Korean J Gastroenterol.  2024 Jun;83(6):233-242. 10.4166/kjg.2024.053.

Risks of Cancer Associated with Therapeutic Drugs for Inflammatory Bowel Disease

• Moon W
• Park JJ

• KMID: 2557110
• DOI: http://doi.org/10.4166/kjg.2024.053

Abstract

Crohn's disease and ulcerative colitis are lifelong chronic inflammatory conditions, with many patients requiring ongoing immunomodulatory drug therapy for maintenance treatment. Recent therapeutic goals in inflammatory bowel disease (IBD) are not only aimed at symptomatic remission but also at achieving mucosal healing to improve the natural course of the disease. In this context, therapeutic approaches are being applied in clinical settings that involve early and appropriate use of drugs, such as immunomodulators or biologics, that have the potential to induce healing of the inflamed intestine before irreversible intestinal damage occurs. All drugs that continuously control intestinal inflammation in IBD can heal the mucosa and potentially reduce the incidence of colitis-associated bowel cancer; however, the continuous use of immunosuppressants can potentially increase the risk of malignancies. The safety issues of the drugs used in clinical practice are partly confirmed during their development processes or shortly after initial marketing, but in other cases, they are estimated through post-marketing case reports or epidemiological studies, sometimes decades after drug approval. This review explores the risks associated with malignancies related to the treatment of IBD, focusing on drugs currently approved in Republic of Korea.

Keyword

Inflammatory bowel disease; Drugs; Cancer; Malignancy; Risk

Reference

1. Park JJ, Yang SK, Ye BD, et al. 2017; Second Korean guidelines for the management of Crohn's disease. Intest Res. 15:38–67. DOI: 10.5217/ir.2017.15.1.38. PMID: 28239314. PMCID: PMC5323307.

2. Choi CH, Moon W, Kim YS, et al. 2017; Second Korean guidelines for the management of ulcerative colitis. Intest Res. 15:7–37. DOI: 10.5217/ir.2017.15.1.7. PMID: 28239313. PMCID: PMC5323310.

3. Beaugerie L, Kirchgesner J. 2019; Balancing benefit vs risk of immunosuppressive therapy for individual patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 17:370–379. DOI: 10.1016/j.cgh.2018.07.013. PMID: 30031174.

4. Jensen AØ, Thomsen HF, Engebjerg MC, et al. 2009; Use of oral glucocorticoids and risk of skin cancer and non-Hodgkin's lymphoma: a population-based case-control study. Br J Cancer. 100:200–205. DOI: 10.1038/sj.bjc.6604796. PMID: 19034275. PMCID: PMC2634665.

5. Rutz HP. 2002; Effects of corticosteroid use on treatment of solid tumours. Lancet. 360:1969–1970. DOI: 10.1016/S0140-6736(02)11922-2. PMID: 12493280.

6. Khan N, Vallarino C, Lissoos T, Darr U, Luo M. 2017; Risk of malignancy in a nationwide cohort of elderly inflammatory bowel disease patients. Drugs Aging. 34:859–868. DOI: 10.1007/s40266-017-0498-y. PMID: 29170864. PMCID: PMC5705754.

7. Wetwittayakhlang P, Tselekouni P, Al-Jabri R, Bessissow T, Lakatos PL. 2023; The optimal management of inflammatory bowel disease in patients with cancer. J Clin Med. 12:2432. DOI: 10.3390/jcm12062432. PMID: 36983432. PMCID: PMC10056442.

8. Qiu X, Ma J, Wang K, Zhang H. 2017; Chemopreventive effects of 5-aminosalicylic acid on inflammatory bowel disease-associated colorectal cancer and dysplasia: a systematic review with meta-analysis. Oncotarget. 8:1031–1045. DOI: 10.18632/oncotarget.13715. PMID: 27906680. PMCID: PMC5352032.

9. Axelrad JE, Lichtiger S, Yajnik V. 2016; Inflammatory bowel disease and cancer: The role of inflammation, immunosuppression, and cancer treatment. World J Gastroenterol. 22:4794–4801. DOI: 10.3748/wjg.v22.i20.4794. PMID: 27239106. PMCID: PMC4873872.

10. Karran P. Thiopurines, DNA damage, DNA repair and therapy-related cancer. Br Med Bull. 2006; 79-80:153–170. DOI: 10.1093/bmb/ldl020. PMID: 17277075.

