Combination Therapy With Infliximab and Immunomodulators: Is the Glass Half Empty?
Article Outline
See “Withdrawal of Immunosuppression in Crohn's Disease Treated With Scheduled Infliximab Maintenance: A Randomized Trial,” by Van Assche et al on page 1861.
Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract characterized by an inappropriate immune response to luminal bacteria. Genetic research has identified polymorphisms in several genes involved in innate immunity suggesting that defective innate immunity or defective barrier function increases Crohn's disease susceptibility through mechanisms that are not yet clear.1 Despite these new genetic data, we currently treat Crohn's disease through approaches that antagonize or suppress the immune response. The most effective therapies for Crohn's disease are immunomodulators, biologics, or combinations of the two. Although several randomized, controlled trials have been performed demonstrating the efficacy of biologic therapy, especially anti-tumor necrosis factor (TNF), for Crohn's disease, many questions remain about its optimal use.
The accompanying study by Van Assche et al2 addresses a critical issue in the management of patients on both immunomodulators and infliximab. The study seeks to determine whether continuation of immunomodulators is better than its discontinuation in patients in remission on the combination of infliximab and immunomodulators for ≥6 months. To understand the relevance of the current study, it is necessary to look at the recent history of immunomodulator and biologic therapy in Crohn's disease.
The immunomodulator drug 6-mercaptopurine (6-MP) and its parent compound azathioprine were first shown to be effective nearly 3 decades ago and are a mainstay of maintenance therapy in a significant group of patients.3 Methotrexate is also effective for steroid discontinuation and maintenance of remission in Crohn's disease.4 Several shortcomings of the immunomodulators resulted in the need for additional therapies. These include a lack of efficacy in more than one third of patients, a prolonged time to achieve therapeutic effect, significant potential side effects (leukopenia, hepatotoxicity, pancreatitis, lymphoma, severe infections, teratogenicity [methotrexate]), and difficulty tolerating the drugs (eg, abdominal pain, nausea). Given the genetic and phenotypic heterogeneity of Crohn's disease, it is understandable that no one therapy will treat all patients so more choices were necessary.
The next era of inflammatory bowel disease therapy was born with the introduction of anti-TNF therapy. The landmark study by Targan et al5 showed that antagonizing TNF-α with infliximab was effective in inducing remission in Crohn's disease. Further studies, most notably ACCENT 1, then demonstrated the superiority of scheduled dosing over episodic on-demand therapy for maintaining remission.6 Since the introduction of infliximab, we have been grappling with the best way to optimize its use.
We learned early on that episodic dosing with infliximab was a bad idea. Episodic dosing with infliximab in the absence of immunomodulators results in a high percentage of patients developing antibodies to infliximab, infusion reactions, and shortened length of response.7 Post hoc analyses of ACCENT 1 demonstrated that scheduled infliximab, with or without immunomodulators, was associated with a low rate of immunogenicity.8 Nevertheless, the early experience with infliximab led us to use combination therapy with immunomodulators and infliximab—primarily for the purposes of mitigating immunogenicity to the biologic.
Given that either infliximab or immunomodulators is effective at maintaining remission in Crohn's disease, we are faced with having to balance the benefits and the risks of dual therapy versus monotherapy once remission has been achieved. The risks have been of particular concern with the description of 13 young patients who developed hepatosplenic T-cell lymphoma on infliximab and azathioprine/6-MP.9 In addition to the concern about malignancies, the risk of opportunistic infections is increased significantly in patients on combination therapies.10 Addition of corticosteroids to any treatment for Crohn's disease significantly compounds the risk for infection.
On this background, the study by Van Assche et al2 addresses whether it is necessary to continue immunomodulators in patients who are stably in remission (for ≥6 months) on the combination of infliximab plus an immunomodulator. The authors evaluated 80 patients who met these criteria and randomized them 1:1 to either continue or discontinue the immunomodulator. At baseline, the groups were similar with respect to type of immunomodulator used (mostly AZA/6-MP), type of infliximab dosing scheme before enrollment, length of time on infliximab and immunomodulator therapy, Crohn's Disease Activity Index (CDAI), and duration and location of disease. The primary endpoint of the study was the need to shorten the interval of infliximab administration or discontinue infliximab. At the end of 2 years, there was no difference between the 2 groups in the likelihood of changing infliximab dosing or need to discontinue infliximab (P = .65). CDAI was also not statistically different between the 2 groups after 2 years.
The simple conclusion is that it is not necessary to continue immunomodulators in patients in remission on combination therapy. These top line results belie other interesting observations from this study. There was no difference in baseline C-reactive protein (CRP) between the 2 groups, but the CRP in the discontinuation group was significantly higher at the end of 2 years (although the CRP in both groups was lower than at the time of study entry). Similarly, infliximab trough levels were not different at baseline; however, using the last observation carried forward for those who had a change in infliximab dosing, there were significantly lower levels of infliximab in the discontinuation group. The trough level in the discontinuation group was <2 (compared with 2.87 in the continuation group). Prior studies have demonstrated that undetectable trough levels of infliximab are associated with a substantial decrease in the rate of remission, increased CRP, and worse endoscopic disease.11 Thus, although there was no difference in the need to change infliximab dosing by the end of 2 years, it is possible that over a longer period of time, the patients who discontinued immunomodulators might lose response at a faster rate. Interestingly, ATIs (measured at the time of the infliximab trough measurement) were low in both groups. This likely underscores the importance of immunomodulators early in the course of biologic therapy and the superiority of scheduled infliximab over episodic treatment. There were also limitations in measuring accurate levels of ATIs because most infliximab levels were >1.7 and may have interfered with the assay.
