乌司奴单克隆抗体治疗克罗恩病的短期临床疗效及影响因素

doi:10.3969/j.issn.1006-5725.2024.07.019

摘要/Abstract

摘要：

目的探讨乌司奴单克隆抗体（UST）治疗克罗恩病（CD）的短期临床疗效及影响因素，为UST的临床应用提供更多的证据支持。方法采用回顾性队列研究方法，收集2020年12月至2022年10月在同济大学附属第十人民医院采用UST治疗的CD患者临床资料。主要分析UST治疗CD第8、16周的短期临床疗效和影响因素，并分析部分患者的内镜缓解率。结果共纳入91例初次使用UST的CD患者。UST治疗CD第8/16周的临床应答率分别为61.5%、71.4%，临床缓解率分别为45%、54.9%。单因素分析表明瘘（包括肛瘘、肛瘘个人史、肠皮瘘）与CD第8/16周的临床缓解有关。多因素COX分析提示，有肛瘘手术史相比于无瘘者是影响UST治疗CD第8周（HR = 0.04，95%CI：0.00 ~ 0.38；P < 0.01）和16周（HR = 0.04，95%CI：0.01 ~ 0.34；P < 0.01）临床缓解的独立保护性因素；狭窄型病变相较于非狭窄非穿透性病变，是CD患者16周临床缓解的独立危险因素（HR = 1.75，95%CI：1.08 ~ 2.84；P < 0.05）。56例于我院复查内镜，16周的内镜缓解率为41.1%。未发现有患者因严重不良反应停止用药。结论 UST能够改善CD第8/16周的临床缓解与临床应答，具有较好的短期临床疗效。有肛瘘个人史的CD患者推荐应用UST单抗，具有狭窄型病变的患者需谨慎应用UST单抗。患者既往是否行手术治疗，以及UST一线或非一线应用，均对临床缓解无明显影响。

关键词: 乌司奴单克隆抗体, 克罗恩病, 临床缓解, 临床应答

Abstract:

Objective To analyze the short?term clinical efficacy and influencing factors of ustekinumab monoclonal antibody （UST） in the treatment of Crohn's disease （CD）. Methods Retrospective cohort study was used to collect the clinical data of CD patients treated with UST in the 10th People's Hospital affiliated to Tongji University from December 2020 to October 2022. The main analysis is the short?term clinical efficacy and influencing factors of UST treatment for CD at weeks 8 and 16， And analyze the endoscopic response rate of some patients. Results A total of 91 CD patients who first used UST were included. The 8?week clinical response rate of UST treatment for CD was 61.5%， and the clinical response rate was 45%； The clinical response rate at 16 weeks was 71.4%， and the clinical response rate was 54.9%. 56 cases underwent endoscopic re?examination in our hospital， and the endoscopic response rate at 16 weeks was 41.1%. Univariate analysis showed that fistula （including anal fistula， personal history of anal fistula， and intestinal skin fistula） is associated with clinical remission in Crohn's disease patients at 8/16 weeks. Further multivariate COX regression analysis showed that the presence of a history of anal fistula surgery was an independent protective factor affecting clinical remission in CD patients treated with UST at 8 weeks （HR = 0.04，95% CI： 0.00 ~ 0.38； P = 0.005） and 16 weeks （HR = 0.04，95% CI： 0.01 ~ 0.34； P = 0.003） compared to those without fistula； Narrow lesions are an independent risk factor for 16 week clinical remission in CD patients compared to non?narrow and non?penetrating lesions （HR = 1.75， 95% CI： 1.08 ~ 2.84； P = 0.023）. No patients were found to have stopped medication due to serious adverse reactions. Conclusions UST can improve the clinical remission and response of CD patients at 8/16 weeks， and has good short?term clinical efficacy. CD patients with a personal history of anal fistula are recommended to use UST monoclonal antibodies， while patients with stenotic lesions should be cautious in using UST monoclonal antibodies. Whether the patient has undergone surgical treatment in the past， as well as whether UST has been used on the first or non?first line， has no significant impact on clinical remission.

Key words: ustekinumab monoclonal antibody, Crohn's disease, clinical remission, clinical response

中图分类号:

R574

王芮,刘嫦钦,张萃,杨清露,杨娇兰,殷鹏云,李晓辉,孙永顺,刘占举,孙晓敏. 乌司奴单克隆抗体治疗克罗恩病的短期临床疗效及影响因素[J]. 实用医学杂志, 2024, 40(7): 989-995.

Rui WANG,Changqin LIU,Cui ZHANG,Qinglu YANG,Jiaolan YANG,Pengyun YIN,Xiaohui LI,Yongshun SUN,Zhanju LIU,Xiaomin. SUN. Short term clinical efficacy and influencing factors of ustekinumab monoclonal antibody in the treatment of Crohn′s disease[J]. The Journal of Practical Medicine, 2024, 40(7): 989-995.

