Impact of treatment with immunomodulators and tumour necrosis factor antagonists on the incidence of infectious events in patients with inflammatory bowel disease

  • Per Andersson Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
  • Pontus Karling Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
Keywords: Anti-TNF, Bowel disease, Crohn’s disease, gender differences, immunomodulators, infectious events, inflammatory ulcerative colitis


Background: Corticosteroids, immunomodulators (IM) and tumour necrosis factor antagonists (anti-TNF) are commonly used in the treatment of inflammatory bowel disease (IBD) but they also supress the defence against infectious disease. The aim of this study was to analyse the incidence of infectious events in patients with IBD and the association to concomitant medical therapy.

Methods: We performed a retrospective medical chart review of patients with IBD aged 18–65 years included in the Swedish Registry of Inflammatory Bowel Disease in the catchment area of Umeå University Hospital, Sweden. Data were collected from the period 01 January 2006, to 31 January 2019. An infectious event was defined as an outpatient prescription of antimicrobials or a positive diagnostic test for infection.

Results: During a period of 5,120 observation-years, we observed 1,394 events in 593 patients. The mean number of infectious events per 100 person-years was 27.2 (standard deviation [SD]: 0.46). There were no differences in mean incidence rates between patients treated with no immunosuppression (23.0 events per 100 person-years, SD: 50.4), patients treated with IM monotherapy (27.6 events per 100 person-years, SD: 49.9), patients treated with anti-TNF monotherapy (34.3 events per 100 person-years, SD: 50.1) and patients on combination therapy (22.5 events per 100-person-years, SD: 44.2). In a multivariate logistic regression, female gender (adjusted odds ratio [AOR]: 2.24; 95% confidence interval [CI]: 1.49–3.37) and combination therapy (AOR: 3.46; 95% CI: 1.52–7.85) were associated with higher risks of infection (>32 events per 100 person years). Also, patients treated with any immunosuppression treatment for 25–75% (AOR: 2.29; 95% CI: 1.21–4.34) and for >75% (AOR: 1.93; 95% CI: 1.19–3.12) of the observation period were at higher risks compared to patients treated with immunosuppression <25% of the observation period.

Conclusion: We observed no significant difference in risk for infections between patients on monotherapy with IM or anti-TNF and patients with low use of immunosuppression, but there was a significant risk for combination therapy.


Download data is not yet available.


  1. Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012;380:1590–605. doi: 10.1016/S0140-6736(12)60026-9

  2. Ford AC, Moayyedi P, Hanauer SB. Ulcerative colitis. BMJ. 2013;346:f432. doi: 10.1136/bmj.f432

  3. Harbord M, Eliakim R, Bettenworth D, Karmiris K, Katsanos K, Kopylov U, et al. Third European evidence-based consensus on diagnosis and management of ulcerative colitis. Part 2: current management. J Crohns Colitis. 2017;11:769–84. doi: 10.1093/ecco-jcc/jjx009

  4. Gomollon F, Dignass A, Annese V, Tilg H, Van Assche G, Lindsay JO, 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

  5. Lichtenstein GR, Rutgeerts P, Sandborn WJ, Sands BE, Diamond RH, Blank M, et al. A pooled analysis of infections, malignancy, and mortality in infliximab- and immunomodulator-treated adult patients with inflammatory bowel disease. Am J Gastroenterol. 2012;107:1051–63. doi: 10.1038/ajg.2012.89

  6. Bonovas S, Fiorino G, Allocca M, Lytras T, Nikolopoulos GK, Peyrin-Biroulet L, et al. Biologic therapies and risk of infection and malignancy in patients with inflammatory bowel disease: a systematic review and network meta-analysis. Clin Gastroenterol Hepatol. 2016;14:1385–97.e10. doi: 10.1016/j.cgh.2016.04.039

  7. Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Price S, et al. Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT registry. Am J Gastroenterol. 2012;107:1409–22. doi: 10.1038/ajg.2012.218

  8. Toruner M, Loftus EV, Jr, Harmsen WS, Zinsmeister AR, Orenstein R, Sandborn WJ, et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology. 2008;134:929–36. doi: 10.1053/j.gastro.2008.01.012

  9. Shah ED, Farida JP, Siegel CA, Chong K, Melmed GY. Risk for overall infection with anti-TNF and anti-integrin agents used in IBD: a systematic review and meta-analysis. Inflamm Bowel Dis. 2017;23:570–7. doi: 10.1097/MIB.0000000000001049

  10. Wheat CL, Ko CW, Clark-Snustad K, Grembowski D, Thornton TA, Devine B. Inflammatory Bowel Disease (IBD) pharmacotherapy and the risk of serious infection: a systematic review and network meta-analysis. BMC Gastroenterol. 2017;17:52. doi: 10.1186/s12876-017-0602-0

  11. Ford AC, Peyrin-Biroulet L. Opportunistic infections with anti-tumor necrosis factor-alpha therapy in inflammatory bowel disease: meta-analysis of randomized controlled trials. Am J Gastroenterol. 2013;108:1268–76. doi: 10.1038/ajg.2013.138

