A paradigm shift in CD clinical practice

Recent evidence shows that very early effective intervention is critically important for patients with moderate-to-severe Crohn’s disease (CD). The window of opportunity has been redefined, with time to diagnosis and time to treatment emerging as key quality-of-care metrics to drive up the standard of care in CD.

Many therapies are available for patients with CD or ulcerative colitis but are we using these treatments appropriately or at the right time? “The data suggests we are not,” said Dr Nuru Noor (University of Cambridge, UK) [1]. “In the USA, the average patient newly diagnosed with CD receives almost 5 courses of steroids before any biologic or small molecule drug is initiated” [2]. Similar findings have been reported in other countries. Therefore, it is clear that the therapeutic ceiling in CD cannot be overcome by simply more novel agents [3]. Dr Noor highlighted that “perhaps management strategy and the way we use our treatments is just as important as developing more therapies.”

“In the last 15 years, we have been talking about a window of opportunity to treat patients with CD,” Dr Noor continued [4]. “We know early treatment is important, but how early is early?” In 2013, a subgroup analysis of the CHARM study showed that initiating biological therapy within 2 years of diagnosis was more efficacious with a trend to fewer side effects than starting this type of treatment in patients with longer disease duration [5]. Subsequently, the CALM study showed that adalimumab maintenance therapy was highly efficacious in patients with CD 1 year after diagnosis [6]. “However, over 50% of the patients still did not achieve endoscopic remission,” commented Dr Noor. A recent study demonstrated higher transmural healing when biological therapy was started within 1 year of diagnosis compared with cases started later [7]. “The question arises as to whether we could treat even earlier, following the approach of our rheumatology colleagues,” said Dr Noor.

The PROFILE trial enrolled participants with moderate-to-severe CD (n=386) who had received their diagnosis less than 6 months before. Participants were randomised 1:1 to a top-down approach, starting with infliximab plus immunomodulators, or to an accelerated step-up approach, in which these drugs were only initiated if a flare was identified [8]. “The median time from diagnosis to enrolment was only about 2 weeks,” emphasised Dr Noor.

At week 48, the primary endpoint of sustained steroid-free remission was reached by 79% of the participants in the top-down strategy arm and by 15% of the participants in the step-up approach arm (P<0.001). Ulcer-free endoscopic remission was achieved by 67% of the participants in the top-down arm and by 44% of those in the step-up arm (P<0.0001). “This 67% rate is much higher than the 20–30% rate normally seen in clinical trials,” added Dr Noor.

The top-down strategy was also linked to fewer adverse events (n=168 vs n=315) and serious adverse events (n=15 vs n=42) than the step-up approach. “Thus, biologic therapy from diagnosis appears to be the most efficacious and safest treatment strategy,” according to Dr Noor. Other studies have supported the finding that the safest treatment is also the most effective [9]. In the PROFILE trial, hospitalisation for CD flare (n=15 vs n=3) and serious infections (n=8 vs n=3) were the serious adverse events that were mostly reduced with early effective therapy [8]. Notably, urgent abdominal surgeries were also less frequent in the top-down arm compared with the step-up arm (n=1 vs n=10; OR 0.095; 95% CI 0.001–0.505). “This finding suggests that we can change the course of the disease by treating patients early with biological therapies,” argued Dr Noor. This benefit is even more striking if these figures are compared with real-world data, provided that the need for abdominal surgery is 10% within the first year post-diagnosis [10]. “Thus, compared with real-world data, we noticed a 20-fold reduction in urgent abdominal surgery in the first year after diagnosis if patients were treated very early with biological therapy”.

“We know this approach is effective and safe, but is it also cost-effective ?” asked Dr Noor. A study among patients with paediatric CD showed that first-line infliximab biosimilar is cost-effective compared with conventional treatment in this population [11,12]. “Moreover, in the UK, the annual cost of adalimumab biosimilar is equal to the monthly cost of prednisolone rectal foam,” stressed Dr Noor. “Although a formal health economic analysis is ongoing, early biologic treatment appears cost-effective.”

A further persistent challenge is the delay in diagnosing CD. “Patients who are diagnosed with CD are likely to have had the disease for quite some time,” explained Dr Noor. “Thus, the clock is already ticking by the time of diagnosis,” said Dr Noor. In addition to long-term follow-up studies and health economic analyses, a translational programme is underway to better understand the biology of early CD.

“To deliver the best possible outcomes for patients with CD, we need early recognition, early diagnosis, and early effective treatment,” Dr Noor concluded.

1. 
   
   1. Noor N. Initial management of Crohn’s disease: time for a new paradigm? IP202, UEG Week 2024, 12–15 October, Vienna, Austria.
   2. Siegel C, et al. Crohn’s and Colitis 360. 2024;6(3):otae040.
   3. Magro F, et al. United European Gastroenterol J. 2023;11(2):202-217.
   4. Pariente B, et al. Inflamm Bowel Dis. 2011;17(6):1415-1422.
   5. Schreiber S, et al. J Crohns Colitis. 2013;7(3):213-221.
   6. Colombel J-F, et al. 2017;390(10114):2779-2789.
   7. Reves J, et al. Clin Gastro Hep. 2024; S1542-3565(24)00769-9.
   8. Noor N, et al. Lancet Gastro. 2024;9(5):415-427.
   9. Ahuja D, et al. Clin Gastro Hep. 2024;22(6):1286-1294.e4.
   10. Kalman TD, et al. Br J Surg. 2020;107(11):1529-1538.
   11. Jongsma MME, et al. Gut. 2022;71(1):34-42.
   12. Vuijk SA, et al. Aliment Pharmacol Ther. 2024;60(1):95-96.

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Posted on 28 November 2024