11. Fraser AG, Orchard TR, Robinson EM, Jewell DP. 2002; Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine. Aliment Pharmacol Ther. 16:1225–1232. DOI: 10.1046/j.1365-2036.2002.01297.x. PMID: 12144571.

12. Gómez-García M, Cabello-Tapia MJ, Sánchez-Capilla AD, De Teresa-Galván J, Redondo-Cerezo E. 2013; Thiopurines related malignancies in inflammatory bowel disease: local experience in Granada, Spain. World J Gastroenterol. 19:4877–4886. DOI: 10.3748/wjg.v19.i30.4877. PMID: 23946592. PMCID: PMC3740417.

13. Connell WR, Kamm MA, Dickson M, Balkwill AM, Ritchie JK, Lennard-Jones JE. 1994; Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet. 343:1249–1252. DOI: 10.1016/S0140-6736(94)92150-4. PMID: 7910274.

14. Korelitz BI, Mirsky FJ, Fleisher MR, Warman JI, Wisch N, Gleim GW. 1999; Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine. Am J Gastroenterol. 94:3248–3253. DOI: 10.1111/j.1572-0241.1999.01530.x. PMID: 10566724.

15. Pasternak B, Svanström H, Schmiegelow K, Jess T, Hviid A. 2013; Use of azathioprine and the risk of cancer in inflammatory bowel disease. Am J Epidemiol. 177:1296–1305. DOI: 10.1093/aje/kws375. PMID: 23514635.

16. Beaugerie L, Carrat F, Colombel JF, et al. 2014; Risk of new or recurrent cancer under immunosuppressive therapy in patients with IBD and previous cancer. Gut. 63:1416–1423. DOI: 10.1136/gutjnl-2013-305763. PMID: 24162591.

17. Ariyaratnam J, Subramanian V. 2014; Association between thiopurine use and nonmelanoma skin cancers in patients with inflammatory bowel disease: a meta-analysis. Am J Gastroenterol. 109:163–169. DOI: 10.1038/ajg.2013.451. PMID: 24419479.

18. Beaugerie L, Brousse N, Bouvier AM, et al. 2009; Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet. 374:1617–1625. DOI: 10.1016/S0140-6736(09)61302-7. PMID: 19837455.

19. Kotlyar DS, Lewis JD, Beaugerie L, et al. 2015; Risk of lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6-mercaptopurine: a meta-analysis. Clin Gastroenterol Hepatol. 13:847–858.e4. quiz e48–50. DOI: 10.1016/j.cgh.2014.05.015. PMID: 24879926.

20. Kopylov U, Vutcovici M, Kezouh A, Seidman E, Bitton A, Afif W. 2015; Risk of lymphoma, colorectal and skin cancer in patients with IBD treated with immunomodulators and biologics: A Quebec Claims Database Study. Inflamm Bowel Dis. 21:1847–1853. DOI: 10.1097/MIB.0000000000000457. PMID: 25993693.

21. Singh H, Nugent Z, Demers AA, Bernstein CN. 2011; Increased risk of nonmelanoma skin cancers among individuals with inflammatory bowel disease. Gastroenterology. 141:1612–1620. DOI: 10.1053/j.gastro.2011.07.039. PMID: 21806945.

22. Mason M, Siegel CA. 2013; Do inflammatory bowel disease therapies cause cancer? Inflamm Bowel Dis. 19:1306–1321. DOI: 10.1097/MIB.0b013e3182807618. PMID: 23470503.

23. Swoger JM, Regueiro M. 2014; Stopping, continuing, or restarting immunomodulators and biologics when an infection or malignancy develops. Inflamm Bowel Dis. 20:926–935. DOI: 10.1097/MIB.0000000000000002. PMID: 24651584.

24. Magro F, Peyrin-Biroulet L, Sokol H, et al. 2014; Extra-intestinal malignancies in inflammatory bowel disease: results of the 3rd ECCO Pathogenesis Scientific Workshop (III). J Crohns Colitis. 8:31–44. DOI: 10.1016/j.crohns.2013.04.006. PMID: 23721759.

25. Gordon J, Ramaswami A, Beuttler M, et al. 2016; EBV Status and thiopurine use in pediatric IBD. J Pediatr Gastroenterol Nutr. 62:711–714. DOI: 10.1097/MPG.0000000000001077. PMID: 26655944.

26. Bachmann J, Le Thi G, Brückner A, et al. 2021; Epstein-barr virus prevalence at diagnosis and seroconversion during follow-up in pediatric inflammatory bowel disease. J Clin Med. 10:5187. DOI: 10.3390/jcm10215187. PMID: 34768707. PMCID: PMC8584287.