  12. Colombel JF, Reinisch W, Mantzaris GJ, Kornbluth A, Rutgeerts P, Tang KL, et al. Randomised clinical trial: deep remission in biologic and immunomodulator naive patients with Crohn’s disease – a SONIC post hoc analysis. Aliment Pharmacol Ther. 2015;41:734–46. doi: 10.1111/apt.13139

  13. Panaccione R, Ghosh S, Middleton S, Marquez JR, Scott BB, Flint L, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014;146:392–400.e3. doi: 10.1053/j.gastro.2013.10.052

  14. Osterman MT, Haynes K, Delzell E, Zhang J, Bewtra M, Brensinger CM, et al. Effectiveness and safety of immunomodulators with anti-tumor necrosis factor therapy in Crohn’s disease. Clin Gastroenterol Hepatol. 2015;13:1293–301.e5; quiz e70, e72. doi: 10.1016/j.cgh.2015.02.017

  15. Kirchgesner J, Lemaitre M, Carrat F, Zureik M, Carbonnel F, Dray-Spira R. Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases. Gastroenterology. 2018;155:337–46.e10. doi: 10.1053/j.gastro.2018.04.012

  16. Martelli L, Lopez A, Strobel S, Danese S, Roblin X, Baumann C, et al. Adherence to infliximab therapy in inflammatory bowel disease patients in a real-life setting. J Dig Dis. 2017;18:566–73. doi: 10.1111/1751-2980.12539

  17. Perry J, Chen A, Kariyawasam V, Collins G, Choong C, Teh WL, et al. Medication non-adherence in inflammatory bowel diseases is associated with disability. Intest Res. 2018;16:571–8. doi: 10.5217/ir.2018.00033

  18. Ludvigsson JF, Andersson M, Bengtsson J, Eberhardson M, Fagerberg UL, Grip O, et al. Swedish Inflammatory Bowel Disease Register (SWIBREG) – a nationwide quality register. Scand J Gastroenterol. 2019;54:1089–101. doi: 10.1080/00365521.2019.1660799

  19. Lindhagen S, Karling P. A more frequent disease monitorering but no increased disease activity in patients with inflammatory bowel disease during the first year of the SARS-CoV-2 pandemic. A retrospective study. Scand J Gastroenterol. 2021;56:1–6. doi: 10.1080/00365521.2021.1993328

  20. Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut. 2006;55:749–53. doi: 10.1136/gut.2005.082909

  21. Roblin X, Boschetti G, Williet N, Nancey S, Marotte H, Berger A, et al. Azathioprine dose reduction in inflammatory bowel disease patients on combination therapy: an open-label, prospective and randomised clinical trial. Aliment Pharmacol Ther. 2017;46:142–9. doi: 10.1111/apt.14106

  22. Yarur AJ, Kubiliun MJ, Czul F, Sussman DA, Quintero MA, Jain A, et al. Concentrations of 6-thioguanine nucleotide correlate with trough levels of infliximab in patients with inflammatory bowel disease on combination therapy. Clin Gastroenterol Hepatol. 2015;13:1118–24.e3. doi: 10.1016/j.cgh.2014.12.026

  23. Ludvigsson JF, Holmgren J, Grip O, Halfvarson J, Askling J, Sachs MC, et al. Adult-onset inflammatory bowel disease and rate of serious infections compared to the general population: a nationwide register-based cohort study 2002–2017. Scand J Gastroenterol. 2021;56:1152–62. doi: 10.1080/00365521.2021.1924259

  24. Debeuckelaere C, De Munter P, Van Bleyenbergh P, De Wever W, Van Assche G, Rutgeerts P, et al. Tuberculosis infection following anti-TNF therapy in inflammatory bowel disease, despite negative screening. J Crohns Colitis. 2014;8:550–7. doi: 10.1016/j.crohns.2013.11.008

  25. Cantini F, Niccoli L, Goletti D. Tuberculosis risk in patients treated with non-anti-tumor necrosis factor-alpha (TNF-alpha) targeted biologics and recently licensed TNF-alpha inhibitors: data from clinical trials and national registries. J Rheumatol Suppl. 2014;91:56–64. doi: 10.3899/jrheum.140103

  26. Naganuma M, Kunisaki R, Yoshimura N, Takeuchi Y, Watanabe M. A prospective analysis of the incidence of and risk factors for opportunistic infections in patients with inflammatory bowel disease. J Gastroenterol. 2013;48:595–600. doi: 10.1007/s00535-012-0686-9

  27. Schroder W, Sommer H, Gladstone BP, Foschi F, Hellman J, Evengard B, et al. Gender differences in antibiotic prescribing in the community: a systematic review and meta-analysis. J Antimicrob Chemother. 2016;71:1800–6. doi: 10.1093/jac/dkw054

How to Cite
Andersson P., & Karling P. (2022). Impact of treatment with immunomodulators and tumour necrosis factor antagonists on the incidence of infectious events in patients with inflammatory bowel disease. Upsala Journal of Medical Sciences, 127(1).