Y-ECCO Literature Review: Chris Roberts

Even prior to PROFILE, evidence was building that earlier introduction of advanced therapies can lead to improved longer-term outcomes for patients [1]. This observation had been supported by post-hoc analysis of data from clinical trials and meta-analyses, demonstrating better outcomes with early treatment – and “early treatment” in this context has typically been considered as starting an advanced therapy within two years of diagnosis [2–4].

One reason for the widespread ongoing use of step-up or accelerated step-up treatment strategies has been the perception that it is not possible to identify which patients would benefit from a top-down approach. This was the premise for development and validation of a blood-based 17-gene biomarker, which was shown to stratify patients into higher and lower risk subgroups (IBDhi or IBDlo) in two prospective observational cohorts [5]. Subsequently, Noor and colleagues sought to conduct the first biomarker-stratified randomised controlled trial in the field. PROFILE aimed to answer two key questions: first, whether this blood-based biomarker could be used to stratify patients at diagnosis and improve outcomes, and second, whether the optimal treatment strategy for patients newly diagnosed with CD is an accelerated step-up or a more top-down treatment strategy.

Methods

Patients with newly diagnosed active CD were randomised. Importantly, the inclusion criteria were pragmatic and patients had to be symptomatic, have raised inflammatory markers and have endoscopic evidence of inflammation. Strikingly, patients in this cohort were treated very early in their disease course, being enrolled within two weeks of diagnosis. Baseline characteristics were well matched between the accelerated step-up and the top-down group based on CD severity. Patients were randomised in a 1:1 ratio (stratified by biomarker status) to receive either accelerated step-up or top-down treatment. Patients were then followed up for 48 weeks until endpoint data were collected. The primary endpoint was the incidence of steroid and surgery-free remission throughout the trial until week 48. Key secondary endpoints included endoscopic remission at week 48, defined by the absence of ulceration (SES-CD ulcer subscore 0) and quality of life (measured using IBD-Q).

Key findings

When focusing on the treatment effect, a significant difference in results was observed with regard to the primary outcome. Those receiving top-down therapy had a rate of remission of 79% compared to only 15% in the accelerated step-up group. Of note, 41% of patients in the accelerated step-up group had been escalated both to an immunomodulator and then to anti-TNF therapy by week 48, so this represented a truly accelerated step-up strategy in PROFILE. Similar to the primary endpoint, all secondary endpoints demonstrated superiority for the top-down approach, including for endoscopic remission and quality of life.

Perhaps the most striking evidence of benefits from a top-down approach was provided by the objective measures. The endoscopic remission rate of 67% at week 48 in the top-down group was  much higher than the 20%–30% endoscopic remission rates reported in most CD clinical trials, which had increasingly been considered a therapeutic ceiling of efficacy. Importantly, there was also a tenfold reduction in need for urgent abdominal surgery with top-down therapy even by week 48. In particular, all patients who had urgent abdominal surgery in the accelerated step-up group required surgery for a stricturing or penetrating complication of their CD, whereas in the top-down group only a single patient required abdominal surgery and this was unrelated to CD.

An important factor which has likely limited use of a top-down approach in real-world clinical practice has been concern over a potential increase in adverse events.  However, in PROFILE there were reduced rates of both adverse events and serious adverse events in the top-down group – at least until the end of one year of data collection.

Given the large treatment effect demonstrated, it is perhaps unsurprising that no evidence of clinical utility was demonstrated for the blood-based biomarker. Indeed, not only did the biomarker blood test show no ability to predict later outcomes, but none of the clinical variables which have historically been associated with disease course showed any ability to predict later outcomes in the PROFILE cohort.

Discussion

The clear finding from PROFILE is that use of a top-down approach delivered better outcomes for patients with newly diagnosed CD compared to an accelerated step-up approach. Indeed, use of a top-down strategy straight after diagnosis was not only shown to be more efficacious but also appeared to be the safer treatment strategy, at least until the end of one-year follow-up. There are, however, several limitations to consider when interpreting these data.

First, although the safety data until the end of primary follow-up are reassuring, it will be important to collect and report on longer-term safety outcomes from a top-down approach straight after diagnosis. In this regard we look forward to data from the PROFILE longer-term extension study. All patients needed raised inflammatory markers and specified thresholds of endoscopic inflammation for inclusion. Although the inclusion criteria do apply to the majority of patients newly diagnosed with luminal CD, caution should be applied before trying to extrapolate these results to patients with very mild CD. Similarly, PROFILE was a clinical trial for patients with CD so these findings cannot be extrapolated to Ulcerative Colitis. PROFILE was an open-label trial, i.e. the treating clinicians were unblinded to the treatment strategy (although they were blinded to the biomarker status throughout the trial). The open-label nature could have introduced bias and exacerbated the differences in outcomes between the two treatment arms. However, it is likely not possible to perform a pragmatic trial of treatment strategies without an open-label approach. Moreover, given the magnitude of difference seen across outcomes, it seems highly unlikely that the open-label nature would have affected the overall results. An important further aspect of the longer-term follow-up will be to report on data regarding treatment continuation, or whether de-escalation of treatment could be attempted in such a population following very early inflammatory control with a top-down approach.

Conclusion

Overall, the findings from PROFILE are likely to have a large impact on clinical practice. The trial provides data to support early treatment decision-making by patients with their clinicians. Use of an effective therapy straight after diagnosis, without the need for prognostication, was shown to be more efficacious and indeed safer than an accelerated step-up strategy for patients meeting the PROFILE inclusion criteria. Going forward, it will be important for centres to audit their local practices and ensure that patients with a new diagnosis of active CD are being offered appropriate access to early, effective therapy.

References

1. Hossain A, Lördal M, Olsson AE, et al. Sustained clinical benefit, improved quality of life, and reduced intestinal surgery from maintenance infliximab treatment in inflammatory bowel disease. Scand J Gastroenterol 2020;55:178–83. doi:10.1080/00365521.2020.1722738.
2. D’Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet 2008;371:660–7. doi:10.1016/S0140-6736(08)60304-9.
3. Safroneeva E, Vavricka SR, Fournier N, et al. Impact of the early use of immunomodulators or TNF antagonists on bowel damage and surgery in Crohn’s disease. Aliment Pharmacol Ther 2015;42:977–89. doi:10.1111/apt.13363.
4. Ben-Horin S, Novack L, Mao R, et al. Efficacy of biologic drugs in short-duration versus long-duration inflammatory bowel disease: a systematic review and an individual-patient data meta-analysis of randomized controlled trials. Gastroenterology 2022;162:482–94. doi:10.1053/j.gastro.2021.10.037.
5. Biasci D, Lee JC, Noor NM, et al. A blood-based prognostic biomarker in IBD. Gut. 2019;68:1386–95. doi:10.1136/gutjnl-2019-318343.

Christopher Roberts - Short Biography

Christopher Roberts is an Academic Clinical Fellow in Gastroenterology based at the Royal Devon and Exeter NHS Foundation Trust in the United Kingdom. He is currently undertaking his Fellowship within the Exeter IBD research group, with a particular focus on translating pharmacogenetic research into clinical practice. His current main research project is on delivering NUDT15 genotype testing into NHS clinical practice.