27. Barnes EL, Herfarth HH. 2017; The usefulness of serologic testing for epstein-barr virus before initiation of therapy for inflammatory bowel disease. Gastroenterology. 153:1167. DOI: 10.1053/j.gastro.2017.04.055. PMID: 28881185.

28. Park SK, Ye BD, Lee C, et al. 2015; Risk and clinical characteristics of lymphoma in Korean patients with inflammatory bowel diseases: a multicenter study. J Clin Gastroenterol. 49:e11–16. DOI: 10.1097/MCG.0000000000000129. PMID: 24705089.

29. Kobayashi T, Uda A, Udagawa E, Hibi T. 2020; Lack of increased risk of lymphoma by thiopurines or biologics in japanese patients with inflammatory bowel disease: A large-scale administrative database analysis. J Crohns Colitis. 14:617–623. DOI: 10.1093/ecco-jcc/jjz204. PMID: 31867632. PMCID: PMC7303594.

30. Kobayashi T, Udagawa E, Hibi T. 2022; Lack of increased risk of lymphoma with thiopurine therapy regardless of dose and duration of treatment in japanese patients with inflammatory bowel diseases. Digestion. 103:169–173. DOI: 10.1159/000519560. PMID: 34983046. PMCID: PMC8985002.

31. Gomollón F, Dignass A, Annese V, et al. 3rd European evidence-based consensus on the diagnosis and management of crohn's disease 2016: Part 1: Diagnosis and medical management. J Crohns Colitis. 2017; 11:3–25. DOI: 10.1093/ecco-jcc/jjw168. PMID: 27660341.

32. O'Donovan P, Perrett CM, Zhang X, et al. 2005; Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science. 309:1871–1874. DOI: 10.1126/science.1114233. PMID: 16166520. PMCID: PMC2426755.

33. Long MD, Herfarth HH, Pipkin CA, Porter CQ, Sandler RS, Kappelman MD. 2010; Increased risk for non-melanoma skin cancer in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 8:268–274. DOI: 10.1016/j.cgh.2009.11.024. PMID: 20005977. PMCID: PMC2838486.

34. Long MD, Martin CF, Pipkin CA, Herfarth HH, Sandler RS, Kappelman MD. 2012; Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. Gastroenterology. 143:390–399.e1. DOI: 10.1053/j.gastro.2012.05.004. PMID: 22584081. PMCID: PMC4065572.

35. Peyrin-Biroulet L, Khosrotehrani K, Carrat F, et al. 2011; Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology. 141:1621–1628.e1-5. DOI: 10.1053/j.gastro.2011.06.050. PMID: 21708105.

36. Peyrin-Biroulet L, Chevaux JB, Bouvier AM, Carrat F, Beaugerie L. 2012; Risk of melanoma in patients who receive thiopurines for inflammatory bowel disease is not increased. Am J Gastroenterol. 107:1443–1444. DOI: 10.1038/ajg.2012.181. PMID: 22951883.

37. Ranjan MK, Kante B, Vuyyuru SK, et al. 2022; Minimal risk of lymphoma and non-melanoma skin cancer despite long-term use of thiopurines in patients with inflammatory bowel disease: A longitudinal cohort analysis from northern India. J Gastroenterol Hepatol. 37:1544–1553. DOI: 10.1111/jgh.15880. PMID: 35501287.

38. Solitano V, D'Amico F, Correale C, Peyrin-Biroulet L, Danese S. 2020; Thiopurines and non-melanoma skin cancer: partners in crime in inflammatory bowel diseases. Br Med Bull. 136:107–117. DOI: 10.1093/bmb/ldaa033. PMID: 33200781.

39. Bourrier A, Carrat F, Colombel JF, et al. 2016; Excess risk of urinary tract cancers in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Aliment Pharmacol Ther. 43:252–261. DOI: 10.1111/apt.13466. PMID: 26549003.

40. Hazenberg HMJL, de Boer NKH, Mulder CJJ, Mom SH, van Bodegraven AA, Tack Md PhD GJ. 2018; Neoplasia and precursor lesions of the female genital tract in IBD: Epidemiology, role of immunosuppressants, and clinical implications. Inflamm Bowel Dis. 24:510–531. DOI: 10.1093/ibd/izx062. PMID: 29462389.

