Crohn’s disease (CD) is a chronic, non-specific intestinal inflammatory disease. A large number of clinical trials have shown that biological agents are effective in inducing remission in patients with CD, and mainte-nance treatment can achieve long-term remission. At present, biological agents are now being widely used in the treatment of CD and have become the main treatment. These include the anti-tumor necrosis factor (TNF)-α monoclo-nal antibodies, anti-integrin antibody, IL-12/23 monoclonal antibody and a Janus kinase (JAK) inhibitor. In this article, we review the progress and selection of biologics in the treatment of CD.

1.吴大鹏, 郑萍. 英夫利西治疗克罗恩病11例疗效观察[J]. 国际消化病杂志, 2010, 30(5): 314-315, 318. DOI: 10.3969/j.issn.1673-534X.2010.05.019. [Wu DP, Zheng P. Efficacy infliximab of treatment in 11 patients with Crohn's disease[J]. International Journal of Digestive Diseases, 2010, 30(5): 314-315, 318.]

2.Vande Casteele N, Ferrante M, Van Assche G, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease[J]. Gastroenterology, 2015, 148(7): 1320-1329.e3. DOI: 10.1053/j.gastro.2015.02.031.

3.Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial[J]. Gastroenterology, 2006, 130(2): 323-333. DOI: 10.1053/j. gastro.2005.11.030.

4.Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial[J]. Ann Intern Med, 2007, 146(12): 829-838. DOI: 10.7326/0003-4819-146-12-200706190-00159.

5.Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn's dis-ease: results of the CLASSIC II trial[J]. Gut, 2007, 56(9): 1232-1239. DOI: 10.1136/gut.2006.106781.

6.Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial[J]. Gastroenterology, 2007, 132(1): 52-65. DOI: 10.1053/j.gastro.2006.11.041.

7.Nesbitt A, Fossati G, Bergin M, et al. Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents[J]. Inflamm Bowel Dis, 2007, 13(11): 1323-1332. DOI: 10.1002/ibd. 20225.

8.Schreiber S, Rutgeerts P, Fedorak RN, et al. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease[J]. Gastroenterology, 2005, 129(3): 807-818. DOI: 10.1053/j.gastro.2005.06.064.

9.Hébuterne X, Lémann M, Bouhnik Y, et al. Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn's disease following treatment with certolizumab pegol[J]. Gut, 2013, 62(2): 201-208. DOI: 10.1136/gutjnl-2012-302262.

10.中华医学会消化病学分会炎症性肠病学组. 抗肿瘤坏死因子α单克隆抗体治疗炎症性肠病专家共识(2017)[J]. 协和医学杂志, 2017, 8(4): 239-243. DOI: 10.3969/j.issn.1674-9081.2017.05.009. [Chinese Society of Gastroen-terology, IBD Working Group. Expert consensus on anti-tumor necrosis factor alpha monoclonal an-tibody in the treatment of inflammatory bowel disease (2017)[J]. Medical Journal of Peking Union Medical College Hospital, 2017, 8(4): 239-243.]

11.林果为，王吉耀，葛均波. 实用内科学（第15版）[M]. 北京: 人民卫生出版社, 2017. [Lin GW, Wang JY, Ge JB. Practical Internal Medicine (15th edition)[M]. Beijing: People's Medical Publishing House, 2017.]

12.Lu ZY, Chen WC, Li YH, et al. TNF-α enhances vascular cell adhesion molecule-1 expression in human bone marrow mesenchymal stem cells via the NF-κB, ERK and JNK signaling pathways[J]. Mol Med Rep, 2016, 14(1): 643-648. DOI: 10.3892/mmr.2016.5314.

13.Zundler S, Becker E, Weidinger C, et al. Anti-adhesion therapies in inflammatory bowel dis-ease-molecular and clinical aspects[J]. Front Immunol, 2017, 8: 891. DOI: 10.3389/fimmu.2017.00891.

14.Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of active Crohn's disease: results of the ENCORE trial[J]. Gastroenterology, 2007, 132(5): 1672-1683. DOI: 10.1053/j.gastro.2007.03.024.

