Mechanistic aspects of inflammation and clinical management of inflammation in acute gouty arthritis.
Mechanistic aspects of inflammation and clinical management of inflammation in acute gouty arthritis.
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DOI：
10.1097/rhu.0b013e31827d8790
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发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Sunkureddi P
中科院分区：
文献类型：
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作者：
Cronstein BN;Sunkureddi P
最近的研究表明，白介素1β(IL-1β)在尿酸钠晶体诱导的炎症反应中起核心作用，而NALP3炎症小体在IL-1β的产生中起主要作用。这些发现为急性痛风性关节炎的发病机制提供了新的见解。在这篇综述中，我们讨论了MSU晶体引起急性炎症的分子机制，并考察了传统抗炎药物(如非类固醇抗炎药、秋水仙碱和糖皮质激素)和生物制剂(如IL-1β拮抗剂Anakinra、利洛那塞和Canakinumab)的作用机制，以了解它们的MOA是如何影响其安全性的。传统的抗炎药可能在一定程度上作用于IL-1β途径，但它们的MOA具有广泛性、非特异性和生物学复杂性。这种缺乏特异性可能解释了与它们相关的一系列全身副作用。NSAIDs、秋水仙碱和糖皮质激素的治疗范围在老年患者以及经常与痛风性关节炎相关的心血管、代谢或肾脏合并症的患者中尤其低。相反，IL-1β拮抗剂作用于非常特定的炎症靶点，这可能会降低全身副作用的可能性，尽管已有报道称很少发生但严重的不良反应(包括感染和给药反应)。由于这些IL-1β拮抗剂针对的是NALP3炎性小体激活下游的早期事件，它们可能提供传统药物的有效替代品，全身副作用最小。正在进行的IL-1β拮抗剂的试验结果可能会澄清它们在急性痛风性关节炎治疗中的潜在作用。
It has been recently demonstrated that interleukin-1β (IL-1β) plays a central role in monosodium urate (MSU) crystal-induced inflammation and that the NALP3 inflammasome plays a major role in IL-1β production. These discoveries have offered new insights into the pathogenesis of acute gouty arthritis. In this review, we discuss the molecular mechanisms by which MSU crystals induce acute inflammation and examine the mechanisms of action (MOAs) of traditional anti-inflammatory drugs (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], colchicine, and glucocorticoids) and biologic agents (eg, the IL-1β antagonists anakinra, rilonacept, and canakinumab) to understand how their MOAs contribute to their safety profiles. Traditional anti-inflammatory agents may act on the IL-1β pathway at some level; however, their MOAs are broad-ranging, unspecific, and biologically complex. This lack of specificity may explain the range of systemic side effects associated with them. The therapeutic margins of NSAIDs, colchicine, and glucocorticoids are particularly low in elderly patients and in patients with cardiovascular, metabolic, or renal comorbidities that are frequently associated with gouty arthritis. In contrast, the IL-1β antagonists act on very specific targets of inflammation, which may decrease the potential for systemic side effects, although infrequent but serious adverse events (including infection and administration reactions) have been reported. Because these IL-1β antagonists target an early event immediately downstream from NALP3 inflammasome activation, they may provide effective alternatives to traditional agents with minimal systemic side effects. Results of ongoing trials of IL-1β antagonists will likely provide clarification of their potential role in the management of acute gouty arthritis.