4MORN）或4毫克晚上服用（BAR4EVE）。主要终点在第12周使用美国风湿病学会标准（ACR20）改善20%进行评估。次要终点是ACR20/50/70以及52周内临床疾病活动指数（CDAI）的变化。使用倾向评分逆概率加权法评估结果，以减少患者背景中的选择偏倚。
与BAR4MORN相比，BAR4EVE在主要终点改善方面效果更好（78.2%对43.3%；p < 0.001）。BAR2EVE和BAR2MORN在主要终点改善方面未观察到差异（75.5%对60.6%；p = 0.10）。然而，BAR2EVE在第4、24和52周的ACR20以及第4和12周的ACR50高于BAR2MORN。与BAR4MORN相比，BAR4EVE在第4、8和12周的ACR20/50以及第8、12和24周的ACR70更高。在第4和8周，BAR4EVE的CDAI变化比BAR4MORN显著降低。
针对细胞因子分泌的时间疗法导致快速的药物反应，为JAK抑制剂提出了一种新的潜在应用。
UMIN000040094，2020年7月1日。
