Brom Martin, Saxer Franziska, Mindeholm Linda, Schieker Matthias, Conaghan Philip G
Translational Medicine, Novartis Biomedical Research, Basel, Switzerland.
Medical Faculty, University of Basel, Basel, Switzerland.
Diabetes Metab Syndr Obes. 2025 May 28;18:1753-1764. doi: 10.2147/DMSO.S520465. eCollection 2025.
There remains a huge unmet need for new osteoarthritis (OA) therapies. A putative reason for the failure of some therapies has been the absence of well-defined phenotypes, which might be more appropriate for specific targeted treatment. Interleukin-1 (IL-1) plays a key role in the development of OA, but the results of clinical trials targeting IL-1 in OA have to date been disappointing.
This narrative review is based on a literature search for publications describing interventions with direct Il-1 pathway inhibitors in patients with knee OA and substantiated by a description of key pre-clinical observations.
Randomized controlled studies using IL-1 inhibition as treatment approach to knee OA have read out negatively, although trends for an improvement in pain and impact on biomarkers could be observed. However, in a post-hoc analysis of the large CANTOS trial data (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) testing an anti-IL-1 monoclonal antibody for the secondary prevention of cardiovascular events treatment arms receiving canakinumab demonstrated a substantial reduction in the incidence rate of joint replacement compared to those receiving placebo. Similar results have been reported from a post-hoc analysis of another cardiovascular risk reduction study, the low-dose colchicine 2 (LoDoCo 2) trial, raising the possibility of a beneficial effect of IL-1 inhibition in the subset of patients with metabolic phenotype.
Based on the above results, it seems timely to revisit the role of IL-1 in OA, its relationship with chronic low-grade inflammation and its relevance in the subset of metabolic OA.
对新型骨关节炎（OA）治疗方法仍存在巨大的未满足需求。一些治疗方法失败的一个可能原因是缺乏明确的表型，而这些表型可能更适合特定的靶向治疗。白细胞介素-1（IL-1）在OA的发展中起关键作用，但迄今为止，针对OA中IL-1的临床试验结果令人失望。
本叙述性综述基于对描述膝关节OA患者使用直接IL-1通路抑制剂干预措施的出版物的文献检索，并通过关键临床前观察结果的描述进行证实。
使用IL-1抑制作为膝关节OA治疗方法的随机对照研究结果为阴性，尽管可观察到疼痛改善和对生物标志物影响的趋势。然而，在大型CANTOS试验数据（卡那单抗抗炎血栓形成结果研究）的事后分析中，测试抗IL-1单克隆抗体用于心血管事件二级预防的治疗组接受卡那单抗的患者与接受安慰剂的患者相比，关节置换发生率大幅降低。另一项心血管风险降低研究——低剂量秋水仙碱2（LoDoCo 2）试验的事后分析也报告了类似结果，这增加了IL-1抑制对代谢表型患者亚组有益的可能性。
基于上述结果，似乎是时候重新审视IL-1在OA中的作用、其与慢性低度炎症的关系以及其在代谢性OA亚组中的相关性了。
