Department of Rheumatology, ASST Gateano Pini-CTO, Milan, Italy.
Department of Clinical Science and Health Community, Università degli Studi di Milano, Milan, Italy.
Drugs. 2019 Nov;79(16):1741-1755. doi: 10.1007/s40265-019-01192-z.
Rheumatoid arthritis (RA) is a systemic, autoimmune disease that affects joints and extra-articular structures. In the last decade, the management of this chronic disease has dramatically changed with the introduction of several targeted mechanisms of action, such as tumor necrosis factor-α inhibition, T-cell costimulation inhibition, B-cell depletion, interleukin-6 blockade, and Janus kinase inhibition. Beyond its well-known hematopoietic role on the proliferation and differentiation of myeloid cells, granulocyte-monocyte colony-stimulating factor (GM-CSF) is a proinflammatory mediator acting as a cytokine, with a proven pathogenetic role in autoimmune disorders such as RA. In vitro studies clearly demonstrated the effect of GM-CSF in the communication between resident tissue cells and activated macrophages at chronic inflammation sites, and confirmed the elevation of GM-CSF levels in inflamed synovial tissue of RA subjects compared with healthy controls. Moreover, a pivotal role of GM-CSF in the perception of pain has been clearly confirmed. Therefore, blockade of the GM-CSF pathway by monoclonal antibodies directed against the cytokine itself or its receptor has been investigated in refractory RA patients. Overall, the safety profile of GM-CSF inhibitors seems to be very favorable, with a particularly low incidence of infectious complications. The efficacy of this new mechanism of action is comparable with main competitors, even though the response rates reported in phase II randomized controlled trials (RCTs) appear to be numerically lower than the response rates observed with other biological disease-modifying antirheumatic drugs already licensed for RA. Mainly because of this reason, nowadays the development program of most GM-CSF blockers for RA has been discontinued, with the exception of otilimab, which is under evaluation in two phase III RCTs with a head-to head non-inferiority design against tofacitinib. These studies will likely be useful for better defining the potential role of GM-CSF inhibition in the therapeutic algorithm of RA. On the other hand, the potential role of GM-CSF blockade in the treatment of other rheumatic diseases is now under investigation. Phase II trials are ongoing with the aim of evaluating mavrilimumab for the treatment of giant cell arteritis, and namilumab for the treatment of spondyloarthritis. Moreover, GM-CSF inhibitors have been tested in osteoarthritis and diffuse subtype of systemic sclerosis. This review aims to describe in detail the available evidence on the GM-CSF blocking pathway in RA management, paving the way to a possible alternative treatment for RA patients. Novel insights regarding the potential use of GM-CSF blockers for alternative indications will be also addressed.
类风湿关节炎（RA）是一种全身性自身免疫性疾病，影响关节和关节外结构。在过去的十年中，随着几种靶向作用机制的引入，如肿瘤坏死因子-α抑制、T 细胞共刺激抑制、B 细胞耗竭、白细胞介素-6 阻断和 Janus 激酶抑制，这种慢性疾病的治疗发生了巨大变化。粒细胞-单核细胞集落刺激因子（GM-CSF）除了在髓样细胞的增殖和分化中具有众所周知的造血作用外，还是一种促炎介质，在 RA 等自身免疫性疾病中具有明确的发病机制作用。体外研究清楚地证明了 GM-CSF 在慢性炎症部位常驻组织细胞与激活的巨噬细胞之间的通讯中的作用，并证实 RA 患者炎症滑膜组织中的 GM-CSF 水平升高与健康对照组相比。此外，GM-CSF 在疼痛感知中具有关键作用已得到明确证实。因此，针对细胞因子本身或其受体的单克隆抗体阻断 GM-CSF 途径已在难治性 RA 患者中进行了研究。总体而言，GM-CSF 抑制剂的安全性谱似乎非常有利，感染并发症的发生率特别低。这种新作用机制的疗效可与主要竞争对手相媲美，尽管在 II 期随机对照试验（RCT）中报告的反应率似乎低于已获准用于 RA 的其他生物疾病修饰抗风湿药物的反应率。主要是由于这个原因，如今，大多数用于 RA 的 GM-CSF 阻滞剂的开发计划已被停止，除了正在两项 III 期 RCT 中进行评估的 otlimab，该 RCT 采用头对头非劣效性设计与 tofacitinib 进行比较。这些研究可能有助于更好地确定 GM-CSF 抑制在 RA 治疗算法中的潜在作用。另一方面，GM-CSF 阻断在治疗其他风湿性疾病中的潜在作用正在研究中。正在进行 II 期试验，目的是评估 mavrilimumab 治疗巨细胞动脉炎和 namilumab 治疗脊柱关节炎。此外，GM-CSF 抑制剂已在骨关节炎和弥漫型系统性硬化症中进行了测试。本综述旨在详细描述 RA 管理中 GM-CSF 阻断途径的现有证据，为 RA 患者开辟可能的替代治疗方法。还将讨论关于 GM-CSF 阻滞剂用于替代适应症的潜在用途的新见解。
