Infliximab Induction Regimens in Steroid-Refractory Acute Severe Colitis

A Multicentre Retrospective Cohort Study With Propensity Score Analysis

Shaji Sebastian; Sally Myers; Konstantinos Argyriou; Gayle Martin; Louis Los; Joseph Fiske; Ravi Ranjan; Benjamin Cooper; Vivek Goodoory; Hey-Long Ching; NishaniLalanthika Jayasooriya; Johanne Brooks; Anjan Dhar; Achut H. Shenoy; Jimmy K. Limdi; Jeffrey Butterworth; Patrick B. Allen; Sunil Samuel; Gordon W. Moran; Richard Shenderey; Gareth Parkes; Alan Lobo; Nicholas A. Kennedy; Sreedar Subramanian; Tim Raine

Disclosures

Aliment Pharmacol Ther. 2019;50(6):330-335. 

In This Article

Discussion

Despite the increasing use of infliximab rescue therapy in patients failing intravenous steroids, a significant proportion of ASUC patients do not respond adequately to standard induction dosing. Pharmacokinetic data have led to increasing use of intensified or accelerated dosing schedules in rescue therapy for ASUC patients. Our large multicentre retrospective study showed no difference in colectomy rates in the overall cohort of patients receiving standard vs accelerated dosing schedules but when provider bias was accounted for in the propensity-matched cohort, we found a reduction in short-term colectomy rates in patients receiving accelerated induction.

The first study to report the potential benefit of more frequent infliximab infusions in ASUC patients was from Gibson et al in Ireland,[16] who in their cohort of 50 hospitalised patients with ASUC showed a reduction in short-term colectomy rates in the 15 patients who received three doses of 5 mg/kg within 24 days when compared to those receiving standard induction regimen (6.7% vs 40%, P = 0.039). This study also suggested shortened time to colectomy in those receiving standard regime although the long-term colectomy rates were similar. Notably, 38% of these patients had lower endoscopic disease severity (Mayo 2), and the authors did not correct for provider bias in the choice of regimen. Furthermore, the definition of accelerated dosing in this study did not include the need for a further dose 7 days after the first dose or increased front-loading dose. Subsequent studies examining the use of increased frequency of infliximab at 5 mg/kg[17,18,21,22] and a recent meta-analysis[19] have not confirmed the benefit as reported by Gibson et al In one study,[21] there was an increased risk of colectomy with accelerated induction. Our colectomy rates in the overall unmatched cohort mirror the results from these studies showing no additional significant benefit in short-term colectomy rates with accelerated induction.

Some studies[21,23] have assessed an early aggressive approach aimed at overcoming proposed faecal losses of infliximab using a front-loading higher dose of 10 mg/kg in ASUC patients. In our study, only four patients received a higher initial dose and hence could not be analysed separately. Results of a randomised controlled trial from Australia (ClinicalTrials.gov Identifier: NCT02770040) comparing various dosing strategies are eagerly awaited.

A number of patient- and disease-related variables have been suggested as high risk for needing colectomy in patients with ASUC.[24,25] These indices were developed in the pre-infliximab rescue therapy era and the relevance of this in patients considered for rescue therapy is uncertain. More recently, a number of other patient-related factors such as serum albumin, serum albumin/CRP ratio and haemoglobin nadir have been proposed as predictive risk factors for colectomy at index admission.[16,26] We have identified CRP/albumin ratio > 2 as a predictor for colectomy (unpublished data). However, at present, there is no consensus on the consistent identification and risk stratification of patients not only needing rescue therapy but also those who may potentially benefit from different dosing strategies. This lack of consensus inevitably leads to variations in the management and dosing regimens[27] as seen in our study. The blood parameters at first and second doses of rescue therapy indicate lack of improvement or indeed worsening which along with clinical symptom may prompt a second dose as accelerated induction (Data S1, Supplementary Table 1 and Supplementary Table 2).

One of the strengths of our study is the attempt to compare the outcomes between the different dosing regimens after accounting for the potential bias of baseline clinical and demographic variables and the potential impact of these in clinicians' choice using a propensity score-matched method. Our model incorporated established disease severity markers such as CRP, serum albumin, CRP/albumin ratio and haemoglobin levels at induction and endoscopic disease severity. This is the first study to report a benefit of accelerated induction regimes when taking into the potential for provider bias based on differing disease severity. Nalagatla et al[23] adjusted for the propensity score in their multivariable model and found no difference in in-hospital colectomy rates (OR 0.70, 95% CI 0.16-3.01). However, the overall colectomy rates in both groups in this study (8%-9%) were substantially lower than our study (17%-21%). This may be related to overall lower disease severity in all parameters in the patients included in this study when compared to our cohort. In a study by Shah et al,[21] after adjusting for patient- and disease-related factors and provider bias in a propensity score-matched model, no reduction in colectomy rates was found in those receiving higher upfront dosing when compared to standard dosing. This study only included patients from a single centre and differed from ours by including patients with prior infliximab exposure before rescue therapy. Furthermore, in this study and in the study by Nalagatla et al,[23] the endoscopic disease severity of patients in the propensity-matched cohort was milder (30% having an endoscopic Mayo score of 2) when compared to our study where 97% of the included patients in our matched cohort had severe disease (Mayo 3) at endoscopy. Thus, our results suggest that early identification of patients with high-risk features for colectomy may reduce colectomy rates by the use of accelerated rescue therapy.

In the unmatched cohort, the duration of hospital stay was significantly shorter in those receiving standard induction. In the matched cohort, on the other hand, there was no difference in the length of stay. Our results were similar to that of Shah et al,[21] where the median length of stay was identical in those receiving standard induction and accelerated induction in the matched cohort. In that study, in the unmatched cohort there were higher complications in the standard-dose group when compared to the high-dose group, a finding not seen in our unmatched cohort. However similar to our results in that study, the overall complication rate including infectious and/or non-infectious complications was not significantly higher in the high-dose group compared to standard-dose group in the propensity-matched cohort. Thus, overall accelerated dosing regimens did not seem to increase the risk of complications. There was one death in the accelerated induction group as a result of post-operative rectal stump leak and sepsis resulting in multiorgan failure.

We acknowledge that our study has a number of limitations. Due to the retrospective nature of the study, we were unable to collect every variable each day following admission with ASUC and were also unable to record the objective assessment of response and remission. We also had no data on serum infliximab levels or biomarkers such as faecal calprotectin in patients receiving rescue therapy. There is increasing focus on the use of therapeutic drug monitoring in IBD patients treated with infliximab and the impact of dose optimisation utilising drug levels on the outcomes could not be ascertained in this study. There were significant differences in the unmatched cohort of patients and also heterogeneity in dosing regimens and timing indicating variations in practice in the real-world setting. Hence, although this was a multicentre study and one of the largest to compare rescue therapy regimes, our attempt to reduce provider variation by propensity score matching led to a relatively small sample size in the matched cohort thus reducing the power of our study for the primary outcome and rate of complications. Furthermore, our model cannot account for the variability in management including dose optimisation during the maintenance period which could have affected the outcome. That said, controlling for bias of treatment choice based on disease in a multicentre cohort is a major strength of our study.

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