托法替尼治疗溃疡性结肠炎的研究进展

吴澎泞; 熊帅; 杨婉卿; 陈敏

doi:10.6039/j.issn.1001-0408.2022.18.25

您当前的位置：

首页 >

文章列表页 >

托法替尼治疗溃疡性结肠炎的研究进展

综述 | 更新时间：2023-02-22

- 托法替尼治疗溃疡性结肠炎的研究进展
- Research advances of tofacitinib in the treatment of ulcerative colitis
- 中国药房 2022年33卷第18期页码：2299-2304
- 作者机构：
  
  1.成都中医药大学附属医院临床医学院，成都　610075
  2.成都中医药大学附属医院肛肠科，成都　610075
- 作者简介：
  
  住院医师，硕士。研究方向：肛肠疾病诊疗。E-mail：1328433248@qq.com
  副主任医师，博士。研究方向：肛肠疾病诊疗。E-mail：cm@cdutcm.edu.cn
- 基金信息：
  
  国家自然科学基金资助项目(81774321)
- DOI：10.6039/j.issn.1001-0408.2022.18.25
  中图分类号： R975
- 纸质出版日期：2022-09-30，
  
  收稿日期：2022-03-31，
  
  修回日期：2022-07-11，
扫描看全文
吴澎泞,熊帅,杨婉卿等.托法替尼治疗溃疡性结肠炎的研究进展^Δ[J].中国药房,2022,33(18):2299-2304.

WU Pengning,XIONG Shuai,YANG Wanqing,et al.Research advances of tofacitinib in the treatment of ulcerative colitis[J].ZHONGGUO YAOFANG,2022,33(18):2299-2304.
吴澎泞,熊帅,杨婉卿等.托法替尼治疗溃疡性结肠炎的研究进展^Δ[J].中国药房,2022,33(18):2299-2304. DOI： 10.6039/j.issn.1001-0408.2022.18.25.

WU Pengning,XIONG Shuai,YANG Wanqing,et al.Research advances of tofacitinib in the treatment of ulcerative colitis[J].ZHONGGUO YAOFANG,2022,33(18):2299-2304. DOI： 10.6039/j.issn.1001-0408.2022.18.25.

摘要

溃疡性结肠炎（UC）是一种多因素导致的慢性炎症性肠病，其病因和发病机制尚不完全清楚。托法替尼是一种小分子物质，主要通过抑制Janus激酶（JAK）治疗UC，可通过口服快速吸收。该药已被美国FDA及欧洲药品管理局批准用于治疗中重度UC，且国外已开展较多托法替尼治疗UC的临床研究，而其在我国尚未见有用于UC的相关报道。本文主要从托法替尼治疗UC的作用机制、临床应用、安全性等方面总结其相关研究进展。结果表明，托法替尼主要通过抑制JAK和促炎因子的表达、调节过表达的信号转导及转录激活因子信号、修复肠黏膜屏障等作用治疗UC。托法替尼在临床显示出较好的疗效，但安全性研究显示其所带来的带状疱疹、血栓形成等风险不容忽视，妊娠期、儿童、青少年、老年患者应慎用该药。由于目前暂未见其在我国用于UC，未来需进一步研究托法替尼在我国UC患者中的疗效和安全性。

Abstract

Ulcerative colitis （UC） is a chronic inflammatory bowel disease caused by multiple factors， and its etiology and pathogenesis remain unclear. Tofacitinib， a small molecule rapidly absorbed by oral administration， treats UC primarily by inhibiting Janus kinase （JAK）. Tofacitinib has been approved by the FDA and the European Medicines Agency for the treatment of moderate to severe UC. Many clinical studies on tofacitinib in the treatment of UC have been carried out abroad， but there is no relevant report on its use in UC in China. This paper summarizes the relevant research advances of tofacitinib in the treatment of UC from its mechanism， clinical application and safety. The results show that tefatinib mainly treats UC by inhibiting the expression of JAK and proinflammatory factors

regulating the overexpressed signaling transducers and activators of transcription

and repairing the intestinal mucosal barrier. Tofacitinib has good clinical efficacy， but safety studies have shown that the risks of herpes zoster and thrombosis should not be ignored， and the drug should be used with caution in pregnant， children， adolescents， and elderly patients. The efficacy and safety of tofacitinib in Chinese population should be further studied in the future， since it has not been used in UC patients in China.

关键词

托法替尼溃疡性结肠炎机制临床研究

Keywords

ulcerative colitismechanismclinical research

references

PÉREZ-JELDRES T，TYLER C J，BOYER J D，et al. Targeting cytokine signaling and lymphocyte traffic via small molecules in inflammatory bowel disease：JAK inhibitors and S1PR agonists[J]. Front Pharmacol，2019，10：212.

KUCHARZIK T，KOLETZKO S，KANNENGIESSER K，et al. Ulcerative colitis-diagnostic and therapeutic algorithms[J]. Dtsch Arztebl Int，2020，117（33/34）：564-574.

RUBIN D T，ANANTHAKRISHNAN A N，SIEGEL C A，et al. ACG clinical guideline：ulcerative colitis in adults[J]. Am J Gastroenterol，2019，114（3）：384-413.

