Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor α inhibitor infliximab
Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor α inhibitor infliximab
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DOI：
10.1002/art.22214
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发表时间：
2006-12-01
影响因子：
--
通讯作者：
Saxne, Tore
中科院分区：
文献类型：
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作者：
Bendtzen, Klaus;Geborek, Pierre;Saxne, Tore
Objective.英夫利西单抗是一种抗肿瘤坏死因子α（抗TNF α）抗体，可有效治疗多种免疫炎症性疾病。然而，许多患者经历原发性或继发性应答失败，这表明个体化治疗方案可能是有益的。本研究旨在研究个体患者英夫利西单抗生物利用度和免疫原性的血清学监测是否有助于优化治疗方案，以提高疗效和耐受性。方法.为了避免使用固相测定法，开发了两种放射免疫测定法：一种用于测量抗英夫利西单抗抗体的水平，另一种用于测量英夫利西单抗引起的TNF α结合。在治疗开始后6个月内检测了106例随机选择的类风湿性关节炎患者的血清，并评估了血清检测结果与疾病活动、输注反应和18个月内发生的治疗失败之间的相关性。结果前2次静脉输注3 mg/kg英夫利西单抗后，患者之间的血清英夫利西单抗谷浓度差异很大（范围为0-22 μ g/ml）。在这个阶段，只有13%的患者是抗英夫利西单抗抗体阳性。在随后的输注中，抗体阳性的频率上升至30%和44%（分别在3个月和6个月时），伴随着英夫利西单抗的谷水平降低。事实上，1.5个月时的低英夫利西单抗水平预示着抗体的产生和随后的治疗失败。高水平的抗体与后期剂量增加、副作用和停止治疗之间存在高度显著的相关性。根据C反应蛋白水平和疾病活动评分判断，基线疾病活动度高与治疗早期英夫利西单抗水平低和后期抗英夫利西单抗抗体产生相关。与甲氨蝶呤的共同治疗导致6个月后抗体水平略有下降;其他疾病缓解抗风湿药物和泼尼松龙没有影响。结论抗英夫利西单抗抗体的产生，预示着输注前血清英夫利西单抗水平较低，与输注反应和治疗失败的风险增加相关。早期监测可能有助于优化个体患者的给药方案，减少副作用，并防止长期使用英夫利西单抗治疗不足。
Objective. Infliximab, an anti-tumor necrosis factor alpha (anti-TNF alpha) antibody, is effective in the treatment of several immunoinflammatory diseases. However, many patients experience primary or secondary response failure, suggesting that individualization of treatment regimens may be beneficial. This study was undertaken to investigate whether serologic monitoring of infliximab bioavailability and immunogenicity in individual patients would be useful in optimizing treatment regimens to improve efficacy and tolerability. Methods. To avoid the use of solid-phase assays, two radioimmunoassays were developed: one for measurement of levels of anti-infliximab antibody, and a functional one for measurement of TNF alpha binding due to infliximab. Sera from 106 randomly selected rheumatoid arthritis patients were tested within 6 months of therapy initiation, and associations between findings of serum assays and disease activity, infusion reactions, and treatment failure occurring within 18 months were assessed. Results. Trough serum infliximab levels after the first 2 intravenous infusions of infliximab at 3 mg/kg varied considerably between patients (range 0-22 mu g/ml). At this stage, only 13% of the patients were anti-infliximab antibody positive. With subsequent infusions, the frequency of antibody positivity rose to 30% and 44% (at 3 months and 6 months, respectively), accompanied by diminished trough levels of infliximab. Indeed, low infliximab levels at 1.5 months predicted antibody development and later treatment failure. There were highly significant correlations between high levels of antibodies and later dose increases, side effects, and cessation of therapy. High baseline disease activity, judged by C-reactive protein level and Disease Activity Score, was associated with low levels of infliximab at the early stage of treatment and later development of anti-infliximab antibodies. Cotreatment with methotrexate resulted in slightly reduced antibody levels after 6 months; other disease-modifying antirheumatic drugs and prednisolone had no effect. Conclusion. Development of anti-infliximab antibodies, heralded by low preinfusion serum infliximab levels, is associated with increased risk of infusion reaction and treatment failure. Early monitoring may help optimize dosing regimens for individual patients, diminish side effects, and prevent prolonged use of inadequate infliximab therapy.