Treatments that block tumour necrosis factor (TNF) have major beneficial effects in several autoimmune and rheumatic diseases, including rheumatoid arthritis. However, some patients do not respond to TNF inhibitor treatment and rare occurrences of paradoxical disease exacerbation have been reported. These limitations on the clinical efficacy of TNF inhibitors can be explained by the differences between TNF receptor 1 (TNFR1) and TNFR2 signalling and by the diverse effects of TNF on multiple immune cells, including FOXP3⁺ regulatory T cells. This basic knowledge sheds light on the consequences of TNF inhibitor therapies on regulatory T cells in treated patients and on the limitations of such treatment in the control of diseases with an autoimmune component. Accordingly, the next generation of drugs targeting TNF is likely to be based on agents that selectively block the binding of TNF to TNFR1 and on TNFR2 agonists. These approaches could improve the treatment of rheumatic diseases in the future.

阻断肿瘤坏死因子 (TNF) 的治疗对多种自身免疫性疾病和风湿性疾病（包括类风湿性关节炎）具有重要的有益作用。然而，一些患者对 TNF 抑制剂治疗没有反应，并且已报道罕见的疾病矛盾恶化。^{TNF 抑制剂临床疗效的这些局限性可以通过 TNF 受体 1 (TNFR1) 和 TNFR2 信号之间的差异以及 TNF 对多种免疫细胞（包括 FOXP3 +}）的不同影响来解释调节性 T 细胞。这一基本知识阐明了 TNF 抑制剂疗法对接受治疗的患者调节性 T 细胞的影响，以及这种疗法在控制具有自身免疫成分的疾病方面的局限性。因此，下一代靶向 TNF 的药物可能基于选择性阻断 TNF 与 TNFR1 结合的药物和 TNFR2 激动剂。这些方法可以改善未来风湿病的治疗。