Reversal of anti-drug antibodies against tumor necrosis factor inhibitors with addition of immunomodulators: A systematic review and meta-analysis



The development of anti-drug antibodies (ADA) to tumor necrosis factor (TNF-α) inhibitors is a significant result contributing to the loss of clinical response in inflammatory bowel disease (IBD).


We performed a systematic review and meta-analysis to assess whether the addition of immunomodulators to TNF-α inhibitors lead to reversal of antibody formation in TNF-α inhibitor-treated IBD patients.


We conducted a comprehensive search of electronic databases from inception through October 2018 in order to identify specific studies describing clinical response in IBD patients following the addition of immunomodulators (methotrexate or thiopurines) to TNF-α inhibitors. Clinical response was expressed as an improvement of symptoms, with a noted decrease or complete elimination of ADA against TNF-α inhibitors. The meta-analysis was performed using the DerSimonian and Laird random-effect model.


Four studies were included in our final meta-analysis, which reported outcomes in 72 patients receiving TNF-α inhibitors. Forty-nine of the seventy-two (68%) patients received either methotrexate (19) or thiopurines (30). The average follow up period was 13.5 months. The overall pooled clinical response was 73.86% (95% confidence interval [CI] = 47.36–94.38, I2 = 60.77%).


In our meta-analysis, addition of immunomodulators to TNF-α inhibitors was shown to restore the clinical response in 74% of the patients by either decreasing or completely eliminating anti-drug antibody levels. Further long-term multicenter studies are needed to validate these findings.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig 2


  1. 1.

    Matsuoka K, Kobayashi T, Ueno F, et al. Evidence-based clinical practice guidelines for inflammatory bowel disease. J Gastroenterol. 2018;53:305–53.

    CAS  Article  Google Scholar 

  2. 2.

    Ford AC, Sandborn WJ, Khan KJ, Hanauer SB, Talley NJ, Moayyedi P. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011;106:644–59, quiz 660.

  3. 3.

    Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359:1541–9.

    CAS  Article  Google Scholar 

  4. 4.

    Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–76.

    CAS  Article  Google Scholar 

  5. 5.

    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. Gastroenterology. 2007;132:52–65.

    CAS  Article  Google Scholar 

  6. 6.

    Ma C, Huang V, Fedorak DK, et al. Outpatient ulcerative colitis primary anti-TNF responders receiving adalimumab or infliximab maintenance therapy have similar rates of secondary loss of response. J Clin Gastroenterol. 2015;49:675–82.

    CAS  Article  Google Scholar 

  7. 7.

    Vande Casteele N, Herfarth H, Katz J, Falck-Ytter Y, Singh S. American Gastroenterological Association Institute technical review on the role of therapeutic drug monitoring in the management of inflammatory bowel diseases. Gastroenterology. 2017;153:835–57.

  8. 8.

    Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348:601–8.

    CAS  Article  Google Scholar 

  9. 9.

    West RL, Zelinkova Z, Wolbink GJ, Kuipers EJ, Stokkers PC, van der Woude CJ. Immunogenicity negatively influences the outcome of adalimumab treatment in Crohn’s disease. Aliment Pharmacol Ther. 2008;28:1122–6.

  10. 10.

    Billiet T, Vande Casteele N, Van Stappen T, et al. Immunogenicity to infliximab is associated with HLA-DRB1. Gut. 2015;64:1344–5.

    CAS  Article  Google Scholar 

  11. 11.

    Brandse JF, Mathot RA, van der Kleij D, et al. Pharmacokinetic features and presence of antidrug antibodies associate with response to infliximab induction therapy in patients with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol. 2016;14:251–8,e251–2.

  12. 12.

    Mohanan D, Slutter B, Henriksen-Lacey M, et al. Administration routes affect the quality of immune responses: a cross-sectional evaluation of particulate antigen-delivery systems. J Control Release. 2010;147:342–9.

    CAS  Article  Google Scholar 

  13. 13.

    Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med. 2007;146:829–38.

    Article  Google Scholar 

  14. 14.

    Ungar B, Kopylov U, Engel T, et al. Addition of an immunomodulator can reverse antibody formation and loss of response in patients treated with adalimumab. Aliment Pharmacol Ther. 2017;45:276–82.

    CAS  Article  Google Scholar 

  15. 15.

    Ben-Horin S, Waterman M, Kopylov U, et al. Addition of an immunomodulator to infliximab therapy eliminates antidrug antibodies in serum and restores clinical response of patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11:444–7.

    CAS  Article  Google Scholar 

  16. 16.

    Katz L, Gisbert JP, Manoogian B, et al. Doubling the infliximab dose versus halving the infusion intervals in Crohn’s disease patients with loss of response. Inflamm Bowel Dis. 2012;18:2026–33.

    Article  Google Scholar 

  17. 17.

    Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383–95.