图/表 4

图1

表1

表2

图2

参考文献 25

1	BAUMGAR D C， SANDBORN W J. Crohn′s disease ［J］. Lancet， 2012，380（9853）：1590-1605. doi:10.1016/s0140-6736(12)60026-9 doi: 10.1016/s0140-6736(12)60026-9
2	WILSON J C， FURLANO R I， JICK S S， et al. Inflammatory bowel disease and the risk of autoimmune diseases ［J］. J Crohns Colitis， 2016，10（2）：186-193. doi:10.1093/ecco-jcc/jjv193 doi: 10.1093/ecco-jcc/jjv193
3	XAVIER R J， PODOLSKY D K. Unravelling the pathogenesis of inflammatory bowel disease ［J］. Nature， 2007， 448（7152）：427-434. doi:10.1038/nature06005 doi: 10.1038/nature06005
4	PEYRIN-BIROULET L， LOFTUS EV J R， COLOMBEL J F， et al. The natural history of adult Crohn′s disease in population-based cohorts ［J］. Am J Gastroenterol， 2010， 105（2）：289-297. doi:10.1038/ajg.2009.579 doi: 10.1038/ajg.2009.579
5	NAKASE H， UCHINO M， SHINZAKI S， et al. Evidence-based clinical practice guidelines for inflammatory bowel disease 2020 ［J］. J Gastroenterol， 2021，56（6）：489-526. doi:10.1007/s00535-021-01784-1 doi: 10.1007/s00535-021-01784-1
6	DEEPAK P， SANDBORN W J. Ustekinumab and Anti-Interleukin-23 Agents in Crohn′s Disease ［J］. Gastroenterol Clin North Am， 2017， 46（3）：603-626. doi:10.1016/j.gtc.2017.05.013 doi: 10.1016/j.gtc.2017.05.013
7	PELUSO I， PALLONE F， MONTELEONE G， et al. Interleukin-12 and Th1 immune response in Crohn′s disease： pathogenetic relevance and therapeutic implication ［J］. World J Gastroenterol， 2006，12（35）：5606-5610. doi:10.3748/wjg.v12.i35.5606 doi: 10.3748/wjg.v12.i35.5606
8	中华医学会消化病学分会炎症性肠病学组.炎症性肠病诊断与治疗的共识意见（2018年，北京）［J］.中华炎性肠病杂志，2018，2（3）：173-190.
9	DEEPAK P， FLETCHER J G， FIDLER J L，et al. Radiological response is associated with better long-term outcomes and is a potential treatment target in patients with small bowel Crohn′s disease［J］. Am J Gastroenterol， 2016，111（7）： 997-1006. doi:10.1038/ajg.2016.177 doi: 10.1038/ajg.2016.177
10	CHAPARRO M， BASTON-REY I， ERNANDEZ-SALGADO E， et al. Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn's Disease Patients： The SUSTAIN Study ［J］. Inflamm Bowel Dis， 2022， 28（11）： 1725-1736.
11	NEWMAN K L， JEHNSON L A， STIDHAM R W， et al. Vedolizumab more likely to be discontinued than ustekinumab in anti-TNF-experienced patients with fistulizing Crohn's disease ［J］. Therap Adv Gastroenterol， 2023， 16： 1098331230. doi:10.1177/17562848221148254 doi: 10.1177/17562848221148254
12	YAO J， ZHANG H， SU T， et al. Ustekinumab Promotes Radiological Fistula Healing in Perianal Fistulizing Crohn's Disease： A Retrospective Real-World Analysis ［J］. J Clin Med， 2023， 12（3）： 939. doi:10.3390/jcm12030939 doi: 10.3390/jcm12030939
13	CHATZIMICHAIL G， GÜNTHER J， STÄNDER S， et al. Drug survival of secukinumab， ustekinumab， and certolizumab pegol in psoriasis： a 2-year， monocentric， retrospective study ［J］. J Dermatolog Treat， 2022， 33（3）： 1749-1753. doi:10.1080/09546634.2020.1854428 doi: 10.1080/09546634.2020.1854428
14	BRESSLER B， JONES J， IN T， et al. Real-World Persistence of Ustekinumab in the Treatment of Inflammatory Bowel Disease ［J］. Adv Ther， 2023， 40（10）： 4421-4439. doi:10.1007/s12325-023-02611-0 doi: 10.1007/s12325-023-02611-0
15	YAO J Y， ZHANG M， WANG W， et al. Ustekinumab trough concentration affects clinical and endoscopic outcomes in patients with refractory Crohn's disease： a Chinese real-world study ［J］. BMC Gastroenterol， 2021， 21（1）： 380. doi:10.1186/s12876-021-01946-8 doi: 10.1186/s12876-021-01946-8
16	陆君涛，徐锡涛，王天蓉，等. 乌司奴单克隆抗体治疗克罗恩病的疗效及安全性分析［J］. 中华炎性肠病杂志， 2023，7（1）：37-42. doi:10.3760/cma.j.cn101480-20220613-00087 doi: 10.3760/cma.j.cn101480-20220613-00087
17	YAO L， ZHU X， SHAO B， et al. Reasons and Factors Contributing to Chinese Patients' Preference for Ustekinumab in Crohn's Disease： A Multicenter Cross-Sectional Study［J］. Front Pharmacol， 2021， 12： 736149. doi:10.3389/fphar.2021.736149 doi: 10.3389/fphar.2021.736149
18	STRAATMIJER T， BIEMANS V， MOES D， et al. Ustekinumab Trough Concentrations Are Associated with Biochemical Outcomes in Patients with Crohn's Disease ［J］. Dig Dis Sci， 2023， 68（6）： 2647-2657. doi:10.1007/s10620-023-07822-7 doi: 10.1007/s10620-023-07822-7
19	JOHNSON A M， BARSKY M， AHMED W， et al. The Real-World Effectiveness and Safety of Ustekinumab in the Treatment of Crohn's Disease： Results From the SUCCESS Consortium ［J］. Am J Gastroenterol， 2023， 118（2）： 317-328.
20	SHIGA H， TARASAWA K， MOROI R， et al. Long-term effectiveness of ustekinumab comparable to antitumor necrosis factor agents in patients with Crohn's disease ［J］. J Gastroenterol Hepatol， 2022， 37（11）： 2105-2112. doi:10.1111/jgh.15992 doi: 10.1111/jgh.15992
21	TURSOI A， MOCCI G， CUOMO A， et al. Real-life efficacy and safety of Ustekinumab as second- or third-line therapy in Crohn's disease： results from a large Italian cohort study ［J］. Eur Rev Med Pharmacol Sci， 2021， 25（4）： 2099-2108.
22	PARRA R S， CHEBLI J， QUEIROZ N， et al. Long-term effectiveness and safety of ustekinumab in bio-naïve and bio-experienced anti-tumor necrosis factor patients with Crohn's disease： a real-world multicenter Brazilian study ［J］. BMC Gastroenterol， 2022， 22（1）： 199. doi:10.1186/s12876-022-02280-3 doi: 10.1186/s12876-022-02280-3
23	ALBSHESH A， BANNON L， SHARAR F T， et al. Comparison of Short- and Long-Term Effectiveness between Anti-TNF and Ustekinumab after Vedolizumab Failure as First-Line Therapy in Crohn's Disease： A Multi-Center Retrospective Cohort Study ［J］. J Clin Med， 2023， 12（7）： 2503. doi:10.3390/jcm12072503 doi: 10.3390/jcm12072503
24	BOKEMEYER B， PLACHAT-DANIELZIK S， DI GIUSEPPE R， et al. Real-world Comparative Effectiveness of Ustekinumab vs Anti-TNF in Crohn's Disease With Propensity Score Adjustment： Induction Phase Results From the Prospective， Observational RUN-CD Study ［J］. Inflamm Bowel Dis， 2023， 29（11）： 1741-1750. doi:10.1093/ibd/izac271 doi: 10.1093/ibd/izac271
25	ZHOU H， WANG F， WAN J， et al. Systematic Review and Meta-Analysis of Observational Studies on the Effectiveness and Safety of Ustekinumab among Patients with Inflammatory Bowel Disease in Eastern and Western Countries ［J］. J Clin Med， 2023，12（5）：1894. doi:10.3390/jcm12051894 doi: 10.3390/jcm12051894