41. Dugué PA, Rebolj M, Hallas J, Garred P, Lynge E. 2015; Risk of cervical cancer in women with autoimmune diseases, in relation with their use of immunosuppressants and screening: population-based cohort study. Int J Cancer. 136:E711–719. DOI: 10.1002/ijc.29209.

42. Allegretti JR, Barnes EL, Cameron A. 2015; Are patients with inflammatory bowel disease on chronic immunosuppressive therapy at increased risk of cervical high-grade dysplasia/cancer? A meta-analysis. Inflamm Bowel Dis. 21:1089–1097. DOI: 10.1097/MIB.0000000000000338. PMID: 25895005. PMCID: PMC4458370.

43. Lu MJ, Qiu XY, Mao XQ, Li XT, Zhang HJ. 2018; Systematic review with meta-analysis: thiopurines decrease the risk of colorectal neoplasia in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 47:318–331. DOI: 10.1111/apt.14436. PMID: 29205426.

44. Wolfe F, Michaud K. 2004; Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum. 50:1740–1751. DOI: 10.1002/art.20311. PMID: 15188349.

45. Mariette X, Cazals-Hatem D, Warszawki J, et al. 2002; Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. Blood. 99:3909–3915. DOI: 10.1182/blood.V99.11.3909. PMID: 12010788.

46. Salliot C, van der Heijde D. 2009; Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis. 68:1100–1104. DOI: 10.1136/ard.2008.093690. PMID: 19060002. PMCID: PMC2689525.

47. Buchbinder R, Barber M, Heuzenroeder L, et al. 2008; Incidence of melanoma and other malignancies among rheumatoid arthritis patients treated with methotrexate. Arthritis Rheum. 59:794–799. DOI: 10.1002/art.23716. PMID: 18512713.

48. Mercer LK, Regierer AC, Mariette X, et al. 2017; Spectrum of lymphomas across different drug treatment groups in rheumatoid arthritis: a European registries collaborative project. Ann Rheum Dis. 76:2025–2030. DOI: 10.1136/annrheumdis-2017-211623. PMID: 28822981. PMCID: PMC5705847.

49. Peyrin-Biroulet L, Deltenre P, de Suray N, Branche J, Sandborn WJ, Colombel JF. 2008; Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: meta-analysis of placebo-controlled trials. Clin Gastroenterol Hepatol. 6:644–653. DOI: 10.1016/j.cgh.2008.03.014. PMID: 18550004.

50. Williams CJ, Peyrin-Biroulet L, Ford AC. 2014; Systematic review with meta-analysis: malignancies with anti-tumour necrosis factor-α therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 39:447–458. DOI: 10.1111/apt.12624. PMID: 24444171.

51. Lichtenstein GR, Rutgeerts P, Sandborn WJ, et al. 2012; A pooled analysis of infections, malignancy, and mortality in infliximab- and immunomodulator-treated adult patients with inflammatory bowel disease. Am J Gastroenterol. 107:1051–1063. DOI: 10.1038/ajg.2012.89. PMID: 22613901. PMCID: PMC3390465.

52. Lichtenstein GR, Feagan BG, Cohen RD, et al. 2018; Infliximab for Crohn's disease: More than 13 years of real-world experience. Inflamm Bowel Dis. 24:490–501. DOI: 10.1093/ibd/izx072. PMID: 29462395. PMCID: PMC6176880.

53. Beukelman T, Xie F, Chen L, et al. 2018; Risk of malignancy associated with paediatric use of tumour necrosis factor inhibitors. Ann Rheum Dis. 77:1012–1016. DOI: 10.1136/annrheumdis-2017-212613. PMID: 29440001. PMCID: PMC6094159.

54. Siegel CA, Marden SM, Persing SM, Larson RJ, Sands BE. 2009; Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn's disease: a meta-analysis. Clin Gastroenterol Hepatol. 7:874–881. DOI: 10.1016/j.cgh.2009.01.004. PMID: 19558997. PMCID: PMC2846413.

55. Herrinton LJ, Liu L, Weng X, Lewis JD, Hutfless S, Allison JE. 2011; Role of thiopurine and anti-TNF therapy in lymphoma in inflammatory bowel disease. Am J Gastroenterol. 106:2146–2153. DOI: 10.1038/ajg.2011.283. PMID: 22031357.

56. D’Haens G, Reinisch W, Panaccione R, et al. 2018; Lymphoma risk and overall safety profile of adalimumab in patients with Crohn's disease with up to 6 years of follow-up in the pyramid registry. Am J Gastroenterol. 113:872–882. DOI: 10.1038/s41395-018-0098-4. PMID: 29867173.

