Treating newly diagnosed Crohn’s disease patients with advanced therapy leads to dramatic improvements in outcomes

A large-scale clinical trial of treatment strategies for Crohn’s disease has shown that offering early advanced treatment to all patients soon after diagnosis can significantly improve outcomes, including reducing the number of cases by tenfold. people requiring urgent abdominal surgery to treat their condition. .

The PROFILE trial, led by researchers at the University of Cambridge, included 386 patients with newly diagnosed active Crohn’s disease. Recruiting from 40 hospitals across the UK, the team sought to test whether a biomarker – a genetic signature – could predict which patients were most at risk of their disease relapsing, and to test two different approaches to treating the disease.

Crohn’s disease is a chronic illness characterized by inflammation of the digestive tract. It affects around one in 350 people in the UK. Even in its mildest form, it can cause symptoms that have a major impact on quality of life, including stomach pain, diarrhea, weight loss and fatigue.

Typically, patients experience “flares” of inflammation, during which their condition worsens over a period of time, producing more symptoms and progressive intestinal damage. Up to one in ten patients will need urgent abdominal surgery to treat their condition in the first year after diagnosis.

The results of the PROFILE trial are published in The Lancet Gastroenterology and Hepatology. Although the biomarker has not proven useful in selecting treatments for individual patients, a “top-down” treatment strategy involving the use of the drug infliximab immediately after diagnosis has shown dramatic results.

Infliximab works by blocking a protein in the body’s immune system, TNF (tumor necrosis factor) alpha, which plays an important role in inflammation. The medicine is given by regular intravenous infusions directly into the bloodstream or by injections under the skin. However, due to historical concerns about cost and side effects, including an increased risk of infection related to immunosuppression, this treatment is currently only offered when patients experience regular flare-ups that do not respond to previous treatments. less powerful.

In the PROFILE trial, patients were randomly assigned to one of two treatment groups. Each group received a different treatment strategy and patients were followed for one year.

The first group was treated using a ‘fast-track’ approach, which is the conventional treatment strategy used in the UK and most countries around the world. In this group, patients only started infliximab if their disease progressed and did not respond to other, simpler treatments.

The second group, however, was treated with top-down therapy, meaning they received infliximab as soon as possible after their diagnosis, regardless of the severity of their symptoms.

The results were dramatic: 80% of people receiving the top-down therapy had their symptoms and inflammatory markers controlled throughout the year, compared to only 15% of people receiving the fast-track therapy.

Two-thirds (67%) of patients in the step-down group had no ulcers when they were tested by an endoscopic camera at the end of the trial, known as endoscopic remission. Endoscopic remission is considered very important because it has been consistently associated with a decreased risk of subsequent complications of Crohn’s disease. Most previous clinical trials of therapies have been considered highly successful, achieving endoscopic remission in 20-30% of patients.

In addition to these findings, patients in the step-down group also had higher quality of life scores, less steroid use, and fewer hospitalizations.

Surprisingly, while approximately one in 20 (5%) patients in the trial’s conventional treatment group required urgent abdominal surgery for their Crohn’s disease, only one in 193 (0.5%) patients receiving the Top-down treatment required such surgical intervention.

Dr Nuru Noor from the Department of Medicine at the University of Cambridge, one of the study’s principal investigators and first author of the trial, said: “Historically, treatment with advanced therapy like infliximab in the two years following diagnosis was considered “early”. ” and an “accelerated ramp-up” approach therefore “good enough”. But our results redefine what should be considered early treatment.

“As soon as a patient is diagnosed with Crohn’s disease, the clock is ticking – and has probably been for some time – in terms of intestinal damage. It is therefore necessary to start advanced treatment such as infliximab as soon as possible. “We have shown that by treating earlier, we can achieve better outcomes for patients than previously reported. “

In fact, researchers say, the improvements seen in trial patients receiving top-down therapy may be even more striking compared with usual clinical care. Few Crohn’s disease patients receiving standard clinical care benefit from the step-up, accelerated approach provided by the trial protocol, and the benefits of implementing a top-down approach in standard clinical care may therefore be even more pronounced.

Importantly, the team found no difference in the risk of serious infection between treatment strategies, suggesting that infliximab immediately after diagnosis was well tolerated, contrary to previous concerns about its safety. In addition, the cost of the drug, which is now an off-patent generic and ‘biosimilar’ medicine, has fallen significantly from around £15,000 to around £3,000 per patient per year.

Chief investigator of the PROFILE trial, Professor Miles Parkes, director of the NIHR Cambridge Biomedical Research Centre, said: “The view until now has been: ‘Why would you use a more costly and potentially overtreating people if there’s a chance” they might get away with it anyway?

“As we have shown, and as previous studies have demonstrated, there is actually a fairly high risk that someone with Crohn’s disease will experience disease flares and complications, even during the course of first year following diagnosis.

“We now know that we can prevent the majority of adverse outcomes, including the need for urgent surgery, by providing a safe and increasingly affordable treatment strategy. If you take a holistic view of safety, including the need for urgent hospitalizations and surgeries, then the safest thing from the patient’s perspective is to offer top-down therapy right after diagnosis rather than having to wait and use gradual treatment.

The PROFILE team is currently actively working on a health economics analysis to see if the benefits of the therapy outweigh its cost.

Professor Parkes added: “We don’t just need to think about the five per cent of people needing surgery. In the intensified arm, many people experienced disease flares without necessarily needing surgery. And every time a person has a flare-up, they need several consultations with specialist doctors and nurses, clinical examinations such as scans and colonoscopies, time off work, absences from education, etc. , all of this has major consequences on the quality of life of individuals. »

Although there are other anti-TNF drugs, such as adalimumab, that work similarly to infliximab and are significantly less expensive, more research is needed to understand whether they would be as effective in terms of clinical.

Ruth Wakeman, director of services, advocacy and evidence at Crohn’s & Colitis UK, said: “Crohn’s disease affects more than 200,000 people in the UK and we know that many of them have symptoms for a long time. before being diagnosed. But diagnosis is not the solution. end of their journey, and the trial and error required to find the right treatment can be difficult and distressing.

“This study shows what a dramatic difference early treatment with advanced therapy can make for newly diagnosed patients. People with Crohn’s disease don’t want to be stuck in the hospital or have surgery, they want to be in the world and live their lives. Anything that speeds up the path to remission can only be a good thing.”