15.Ford AC, Sandborn WJ, Khan KJ, et al. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis[J]. Am J Gastroenterol, 2011, 106(4): 644-659. DOI: 10.1038/ajg.2011.73.

16.Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease[J]. N Engl J Med, 2013, 369(8): 711-721. DOI: 10.1056/NEJMoa1215739.

17.Singh S, Garg SK, Pardi DS, et al. Comparative efficacy of biologic therapy in biologic-naïve patients with Crohn disease: a systematic review and network meta-analysis[J]. Mayo Clin Proc, 2014, 89(12): 1621-1635. DOI: 10.1016/j.mayocp.2014.08.019.

18.Barré A, Colombel JF, Ungaro R. Review article: predictors of response to vedolizumab and usteki-numab in inflammatory bowel disease[J]. Aliment Pharmacol Ther, 2018, 47(7): 896-905. DOI: 10.1111/apt.14550.

19.Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natali-zumab therapy for Crohn's disease[J]. N Engl J Med, 2005, 353(4): 362-368. DOI: 10.1056/NEJMoa051586.

20.Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis[J]. N Engl J Med, 2005, 353(4): 369-374. DOI: 10.1056/NEJMoa051782.

21.Langer-Gould A, Atlas SW, Green AJ, et al. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab[J]. N Engl J Med, 2005, 353(4): 375-381. DOI: 10.1056/NEJMoa051847.

22.Colombel JF, Sands BE, Rutgeerts P, et al. The safety of vedolizumab for ulcerative colitis and Crohn's disease[J]. Gut, 2017, 66(5): 839-851. DOI: 10.1136/gutjnl-2015- 311079.

23.Soler D, Chapman T, Yang LL, et al. The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases[J]. J Pharmacol Exp Ther, 2009, 330(3): 864-875. DOI: 10.1124/jpet.109.153973.

24.Moschen AR, Tilg H, Raine T. IL-12，IL-23 and IL-17 in IBD: immunobiology and therapeutic targeting[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(3): 185-196. DOI: 10.1038 /s41575-018-0084-8.

25.Greving CA, Towne J. A role for IL-12 in IBD after all?[J]. Immunity, 2019, 51(2): 209-211. DOI: 10.1016/j.immuni.2019.07.008.

26.Sun H, Sun C, Xiao W, et al. Tissue-resident lymphocytes: from adaptive to innate immunity[J]. Cell Mol Immunol, 2019, 16(3): 205-215. DOI: 10.1038/s41423-018-0192-y.

27.Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn's disease[J]. N Engl J Med, 2016, 375(20): 1946-1960. DOI: 10.1056/NEJMoa1602773.

28.Hanauer SB, Sandborn WJ, Feagan BG, et al. IM-UNITI: three-year efficacy, safety, and immunogenicity of ustekinumab treatment of Crohn's disease[J]. J Crohns Colitis, 2020, 14(1): 23-32. DOI: 10.1093/ecco-jcc/jjz110.

29.姚嘉茵, 宋孝美, 余乔, 等. 乌司奴单克隆抗体治疗难治性克罗恩病的短期疗效分析：一项多中心回顾性观察性研究[J].中华炎性肠病杂志, 2021, 5(2): 151-155. DOI: 10.3760/cma.j.cn101480-20210326-00025. [Yao JY, Song XM, Yu Q, et al. Analysis of the short-term efficacy of ustekinumab for intractable Crohn's disease: a multicenter retrospective observational study[J]. Chinese Journal of Inflammatory Bowel Diseases, 2021, 5(2): 151-155.]

30.Sandborn WJ, Rutgeerts P, Gasink C, et al. Long-term efficacy and safety of ustekinumab for Crohn's disease through the second year of therapy[J]. Aliment Pharmacol Ther, 2018, 48(1): 65-77. DOI: 10.1111/apt.14794.

31.Apostolos K, Kotlyar A, Laurence A, et al. Jakinibs: a new class of kinase inhibitors in cancer and au-toimmune disease[J]. Curr Opin Pharmacol, 2012, 12(4): 464-470.DOI: 10.1016/j.coph.2012.06.008.

32.Sandborn WJ, Ghosh S, Panes J, et al. A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn's disease[J]. Clin Gastroenterol Hepatol, 2014, 12(9): 1485-1493.e2. DOI: 10.1016/j.cgh.2014.01.029.

