Tumor necrosis factor inhibitors (TNFi) have significantly improved treatment outcome of rheumatic diseases since their incorporation into treatment protocols two decades ago. Nevertheless, a substantial fraction of patients experiences either primary or secondary failure to TNFi due to ineffectiveness of the drug or adverse reactions. Secondary failure and adverse events can be related to the development of anti-drug antibodies (ADA). The earliest studies that reported ADA toward TNFi mainly used drug-sensitive assays. Retrospectively, we recognize this has led to an underestimation of the amount of ADA produced due to drug interference. Drug-tolerant ADA assays also detect ADA in the presence of drug, which has contributed to the currently reported higher incidence of ADA development. Comprehension and awareness of the assay format used for ADA detection is thus essential to interpret ADA measurements correctly. In addition, a concurrent drug level measurement is informative as it may provide insight in the extent of underestimation of ADA levels and improves understanding the clinical consequences of ADA formation. The clinical effects are dependent on the ratio between the amount of drug that is neutralized by ADA and the amount of unbound drug. Pharmacokinetic modeling might be useful in this context. The ADA response generally gives rise to high affinity IgG antibodies, but this response will differ between patients. Some patients will not reach the phase of affinity maturation while others generate an enduring high titer high affinity IgG response. This response can be transient in some patients, indicating a mechanism of tolerance induction or B-cell anergy. In this review several different aspects of the ADA response toward TNFi will be discussed. It will highlight the ADA assays, characteristics and regulation of the ADA response, impact of immunogenicity on the pharmacokinetics of TNFi, clinical implications of ADA formation, and possible mitigation strategies.

肿瘤坏死因子抑制剂（TNFi）自从二十年前被纳入风湿病治疗方案以来，已显着改善了风湿病的治疗效果。然而，由于药物无效或不良反应，相当一部分患者经历了TNFi的原发性或继发性衰竭。继发性衰竭和不良事件可能与抗药物抗体（ADA）的发展有关。最早报道针对TNFi的ADA的研究主要使用药物敏感性测定。回顾性地，我们认识到这导致了对由于药物干扰而产生的ADA数量的低估。药物耐受性ADA分析还可以在药物存在下检测ADA，这导致了目前报道的ADA发生率更高。因此，理解和认识用于ADA检测的测定形式对于正确解释ADA测量至关重要。另外，同时进行的药物水平测量是有益的，因为它可以提供对ADA水平低估程度的洞察力，并增进对ADA形成的临床后果的了解。临床效果取决于被ADA中和的药物量与未结合的药物量之间的比率。在这种情况下，药代动力学建模可能会有用。ADA反应通常会产生高亲和力IgG抗体，但患者之间的反应会有所不同。一些患者将无法达到亲和力成熟阶段，而其他患者则会产生持久的高滴度高亲和力IgG反应。在某些患者中，这种反应可能是短暂的，表明耐受诱导或B细胞无反应的机制。在这篇综述中，将讨论ADA对TNFi反应的不同方面。它将重点介绍ADA分析，ADA反应的特征和调节，免疫原性对TNFi药代动力学的影响，ADA形成的临床意义以及可能的缓解策略。