Comparative Risk of Serious Infections With Biologic and/or Immunosuppressive Therapy in Patients With Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis

doi:10.1016/j.cgh.2019.02.044

Clinical Gastroenterology and Hepatology

Volume 18, Issue 1, January 2020, Pages 69-81.e3

https://doi.org/10.1016/j.cgh.2019.02.044 Get rights and content

Background & Aims

We performed a systematic review and meta-analysis to evaluate the comparative risk of serious infections with tumor necrosis factor (TNF) antagonists, non-TNF targeted biologics, tofacitinib, and immunosuppressive agents in patients with inflammatory bowel diseases (IBDs).

Methods

In a systematic search of publications, through March 18, 2018, we identified 15 observational studies (>500 person-years) of patients with IBD treated with TNF antagonists, non-TNF targeted biologics, tofacitinib, and/or immunosuppressive agents (thiopurines, methotrexate) that reported risk of serious infections. Only studies with active comparators were included, to allow appropriate comparative synthesis. We performed random-effects meta-analysis and estimated relative risk (RR) and 95% CIs.

Results

Compared with anti-TNF monotherapy, risk of serious infection increased with the combination of anti-TNF and an immunosuppressive agent (in 6 cohorts: RR, 1.19; 95% CI, 1.03–1.37), with anti-TNF and a corticosteroid (in 4 cohorts: RR, 1.64; 95% CI, 1.33–2.03), or with all 3 drugs (in 2 cohorts: RR, 1.35; 95% CI, 1.04–1.77); there was minimal heterogeneity among studies. In contrast, monotherapy with an immunosuppressive agent was associated with a lower risk of serious infections than monotherapy with a TNF antagonist (7 cohorts: RR, 0.61; 95% CI 0.44–0.84) or a TNF antagonist with an immunosuppressive agent (2 cohorts: RR, 0.56; 95% CI, 0.39–0.81). Infliximab-based therapy was associated with a lower risk of serious infections compared with adalimumab-based therapy in patients with ulcerative colitis (4 cohorts: RR, 0.57; 95% CI, 0.33–0.97), but not Crohn’s disease (4 cohorts: RR, 0.91; 95% CI, 0.49–1.70). Few data were available on the comparative safety of biologic agents that do not inhibit TNF and tofacitinib.

Conclusions

Combination therapies for IBD that include TNF antagonists, especially with corticosteroids, are associated with a higher risk of serious infection, whereas monotherapy with an immunosuppressive agent is associated with a lower risk, compared with monotherapy with a TNF antagonist. Studies are needed to evaluate the comparative safety of non-TNF targeted biologics and small molecules for treatment of IBD.

Section snippets

Methods

This systematic review is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement and was conducted following an a priori established protocol.¹⁰

Results

From 11,947 unique studies identified using our search strategy, the full text of 115 studies were reviewed in detail, and eventually 15 studies were included in the quantitative analysis15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29; in addition, 3 studies comparing TNFi-based therapy vs chronic corticosteroids and non-TNFi biologics vs TNFi-based therapy were evaluated qualitatively.30, 31, 32 Figure 1 shows the study selection flowsheet. Of these 15 studies, 9 used administrative

Discussion

In this systematic review and meta-analysis of 15 cohort studies on the comparative risk of serious infections with TNFi, non-TNFi biologics, and immunosuppressive agents in patients with IBD, we made several key observations. First, combination therapy with TNFi + IS was associated only with a modestly higher risk (19%) of serious infections as compared with TNFi monotherapy. Second, TNFi monotherapy was associated with a 64% higher risk of serious infection as compared with immunosuppressive

Acknowledgments

The authors sincerely thank Kellee Kaulback, Medical Information Officer, Health Quality Ontario, for helping in the literature search for this technical review.

