Providing Early Advanced Therapy for Crohn’s Disease Dramatically Improves Outcomes

Research led by investigators from the University of Cambridge has shown that administration of the drug infliximab for newly-diagnosed patients of Crohn’s disease dramatically improves outcomes—including the reduction of people needing abdominal surgery for treatment by ten-fold. Results of the trial were published this week in The Lancet.

Called the PROFILE trial, researchers initially sought to determine whether a biomarker of Crohn’s disease that could predict which patients were at greater risk of symptom relapses, and to test different approaches to treatment. While the biomarker proved not to be effective in identifying patients at risk of relapse for individual patients, the trial did reveal that taking a “top-down” strategy for treating the disease using infliximab showed significant improvements in treating patients.

Infliximab works by blocking a protein found in the body’s immune system, TNF (tumor necrosis factor)-alpha, which plays an important role in inflammation. Until now, infliximab has been restricted to treating only those patients who experience regular Crohn’s flare-ups, due to concerns about side effects and cost. Patients who receive the drug are at increased risk of developing infection due to the immunosuppressive effects of the drug.

The PROFILE trial sought to better understand how infliximab could improve treatment for those newly diagnosed with the disease. In this study, Crohn’s disease patients were randomly assigned to one of two treatment groups, each with a different treatment strategy. Patients were then followed over a one-year period to determine outcomes.

One cohort in the trial received what was termed an “accelerated step-up” approach that incorporated the traditional treatment strategy for those newly diagnosed. In this group, patients were only progressed to treatment with infliximab if their disease was progressing and they weren’t responding to their early treatments. The other patient cohort was treated via the top-down approach with infliximab provided as treatment as soon as possible after a patient’s initial Crohn’s disease diagnosis.

The findings were eye opening, showing that 80% of those who were in the top-down treatment arm had both their symptoms and inflammatory biomarkers controlled for duration of the one-year study, compared with only 15% in group that only moved patients to infliximab if initial treatments weren’t having an effect. Significantly, the research also showed that while roughly one-in-20 patients—or 5%—in the conventional treatment group needed abdominal surgery for their Crohn’s disease, only one person of 193 patients in the top-down group required such surgery.

“Historically, treatment with an advanced therapy like infliximab within two years of diagnosis has been considered ‘early’ and an ‘accelerated step-up’ approach therefore ‘good enough,’ said co-lead researcher Nuru Noor, PhD, a clinical fellow in the Department of Medicine at the University of Cambridge. “But our findings redefine what should be considered early treatment.

“As soon as a patient is diagnosed with Crohn’s disease, the clock is ticking—and has likely been ticking for some time—in terms of damage happening to the bowel, so there’s a need to start on an advanced therapy such as infliximab as soon as possible. We’ve shown that by treating earlier, we can achieve better outcomes for patients than have previously been reported.”

The researchers further noted that the top-down approach may show even greater improvements as measured against those receiving the usual clinical care as few patients in the real-world setting receive even the accelerated step-up approach.

Another significant finding of the trial was that there was no difference of serious infection between the two different treatment strategies, showing that the early administration of infliximab was well-tolerated, which runs counter to historic concerns about how safe it is to prescribe the drug early. Further, the cost of the drug has decreased considerably due to it going off patent and generic versions have become available. Previously the cost per patient was around £15,000 per year, and now it is one-fifth of that amount at roughly £3,000 per year.

“We now know we can prevent the majority of adverse outcomes, including need for urgent surgery, by providing a treatment strategy that is safe and becoming increasingly affordable,” said Miles Parkes, director of the NIHR Cambridge Biomedical Research Centre, and the PROFILE study’s chief investigator. “If you take a holistic view of safety, including the need for hospitalisations and urgent surgery, then the safest thing from a patient point of view is to offer ‘top-down’ therapy straight after diagnosis rather than having to wait and use ‘step-up’ treatment.”

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