Department of Gastroenterology, Beaumont Hospital, RCSI Hospital Group, Dublin 9, Ireland.
Department of Gastroenterology, James Connolly Hospital, RCSI Hospital Group, Dublin 15, Ireland.
Inflamm Bowel Dis. 2024 Mar 1;30(3):423-428. doi: 10.1093/ibd/izad073.
Ustekinumab (UST), a human monoclonal antibody that binds the p40 subunit of interleukin 12 (IL-12) and IL-23, is licensed for induction and maintenance therapy of moderate to severe inflammatory bowel disease (IBD). To date, there is limited data published on any potential association between ustekinumab serum trough levels and mucosal healing in order to guide treatment strategies and appropriate dosing.
This study aims to identify a relationship between maintenance ustekinumab serum trough levels and mucosal healing and/or response in patients with Crohn's disease in an observational cohort study.
Ustekinumab serum trough levels and antibody titres were analyzed in patients on maintenance drug using an ELISA drug-tolerant assay. Mucosal response (MR) was defined as ≥50% reduction in fecal calprotectin level (FC) and/or ≥50% reduction in the Simple Endoscopic Score for Crohn's Disease (SES-CD score). Mucosal healing (MH) was defined as FC ≤150 µg/mL and/or global SES-CD score ≤5. Median trough levels were analyzed using the Kruskal-Wallis test, and logistic regression was used to determine sensitivity and specificity of levels predicting mucosal response.
Forty-seven patients on maintenance ustekinumab for Crohn's disease were included in this study. The majority were female (66%), with a median age of 40 years (21-78 years). The majority of patients were biologic-experienced (89.4%, n = 42). Patients with histologically confirmed Crohn's disease represented 100% (n = 47) of the cohort. Over one-third of patients (n = 18, 38.3%) were on higher than standard dosing of 90 mg every 8 weeks. Patients with mucosal healing (n = 30) had significantly higher mean serum ustekinumab levels (5.7 µg/mL, SD 6.4) compared with those with no response (1.1 µg/mL, SD 0.52; n = 7, P < .0001). A serum ustekinumab trough level greater than 2.3 µg/mL was associated with MH, with a sensitivity of 100% and specificity of 90.6% (likelihood ratio 10.7). Similarly, for patients with MR (n = 40), we observed a higher mean serum ustekinumab trough level (5.1 µg/mL, SD 6.1) compared with those with no response (1.1 µg/mL, SD 0.52; n = 7, P < .0001). Furthermore, a serum ustekinumab trough level greater than 2.3 µg/mL was associated with a 10-fold increased likelihood of mucosal response vs mucosal nonresponse (sensitivity 100%, specificity 90.5%, likelihood ratio 10.5).
This study demonstrates that higher ustekinumab serum trough levels are associated with a greater likelihood of achieving mucosal healing and mucosal response in patients with Crohn's disease regardless of prior biologic exposure. Further prospective studies are required to correlate target maintenance trough levels and the optimal time to dose-escalate in order to improve patient outcomes.
乌司奴单抗（UST）是一种人源化单克隆抗体，可与白细胞介素 12（IL-12）和 IL-23 的 p40 亚单位结合，用于中度至重度炎症性肠病（IBD）的诱导和维持治疗。迄今为止，关于乌司奴单抗血清谷浓度与黏膜愈合之间的任何潜在关联的相关数据有限，无法为治疗策略和适当的剂量调整提供指导。
本研究旨在通过观察性队列研究，确定维持性乌司奴单抗血清谷浓度与克罗恩病患者黏膜愈合和/或缓解之间的关系。
采用酶联免疫吸附试验（ELISA）药物耐受检测法分析接受维持性药物治疗的患者的乌司奴单抗血清谷浓度和抗体滴度。黏膜反应（MR）定义为粪便钙卫蛋白（FC）水平降低≥50%，或简单克罗恩病内镜评分（SES-CD 评分）降低≥50%。黏膜愈合（MH）定义为 FC≤150μg/mL 和/或全球 SES-CD 评分≤5。采用 Kruskal-Wallis 检验分析中位数谷浓度，采用逻辑回归确定预测黏膜反应的浓度的敏感性和特异性。
本研究纳入了 47 例接受维持性乌司奴单抗治疗的克罗恩病患者。大多数为女性（66%），中位年龄为 40 岁（21-78 岁）。大多数患者有生物制剂治疗史（89.4%，n=42）。100%（n=47）的患者有组织学证实的克罗恩病。超过三分之一的患者（n=18，38.3%）接受了高于标准剂量（90mg，每 8 周）的治疗。与无缓解者（1.1μg/mL，0.52 SD；n=7，P<0.0001）相比，黏膜愈合者（n=30）的血清乌司奴单抗水平明显更高（5.7μg/mL，6.4 SD）。血清乌司奴单抗谷浓度大于 2.3μg/mL 与 MH 相关，敏感性为 100%，特异性为 90.6%（优势比 10.7）。同样，对于 MR 患者（n=40），与无缓解者相比，我们观察到血清乌司奴单抗谷浓度更高（5.1μg/mL，6.1 SD；n=7，P<0.0001）。此外，血清乌司奴单抗谷浓度大于 2.3μg/mL 与黏膜反应的可能性增加 10 倍相关（敏感性 100%，特异性 90.5%，优势比 10.5）。
本研究表明，无论先前是否使用过生物制剂，较高的乌司奴单抗血清谷浓度与克罗恩病患者黏膜愈合和黏膜反应的可能性增加相关。需要进一步的前瞻性研究来评估目标维持性谷浓度和最佳的剂量升级时间，以改善患者的预后。