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: This article has an accompanying continuing medical education activity, also eligible for MOC credit, on page e7. Learning Objective–Upon completion of this activity, successful learners will be able to list the relative risk of serious infection with various treatment strategies in patients with inflammatory bowel disease; and in addition to biologic and immunomodulator therapies, list risk factors for serious infections in patients with inflammatory bowel diseases.

: Conflicts of interest These authors disclose the following: Siddharth Singh has received research grant support from Pfizer and AbbVie, and has received consulting fees from AbbVie, Takeda, Pfizer, and AMAG Pharmaceuticals; Parambir S. Dulai has received research grant support from Takeda, Pfizer, Janssen, Prometheus, Polymedco, and ALPCO, has served as a consultant for Takeda, Janssen, and AbbVie, and has received speaker honoraria from Takeda; Vipul Jairath has received consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena Pharmaceuticals, Genetech, Pendopharm, Sandoz, Merck, Takeda, Janssen, Robarts Clinical Trials, Topivert, and Celltrion, has received speaker’s fees from Takeda, Janssen, Shire, Ferring, AbbVie, and Pfizer, and salary support from the John and Susan McDonald Endowed Chair at Western University, London, Ontario, Canada; and William J. Sandborn has received research grant support from Atlantic Healthcare Limited, Amgen, Genentech, Gilead Sciences, AbbVie, Janssen, Takeda, Lilly, and Celgene/Receptos, has received consulting fees from AbbVie, Allergan, Amgen, Boehringer Ingelheim, Celgene, Conatus, Cosmo, Escalier Biosciences, Ferring, Genentech, Gilead, Gossamer Bio, Janssen, Lilly, Miraca Life Sciences, Nivalis Therapeutics, Novartis Nutrition Science Partners, Oppilan Pharma, Otsuka, Paul Hastings, Pfizer, Precision IBD, Progenity, Prometheus Laboratories, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by Health Academic Research Trust), Salix, Shire, Seres Therapeutics, Sigmoid Biotechnologies, Takeda, Tigenix, Tillotts Pharma, UCB Pharma, Vivelix, and has received stock options from Ritter Pharmaceuticals, Oppilan Pharma, Escalier Biosciences, Gossamer Bio, Precision IBD, and Progenity. The remaining author discloses no conflicts.

: Funding Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award number K23DK117058 (S.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health

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Systematic review and meta-analysisComparative Risk of Serious Infections With Biologic and/or Immunosuppressive Therapy in Patients With Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis

Background & Aims

Methods

Results

Conclusions

Section snippets

Methods

Results

Discussion

Acknowledgments

Clin Gastroenterol Hepatol

Clin Gastroenterol Hepatol

Control Clin Trials

Gastroenterology

Clin Gastroenterol Hepatol

Clin Gastroenterol Hepatol

Dig Liver Dis

Gastroenterology

Clin Gastroenterol Hepatol

Lancet

Gastroenterology

Infections and cardiovascular complications are common causes for hospitalization in older patients with inflammatory bowel diseases

Inflamm Bowel Dis

Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREATTM registry

Am J Gastroenterol

Crohn's disease activity and concomitant immunosuppressants affect the risk of serious and opportunistic infections in patients treated with adalimumab

Am J Gastroenterol

Infectious and malignant complications of TNF inhibitor therapy in IBD

Am J Gastroenterol

Infection risk with biologic therapy in patients with inflammatory bowel disease

Clin Pharmacol Ther

Systematic review and network meta-analysis: first- and second-line biologic therapies for moderate-severe Crohn's disease

Aliment Pharmacol Ther

Systematic review with network meta-analysis: first- and second-line pharmacotherapy for moderate-severe ulcerative colitis

Aliment Pharmacol Ther

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

Ann Intern Med

Assessing bias in studies of prognostic factors

Ann Intern Med

Measuring inconsistency in meta-analyses

BMJ

Systematic review and meta-analysis
Comparative Risk of Serious Infections With Biologic and/or Immunosuppressive Therapy in Patients With Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis