Musculoskeletal Research Group and Arthritis Research UK Centre of Excellence in Rheumatoid Arthritis Pathogenesis, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle upon Tyne, UK.
Ann Rheum Dis. 2018 Feb;77(2):175-187. doi: 10.1136/annrheumdis-2017-211555. Epub 2017 Aug 1.
The past three decades have witnessed remarkable advances in our ability to target specific elements of the immune and inflammatory response, fuelled by advances in both biotechnology and disease knowledge. As well as providing superior treatments for immune-mediated inflammatory diseases (IMIDs), such therapies also offer unrivalled opportunities to study the underlying immunopathological basis of these conditions.In this review, we explore recent approaches to the treatment of IMIDs and the insights to pathobiology that they provide. We review novel biologic agents targeting the T-helper 17 axis, including therapies directed towards interleukin (IL)-17 (secukinumab, ixekizumab, bimekizumab), IL-17R (brodalumab), IL-12/23p40 (ustekinumab, briakinumab) and IL-23p19 (guselkumab, tildrakizumab, brazikumab, risankizumab, mirikizumab). We also present an overview of biologics active against type I and II interferons, including sifalumumab, rontalizumab, anifrolumab and fontolizumab. Emerging strategies to interfere with cellular adhesion processes involved in lymphocyte recruitment are discussed, including both integrin blockade (natalizumab, vedolizumab, etrolizumab) and sphingosine-1-phosphate receptor inhibition (fingolimod, ozanimod). We summarise the development and recent application of Janus kinase (JAK) inhibitors in the treatment of IMIDs, including first-generation pan-JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib) and second-generation selective JAK inhibitors (decernotinib, filgotinib, upadacitinib). New biologics targeting B-cells (including ocrelizumab, veltuzumab, tabalumab and atacicept) and the development of novel strategies for regulatory T-cell modulation (including low-dose IL-2 therapy and Tregitopes) are also discussed. Finally, we explore recent biotechnological advances such as the development of bispecific antibodies (ABT-122, COVA322), and their application to the treatment of IMIDs.
过去三十年见证了我们靶向免疫和炎症反应特定元素的能力取得了显著进展，这得益于生物技术和疾病知识的进步。这些疗法不仅为免疫介导的炎症性疾病 (IMIDs) 提供了更优越的治疗方法，还为研究这些疾病的潜在免疫病理基础提供了无与伦比的机会。在这篇综述中，我们探讨了治疗 IMIDs 的最新方法以及它们为病理生物学提供的见解。我们回顾了靶向 Th17 轴的新型生物制剂，包括针对白细胞介素 (IL)-17（司库珠单抗、依奇珠单抗、比美克珠单抗）、IL-17R（布罗达单抗）、IL-12/23p40（乌司奴单抗、布利昔单抗）和 IL-23p19（古塞库单抗、替度鲁单抗、巴瑞克珠单抗、瑞莎珠单抗、米利珠单抗）的治疗方法。我们还概述了针对 I 型和 II 型干扰素的生物制剂，包括西法卢单抗、罗那鲁单抗、阿尼鲁单抗和丰托利珠单抗。讨论了干扰淋巴细胞募集中细胞黏附过程的新兴策略，包括整合素阻断（那他珠单抗、维多珠单抗、埃特罗利珠单抗）和鞘氨醇-1-磷酸受体抑制（芬戈莫德、奥扎尼莫德）。我们总结了 Janus 激酶 (JAK) 抑制剂在治疗 IMIDs 中的开发和最新应用，包括第一代泛 JAK 抑制剂（托法替尼、巴瑞替尼、鲁索利替尼、培非替尼）和第二代选择性 JAK 抑制剂（德塞替尼、菲戈替尼、乌帕替尼）。还讨论了针对 B 细胞的新型生物制剂（包括奥瑞珠单抗、veltuzumab、tabalumab 和 atacicept）和调节性 T 细胞调节的新策略的开发（包括低剂量 IL-2 治疗和 Tregitopes）。最后，我们探讨了最近的生物技术进展，例如双特异性抗体（ABT-122、COVA322）的开发及其在治疗 IMIDs 中的应用。
