Early Trough Levels and Antibodies to Infliximab Predict Safety and Success of Reinitiation of Infliximab Therapy

Published:January 31, 2014DOI:https://doi.org/10.1016/j.cgh.2014.01.033

      Background & Aims

      Few agents are available for the treatment of inflammatory bowel diseases, and patients frequently become unresponsive to biologics. We investigated the feasibility of reinitiating infliximab therapy for patients who previously received only episodic therapy with, lost response to, or had infusion reactions to infliximab. We also aimed to identify factors associated with the success and safety of restarting infliximab, such as antibodies to infliximab and trough levels of the drug.

      Methods

      From the inflammatory bowel disease biobank, we identified 128 consecutive patients (105 patients with Crohn's disease, 23 patients with ulcerative colitis) who restarted infliximab after a median 15-month discontinuation (range, 6–125 mo; 28 patients for loss of response or infusion reactions, 100 patients for remission or pregnancy). We also analyzed serum samples that had been collected during the first period of infliximab therapy (T-1), when therapy was reinitiated (T0), and at later time points (T+1, T+2) for trough levels and antibodies to infliximab. We investigated correlations among response to treatment, infusion reactions, treatment modalities, trough levels, and antibodies to infliximab.

      Results

      Reinitiation of infliximab therapy produced a response in 84.5% of patients at week 14, 70% of patients at 1 year, and in 61% of patients at more than 4 years. Fifteen patients had acute infusion reactions and 10 patients had delayed infusion reactions. The absence of antibodies to infliximab at T+1 (hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.026–0.74; P = .021) and reinitiation with concomitant immunomodulator therapy were associated with short-term responses (HR, 6.0; 95% CI, 1.3–27; P = .019). Pregnancy or remission as reason for discontinuation (HR, 2.70; 95% CI, 1.09–6.67; P = .033) and higher trough levels at T+1 (HR, 2.94; 95% CI, 1.18–7.69; P = .021) were associated with long-term response. Undetectable antibodies to infliximab at T+1 were associated with the safety of reinitiating therapy (HR for infusion reaction with detectable antibodies to infliximab, 7.7; 95% CI, 1.88–31.3; P = .004).

      Conclusions

      Reinitiating infliximab therapy can be safe and effective for patients with Crohn's disease or ulcerative colitis after a median 15-month discontinuation period.

      Keywords

      Abbreviations used in this paper:

      ATI (antibodies to infliximab), CI (confidence interval), CRP (C-reactive protein), HR (hazard ratio), IBD (inflammatory bowel disease), IFX (infliximab), IMM (immunomodulator), IR (infusion reaction), IV (intravenous), LOR (loss of response), ROC (receiver operating curve), TL (trough level), TNF (tumor necrosis factor)
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      References