When all patients were pooled to look at infliximab trough levels and their relationship to CRP and CDAI, the authors found that those in the lower half of trough levels (<2.23) had a significantly higher CRP, and those in the bottom quartile of trough levels (<0.9) had a significantly higher CDAI. These findings again highlight the relevance of infliximab levels and the potential for differences in response over longer periods of time. The good news is that both groups had durable mucosal healing at the end of 2 years.
The other important point to be made about this study is that more than half the patients, regardless of concurrent immunomodulator use, needed to shorten the interval between infusions by the end of the 2-year study. Here lies the “glass half empty.” It seems like a good idea to discontinue immunomodulators, but in part it is because both groups experience dose escalation to the same extent, so why incur the potential burden of combined therapy? Leading up to the study, patients had already been on infliximab for a mean of 2–3 years as shown in Table 1 of the paper. The observation that the majority of patients need to dose escalate infliximab is consistent with the ACCENT 1 study in which 30% or 26% of patients randomized to 5 or 10 mg/kg every 8 weeks, respectively, also needed to increase their dose during the 1-year study.12
Given that the rate of loss of response was high despite low ATI rates, these data speak to other, more complex mechanisms of loss of response besides immunogenicity. Evidence to support the notion that certain patients experience a change in the mechanism of inflammation and become anti-TNF refractory can be gleaned from studies such as GAIN in which patients with a previous response to infliximab were treated with a different anti-TNF, adalimumab.13 Patients in the GAIN study had a relatively low rate of remission (21%) compared with patients naïve to anti-TNF therapy in the adalimumab CLASSIC study (36%).14 Unfortunately, loss of response to a first anti-TNF agent bodes poorly for use of subsequent anti-TNFs.
Several important methodologic limitations of the study should be pointed out. The patients were randomized, but neither the patients nor the treating physicians were blinded to treatment; this may introduce bias in the study. The authors' presumption of superiority of combination therapy precluded identification of small differences between the 2 groups, but as the authors acknowledge, the numbers needed for a noninferiority study would have been significantly higher.
We are not apprised of whether all patients in the study failed monotherapy with an immunomodulator before starting on infliximab. It is possible that patients were started on both drugs simultaneously or before the immunomodulator's complete therapeutic effect. This has important implications with respect to justifying discontinuation of the immunomodulator. We now know from a recent “top-down” study that patients receiving 3 doses of infliximab followed by maintenance therapy with an immunomodulator can discontinue the infliximab and maintain remission on the immunomodulator alone.15 Indeed, only one third of patients in the top-down arm required additional doses of infliximab during the ensuing 2 years. Thus, it is important to determine which drug should be stopped.
The authors should be commended for providing clinicians with important data that will inform clinical decisions. They provide compelling data that stopping immunomodulators in patients in remission on combination therapy is an acceptable strategy. Under what circumstances should the results of this study be applied? We can reasonably apply these results to patients who have failed monotherapy with an immunomodulator and whose remission was subsequently induced by infliximab. Given that patients who discontinue the immunomodulator tend to have higher CRP and lower trough levels of infliximab, caution should be applied in patients who are at risk for significant morbidity and/or mortality if their disease becomes active. Examples of this include patients with extensive small bowel disease, multiple surgeries, or severe perianal disease. For patients who were started on both immunomodulators and anti-TNFs simultaneously, it is reasonable to consider stopping the biologic. The decision to stop either the immunomodulator or the biologic is made harder in patients who are not completely in remission on combination therapy. For this group of patients, it is important to evaluate whether inflammatory disease explains their symptoms and assess whether alternative biologics (eg, natalizumab) or alternative immunomodulators (such as methotrexate) should be tried.
The next question clinicians should ask themselves is whether the results of this study can be applied to other anti-TNFs. Adalimumab is a recombinant human anti-TNF and certolizumab is a humanized, pegylated Fab fragment. Both newer anti-TNFs induce immunogenicity, which can be lessened by concurrent immunomodulators. Thus, we should be able to extrapolate the results of the current study to newer anti-TNFs.
As our colleague Daniel Present has famously proclaimed, “Crohn's disease is a disease of a lifetime.” We should use the data from this study to make informed decisions for individual patients, recognizing that all clinical trials are limited in duration and extrapolating beyond the length of the study must be done with caution. Furthermore, no one study should lead us to make radical changes in patients who are doing well on combination therapy without significant side effects. However, recognition of the premise that prompted this trial and the comparable clinical outcomes observed suggests that discontinuation of immunomodulators may be a reasonable strategy for appropriately selected patients.
References
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- Treatment of Crohn's disease with 6-mercaptopurine (A long-term, randomized, double-blind study). N Engl J Med. 1980;302:981–987
- Methotrexate for the treatment of Crohn's disease (The North American Crohn's Study Group Investigators). [comment] N Engl J Med. 1995;332:292–297
- A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease (Crohn's Disease cA2 Study Group). N Engl J Med. 1997;337:1029–1035
- Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2002;359:1541–1549
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- Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn's disease. Clin Gastroenterol Hepatol. 2004;2:542–553
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- Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology. 2008;134:929–936
- Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn's disease. Clin Gastroenterol Hepatol. 2006;4:1248–1254
- Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease. Gastroenterology. 2004;126:402–413
- Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med. 2007;146:829–838
- Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology. 2006;130:323–333
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PII: S0016-5085(08)00754-3
doi:10.1053/j.gastro.2008.04.029
© 2008 AGA Institute. Published by Elsevier Inc. All rights reserved.
Refers to article:
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Withdrawal of Immunosuppression in Crohn's Disease Treated With Scheduled Infliximab Maintenance: A Randomized Trial
, 10 March 2008
