Jarneborn Anders, Kopparapu Pradeep Kumar, Jin Tao
Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 413 46 Gothenburg, Sweden.
Department of Rheumatology, Sahlgrenska University Hospital, 413 46 Gothenburg, Sweden.
Pathogens. 2025 Mar 27;14(4):324. doi: 10.3390/pathogens14040324.
Janus kinase inhibitors (JAKis) represent a relatively new class of immunomodulatory drugs with potent effects on various cytokine signalling pathways. They have revolutionized the treatment landscape for autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. However, their ability to modulate immune responses presents a dual-edged nature, influencing both protective immunity and pathological inflammation. This review explores the complex role of JAKis in infectious settings, highlighting both beneficial and detrimental effects. On the one hand, experimental models suggest that JAK inhibition can impair host defence mechanisms, increasing susceptibility to certain bacterial and viral infections. For example, tofacitinib-treated mice exhibited more severe joint erosions in () septic arthritis and showed impaired viral clearance in herpes simplex encephalitis. Additionally, clinical data confirm an increased risk of herpes zoster in patients receiving JAKis, underscoring the need for rigorous monitoring. On the other hand, JAK inhibition has demonstrated protective effects in certain infectious and hyperinflammatory conditions. In sepsis models, including cecal ligation and puncture (CLP) and bacteraemia, tofacitinib improved survival by attenuating excessive inflammation. Furthermore, JAKis, particularly baricitinib, have shown substantial efficacy in mitigating cytokine storms during severe COVID-19 infections, leading to improved clinical outcomes and reduced mortality. These observations suggest that JAKis have a role in modulating hyperinflammatory responses in select infectious contexts. In conclusion, JAKis present a complex interplay between immunosuppression and immunomodulation. While they increase the risk of certain infections, they also show potential in managing hyperinflammatory conditions such as cytokine storms. The key challenge is determining which patients and situations benefit most from JAKis while minimizing risks, requiring a careful and personalized treatment approach.
Janus激酶抑制剂（JAKis）是一类相对较新的免疫调节药物，对各种细胞因子信号通路具有强大作用。它们彻底改变了类风湿性关节炎、银屑病关节炎和溃疡性结肠炎等自身免疫性疾病的治疗格局。然而，它们调节免疫反应的能力具有双刃剑性质，既影响保护性免疫，也影响病理性炎症。本综述探讨了JAKis在感染情况下的复杂作用，强调了其有益和有害影响。一方面，实验模型表明JAK抑制会损害宿主防御机制，增加对某些细菌和病毒感染的易感性。例如，托法替布治疗的小鼠在（）脓毒性关节炎中表现出更严重的关节侵蚀，在单纯疱疹性脑炎中病毒清除受损。此外，临床数据证实接受JAKis治疗的患者带状疱疹风险增加，凸显了严格监测的必要性。另一方面，JAK抑制在某些感染性和高炎症性疾病中已显示出保护作用。在脓毒症模型中，包括盲肠结扎和穿刺（CLP）和菌血症，托法替布通过减轻过度炎症改善了生存率。此外，JAKis，特别是巴瑞替尼，在减轻严重COVID-19感染期间的细胞因子风暴方面显示出显著疗效，导致临床结果改善和死亡率降低。这些观察结果表明JAKis在特定感染情况下调节高炎症反应中发挥作用。总之，JAKis在免疫抑制和免疫调节之间呈现出复杂的相互作用。虽然它们增加了某些感染的风险，但它们在管理细胞因子风暴等高炎症性疾病方面也显示出潜力。关键挑战在于确定哪些患者和情况从JAKis中获益最大，同时将风险降至最低，这需要谨慎和个性化的治疗方法。
