Dynamics of circulating TNF during adalimumab treatment using a drug-tolerant TNF assay
Dynamics of circulating TNF during adalimumab treatment using a drug-tolerant TNF assay
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DOI：
10.1126/scitranslmed.aat3356
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发表时间：
2019-01-30
影响因子：
17.1
通讯作者：
Rispens, Theo
中科院分区：
文献类型：
--
作者：
Berkhout, Lea C.;I'Ami, Merel J.;Rispens, Theo
类风湿性关节炎（RA）患者可以成功治疗肿瘤坏死因子（TNF）抑制剂，包括单克隆抗体阿达木单抗。一旦缓解，一部分患者可以成功停止治疗，这表明阻断TNF不再是控制疾病所必需的。为了探索阿达木单抗治疗期间循环TNF的动力学，我们开发了一种竞争性酶联免疫吸附试验，该试验可以在存在大量TNF抑制剂的情况下定量TNF，即，“耐药性”测定。在193例连续接受阿达木单抗治疗的RA患者中，我们证明了治疗后循环TNF平均增加>50倍，并且大多数患者及时达到稳定浓度。在30名健康志愿者中，阿达木单抗单次给药后，发现TNF水平出现类似升高。这意味着抗TNF治疗期间循环中的TNF与疾病活动性主要无关。治疗期间，TNF与阿达木单抗复合，并可作为无活性的3：1阿达木单抗-TNF复合物回收。TNF和阿达木单抗浓度之间未发现定量相关性。第4周的低TNF浓度与随后时间点的抗药抗体（ADA）频率较高、基线时甲氨蝶呤使用频率较低以及52周后缓解频率较低相关。同样在健康志愿者中，早期低TNF浓度与ADA相关。总之，阿达木单抗治疗期间纵向TNF浓度基本稳定，因此可能无法预测成功停药。然而，早期低TNF与ADA形成密切相关，可用作阿达木单抗治疗无应答的及时预测因子。
Patients with rheumatoid arthritis (RA) can be successfully treated with tumor necrosis factor (TNF) inhibitors, including the monoclonal antibody adalimumab. Once in remission, a proportion of patients can successfully discontinue treatment, indicating that blocking TNF is no longer required for disease control. To explore the dynamics of circulating TNF during adalimumab treatment, we developed a competition enzyme-linked immunosorbent assay that can quantify TNF in the presence of large amounts of TNF inhibitor, i.e., a "drug-tolerant" assay. In 193 consecutive adalimumab-treated patients with RA, we demonstrated that circulating TNF increased in average of >50-fold upon treatment and reached a stable concentration in time for most patients. A similar increase in TNF was found in 30 healthy volunteers after one dose of adalimumab. This implies that TNF in circulation during anti-TNF treatment is not primarily associated with disease activity. During treatment, TNF was in complex with adalimumab and could be recovered as inactive 3:1 adalimumab-TNF complexes. No quantitative association was found between TNF and adalimumab concentrations. Low TNF concentrations at week 4 were associated with a higher frequency of antidrug antibodies (ADAs) at subsequent time points, less frequent methotrexate use at baseline, and less frequent remission after 52 weeks. Also in healthy volunteers, early low TNF concentrations are associated with ADAs. In conclusion, longitudinal TNF concentrations are mostly stable during adalimumab treatment and may therefore not predict successful treatment discontinuation. However, early low TNF is strongly associated with ADA formation and may be used as timely predictor of nonresponse toward adalimumab treatment.