57. Lemaitre M, Kirchgesner J, Rudnichi A, et al. 2017; Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease. JAMA. 318:1679–1686. DOI: 10.1001/jama.2017.16071. PMID: 29114832. PMCID: PMC5818785.

58. Deepak P, Sifuentes H, Sherid M, Stobaugh D, Sadozai Y, Ehrenpreis ED. 2013; T-cell non-Hodgkin's lymphomas reported to the FDA AERS with tumor necrosis factor-alpha (TNF-α) inhibitors: results of the REFURBISH study. Am J Gastroenterol. 108:99–105. DOI: 10.1038/ajg.2012.334. PMID: 23032984.

59. Narous M, Nugent Z, Singh H, Bernstein CN. 2023; Risks of melanoma and nonmelanoma skin cancers pre- and post-inflammatory bowel disease diagnosis. Inflamm Bowel Dis. 29:1047–1056. DOI: 10.1093/ibd/izac171. PMID: 35929649.

60. McAuliffe ME, Lanes S, Leach T, et al. 2015; Occurrence of adverse events among patients with inflammatory bowel disease in the HealthCore Integrated Research Database. Curr Med Res Opin. 31:1655–1664. DOI: 10.1185/03007995.2015.1065242. PMID: 26135040.

61. Nyboe Andersen N, Pasternak B, Basit S, et al. 2014; Association between tumor necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease. JAMA. 311:2406–2413. DOI: 10.1001/jama.2014.5613. PMID: 24938563.

62. Hutfless S, Fireman B, Kane S, Herrinton LJ. 2008; Screening differences and risk of cervical cancer in inflammatory bowel disease. Aliment Pharmacol Ther. 28:598–605. DOI: 10.1111/j.1365-2036.2008.03766.x. PMID: 18549465.

63. Marabotto E, Kayali S, Buccilli S, et al. 2022; Colorectal cancer in inflammatory bowel diseases: Epidemiology and prevention: A review. Cancers (Basel). 14:4254. DOI: 10.3390/cancers14174254. PMID: 36077786. PMCID: PMC9454776.

64. Hsiao SW, Yen HH, Chen YY. 2022; Chemoprevention of colitis-associated dysplasia or cancer in inflammatory bowel disease. Gut Liver. 16:840–848. DOI: 10.5009/gnl210479. PMID: 35670121. PMCID: PMC9668496.

65. Park JJ. 2020; Mechanism-based drug therapy of inflammatory bowel disease with special reference to rheumatic disease. J Rheum Dis. 27:128–135. DOI: 10.4078/jrd.2020.27.3.128.

66. Luthra P, Peyrin-Biroulet L, Ford AC. 2015; Systematic review and meta-analysis: opportunistic infections and malignancies during treatment with anti-integrin antibodies in inflammatory bowel disease. Aliment Pharmacol Ther. 41:1227–1236. DOI: 10.1111/apt.13215. PMID: 25903741.

67. Yajnik V, Khan N, Dubinsky M, et al. 2017; Efficacy and safety of vedolizumab in ulcerative colitis and Crohn's disease patients stratified by age. Adv Ther. 34:542–559. DOI: 10.1007/s12325-016-0467-6. PMID: 28070861. PMCID: PMC5331094.

68. Bye WA, Jairath V, Travis SPL. 2017; Systematic review: the safety of vedolizumab for the treatment of inflammatory bowel disease. Aliment Pharmacol Ther. 46:3–15. DOI: 10.1111/apt.14075. PMID: 28449273.

69. Colombel JF, Sands BE, Rutgeerts P, et al. 2017; The safety of vedolizumab for ulcerative colitis and Crohn's disease. Gut. 66:839–851. DOI: 10.1136/gutjnl-2015-311079. PMID: 26893500. PMCID: PMC5531223.

70. Papp KA, Griffiths CE, Gordon K, et al. 2013; Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up. Br J Dermatol. 168:844–854. DOI: 10.1111/bjd.12214. PMID: 23301632.

71. Fiorentino D, Ho V, Lebwohl MG, et al. 2017; Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry. J Am Acad Dermatol. 77:845–854.e5. DOI: 10.1016/j.jaad.2017.07.013. PMID: 28893407.

