Department of Internal Medicine IV (Gastroenterology, Hepatology and Infectious Diseases), Jena University Hospital, Am Klinikum 1, Jena, 07747, Germany.
Institute of Medical Statistics, Computer and Data Sciences, Jena University Hospital, Jena, Germany.
Int J Colorectal Dis. 2023 Feb 25;38(1):54. doi: 10.1007/s00384-023-04349-1.
Loss of therapeutic response (LOR) due to anti-drug antibodies (ADA) against tumor necrosis factor (TNF) inhibitors is common in patients with inflammatory bowel disease (IBD). We aimed to investigate whether immunomodulator comedication can reverse the immunogenic LOR to TNF inhibitors in IBD.
In this real-world retrospective cohort study, 123 IBD patients with neutralizing ADA to infliximab or adalimumab and concomitant subtherapeutic trough levels were screened for clinical LOR. Subsequent ADA and trough level measurements and clinical outcomes were analyzed for patients who received either immunomodulator comedication or dose intensification of infliximab or adalimumab to overcome LOR.
Following immunogenic LOR, the initial anti-TNF regimen was optimized in 33 patients. In univariable and multivariable logistic regression analyses, immunomodulator comedication was identified as the crucial factor for regaining clinical remission and ADA clearance. Detectable trough levels (≥ 0.98 or ≥ 1.00 mg/L, respectively) had optimal predictive performance for both endpoints in receiver operating characteristics curves [area under the curve 0.86 (95% confidence interval 0.68-1.00) for regaining clinical remission, 0.87 (0.71-1.00) for ADA clearance]. Furthermore, 11/20 patients (55%) on a comedication with azathioprine or methotrexate and 2/13 patients (15%) receiving anti-TNF dose intensification exclusively (P = 0.032) exhibited ADA elimination, regain of therapeutic trough levels, and clinical remission. Regain of clinical remission alone was achieved in 17/20 (85%) patients receiving comedication and 2/13 (15%) patients receiving anti-TNF dose intensification (P = 1.6 × 10).
Immunogenic LOR to infliximab or adalimumab in IBD can be successfully reversed using immunomodulator comedication.
肿瘤坏死因子（TNF）抑制剂的抗药物抗体（ADA）导致炎症性肠病（IBD）患者治疗应答丧失（LOR）较为常见。本研究旨在探讨免疫调节剂联合用药是否可以逆转 IBD 患者对 TNF 抑制剂的免疫源性 LOR。
本真实世界回顾性队列研究筛选了 123 例对英夫利昔单抗或阿达木单抗产生中和性 ADA 且伴随治疗谷浓度下药物浓度低于治疗范围的 IBD 患者，以评估临床 LOR。对接受免疫调节剂联合用药或英夫利昔单抗或阿达木单抗剂量强化以克服 LOR 的患者进行后续 ADA 和谷浓度测量及临床结局分析。
发生免疫源性 LOR 后，33 例患者对初始抗 TNF 方案进行了优化。在单变量和多变量逻辑回归分析中，免疫调节剂联合用药是恢复临床缓解和 ADA 清除的关键因素。可检测到的谷浓度（分别为≥0.98 或≥1.00μg/ml）在接受者操作特征曲线中对这两个终点均具有最佳预测性能[曲线下面积 0.86（95%置信区间 0.68-1.00）用于恢复临床缓解，0.87（0.71-1.00）用于 ADA 清除]。此外，20 例接受硫唑嘌呤或甲氨蝶呤联合用药的患者中有 11 例（55%）和 13 例仅接受抗 TNF 剂量强化的患者中有 2 例（15%）（P=0.032）出现 ADA 消除、治疗谷浓度恢复和临床缓解。接受联合用药的患者中有 17 例（85%）仅恢复临床缓解，接受抗 TNF 剂量强化的患者中有 2 例（15%）（P=1.6×10）。
IBD 患者对英夫利昔单抗或阿达木单抗的免疫源性 LOR 可通过免疫调节剂联合用药成功逆转。
