Gurevic Ilya, Meudec Loic, Mariette Xavier, Nocturne Gaetane, McCoy Sara S
Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America.
Center for Immunology of Viral Infections and Autoimmune Diseases, INSERM UMR, Université Paris-Saclay, Le Kremlin-Bicêtre, Paris, France.
PLoS One. 2025 Jun 16;20(6):e0311706. doi: 10.1371/journal.pone.0311706. eCollection 2025.
Our objective was to define the effect of JAK inhibitor (JAKinib) withdrawal on JAK/STAT biochemical response in the context of systemic rheumatic diseases.
We tested Type I (bind kinase active conformation) and Type II (bind kinase inactive conformation) JAKinibs in vitro using mesenchymal stromal cells (MSCs) and human umbilical vein endothelial cells (HUVECs). We translated our findings in vivo studying NK cells from rheumatoid arthritis (RA) patients treated with Type I JAKinibs or methotrexate.
Type I JAKinibs (ruxolitinib and baricitinib) increased phosphoJAK1 (pJAK1) and pJAK2 of IFNγ-stimulated MSCs and HUVECs in a time- and dose- dependent manner, with effect peaking after 24 hours. As expected, pSTAT1 was completely suppressed by JAKinibs. We found a marked and rapid increase of pSTATs upon discontinuation of Type I JAKinibs, that occurred to a lesser extent after Type II JAKinib withdrawal. Type I JAKinib withdrawal increased interferon and urokinase expression when compared to Type II JAKinib withdrawal. We found NK cells from RA patients taking Type I JAKinibs had a pro-inflammatory profile after JAKinib withdrawal compared to patients on methotrexate.
Type I JAKinibs paradoxically accumulate functionally defective pJAK. Upon withdrawal, the primed pJAKs are de-repressed and initiate a pSTAT signaling cascade, resulting in high interferon and urokinase. Type II JAKinibs do not cause pJAK accumulation, pSTAT cascade, and subsequent pro-inflammatory transcripts. The resultant cytokines and proteins produced from this cascade might explain adverse cardiac outcomes. Thus, JAKinib withdrawal is a possible mechanism contributing to the major adverse cardiac events described with JAKinib therapy.
我们的目的是在系统性风湿性疾病的背景下，确定停用JAK抑制剂（JAKinib）对JAK/STAT生化反应的影响。
我们在体外使用间充质基质细胞（MSC）和人脐静脉内皮细胞（HUVEC）测试了I型（结合激酶活性构象）和II型（结合激酶非活性构象）JAKinib。我们通过研究接受I型JAKinib或甲氨蝶呤治疗的类风湿性关节炎（RA）患者的NK细胞，将我们的研究结果转化到体内进行验证。
I型JAKinib（鲁索替尼和巴瑞替尼）以时间和剂量依赖性方式增加了IFNγ刺激的MSC和HUVEC的磷酸化JAK1（pJAK1）和pJAK2，作用在24小时后达到峰值。正如预期的那样，pSTAT1被JAKinib完全抑制。我们发现停用I型JAKinib后pSTATs显著且迅速增加，而停用II型JAKinib后这种情况的发生程度较小。与停用II型JAKinib相比，停用I型JAKinib会增加干扰素和尿激酶的表达。我们发现，与服用甲氨蝶呤的患者相比，服用I型JAKinib的RA患者在停用JAKinib后，其NK细胞具有促炎特征。
I型JAKinib反常地积累功能缺陷的pJAK。停药后，预激活的pJAK被去抑制并启动pSTAT信号级联反应，导致高干扰素和尿激酶水平。II型JAKinib不会导致pJAK积累、pSTAT级联反应以及随后的促炎转录本。由该级联反应产生的细胞因子和蛋白质可能解释了不良心脏结局。因此，停用JAKinib可能是导致JAKinib治疗中出现主要不良心脏事件的一种机制。
