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Effect of Concomitant Therapy With Steroids and Tumor Necrosis Factor Antagonists for Induction of Remission in Patients With Crohn’s Disease: A Systematic Review and Pooled Meta-analysis

  • Author Footnotes
    a Authors share co-first authorship.
    David M. Faleck
    Correspondence
    Reprint requests Address requests for reprints to: David M. Faleck, MD, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065; fax: (212) 639-2766.
    Footnotes
    a Authors share co-first authorship.
    Affiliations
    Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York

    Gastroenterology, Hepatology and Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
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  • Author Footnotes
    a Authors share co-first authorship.
    Eugenia Shmidt
    Footnotes
    a Authors share co-first authorship.
    Affiliations
    Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York

    Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, Minnesota
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  • Ruiqi Huang
    Affiliations
    Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Leah G. Katta
    Affiliations
    Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York

    Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida
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  • Neeraj Narula
    Affiliations
    Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
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  • Rachel Pinotti
    Affiliations
    Levy Library, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Mayte Suarez-Farinas
    Affiliations
    Department of Population Health Science and Policy, Department of Genetics and Genomics Science, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Jean-Frederic Colombel
    Affiliations
    Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Author Footnotes
    a Authors share co-first authorship.

      Background & Aims

      It is not clear whether concomitant therapy with corticosteroids and anti-tumor necrosis factor (TNF) agents is more effective at inducing remission in patients with Crohn’s disease (CD) than anti-TNF monotherapy. We aimed to determine whether patients with active CD receiving corticosteroids during induction therapy with anti-TNF agents had higher rates of clinical improvement than patients not receiving corticosteroids during induction therapy.

      Methods

      We systematically searched the MEDLINE, Embase, and CENTRAL databases, through January 20, 2016, for randomized trials of anti-TNF agents approved for treatment of CD and identified 14 trials (5 of adalimumab, 5 of certolizumab, and 4 of infliximab). We conducted a pooled meta-analysis of individual patient and aggregated data from these trials. We compared data from participants who continued oral corticosteroids during induction with anti-TNF therapy to those treated with anti-TNF agents alone. The endpoints were clinical remission (CD activity index [CDAI] scores <150) and clinical response (a decrease in CDAI of 100 points) at the end of induction (weeks 4–14 of treatment).

      Results

      We included 4354 patients who received induction therapy with anti-TNF agents, including 1653 [38.0%] who were receiving corticosteroids. The combination of corticosteroids and an anti-TNF agent induced clinical remission in 32.0% of patients, whereas anti-TNF monotherapy induced clinical remission in 35.5% of patients (odds ratio [OR], 0.93; 95% CI, 0.74–1.17). The combination of corticosteroids and an anti-TNF agent induced a clinical response in 42.7% of patients, whereas anti-TNF monotherapy induced a clinical response in 46.8% (OR 0.84; 95% CI, 0.73–0.96). These findings did not change with adjustment for baseline CDAI scores and concurrent use of immunomodulators.

      Conclusions

      Based on a meta-analysis of data from randomized trials of anti-TNF therapies in patients with active CD, patients receiving corticosteroids during induction therapy with anti-TNF agents did not have higher rates of clinical improvement compared with patients not receiving corticosteroids during induction therapy. Given these findings and the risks of corticosteroid use, clinicians should consider early weaning of corticosteroids during induction therapy with anti-TNF agents for patients with corticosteroid-refractory CD.

      Keywords

      Abbreviations used in this paper:

      CD (Crohn’s disease), CDAI (Crohn’s disease activity index), CI (confidence interval), IBD (inflammatory bowel disease), IPD (individual participant data), OR (odds ratio), RCT (randomized controlled clinical trial), TNF (tumor necrosis factor)
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      References