72. Gordon KB, Papp KA, Langley RG, et al. 2012; Long-term safety experience of ustekinumab in patients with moderate to severe psoriasis (Part II of II): results from analyses of infections and malignancy from pooled phase II and III clinical trials. J Am Acad Dermatol. 66:742–751. DOI: 10.1016/j.jaad.2011.06.041. PMID: 21978572.

73. Feagan BG, Sandborn WJ, Gasink C, et al. 2016; Ustekinumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 375:1946–1960. DOI: 10.1056/NEJMoa1602773. PMID: 27959607.

74. Wils P, Bouhnik Y, Michetti P, et al. 2018; Long-term efficacy and safety of ustekinumab in 122 refractory Crohn's disease patients: a multicentre experience. Aliment Pharmacol Ther. 47:588–595. DOI: 10.1111/apt.14487. PMID: 29315694.

75. Sands BE, Sandborn WJ, Panaccione R, et al. 2019; Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 381:1201–1214. DOI: 10.1056/NEJMoa1900750. PMID: 31553833.

76. Afif W, Arasaradnam RP, Abreu MT, et al. 2024; Efficacy and safety of ustekinumab for ulcerative colitis through 4 years: Final results of the UNIFI long-term maintenance study. Am J Gastroenterol. 119:910–921. DOI: 10.14309/ajg.0000000000002621. PMID: 38095692. PMCID: PMC11062601.

77. Lichtenstein GR, Rogler G, Ciorba MA, Su C, et al. 2021; Tofacitinib, an oral janus kinase inhibitor: Analysis of malignancy (excluding nonmelanoma skin cancer) events across the ulcerative colitis clinical program. Inflamm Bowel Dis. 27:816–825. DOI: 10.1093/ibd/izaa199. PMID: 32766762. PMCID: PMC8128409.

78. Panés J, D'Haens GR, Sands BE, et al. Analysis of tofacitinib safety in ulcerative colitis from the completed global clinical developmental program up to 9.2 years of drug exposure. United European Gastroenterol J. 2024; May. 22. doi: 10.1002/ueg2.12584. DOI: 10.1002/ueg2.12584. PMID: 38778549.

79. Ytterberg SR, Bhatt DL, Mikuls TR, et al. 2022; Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 386:316–326. DOI: 10.1056/NEJMoa2109927. PMID: 35081280.

80. FDA Drug Safety Podcast. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. 2022 Jan 14.

81. Danese S, Vermeire S, Zhou W, et al. 2022; Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet. 399:2113–2128. DOI: 10.1016/S0140-6736(22)00581-5. PMID: 35644166.

82. Loftus EV Jr, Panés J, Lacerda AP, et al. 2023; Upadacitinib induction and maintenance therapy for Crohn's disease. N Engl J Med. 388:1966–1980. DOI: 10.1056/NEJMoa2212728. PMID: 37224198.

83. Panaccione R, Lichtenstein G, Nakase H. 2023; P518 safety of upadacitinib in ulcerative colitis: long-term data from the phase 3 open-label extension study (U-ACTIVATE). J Crohns Colitis. 17:i644–646. DOI: 10.1093/ecco-jcc/jjac190.0648.

84. Feagan BG, Danese S, Loftus EV Jr, et al. 2021; Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. Lancet. 397:2372–2384. DOI: 10.1016/S0140-6736(21)00666-8. PMID: 34090625.

85. Efficacy and safety outcomes up to ~4 years of treatment with filgotinib 200 mg among patients with ulcerative colitis: Results from the SELECTIONLTE study. Gastroenterol Hepatol (N Y). 2023; 19(4 Suppl 1):10–11.

86. Becher N, Swaminath A, Sultan K. 2022; A literature review of ozanimod therapy in inflammatory bowel disease: From concept to practical application. Ther Clin Risk Manag. 18:913–927. DOI: 10.2147/TCRM.S336139. PMID: 36106049. PMCID: PMC9467694.

87. Sandborn WJ, Feagan BG, D'Haens G, et al. 2021; Ozanimod as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 385:1280–1291. DOI: 10.1056/NEJMoa2033617. PMID: 34587385.

88. Sandborn WJ, Feagan BG, Hanauer S, et al. 2021; Long-term efficacy and safety of ozanimod in moderately to severely active ulcerative colitis: Results From the open-label extension of the randomized, phase 2 TOUCHSTONE Study. J Crohns Colitis. 15:1120–1129. DOI: 10.1093/ecco-jcc/jjab012. PMID: 33438008. PMCID: PMC8256627.