FEUERSTEIN J D，ISAACS K L，SCHNEIDER Y，et al. AGA clinical practice guidelines on the management of moderate to severe ulcerative colitis[J]. Gastroenterology，2020，158（5）：1450-1461.

SALAS A，HERNANDEZ-ROCHA C，DUIJVESTEIN M，et al. JAK-STAT pathway targeting for the treatment of inflammatory bowel disease[J]. Nat Rev Gastroenterol Hepatol，2020，17（6）：323-337.

MORRIS R，KERSHAW N J，BABON J J. The molecular details of cytokine signaling via the JAK/STAT pathway[J]. Protein Sci，2018，27（12）：1984-2009.

O’SHEA J J，PLENGE R. JAK and STAT signaling mo-lecules in immunoregulation and immune-mediated di-sease[J]. Immunity，2012，36（4）：542-550.

STARK G R，DARNELL J E. The JAK-STAT pathway at twenty[J]. Immunity，2012，36（4）：503-514.

SOENDERGAARD C，BERGENHEIM F H，BJERRUM J T，et al. Targeting JAK-STAT signal transduction in IBD[J]. Pharmacol Ther，2018，192：100-111.

O’SHEA J J，HOLLAND S M，STAUDT L M. JAKs and STATs in immunity，immunodeficiency，and cancer[J]. N Engl J Med，2013，368（2）：161-170.

VILLARINO A V，KANNO Y，O'SHEA J J. Mechanisms and consequences of JAK-STAT signaling in the immune system[J]. Nat Immunol，2017，18（4）：374-384.

MCGOVERN D P，GARDET A，TÖRKVIST L，et al. Genome-wide association identifies multiple ulcerative colitis susceptibility loci[J]. Nat Genet，2010，42（4）：332-337.

ANDERSON C A，BOUCHER G，LEES C W，et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci，increasing the number of confirmed associations to 47[J]. Nat Genet，2011，43（3）：246-252.

JOSTINS L，RIPKE S，WEERSMA R K，et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease[J]. Nature，2012，491（7422）：119-124.

BOLAND B S，SANDBORN W J，CHANG J T. Update on Janus kinase antagonists in inflammatory bowel disease[J]. Gastroenterol Clin North Am，2014，43（3）：603-617.

FERNÁNDEZ-CLOTET A，CASTRO-POCEIRO J，PANÉS J. Tofacitinib for the treatment of ulcerative colitis[J]. Expert Rev Clin Immunol，2018，14（11）：881-892.

SPALINGER M R，SAYOC-BECERRA A，ORDOOKHANIAN C，et al. The JAK inhibitor tofacitinib rescues intestinal barrier defects caused by disrupted epithelial-macrophage interactions[J]. J Crohns Colitis，2021，15（3）：471-484.

SAYOC-BECERRA A，KRISHNAN M，FAN S J，et al. The JAK-inhibitor tofacitinib rescues human intestinal epithelial cells and colonoids from cytokine-induced barrier dysfunction[J]. Inflamm Bowel Dis，2020，26（3）：407-422.

CORDES F，LENKER E，SPILLE L J，et al. Tofacitinib reprograms human monocytes of IBD patients and healthy controls toward a more regulatory phenotype[J]. Inflamm Bowel Dis，2020，26（3）：391-406.

DOWTY M E，LIN J Y，RYDER T F，et al. The pharmacokinetics，metabolism，and clearance mechanisms of tofacitinib，a Janus kinase inhibitor，in humans[J]. Drug Metab Dispos，2014，42（4）：759-773.

Pfizer. Pfizer announces U.S. FDA approves Xeljanz（tofacitinib）for the treatment of moderately to severely active ulcerative colitis[EB/OL].（2018-05-30）[2022-02-08].https：//www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_u_s_fda_approves_xeljanz_tofacitinib_for_the_treatment_of_moderately_to_severely_ active_ulcerative_colitis-0https://www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_u_s_fda_approves_xeljanz_tofacitinib_for_the_treatment_of_moderately_to_severely_active_ulcerative_colitis-0.

MUKHERJEE A，HAZRA A，SMITH M K，et al. Exposure-response characterization of tofacitinib efficacy in moderate to severe ulcerative colitis：results from a dose-ranging phase 2 trial[J]. Br J Clin Pharmacol，2018，84（6）：1136-1145.

SANDBORN W J，GHOSH S，PANES J，et al. Tofacitinib，an oral Janus kinase inhibitor，in active ulcerative colitis[J]. N Engl J Med，2012，367（7）：616-624.

SANDBORN W J，SU C，SANDS B E，et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis[J]. N Engl J Med，2017，376（18）：1723-1736.

VERMEIRE S，SU C，LAWENDY N，et al. Outcomes of tofacitinib dose reduction in patients with ulcerative colitis in stable remission from the randomised RIVETING trial[J]. J Crohns Colitis，2021，15（7）：1130-1141.

