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Back to the Beginning: Restarting Infliximab in Inflammatory Bowel Disease Patients With Prior Loss of Response

Published:April 14, 2014DOI:https://doi.org/10.1016/j.cgh.2014.04.011
      Podcast interview: www.gastro.org/cghpodcast. Also available on iTunes.
      Infliximab was the first anti–tumor necrosis factor (TNF) biologic for Crohn's disease (CD) and still is used frequently for its efficacy in both CD and ulcerative colitis. When infliximab initially became available, it was approved only for induction therapy. Many patients were ill-served by this approach because we now realize that intermittent dosing promotes immunogenicity. Some patients discontinue biologics when in remission and we now have the data from the STORI (infliximab diSconTinuation in CrOhn's disease patients in stable Remission on combined therapy with Immunosuppressors) trial to better guide which CD patients are likely to stop infliximab successfully.
      • Louis E.
      • Mary J.Y.
      • Vernier-Massouille G.
      • et al.
      Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped.
      What is more common, however, is that patients lose response to infliximab or develop infusion reactions and thereafter discontinue infliximab. Studies have shown that loss of response to infliximab is about 13% per patient-year of treatment.
      • Gisbert J.P.
      • Panés J.
      Loss of response and requirement of infliximab dose intensification in Crohn's disease: a review.
      Immunogenicity against the drug (antibodies to infliximab [ATI]) plays a key role in the loss of response. Patients with ATI are at a higher risk of developing infusion reactions and having lower trough infliximab levels.
      • Nanda K.S.
      • Cheifetz A.S.
      • Moss A.C.
      Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis.
      • Baert F.
      • Noman M.
      • Vermeire S.
      • et al.
      Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease.
      A potential strategy when this happens is to switch to another anti-TNF such as adalimumab, certolizumab pegol (in patients with CD), or golimumab (in patients with ulcerative colitis), but studies have shown that the second or third anti-TNF generally is less effective than the first.
      • Sandborn W.J.
      • Rutgeerts P.
      • Enns R.
      • et al.
      Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial.
      • 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.
      For many patients, infliximab was the first anti-TNF and the one with the best efficacy. Clinicians understandably have been reluctant to rechallenge patients with infliximab given the fear of immediate or delayed hypersensitivity reactions with dose interruptions. The question is: is it safe or effective to restart patients on infliximab even when they had lost response or had infusion reactions in the past?
      In this issue of Clinical Gastroenterology and Hepatology, Baert et al
      • Baert F.
      • Drobne D.
      • Gils A.
      • et al.
      Early trough levels and antibodies to infliximab predict safety and success of reinitiation of infliximab therapy.
      described the outcomes of a cohort of patients who were restarted on infliximab after a drug holiday. Although most patients discontinued the first course of infliximab because of remission, pregnancy, or patient decision, 22% were restarted on infliximab after loss of response despite dose optimization or a serious infusion reaction. The average duration of infliximab holiday was 15 months. The investigators obtained measurements of ATIs before restarting infliximab to determine if this helped predict infusion reactions or efficacy.
      Restarting infliximab was successful in most patients, including a subset of those who previously had lost response to the drug. None of the patients had ATIs before reinduction. ATIs before the second infliximab induction dose were associated with decreased response. On the other hand, co-treatment with immunomodulators at the time infliximab was restarted had a beneficial effect, and patients did better if they had discontinued the infliximab. For long-term outcomes, patients did better if they discontinued the infliximab originally when they were in remission rather than because of loss of response or an infusion reaction. In this cohort, most patients discontinued infliximab when in remission. High trough levels after the first dose, before the second induction dose, also correlated with better long-term efficacy of infliximab.
      The first important message in this study was that restarting infliximab after a drug holiday is feasible. Patients who were in remission at the time infliximab was discontinued were the best candidates, with a 78% response rate at 1 year. In patients with a previous loss of response or an infusion reaction, the strategy was effective in 45% of patients at 1 year, which was much less than the other group, but this may be enough in cases where the patient has failed other anti-TNFs. Therefore, if other anti-TNFs have failed in patients with previous loss of response to infliximab, restarting infliximab is an option. The results of these studies may be skewed because it appears that unlike patients in the United States, most patients at the academic center in Leuven stopped infliximab while in remission, whereas most patients in the United States discontinued because of loss of response and thus this needs to be taken into account in making clinical decisions.