    CAS  Article  Google Scholar 

  18. 18.

    Colombel JF, Narula N, Peyrin-Biroulet L. Management strategies to improve outcomes of patients with inflammatory bowel diseases. Gastroenterology. 2017;152:351–61, e355.

  19. 19.

    Lichtenstein GR, Feagan BG, Cohen RD, 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.

    CAS  Article  Google Scholar 

  20. 20.

    Feuerstein JD, Nguyen GC, Kupfer SS, et al. American Gastroenterological Association Institute guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology. 2017;153:827–34.

    Article  Google Scholar 

  21. 21.

    Bond A, Clark K, Gregg B, et al. PTH-049 successful reversal of high titre antibodies to infliximab and adalimumab with the addition of immunomodulator therapy. Gut. 2016;65:A243.

  22. 22.

    Strik AS, van den Brink GR, Ponsioen C,  Mathot R, Löwenberg M, D'Haens GR. Suppression of anti-drug antibodies to infliximab or adalimumab with the addition of an immunomodulator in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2017;45:1128–34.

  23. 23.

    Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25:603–5.

    Article  Google Scholar 

  24. 24.

    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.

    CAS  Article  Google Scholar 

  25. 25.

    Sutton AJ, Abrams KR, Jones DR, et al. Methods for Meta-analysis in Medical Research. Vol. 2000. New York: Wiley; 2000. p. 205–28.

  26. 26.

    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.

  27. 27.

    Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 7. Rating the quality of evidence--inconsistency. J Clin Epidemiol. 2011;64:1294–302.

    Article  Google Scholar 

  28. 28.

    Kanwal F, White D. “Systematic reviews and meta-analyses” in clinical gastroenterology and hepatology. Clin Gastroenterol Hepatol. 2012;10:1184–6.

    Article  Google Scholar 

  29. 29.

    Danese S, Fiorino G, Reinisch W. Review article: causative factors and the clinical management of patients with Crohn’s disease who lose response to anti-TNF-alpha therapy. Aliment Pharmacol Ther. 2011;34:1–10.

    CAS  Article  Google Scholar 

  30. 30.

    Roda G, Jharap B, Neeraj N, Colombel JF. Loss of response to anti-TNFs: definition, epidemiology, and management. Clin Transl Gastroenterol. 2016;7:e135.

  31. 31.

    Vermeire S, Gils A, Accossato P, Lula S, Marren A. Immunogenicity of biologics in inflammatory bowel disease. Therap Adv Gastroenterol. 2018;11:1756283X17750355.

  32. 32.

    Hindryckx P, Novak G, Vande Casteele N, et al. Incidence, prevention and management of anti-drug antibodies against therapeutic antibodies in inflammatory bowel disease: a practical overview. Drugs. 2017;77:363–77.

    CAS  Article  Google Scholar 

  33. 33.

    Qiu Y, Mao R, Chen BL, et al. Effects of combination therapy with immunomodulators on trough levels and antibodies against tumor necrosis factor antagonists in patients with inflammatory bowel disease: a meta-analysis. Clin Gastroenterol Hepatol. 2017;15:1359–72, e6.

  34. 34.

    Tiede I, Fritz G, Strand S, et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest. 2003;111:1133–45.

    CAS  Article  Google Scholar 

  35. 35.

    Jani M, Barton A, Warren RB, Griffiths CE, Chinoy H. The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology. 2014;53:213–22.

  36. 36.

    Terdiman JP, Gruss CB, Heidelbaugh JJ, Sultan S, Falck-Ytter YT; AGA Institute Clinical Practice and Quality Management Committee. American Gastroenterological Association Institute guideline on the use of thiopurines, methotrexate, and anti-TNF-alpha biologic drugs for the induction and maintenance of remission in inflammatory Crohn’s disease. Gastroenterology. 2013;145:1459–63.

Download references

Author information



Corresponding author

Correspondence to Derrick Eichele.

Ethics declarations

Conflict of interest

BSD, AD, HSM, SMS, HS, MM, GO, and DE  declare that they have no conflict of interest.

Ethics statement

The study was performed conforming to the Helsinki declaration of 1975, as revised in 2000 and 2008 concerning human and animal rights, and the authors followed the policy concerning informed consent as shown on


The authors are solely responsible for the data and the contents of the paper. In no way, the Honorary Editor-in-Chief, Editorial Board Members, or the printer/publishers are responsible for the results/findings and content of this article.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dhindsa, B.S., Dhaliwal, A., Mashiana, H.S. et al. Reversal of anti-drug antibodies against tumor necrosis factor inhibitors with addition of immunomodulators: A systematic review and meta-analysis. Indian J Gastroenterol 39, 153–160 (2020).

Download citation


  • Anti-drug antibodies
  • Immunomodulators
  • Inflammatory bowel disease
  • TNF-α inhibitors