Abstract
Background and aims
Few data are available to support the clinical relevance of infliximab (IFX) trough levels for prediction of endoscopic disease activity in Crohn’s disease (CD). This study evaluated the endoscopic disease activities in relation to clinical outcome using several laboratory markers including serum IFX trough levels in patients with CD undergoing scheduled IFX maintenance treatment.
Materials and methods
A total of 78 sessions of endoscopy were performed on 45 patients with CD. Endoscopic activity was assessed using the modified Rutgeerts scoring system. IFX trough levels and anti-IFX antibodies (ATIs) were determined by immunoassays.
Results
Endoscopic activity negatively correlated with serum IFX trough levels (Spearman’s rank correlation coefficient (ρ) = −0.54, P < 0.0001) and serum albumin levels (ρ = −0.46, P < 0.0001), and positively correlated with CRP (C-reactive protein) levels (ρ = 0.55, P < 0.0001), ESR (erythrocyte sedimentation rate) (ρ = 0.47, P < 0.0001) and fecal calprotectin levels. IFX trough levels and serum albumin levels were significantly elevated in the mucosal healing (MH) group, but ATIs, CRP, ESR and fecal calprotectin levels were significantly elevated in the nonmucosal healing group. Receiver operation curve revealed that the optimal cutoff value of IFX trough levels for identifying normal laboratory markers was 0.6 μg/ml for CRP, 1.0 μg/ml for serum albumin and 1.1 μg/ml for fecal calprotectin. Identification of mucosal healing needed a higher cutoff value of 4.0 μg/ml. Thiopurine treatment did not affect IFX trough and ATI levels.
Conclusion
Mucosal healing requires higher IFX trough levels, compared to those to achieve normalization of routine clinical markers.
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References
Allez M, Vermeire S, Mozziconacci N, et al. The efficacy and safety of a third anti-TNF monoclonal antibody in Crohn’s disease after failure of two other anti-TNF antibodies. Aliment Pharmacol Ther. 2010;31:92–101.
Danese S, Colombel JF, Reinisch W, et al. Review article: infliximab for Crohn’s disease treatment—shifting therapeutic strategies after 10 years of clinical experience. Aliment Pharmacol Ther. 2011;33:857–69.
Mayer L. Evolving paradigms in the pathogenesis of IBD. J Gastroenterol. 2010;45:9–16.
Hanauer SB, Kornbluth AA, Messick J, et al. Clinical scenarios in IBD: optimizing the use of conventional and biologic agents. Inflamm Bowel Dis. 2010;16(Suppl 1):S1–11.
Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359:1541–9.
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.
Ueno F, Matsui T, Matsumoto T, et al. Evidence-based clinical practice guidelines for Crohn’s disease, integrated with formal consensus of experts in Japan. J Gastroenterol. 2013;48:31–72.
Andoh A, Kuzuoka H, Tsujikawa T, et al. Multicenter analysis of fecal microbiota profiles in Japanese patients with Crohn’s disease. J Gastroenterol. 2012;47:1298–307.
D’Haens GR, Panaccione R, Higgins PD, et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn’s and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol. 2011;106:199–212 (quiz 213).
Schnitzler F, Fidder H, Ferrante M, et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn’s disease: results from a single-centre cohort. Gut. 2009;58:492–500.
Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004;350:876–85.
Van Assche G, Magdelaine-Beuzelin C, D’Haens G, et al. Withdrawal of immunosuppression in Crohn’s disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology. 2008;134:1861–8.
Gisbert JP, Panes J. Loss of response and requirement of infliximab dose intensification in Crohn’s disease: a review. Am J Gastroenterol. 2009;104:760–7.
Yanai H, Hanauer SB. Assessing response and loss of response to biological therapies in IBD. Am J Gastroenterol. 2011;106:685–98.
Bortlik M, Duricova D, Malickova K, et al. Infliximab trough levels may predict sustained response to infliximab in patients with Crohn’s disease. J Crohns Colitis. 2012. doi:10.1016/j.crohns.2012.10.019.
Maser EA, Villela R, Silverberg MS, et al. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol. 2006;4:1248–54.
Cassinotti A, Travis S. Incidence and clinical significance of immunogenicity to infliximab in Crohn’s disease: a critical systematic review. Inflamm Bowel Dis. 2009;15:1264–75.
Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease. Clin Gastroenterol Hepatol. 2004;2:542–53.
Vermeire S, Noman M, Van Assche G, et al. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut. 2007;56:1226–31.
Imaeda H, Andoh A, Fujiyama Y. Development of a new immunoassay for the accurate determination of anti-infliximab antibodies in inflammatory bowel disease. J Gastroenterol. 2012;47:136–43.
Nanda KS, Cheifetz AS, Moss AC. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis. Am J Gastroenterol. 2013;108:40–7.
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.
Baert F, Moortgat L, Van Assche G, et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn’s disease. Gastroenterology. 2010;138:463–8 (quiz e410–461).
Schnitzler F, Fidder H, Ferrante M, et al. Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohn’s disease. Inflamm Bowel Dis. 2009;15:1295–301.
Rutgeerts P, Geboes K, Vantrappen G, et al. Predictability of the postoperative course of Crohn’s disease. Gastroenterology. 1990;99:956–63.
Mary JY, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn’s disease: a prospective multicentre study. Groupe d’Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Gut. 1989;30:983–9.
Daperno M, D’Haens G, Van Assche G, et al. Development and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD. Gastrointest Endosc. 2004;60:505–12.
af Bjorkesten CG, Nieminen U, Turunen U, et al. Endoscopic monitoring of infliximab therapy in Crohn’s disease. Inflamm Bowel Dis. 2011;17:947–53.
Neurath MF, Travis SP. Mucosal healing in inflammatory bowel diseases: a systematic review. Gut. 2012;61:1619–35.
Colombel JF, Rutgeerts P, Reinisch W, et al. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology. 2011;141:1194–201.
Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn’s disease. Gastrointest Endosc. 2006;63:433–42 (quiz 464).
Steenholdt C, Bendtzen K, Brynskov J, et al. Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn’s disease. Scand J Gastroenterol. 2011;46:310–8.
Hibi T, Sakuraba A, Watanabe M, et al. Retrieval of serum infliximab level by shortening the maintenance infusion interval is correlated with clinical efficacy in Crohn’s disease. Inflamm Bowel Dis. 2012;18:1480–7.
Fasanmade AA, Adedokun OJ, Olson A, et al. Serum albumin concentration: a predictive factor of infliximab pharmacokinetics and clinical response in patients with ulcerative colitis. Int J Clin Pharmacol Ther. 2010;48:297–308.
Acknowledgments
The first two authors (H.I. and S.B.) equally contributed to this work. This study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (21590809) and by the Health and Labour Sciences Research Grants for Research on Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan.
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The authors have declared that no conflict of interest exists.
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Imaeda, H., Bamba, S., Takahashi, K. et al. Relationship between serum infliximab trough levels and endoscopic activities in patients with Crohn’s disease under scheduled maintenance treatment. J Gastroenterol 49, 674–682 (2014). https://doi.org/10.1007/s00535-013-0829-7
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DOI: https://doi.org/10.1007/s00535-013-0829-7