因素	单因素COX分析			多因素COX分析
因素	P值	HR	95%CI	P值	HR	95%CI
性别	0.377	1.29	0.74 ~ 2.24	0.448	1.29	0.67 ~ 2.49
手术	0.472	0.80	0.44 ~ 1.46	0.250	0.66	0.33 ~ 1.34
发病年龄	0.054	1.02	1.00 ~ 1.04	0.592	1.01	0.96 ~ 1.05
病程	0.259	0.98	0.94 ~ 1.02	0.490	0.99	0.94 ~ 1.03
CDAI评分	0.498	1.00	0.99 ~ 1.01	0.519	1.01	0.96 ~ 1.06
发病部位	0.857			0.530
L2 vs. L1	0.977	1.01	0.47 ~ 2.19	0.480	1.17	0.76 ~ 1.79
L3 vs. L1	0.590	0.82	0.39 ~ 1.70	0.519	0.56	1.04 ~ 4.36
L4 vs. L1
疾病行为	0.039			0.093
B2 vs. B1	0.512	0.73	0.29 ~ 1.86	0.074	1.60	0.96 ~ 2.67
B3 vs. B1	0.301	0.83	0.66 ~ 3.86	0.132	0.56	0.96 ~ 1.54
发病年龄	0.257			0.527
A2 vs. A1	0.104	0.43	0.16 ~ 1.19	0.472	1.41	0.55 ~ 3.59
A3 vs. A1	0.526	0.80	0.39 ~ 1.61	0.861	1.29	0.73 ~ 1.56
UST非一线 vs. 一线	0.757	1.10	0.60 ~ 2.00	0.539	0.49	0.05 ~ 4.81
既往抗TNF?α vs. 无	0.727	1.12	0.61 ~ 1.10	0.352	2.84	0.32 ~ 25.68
既往VDZ vs. 无	0.608	1.22	0.57 ~ 2.60	0.097	2.23	0.86 ~ 5.75
合用激素 vs. 无	0.470	1.44	0.53 ~ 3.89	0.898	1.08	0.32 ~ 3.62
合用免疫抑制剂 vs. 无	0.201	1.91	0.71 ~ 5.13	0.132	2.49	0.76 ~ 8.15
瘘	0.010			0.044
肛瘘 vs. 无瘘	0.002	0.08	0.02 ~ 0.40	0.112	0.22	0.04 ~ 1.42
肛瘘手术史 vs. 无瘘	0.002	0.03	0.00 ~ 0.28	0.005	0.04	0.00 ~ 0.38
肠瘘 vs. 无瘘	0.003	0.08	0.02 ~ 0.42	0.108	0.22	0.03 ~ 1.40

