Gudbrandsdottir S, Larsen R, Sørensen L K, Nielsen S, Hansen M B, Svenson M, Bendtzen K, Müller K
Paediatric Department, Institute of Inflammation Research, Rigshospitalet, Copenhagen, Denmark.
Clin Exp Rheumatol. 2004 Jan-Feb;22(1):118-24.
Etanercept (Enbrel) induces a rapid and sustained decline in disease activity in the majority of patients with refractory juvenile idiopathic arthritis (JIA). For unknown reasons, however, a number of JIA patients fail to respond to this therapy. During this treatment neutralisation of tumour necrosis factor (TNF, previously termed TNF alpha) and lymphotoxin (LT, previously termed TNF beta) may be mediated by etanercept itself as well as by naturally occurring soluble TNF receptors. In light of this, it was of interest to study the total TNF neutralizing capacity in plasma before and during treatment with etanercept.
In initial experiments plasma samples from healthy individuals were incubated with etanercept, and spiked with TNF or LT to a final concentration of 1000 pg/mL. Detection of TNF and LT by ELISA was found to be reduced by approximately 50% and 80% respectively, at a concentration of etanercept of 5-500 ng/mL, which is close to the pharmacological plasma concentrations. Plasma samples (n = 80) were then collected from 12 JIA patients (5 with pauciarticular, 5 with polyarticular and 2 with the systemic onset type) during treatment with etanercept (0.4 mg/kg twice weekly) for a period of 20.8 (15.6-23.9) months (median, range). The plasma samples were spiked with LT, and the inhibition of LT detection in ELISA was measured. In samples obtained 3 months after the start of etanercept, the inhibition of LT detection was augmented [72% (60-85)] compared with pre-treatment samples [16% (0.32)] (p = 0.0039). These findings were confirmed in binding assays using radiolabelled TNF. Among patients who responded insufficiently to therapy, reduced LT binding capacity, coinciding with flares of disease activity, was observed.
We have developed an assay by which LT binding capacity, reflecting the level of free, pharmacologically active etanercept, may be monitored in the blood of patients treated with etanercept. This assay may prove to be useful in guiding dose adjustments in patients with an incomplete response to etanercept.
依那西普（恩利）可使大多数难治性幼年特发性关节炎（JIA）患者的疾病活动迅速且持续下降。然而，出于未知原因，一些JIA患者对这种治疗没有反应。在这种治疗过程中，肿瘤坏死因子（TNF，以前称为TNFα）和淋巴毒素（LT，以前称为TNFβ）的中和可能由依那西普本身以及天然存在的可溶性TNF受体介导。鉴于此，研究依那西普治疗前和治疗期间血浆中的总TNF中和能力很有意义。
在最初的实验中，将健康个体的血浆样本与依那西普一起孵育，并用TNF或LT加样至最终浓度1000 pg/mL。发现当依那西普浓度为5 - 500 ng/mL（接近药理血浆浓度）时，通过ELISA检测到的TNF和LT分别降低了约50%和80%。然后在12例JIA患者（5例少关节型、5例多关节型和2例全身发病型）接受依那西普（0.4 mg/kg，每周两次）治疗20.8（15.6 - 23.9）个月（中位数，范围）期间收集血浆样本（n = 80）。向血浆样本中加入LT，并测量ELISA中LT检测的抑制情况。在依那西普开始治疗后三个月获得的样本中，与治疗前样本[16%（0.32）]相比，LT检测的抑制增强了[72%（60 - 85）]（p = 0.0039）。这些发现在用放射性标记的TNF进行的结合试验中得到了证实。在对治疗反应不足的患者中，观察到LT结合能力降低，这与疾病活动的发作同时出现。
我们开发了一种检测方法，通过该方法可以监测接受依那西普治疗患者血液中反映游离的、具有药理活性的依那西普水平的LT结合能力。该检测方法可能有助于指导对依那西普反应不完全的患者进行剂量调整。