33.Chudy-Onwugaje KO, Christian KE, Farraye FA, et al. A state-of-the-art review of new and emerging therapies for the treatment of IBD[J]. Inflamm Bowel Dis, 2019, 25(5): 820-830. DOI: 10.1093/ibd/izy327.

34.Panés J, Sandborn WJ, Schreiber S, et al. Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials[J]. Gut, 2017, 66(6): 1049-1059. DOI: 10.1136/ gutjnl-2016-312735.

35.Feuerstein JD, Ho EY, Shmidt E, et al. AGA clinical practice guidelines on the medical management of moderate to severe luminal and perianal fistulizing Crohn's disease[J]. Gastroenterology, 2021, 160(7): 2496-2508.DOI: 10.1053/j.gastro.2021.04.022.

36.Cholapranee A, Hazlewood GS, Kaplan GG, et al. Systematic review with meta-analysis: comparative efficacy of biologics for induction and maintenance of mucosal healing in Crohn's disease and ulcera-tive colitis controlled trials[J]. Aliment Pharmacol Ther, 2017, 45(10): 1291-1302. DOI: 10.1111/apt.14030.

37.Lichtenstein GR, Yan S, Bala M, et al. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn's disease[J]. Gastroenterology, 2005, 128(4): 862-869. DOI: 10.1053/j. gas-tro.2005.01.048.

38.Colombel JF, Schwartz DA, Sandborn WJ, et al. Adalimumab for the treatment of fistulas in patients with Crohn's disease[J]. Gut, 2009, 58(7): 940-948. DOI: 10.1136/gut.2008.159251.

39.Yanai H, Lichtenstein L, Assa A, et al. Levels of drug and antidrug antibodies are associated with out-come of interventions after loss of response to infliximab or adalimumab[J]. Clin Gastroenterol Hepa-tol, 2015, 13(3): 522-530. DOI: 10.1016/j.cgh.2014.07.029. 

40.Alric H, Amiot A, Kirchgesner J, et al. The effectiveness of either ustekinumab or vedolizumab in 239 patients with Crohn's disease refractory to anti-tumour necrosis factor[J]. Aliment Pharmacol Ther, 2020, 51(10): 948-957. DOI: 10.1111/apt.15706.

41.杨红, 金梦, 钱家鸣. 选择不同生物制剂治疗炎症性肠病：如何平衡风险和获益[J]. 中华炎性肠病杂, 2020, 4(1): 25-29. DOI: 10.3760/cma.j.issn.2096-367X.2020.01.007. [Yang H, Jin M, Qian JM. Choice of different bi-ological agents in inflammatory bowel disease: how to balance risks and benefits[J]. Chinese Journal of Inflammatory Bowel Diseases, 2020, 4(1): 25-29.]

42.Puchner A, Gröchenig HP, Sautner J, et al. Immunosuppressives and biologics during pregnancy and lactation: a consensus report issued by the Austrian Societies of Gastroenterology and Hepatology and Rheumatology and Rehabilitation[J]. Wien Klin Wochenschr, 2019, 131: 29-44. DOI: 10.1007/s00508-019-1448-y. 

43.Aliyev ER, Hay JW, Hwang C. Cost-effectiveness comparison of ustekinumab, infliximab, or adalimumab for the treatment of moderate-severe Crohn's disease in biologic-naïve patients[J]. Pharmacotherapy, 2019, 39(2): 118-128. DOI: 10.1002/phar.2208. 

44.Holko P, Kawalec P, Pilc A. Cost-effectiveness analysis of Crohn's disease treatment with vedolizumab and ustekinumab after failure of tumor necrosis factor-α antagonist[J]. Pharmacoeconomics, 2018, 36(7): 853-865. DOI: 10.1007/s40273-018-0653-2.

45.Reinglas J, Gonczi L, Kurt Z, et al. Positioning of old and new biologicals and small molecules in the treatment of inflammatory bowel diseases[J]. World J Gastroenterol, 2018, 24(32): 3567-3582. DOI: 10.3748/wjg.v24.i32.3567.