Y-ECCO Literature Review: Aravind Gokul Tamilarasan

Methods

This was a retrospective, cohort study comparing infliximab monotherapy to combination therapy (infliximab with concomitant azathioprine). The investigators included 149 IBD patients (94 with Crohn’s Disease and 55 with Ulcerative Colitis) from a tertiary university referral centre between 2011 and 2016. Patients were commenced on infliximab therapy if they had failed (or were intolerant) to azathioprine therapy. Typically, if patients were intolerant to azathioprine they would move on to infliximab monotherapy, whereas if azathioprine was ineffective (but was tolerated without side effects) the patients would be treated with combination therapy. Once clinical (absence of abdominal pain, normal bowel habit, absence of rectal bleeding) and biochemical (normalisation of CRP and/or faecal calprotectin) remission had been attained, azathioprine was stopped and infliximab continued.

Infliximab therapy in both cohorts was optimised according to therapeutic drug monitoring. Infliximab drug levels were taken after induction and then yearly for those in remission, or at times of disease flare. A trough level of 3–7 µg/ml was targeted; however, if remission was not attained at this level, the infliximab dose was escalated up to a maximum dose of 10 mg/kg every 4 weeks (provided anti-infliximab antibodies were not detected). 

Clinical outcomes and infliximab drug consumption were assessed at three time points: early (end of the induction period), intermediate (end of the first year of therapy) and late (end of follow-up). At these time points, the proportion of patients with infliximab failure was calculated and drug retention rates were assessed by Kaplan-Meier analysis. At one year, the proportion of patients with normal CRP (≤5) and the proportion of patients using systemic steroids were calculated. To standardise comparisons, infliximab doses were expressed as equivalents of mg/kg q 8 weeks. In addition, the investigators introduced a drug-to-trough level ratio to enable more accurate study of the effect of azathioprine on infliximab pharmacokinetics. This was calculated as: infliximab dose (mg)/[body weight (kg) x dosing frequency (weeks) x trough level (µg/ml)]. 

Key findings

Of the 149 patients studied, 78 (52%) were commenced on infliximab monotherapy and 71 (48%) were commenced on combination therapy. No significant differences were noted in the proportion of patients who remained on infliximab at any of the determined time points over the follow-up period (median of 19 months, IQR 12–40 months). The infliximab failure rates at the end of induction were 3/78 (4%) in the monotherapy arm and 2/71 (2%) in the combination therapy arm (p=0.73). At the intermediate time point, the results were similar between the two groups, 8/78 (10%) vs 12/71 (17%) (p=0.23). In the combination arm, 65% (13/20) lost response after cessation of azathioprine at a median of 7 months, the remainder having lost response whilst still on azathioprine.

There were no differences between the two groups at the end of the first year with regard to the use of systemic steroids or hospitalisations. Nor were there differences in rates of CRP normalisation or mucosal healing throughout the follow-up period. Endoscopic assessment was performed in 113 out of 149 patients (76%), with 65.5% demonstrating mucosal healing (Mayo 0 or 1 in UC, or the absence of ulcers for CD). There were no significant differences between the two groups when it came to the reasons for infliximab failure (drug inefficacy, IBD surgery and infusion reaction) or the rate of infusion reactions. 

Combination therapy did make a difference to the infliximab dose and infliximab trough levels at the intermediate and late time points. After one year, those in the combination therapy group were receiving a median dose of 6.4 mg/kg q 8 weeks vs 7.6 mg/kg q 8 weeks in the monotherapy arm (p=0.019), which correlated to median infliximab trough levels of 5.0 µg/ml vs 1.7 µg/ml (p=0.012) respectively. Notably, this effect wore off at the end of follow-up, which was a median of 14 months after azathioprine was ceased. The improvement in infliximab pharmacokinetics in the combination therapy group was also seen in the drug-to-trough level ratio, which was significantly lower in this group at the intermediate time point (1.46 vs 3.85, p<0.001). As might have been expected, this effect also wore off at the end of follow-up.

Conclusion

This study reinforces the notion that azathioprine improves infliximab pharmacokinetics and allows patients to achieve higher infliximab trough levels with the use of lower infliximab doses. There are, however, weaknesses in the study that warrant discussion. Firstly, the infliximab dose adjustments in both arms were not standardised and the criteria for dose escalation were not in keeping with current guidance. For example, escalation of infliximab doses due to active disease, in the presence of adequate drug levels, i.e. 3–7 µg/ml, is not supported in the literature [2]. In addition, a dose of 10 mg/kg every 4 weeks would not be supported by some institutions responsible for paying for infliximab therapy (including many clinical commissioning groups in the UK’s NHS). Admittedly this is a remnant from the pre-biosimilar era; nonetheless, the restrictions remain in place and therefore affect the ability of clinicians to use the drug doses suggested in this study.

The retrospective design of the study allows a significant amount of heterogeneity into the study, including with respect to the dosing of azathioprine (which was not optimised with thiopurine metabolite monitoring), the duration of combination treatment (median duration of 9 months) and the inherent difficulties of attempting to determine mucosal healing endpoints retrospectively. As a result, the findings of the study are insufficiently conclusive to advocate the use of infliximab monotherapy and avoidance of concomitant azathioprine. Further prospective studies into the effect of combination therapy are in the pipeline [3], the results of which will hopefully add to our ever-expanding knowledge of how best to use infliximab.

References

1. 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.
2. Kennedy NA, Heap GA, Hamilton B et al. Predictors of anti-TNF treatment failure in anti-TNF-naïve patients with active luminal Crohn’s disease: a prospective, multi-centre, cohort study. Lancet 2019; published online, February 26, 2019. http://dx.doi.org/10.1016/S2468-1253(19)30012-3 
3. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier: NCT02177071. A prospective randomized controlled trial comparing infliximab-antimetabolites combination therapy to anti-metabolites monotherapy and Infliximab monotherapy in Crohn's Disease Patients in Sustained Steroid-free Remission on Combination Therapy (SPARE). Available from https://clinicaltrials.gov/ct2/show/NCT02177071. 

Aravind Gokul Tamilarasan currently works as an IBD Clinical Fellow at Guy's and St Thomas' Hospitals (London, UK), having previously trained in Sydney, Australia. His current research interests are vedolizumab therapeutic drug monitoring and the utility of faecal microbiota transplant.