        • Peyrin-Biroulet L.
        Anti-TNF therapy in inflammatory bowel diseases: a huge review.
        Minerva Gastroenterol Dietol. 2010; 56: 233-243
        • Chaparro M.
        • Martinez-Montiel P.
        • Van Domselaar M.
        • et al.
        Intensification of infliximab therapy in Crohn's disease: efficacy and safety.
        J Crohns Colitis. 2012; 6: 62-67
        • Billioud V.
        • Sandborn W.J.
        • Peyrin-Biroulet L.
        Loss of response and need for adalimumab dose intensification in Crohn's disease: a systematic review.
        Am J Gastroenterol. 2011; 106: 674-684
        • Baert F.
        • Glorieus E.
        • Reenaers C.
        • et al.
        Adalimumab dose escalation and dose de-escalation success rate and predictors in a large national cohort of Crohn's patients.
        J Crohns Colitis. 2013; 7: 154-160
        • Gisbert J.P.
        • Panés J.
        Loss of response and requirement of infliximab dose intensification in Crohn's disease: a review.
        Am J Gastroenterol. 2009; 104: 760-767
        • 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 therapy.
        Aliment Pharmacol Ther. 2011; 34: 1-10
        • 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: 601-608
        • Baert F.
        • De Vos M.
        • Louis E.
        • et al.
        Immunogenicity of infliximab: how to handle the problem?.
        Acta Gastroenterol Belg. 2007; 70: 163-170
        • Wang S.L.
        • Ohrmund L.
        • Hauenstein S.
        • et al.
        Development and validation of a homogeneous mobility shift assay for the measurement of infliximab and antibodies-to-infliximab levels in patient serum.
        J Immunol Methods. 2012; 382: 177-188
        • Vande Casteele N.
        • Gils A.
        • Singh S.
        • et al.
        Antibody response to infliximab and its impact on pharmacokinetics can be transient.
        Am J Gastroenterol. 2013; 108: 962-971
        • Van de Casteele N.
        • Buurman D.J.
        • Sturkenboom M.G.
        • et al.
        Detection of infliximab levels and anti-infliximab antibodies: a comparison of three different assays.
        Aliment Pharmacol Ther. 2012; 36: 765-771
        • Farrell R.J.
        • Alsahli M.
        • Jeen Y.T.
        • et al.
        Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn's disease.
        Gastroenterology. 2003; 124: 917-924
        • Steenholdt C.
        • Svenson M.
        • Ainsworth M.A.
        • et al.
        Comparison of techniques for monitoring infliximab bioavailability and immunogenicity in Crohn's disease.
        Gastroenterology. 2012; 142 (S-781)
        • Seow C.H.
        • Newman A.
        • Irwin S.P.
        • et al.
        Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis.
        Gut. 2010; 59: 49-54
        • Vande Casteele N.
        • Ballet V.
        • Van Assche G.
        • et al.
        Early serial trough and antidrug antibody level measurements predict clinical outcome of infliximab and adalimumab treatment.
        Gut. 2012; 61: 321
        • Cornillie F.
        • Hanauer S.
        • Diamond R.H.
        • et al.
        Can clinical, biological or pharmacological markers predict sustained response to infliximab? A retrospective analysis of ACCENT 1.
        Gut. 2011; 60: A296
        • Arias M.T.
        • Vande Casteele N.
        • Drobne D.
        • et al.
        Importance of trough levels and antibodies on the long term treatment efficacy of infliximab therapy in ulcerative colitis.
        J Crohn Colitis. 2012; 6: S5
        • Colombel J.F.
        • Sandborn W.J.
        • Allez M.
        • et al.
        Certolizumab pegol plasma concentrations and endoscopic response and remission in Crohn's disease.
        Gut. 2012; 61: A81
        • Lichtenstein G.R.
        • Diamond R.H.
        • Wagner C.L.
        • et al.
        Benefits and risks of immunomodulators and maintenance infliximab for IBD-subgroup analyses across four randomized trials.
        Aliment Pharmacol Ther. 2009; 30: 210-226
        • Drobne D.
        • Bossuyt P.J.
        • Breynaert C.
        • et al.
        Infliximab trough levels and CRP during infliximab-immunomodulator combination treatment for Crohn's disease are associated with clinical outcome after immunomodulator withdrawal.
        Gastroenterology. 2011; 140 (S-279)
        • Ungar B.
        • Chowers Y.
        • Yavzori M.
        • et al.
        The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab.
        Gut. 2014; 63: 1258-1264
        • Ben-Horin S.
        • Waterman M.
        • Kopylov U.
        • et al.
        Addition of an immunomodulator to infliximab therapy eliminates anti-drug antibodies in serum and restores clinical response of patients with inflammatory bowel disease.
        Clin Gastroenterol Hepatol. 2013; 11: 444-447
        • Ordas I.
        • Mould D.R.
        • Feagan B.G.
        • et al.
        Anti-TNF monoclonal antibodies in IBD: pharmacokinetics-based dosing paradigms.
        Clin Pharmacol Ther. 2012; 91: 635-646
        • Vande Casteele N.
        • Compernolle G.
        • Ballet V.
        • et al.
        OP11 Individualised infliximab treatment using therapeutic drug monitoring: A prospective controlled Trough level Adapted infliXImab treatment (TAXIT) trial.
        J Crohns Colitis. 2012; 6 (S-6)

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