        • Torres J.
        • Mehandru S.
        • Colombel J.F.
        • et al.
        Crohn's disease.
        Lancet. 2017; 389: 1741-1755
        • Ford A.C.
        • Bernstein C.N.
        • Khan K.J.
        • et al.
        Glucocorticosteroid therapy in inflammatory bowel disease: systematic review and meta-analysis.
        Am J Gastroenterol. 2011; 106 (quiz 600): 590-599
        • Cohen B.L.
        • Sachar D.B.
        Update on anti-tumor necrosis factor agents and other new drugs for inflammatory bowel disease.
        BMJ. 2017; 357: j2505
        • Summers R.W.
        • Switz D.M.
        • Sessions Jr., J.T.
        • et al.
        National Cooperative Crohn's Disease Study: results of drug treatment.
        Gastroenterology. 1979; 77: 847-869
        • Yang Y.X.
        • Lichtenstein G.R.
        Corticosteroids in Crohn's disease.
        Am J Gastroenterol. 2002; 97: 803-823
        • Waljee A.K.
        • Wiitala W.L.
        • Govani S.
        • et al.
        Corticosteroid use and complications in a US inflammatory bowel disease cohort.
        PLoS One. 2016; 11e0158017
        • Targownik L.E.
        • Nugent Z.
        • Singh H.
        • et al.
        Prevalence of and outcomes associated with corticosteroid prescription in inflammatory bowel disease.
        Inflamm Bowel Dis. 2014; 20: 622-630
        • Loftus Jr., E.V.
        • Schoenfeld P.
        • Sandborn W.J.
        The epidemiology and natural history of Crohn's disease in population-based patient cohorts from North America: a systematic review.
        Aliment Pharmacol Ther. 2002; 16: 51-60
        • Lichtenstein G.R.
        • Feagan B.G.
        • Cohen R.D.
        • 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: 1409-1422
        • Lewis J.D.
        • Scott F.I.
        • Brensinger C.M.
        • et al.
        Increased mortality rates with prolonged corticosteroid therapy when compared with antitumor necrosis factor-alpha-directed therapy for inflammatory bowel disease.
        Am J Gastroenterol. 2018; 113: 405-417
        • Osterman M.T.
        • Sandborn W.J.
        • Colombel J.F.
        • et al.
        Crohn's disease activity and concomitant immunosuppressants affect the risk of serious and opportunistic infections in patients treated with adalimumab.
        Am J Gastroenterol. 2016; 111: 1806-1815
        • Grijalva C.G.
        • Chen L.
        • Delzell E.
        • et al.
        Initiation of tumor necrosis factor-α antagonists and the risk of hospitalization for infection in patients with autoimmune diseases.
        JAMA. 2011; 306: 2331-2339
        • Tsiodras S.
        • Samonis G.
        • Boumpas D.T.
        • et al.
        Fungal infections complicating tumor necrosis factor alpha blockade therapy.
        Mayo Clin Proc. 2008; 83: 181-194
        • Raval A.
        • Akhavan-Toyserkani G.
        • Brinker A.
        • et al.
        Brief communication: characteristics of spontaneous cases of tuberculosis associated with infliximab.
        Ann Intern Med. 2007; 147: 699-702
        • Feagan B.G.
        • McDonald J.W.
        • Panaccione R.
        • et al.
        Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn's disease.
        Gastroenterology. 2014; 146: 681-688 e1
        • Sandborn W.J.
        • Rutgeerts P.
        • Enns R.
        • et al.
        Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial.
        Ann Intern Med. 2007; 146: 829-838
        • Lemann M.
        • Mary J.Y.
        • Duclos B.
        • et al.
        Infliximab plus azathioprine for steroid-dependent Crohn's disease patients: a randomized placebo-controlled trial.
        Gastroenterology. 2006; 130: 1054-1061
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • et al.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        PLoS Med. 2009; 6e1000097
        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • et al.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • Sterne J.A.
        • Sutton A.J.
        • Ioannidis J.P.
        • et al.
        Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials.
        BMJ. 2011; 343: d4002
        • Schwarzer G.
        meta: an R package for meta-analysis.
        R News. 2007; 7: 40-45
        • Viechtbauer W.
        Conducting meta-analyses in R with the metafor package.
        J Stat Softw. 2010; 36: 1-48
        • Schreiber S.
        • Rutgeerts P.
        • Fedorak R.N.
        • et al.
        A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease.
        Gastroenterology. 2005; 129: 807-818
        • Sandborn W.J.
        • Feagan B.G.
        • Stoinov S.
        • et al.
        Certolizumab pegol for the treatment of Crohn's disease.
        N Engl J Med. 2007; 357: 228-238
        • Schreiber S.
        • Khaliq-Kareemi M.
        • Lawrance I.C.
        • et al.
        Maintenance therapy with certolizumab pegol for Crohn's disease.
        N Engl J Med. 2007; 357: 239-250
        • Sandborn W.J.
        • Abreu M.T.
        • D'Haens G.
        • et al.
        Certolizumab pegol in patients with moderate to severe Crohn's disease and secondary failure to infliximab.
        Clin Gastroenterol Hepatol. 2010; 8: 688-695 e2
        • Sandborn W.J.
        • Schreiber S.
        • Feagan B.G.
        • et al.
        Certolizumab pegol for active Crohn's disease: a placebo-controlled, randomized trial.
        Clin Gastroenterol Hepatol. 2011; 9: 670-678 e3
        • Hanauer S.B.
        • Sandborn W.J.
        • Rutgeerts P.
        • et al.
        Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial.
        Gastroenterology. 2006; 130 (quiz 591): 323-333
        • Colombel J.F.
        • Sandborn W.J.
        • Rutgeerts P.
        • et al.
        Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial.
        Gastroenterology. 2007; 132: 52-65
        • Watanabe M.
        • Hibi T.
        • Lomax K.G.
        • et al.
        Adalimumab for the induction and maintenance of clinical remission in Japanese patients with Crohn's disease.
        J Crohns Colitis. 2012; 6: 160-173
        • Rutgeerts P.
        • Van Assche G.
        • Sandborn W.J.
        • et al.
        Adalimumab induces and maintains mucosal healing in patients with Crohn's disease: data from the EXTEND trial.
        Gastroenterology. 2012; 142: 1102-1111 e2
        • Present D.H.
        • Rutgeerts P.
        • Targan S.
        • et al.
        Infliximab for the treatment of fistulas in patients with Crohn's disease.
        N Engl J Med. 1999; 340: 1398-1405
        • Hanauer S.B.
        • Feagan B.G.
        • Lichtenstein G.R.
        • et al.
        Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial.
        Lancet. 2002; 359: 1541-1549
        • Sands B.E.
        • Anderson F.H.
        • Bernstein C.N.
        • et al.
        Infliximab maintenance therapy for fistulizing Crohn's disease.
        N Engl J Med. 2004; 350: 876-885
        • Colombel J.F.
        • Sandborn W.J.
        • Reinisch W.
        • et al.
        Infliximab, azathioprine, or combination therapy for Crohn's disease.
        N Engl J Med. 2010; 362: 1383-1395
        • Meyer A.
        • Rudant J.
        • Drouin J.
        • et al.
        Effectiveness and safety of reference infliximab and biosimilar in Crohn disease: a French equivalence study.
        Ann Intern Med. 2019; 170: 99-107
        • Raffals L.E.
        • Nguyen G.C.
        • Rubin D.T.
        Switching between biologics and biosimilars in inflammatory bowel disease.
        Clin Gastroenterol Hepatol. 2019; 17: 818-823