Withdrawal of Immunomodulators After Co-treatment Does Not Reduce Trough Level of Infliximab in Patients With Crohn’s Disease  David Drobne, Peter Bossuyt, Christine Breynaert, Tom Cattaert, Niels Vande Casteele, Griet Compernolle, Matthias Jürgens, Marc Ferrante, Vera Ballet, Willem-Jan Wollants, Isabelle Cleynen, Kristel Van Steen, Ann Gils, Paul Rutgeerts, Severine Vermeire, Gert Van Assche  Clinical Gastroenterology and Hepatology  Volume 13, Issue 3, Pages 514-521.e4 (March 2015) DOI: 10.1016/j.cgh.2014.07.027 Copyright © 2015 AGA Institute Terms and Conditions

Figure 1 Flow chart of patients. Clinical Gastroenterology and Hepatology 2015 13, 514-521.e4DOI: (10.1016/j.cgh.2014.07.027) Copyright © 2015 AGA Institute Terms and Conditions

Figure 2 (A) Time to infliximab (IFX) dose escalation after withdrawal of immunomodulator (IMM). (B) Time to discontinuation of infliximab after withdrawal of immunomodulator. Clinical Gastroenterology and Hepatology 2015 13, 514-521.e4DOI: (10.1016/j.cgh.2014.07.027) Copyright © 2015 AGA Institute Terms and Conditions

Figure 3 (A) Time to first infliximab (IFX) dose escalation after withdrawal of immunomodulator (IMM) as a function of infliximab trough levels (IFX TL) at time of immunomodulator withdrawal. (B) Discontinuation of infliximab as a result of loss of response after withdrawal of immunomodulator as a function of infliximab trough levels at time of immunomodulator withdrawal. Kaplan–Meier curves are stratified by infliximab trough levels at time of immunomodulator withdrawal: >5 μg/mL (27 of 81 patients: filled diamonds), detectable <5 μg/mL (47 of 81 patients: open triangles), undetectable (7 of 81 patients: open squares). Three distinct subgroups of patients are based on clinical outcome after immunomodulator withdrawal. Infliximab trough level value of 5 μg/mL was selected because none of the 27 patients with infliximab trough levels ≥5 μg/mL lost response to infliximab during entire follow-up of the study. The cutoff value detectable/undetectable was identified by the ROC curve analysis. P values for log-rank tests comparing 3 subgroups of patients are not corrected for multiple testing. Clinical Gastroenterology and Hepatology 2015 13, 514-521.e4DOI: (10.1016/j.cgh.2014.07.027) Copyright © 2015 AGA Institute Terms and Conditions

Figure 4 Proposed algorithm for discontinuation of immunomodulator (IMM) in patients with durable response under combination treatment. ADA, adalimumab; IFX, infliximab; TL, trough level; TNF, tumor necrosis factor. Clinical Gastroenterology and Hepatology 2015 13, 514-521.e4DOI: (10.1016/j.cgh.2014.07.027) Copyright © 2015 AGA Institute Terms and Conditions

Supplementary Figure 1 Clinical outcome according to initial treatment strategy (combination treatment strategy vs infliximab [IFX] monotherapy treatment strategy). During median follow-up of 34 months (IQR, 19–58), overall 109 of 223 patients (49%) experienced a disease flare and needed infliximab dose escalation, 22 of 223 (9.9%) had IBD-related surgery, and 59 of 223 patients (26%) discontinued infliximab permanently because of infliximab failure (39 patients because of loss of response, 20 because of side effects). Cox proportional hazard regression detected no differences between the 2 treatment strategies for risk of infliximab dose escalation (A) or discontinuation of infliximab (B). Clinical Gastroenterology and Hepatology 2015 13, 514-521.e4DOI: (10.1016/j.cgh.2014.07.027) Copyright © 2015 AGA Institute Terms and Conditions

Supplementary Figure 2 Longitudinal evolution of infliximab (IFX) trough levels according to initial treatment strategy (combination treatment strategy vs infliximab monotherapy treatment strategy). This figure shows evolution of infliximab trough levels over time in the 2 treatment strategies including all available infliximab trough levels (ie, it also includes infliximab trough levels after infliximab dose escalations). Combination treatment strategy from the start (upper curve: IFX+immunomodulator [IMM]) resulted in higher infliximab trough levels than the infliximab monotherapy treatment strategy (lower curve: IFX mono) (linear mixed models estimation: 1.44, 95% CI, 1.07–1.92; P = .02). This difference was observed shortly after initiation of infliximab treatment and was maintained throughout the study (ie, evolution of infliximab trough levels over time was similar in both treatment strategies). Patients who received combination treatment initially were less likely to develop undetectable infliximab trough levels (combination strategy: 35/158 [22%] patients vs infliximab monotherapy strategy: 25/65 [38%] patients, P = .01; relative risk, 0.58 [0.38–0.88]). Also, ATI formation was lower in patients on combination strategy (14/158, 9%), compared with patients in infliximab monotherapy strategy (15/65, 23%) (P = .004; relative risk, 0.38 [0.20–0.75]). Smoothing of longitudinal profiles was performed by using linear regression splines. Boostrap-based, bias-reduced mean profiles (dashed line) and 95% confidence bands (dotted lines) were obtained by using 1000 bootstrap samples. IFX+IMM curve ends at 99 months because no samples were available after this time point. Widening of CIs over time is the consequence of reduced number of samples available for the analysis over time. Clinical Gastroenterology and Hepatology 2015 13, 514-521.e4DOI: (10.1016/j.cgh.2014.07.027) Copyright © 2015 AGA Institute Terms and Conditions