Circulating tumour necrosis factor-alpha bioactivity in rheumatoid arthritis patients treated with infliximab: link to clinical response.
Circulating tumour necrosis factor-alpha bioactivity in rheumatoid arthritis patients treated with infliximab: link to clinical response.
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DOI：
10.1186/ar1465
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发表时间：
2005
影响因子：
4.9
通讯作者：
Miossec P
中科院分区：
文献类型：
--
作者：
Marotte H;Maslinski W;Miossec P
我们的目的是阐明类风湿关节炎（RA）患者对英夫利西单抗治疗反应的异质性;为此，设计了一种生物测定法，以探索循环肿瘤坏死因子（TNF）-α生物活性的贡献及其与反应的可能联系。该生物测定基于滑膜细胞响应TNF-α诱导IL-6和骨保护素（OPG）产生。RA滑膜细胞用TNF-α（5 ng/ml）培养，并在开始治疗前采集42份RA血浆样本。测定培养上清中IL-6和OPG的水平。在20名患者中，以相同的方式检测了第一次和第九次输注前和输注后4小时采集的血浆样品。采用ELISA法测定血浆TNF-α、p55和p75可溶性受体浓度。TNF-α诱导滑膜细胞产生IL-6和OPG，患者血浆稀释液进一步增加，英夫利西单抗抑制。在首次输注前获得的血浆样本中，具有良好临床应答的患者中IL-6诱导的产生大于不良应答者（44.4 ± 23.3 ng/ml对27.4 ± 20.9 ng/ml; P = 0.05）。首次输注英夫利西单抗后，这种高循环TNF-α生物活性被强烈抑制。在具有良好临床应答的患者中，首次输注前和输注后4小时获得的血浆样本诱导的IL-6水平之间的差异更大（40.0 ± 23.7 ng/ml vs 3.4 ± 10.0 ng/ml; P = 0.001）。OPG的产生也得到类似的结果（7.0 ± 6.2ng/ml对0.0 ± 3.0ng/ml; P < 0.05）。循环TNF-α生物活性水平可预测对TNF-α抑制的临床应答，证实TNF-α在这些RA患者中的关键作用。
Our objective was to clarify the heterogeneity in response to infliximab treatment in rheumatoid arthritis (RA); to this end, a bioassay was designed to explore the contribution of circulating tumour necrosis factor (TNF)-α bioactivity and its possible link to response. The bioassay is based on the induction of IL-6 and osteoprotegerin (OPG) production by synoviocytes in response to TNF-α. RA synoviocytes were cultured with TNF-α (5 ng/ml) and 42 RA plasma samples collected just before starting therapy. Levels of IL-6 and OPG were measured in supernatants. In 20 of the patients, plasma samples collected before and 4 hours after the first and the ninth infusions were tested in the same way. Plasma concentrations of TNF-α and p55 and p75 soluble receptors were measured using ELISA. TNF-α induced IL-6 and OPG production by synoviocytes, which was further increased with patient plasma dilutions and inhibited by infliximab. With plasma samples obtained before the first infusion, the IL-6-induced production was greater in patients with a good clinical response than in the poor responders (44.4 ± 23.3 ng/ml versus 27.4 ± 20.9 ng/ml; P = 0.05). This high circulating TNF-α bioactivity was strongly inhibited with the first infliximab infusion. The difference between IL-6 levels induced with plasma samples obtained before and 4 hours after the first infusion was greater in patients with a good clinical response (40.0 ± 23.7 ng/ml versus 3.4 ± 10.0 ng/ml; P = 0.001). Similar findings were obtained for OPG production (7.0 ± 6.2 ng/ml versus 0.0 ± 3.0 ng/ml; P < 0.05). Levels of circulating TNF-α bioactivity were predictive of clinical response to TNF-α inhibition, confirming a key role for TNF-α in these RA patients.
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