SANDS B E，ARMUZZI A，MARSHALL J K，et al. Efficacy and safety of tofacitinib dose de-escalation and dose escalation for patients with ulcerative colitis：results from OCTAVE open[J]. Aliment Pharmacol Ther，2020，51（2）：271-280.

PANÉS J，VERMEIRE S，DUBINSKY M C，et al. Efficacy and safety of tofacitinib re-treatment for ulcerative colitis after treatment interruption：results from the OCTAVE clinical trials[J]. J Crohns Colitis，2021，15（11）：1852-1863.

PANÉS J，VERMEIRE S，LINDSAY J O，et al. Tofacitinib in patients with ulcerative colitis：health-related qua-lity of life in phase 3 randomised controlled induction and maintenance studies[J]. J Crohns Colitis，2018，12（2）：145-156.

JAMESHORANI M，VAHEDI H，SADEGHI A，et al. Efficacy and safety of tofacitinib for treatment of moderate to severe active ulcerative colitis：first report from Iran[J]. Arch Iran Med，2021，24（5）：354-363.

LAIR-MEHIRI L，STEFANESCU C，VAYSSE T，et al. Real-world evidence of tofacitinib effectiveness and safety in patients with refractory ulcerative colitis[J]. Dig Liver Dis，2020，52（3）：268-273.

BIEMANS V B C，SLEUTJES J A M，DE VRIES A C，et al. Tofacitinib for ulcerative colitis：results of the prospective Dutch Initiative on Crohn and Colitis（ICC）registry[J]. Aliment Pharmacol Ther，2020，51（9）：880-888.

UZZAN M，BRESTEAU C，LAHARIE D，et al. Tofacitinib as salvage therapy for 55 patients hospitalised with refractory severe ulcerative colitis：a GETAID cohort[J]. Aliment Pharmacol Ther，2021，54（3）：312-319.

BERINSTEIN J A，SHEEHAN J L，DIAS M，et al. Tofacitinib for biologic-experienced hospitalized patients with acute severe ulcerative colitis：aretrospective case-control study[J]. Clin Gastroenterol Hepatol，2021，19（10）：2112-2120.e1.

SHAFFER S R，HUANG E，PATEL S，et al. Cost-effectiveness of 5-aminosalicylate therapy in combination with biologics or tofacitinib in the treatment of ulcerative colitis[J]. Am J Gastroenterol，2021，116（1）：125-133.

MAHADEVAN U，DUBINSKY M C，SU C，et al. Outcomes of pregnancies with maternal/paternal exposure in the tofacitinib safety databases for ulcerativecolitis[J]. Inflamm Bowel Dis，2018，24（12）：2494-2500.

ALAJMI R，ALABDULHADI M，ALALI A A，et al. Tofacitinib for a child with refractory steroid-dependent ulcerative colitis：acase report and review of the literature[J]. Am J Case Rep，2021，22：e934460.

MOORE H，DUBES L，FUSILLO S，et al. Tofacitinib therapy in children and young adults with pediatric-onset medically refractory inflammatory bowel disease[J]. J Pediatr Gastroenterol Nutr，2021，73（3）：e57-e62.

SANDBORN W J，PANÉS J，D'HAENS G R，et al. Safety of tofacitinib for treatment of ulcerative colitis，based on 4.4 years of data from global clinical trials[J]. Clin Gastroenterol Hepatol，2019，17（8）：1541-1550.

CLARK J D，FLANAGAN M E，TELLIEZ J B. Disco-very and development of Janus kinase（JAK）inhibitors for inflammatory diseases[J]. J Med Chem，2014，57（12）：5023-5038.

LAMB C A，KENNEDY N A，RAINE T，et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults[J]. Gut，2019，68（Suppl 3）：s1-s106.

DEEPAK P，ALAYO Q A，KHATIWADA A，et al. Safety of tofacitinib in a real-world cohort of patients with ulce-rative colitis[J]. Clin Gastroenterol Hepatol，2021，19（8）：1592-1601.e3.

WINTHROP K L，MELMED G Y，VERMEIRE S，et al. Herpes zoster infection in patients with ulcerative colitis receiving tofacitinib[J]. Inflamm Bowel Dis，2018，24（10）：2258-2265.

SANDBORN W J，PANÉS J，SANDS B E，et al. Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme[J]. Aliment Pharmacol Ther，2019，50（10）：1068-1076.

LIGHTNER A L，VAIDYA P，HOLUBAR S，et al. Peri- operative safety of tofacitinib in surgical ulcerative colitis patients[J]. Colorectal Dis，2021，23（8）：2085-2090.

PETRYSZYN P，EKK-CIERNIAKOWSKI P，ZURAKOWSKI G. Infliximab，adalimumab，golimumab，vedolizumab and tofacitinib in moderate to severe ulcerative colitis： comparative cost-effectiveness study in Poland[J]. Therap Adv Gastroenterol，2020，13：1-14.

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

阿司匹林联合氯吡格雷抗血小板治疗的研究进展

我国临床研究受试者知情同意现状及改善措施

基因治疗药物Alipogene tiparvovec的研究进展

肺动脉高压新型靶向治疗药物的临床研究进展

新型多靶点抗精神病药依匹哌唑的研究进展