因素	单因素COX分析			多因素COX分析
因素	P值	HR	95%CI	P值	HR	95%CI
性别	0.259	1.35	0.80 ~ 2.25	0.257	1.43	0.77 ~ 2.66
手术	0.774	0.92	0.54 ~ 1.59	0.337	0.72	0.37 ~ 1.47
发病年龄	0.127	1.02	0.99 ~ 1.04	0.667	1.01	0.97 ~ 0.52
病程	0.514	0.99	0.96 ~ 1.02	0.711	0.99	0.96 ~ 1.03
CDAI评分	0.881	1.00	0.99 ~ 1.01	0.955	1.00	0.99 ~ 1.00
发病部位	0.978			0.341
L2 vs. L1	0.924	1.05	0.43 ~ 2.56	0.369	1.21	0.80 ~ 1.83
L3 vs. L1	0.840	1.08	0.50 ~ 2.33	0.287	1.63	0.95 ~ 1.57
L4 vs. L1
疾病行为	0.170			0.092
B2 vs. B1	0.524	0.78	0.32 ~ 1.79	0.023	1.75	1.08 ~ 2.84
B3 vs. B1	0.206	1.71	0.75 ~ 3.89	0.219	1.55	0.74 ~ 2.96
发病年龄	0.468			0.441
A2 vs. A1	0.223	0.58	0.24 ~ 1.40	0.663	1.21	0.51 ~ 2.86
A3 vs. A1	0.559	0.82	0.42 ~ 1.60	0.237	1.68	0.77 ~ 2.14
UST非一线 vs. 一线	0.832	1.06	0.61 ~ 1.85	0.414	0.39	0.04 ~ 3.69
既往抗TNF?α vs. 无	0.797	1.07	0.62 ~ 1.85	0.302	3.12	0.36 ~ 7.01
既往VDZ vs. 无	0.356	1.38	0.70 ~ 2.74	0.054	2.36	0.98 ~ 5.65
合用激素 vs. 无	0.295	1.70	0.63 ~ 4.16	0.330	1.91	0.52 ~ 7.01
合用免疫抑制剂 vs. 无	0.258	1.51	0.74 ~ 3.06	0.368	1.51	0.61 ~ 3.73
瘘	0.110			0.260
肛瘘 vs. 无瘘	0.001	0.81	0.16 ~ 0.40	0.780	0.20	0.03 ~ 1.19
肛瘘手术史 vs. 无瘘	0.001	0.04	0.01 ~ 0.30	0.003	0.04	0.01 ~ 0.34
肠瘘 vs. 无瘘	0.002	0.08	0.02 ~ 0.42	0.097	0.22	0.04 ~ 1.32

[1]	何伟涛,申晓迪,王杨迪,杜金芳,李雪华,熊珊珊,李周雷,林少春. 基于术前磁共振小肠成像预测克罗恩病患者首次肠切除术后早期吻合口复发风险[J]. 实用医学杂志, 2024, 40(5): 664-671.
[2]	蔡云平陶钱红王家辉姚鸿迪方诗洁吕文. 血清C⁃反应蛋白、白蛋白及腹部超声弹性成像技术对活动期克罗恩病患者抗肿瘤坏死因子单克隆抗体治疗疗效的预测价值⁃α [J]. 实用医学杂志, 2021, 37(20): 2630-2635.