      How safe is the strategy? Of the 128 patients re-treated, 7 had severe infusion reactions, generally during the second or third induction dose. Although most patients with infusion reactions were ATI-positive, most ATI-positive patients responded to treatment and did not develop a reaction, so ATI positivity alone should not prevent the use of infliximab. Most patients that were ATI positive did not develop an infusion reaction, and therefore ATI positivity alone should not prevent the use of infliximab. Unfortunately, premedication did not protect against all infusion reactions but concomitant immunomodulators did. Therefore, immunomodulator therapy should be strongly considered in these patients. For those who are ATI positive, the patient and staff should be aware of the risk of infusion reactions and provide a slow infusion protocol and possibly steroids before the administration of the drug.
      • Cheifetz A.
      • Smedley M.
      • Martin S.
      • et al.
      The incidence and management of infusion reactions to infliximab: a large center experience.
      The study bolsters the use of concomitant immunomodulator therapy. Most studies have shown that concurrent immunomodulators not only increase infliximab levels, but also decrease immunogenicity and potentially can decrease the ATI levels when they are added to an ongoing infliximab regimen.
      • Baert F.
      • Noman M.
      • Vermeire S.
      • et al.
      Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease.
      • 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.
      Also, the combination of both drugs has been shown to be more efficacious than infliximab alone, reducing hospitalizations and surgical rates.
      • Colombel J.F.
      • Sandborn W.J.
      • Reinisch W.
      • et al.
      Infliximab, azathioprine, or combination therapy for Crohn's disease.
      • Abraham B.P.
      • Richardson P.
      • Castillo D.
      • et al.
      Dual therapy with infliximab and immunomodulator reduces one-year rates of hospitalization and surgery among veterans with inflammatory bowel disease.
      Combination therapy should be encouraged in patients who have disease not responding to several anti-TNFs and for whom infliximab is being considered after a drug holiday, but the decision of continuing immunomodulators after a period of time in remission still is controversial.
      This study also was key in guiding clinicians on using infliximab levels and ATIs for selecting patients who would be most likely to benefit from restarting infliximab after a period of time off the drug. It seems reasonable to check drug levels and antibodies before the second infliximab dose. Infliximab trough levels greater than 2 μg/mL and undetectable ATIs early after restarting the drug were associated with good short- and long-term responses. The actual value of the infliximab trough that is ideal may vary depending on the laboratory where it is performed. An important question would be how many patients can be rescued by increasing the dose of infliximab to achieve the target level. Baert et al
      • Baert F.
      • Drobne D.
      • Gils A.
      • et al.
      Early trough levels and antibodies to infliximab predict safety and success of reinitiation of infliximab therapy.
      identified detectable ATIs as a predictive factor for loss of response, however, the presence of ATIs should not always prompt discontinuation of therapy because studies have shown that many of these ATIs are transient and can disappear over time.
      • Ungar B.
      • Chowers Y.
      • Yavzori M.
      • et al.
      The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab.
      Vande Casteele et al
      • Vande Casteele N.
      • Gils A.
      • Singh S.
      • et al.
      Antibody response to infliximab and its impact on pharmacokinetics can be transient.
      showed that patients who lose response to infliximab and have ATIs can also be optimized by increasing the biologic dose when the ATI levels are less than 9.1 U/mL. This phenomenon was seen in this study as well. After infliximab re-exposure, ATIs were detectable in 40% of patients before the second infliximab dose but in only 29% of patients before the third dose. There is also a question regarding testing for infliximab levels and ATI vs increasing the dose empirically. Velayos et al
      • Velayos F.S.
      • Kahn J.G.
      • Sandborn W.J.
      • et al.
      A test-based strategy is more cost effective than empiric dose escalation for patients with Crohn's disease who lose responsiveness to infliximab.
      found that the former may be cost effective, but these results may depend on the type and cost of the assay used.
      How can clinicians apply the current data to their IBD patients? The best scenarios are patients who discontinued infliximab because they were in remission. In this case, a relapse should be treated first with infliximab rather than change anti-TNFs. Conversely, for patients who lost response to infliximab and tried and failed other anti-TNFs it is reasonable to start (or restart) an immunomodulator along with infliximab. The long-term 45% rate of response is likely to be similar to a second or third anti-TNF course. Therefore, restarting infliximab can be positioned after a second or third anti-TNF for most patients with previous loss of response to infliximab. ATIs and trough levels after the first induction dose can be used to stratify how successful infliximab will be and to make early interventions, especially increasing the dose of infliximab to increase trough levels. For patients with high ATIs (≥9.1 U/mL), another drug should be considered because they likely will not respond to therapy or drug optimization. Incorporation of testing drug levels and ATIs appears useful and allows a more personalized approach to their care. With the recent approval of vedolizumab, we expect that patients who have a lack of response in spite of adequate trough levels of anti-TNF will benefit from a change in mechanism of biologic action.

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