Khanna Dinesh, McMahon Maureen, Furst Daniel E
Division of Rheumatology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Drug Saf. 2004;27(5):307-24. doi: 10.2165/00002018-200427050-00003.
Tumour necrosis factor-alpha (TNFalpha) is a proinflammatory cytokine that is synthesised by a variety of cell types in response to infectious or inflammatory stimuli. Although TNFalpha plays an adaptive role in immune protection and wound healing at 'physiological' levels, excess TNFalpha production can lead to adverse consequences. TNFalpha is a pivotal cytokine involved in the pathogenesis and progression of rheumatoid arthritis (RA). TNFalpha antagonists have been shown to be effective in the treatment of signs and symptoms of RA and the US FDA has approved three TNFalpha antagonists, etanercept, infliximab, and most recently, adalimumab, for the treatment of RA. However, differences have emerged, with respect to their demonstrated efficacy in other diseases (e.g. Crohn's disease). Worldwide, over half a million patients have been treated with TNFalpha antagonists and concerns regarding their safety have been raised. There is a risk of reactivation of granulomatous diseases, especially tuberculosis, with all three agents and appropriate measures should be taken for detection and treatment of latent infections. An association between non-Hodgkin's lymphoma and treatment with TNFalpha antagonists has been reported, although patients with active, long-standing RA are already known to have an increased incidence of non-Hodgkin's lymphoma. No associations with solid tumours have been found to date. The biological plausibility of lymphomas associated with immunomodulatory agents raises concern and vigilance is appropriate until the relationship is fully characterised. Large phase II and III trials have shown a detrimental effect of TNFalpha antagonists in advanced heart failure and these agents should be avoided in this population. Rare case reports of drug-induced lupus, seizure disorder, pancytopenia and demyelinating diseases have been noted after TNFalpha antagonists and continued vigilance is warranted in patients on TNFalpha antagonists for the development of these diseases. At present there is no evidence implicating TNFalpha antagonists with embryotoxicity, teratogenicity or increased pregnancy loss.
肿瘤坏死因子-α（TNFα）是一种促炎细胞因子，由多种细胞类型在受到感染或炎症刺激时合成。尽管TNFα在“生理”水平的免疫保护和伤口愈合中发挥适应性作用，但过量产生TNFα会导致不良后果。TNFα是类风湿性关节炎（RA）发病机制和病情进展中的关键细胞因子。TNFα拮抗剂已被证明对治疗RA的体征和症状有效，美国食品药品监督管理局（US FDA）已批准三种TNFα拮抗剂，即依那西普、英夫利昔单抗，以及最近的阿达木单抗，用于治疗RA。然而，就它们在其他疾病（如克罗恩病）中的疗效而言，已出现差异。在全球范围内，超过50万患者接受了TNFα拮抗剂治疗，人们对其安全性也提出了担忧。使用这三种药物都有肉芽肿性疾病重新激活的风险，尤其是结核病，应采取适当措施检测和治疗潜伏感染。已有报道称非霍奇金淋巴瘤与TNFα拮抗剂治疗之间存在关联，尽管已知活动性、长期RA患者患非霍奇金淋巴瘤的发生率会增加。迄今为止，尚未发现与实体瘤有关联。与免疫调节剂相关的淋巴瘤在生物学上的合理性引发了关注，在这种关系得到充分阐明之前，保持警惕是恰当的。大型II期和III期试验表明，TNFα拮抗剂对晚期心力衰竭有不利影响，在这一人群中应避免使用这些药物。在使用TNFα拮抗剂后，已有罕见的药物性狼疮、癫痫障碍、全血细胞减少和脱髓鞘疾病的病例报告，因此对接受TNFα拮抗剂治疗的患者，仍需持续警惕这些疾病的发生。目前没有证据表明TNFα拮抗剂具有胚胎毒性、致畸性或增加流产风险。
