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

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, and in collaboration with the National Institute for Health and Care Research (NIHR) Clinical Research Network, it sought to test whether a biomarker – a genetic signature – could predict May determine which patients are at highest risk of relapse. To examine their condition, and two different methods of treating the disease.

Crohn’s disease is a lifelong condition characterized by inflammation of the digestive tract. It affects one in 350 people in the UK. Even at its mildest, it can cause symptoms that have a major impact on quality of life including: abdominal pain, diarrhea, weight loss and fatigue. Patients usually experience ‘flares’ of inflammation, where their condition worsens for a period of time, leading to more symptoms and further damage to the gut. One in 10 patients will need urgent abdominal surgery to treat their condition within the first year of diagnosis.

The results of the PROFILE trial, run by Cambridge University Hospitals (CUH) NHS Foundation Trust and the University of Cambridge, have been published today. Lancet Gastroenterology and Hepatology. Although the biomarker has not proven useful in selecting treatment for individual patients, a ‘top-down’ treatment strategy involving the use of the drug infliximab soon after diagnosis has shown dramatic results.

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. Drugs are given through a regular intravenous line directly into the bloodstream or by injection under the skin. However, because of historical concerns about cost and side effects — including an increased risk of infections related to immunosuppression — it is currently offered only when patients experience regular flares that are less potent. Do not respond to treatment.

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

The first group was treated using an ‘accelerated step-up’ approach, which is the traditional treatment strategy used in the UK and most of the world. In this group, patients started using infliximab only if their disease was progressing and not responding to other simple treatments.

However, the other group was treated with ‘top-down’ therapy – that is, they were given infliximab as soon as possible after their diagnosis, regardless of the severity of their symptoms.

The results were dramatic: 80% of people who received top-down therapy had both symptoms and inflammatory markers controlled over the course of a year, compared with only 15% of people who received rapid step-up therapy.

Two-thirds (67%) of patients in the ‘top-down’ group had no ulcers seen on their endoscopy camera tests at the end of the trial — known as endoscopic remission. Endoscopic remission is considered important because it has been consistently associated with a reduced risk of later complications in Crohn’s disease. Most previous clinical trials of treatment have been considered highly successful based on 20 to 30% of patients achieving endoscopic remission.

In addition to these results, patients in the upper-lower arm had better quality of life, less use of steroid medications, and fewer hospitalizations.

Surprisingly, while about one in 20 patients (5%) in the conventional treatment arm of the trial required urgent abdominal surgery for their Crohn’s disease, only one in 193 (0.5%) ‘ A recipient of ‘top-down’ therapy required such surgery.

Dr Noor Noor, from the University of Cambridge’s Department of Medicine, one of the study’s lead researchers and first author of the trial, said: “Historically, treatment with advanced therapies such as infliximab has been within two years of diagnosis. is considered ‘initial’ and a ‘step-up’ approach is therefore ‘good enough’.

“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 bowel damage, so advanced therapies like infliximab Need to start. As early as possible, we’ve shown that by treating earlier, we can get better outcomes for patients than previously reported.”

In fact, the researchers say, the improvements seen in trial patients receiving ‘top-down’ therapy may be even more pronounced than with usual medical care. Few Crohn’s disease patients in standard clinical care receive the rapid, ‘rapid step-up’ approach provided by trial protocols, and so the benefits of implementing a ‘top-down’ approach in standard clinical care are even greater. Can be clear.

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

Prof Myles Parkes, director of the NIHR Cambridge Biomedical Research Centre, chief investigator of the PROFILE trial, said: “Until now, the view has been ‘why would you use a more expensive treatment strategy and potentially treat more people? Will do if there’s a chance. Can they fix it anyway?’

“As we have shown, and as previous studies have shown, there is actually a very high risk that a person with Crohn’s disease will experience flare-ups and complications even in the first year after diagnosis. .

“We now know that we can prevent most of the adverse outcomes, including the need for immediate surgery, by providing treatment strategies that are safe and increasingly affordable. Then the safest thing from a patient’s perspective. It is to offer ‘top-down’ therapy immediately after diagnosis rather than waiting and using ‘step-up’ treatment.”

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

Professor Parkes added: “It’s not just the five per cent of people who need surgery that we need to think about. Many people in the ‘step-up’ arm had flare-ups that required surgery. “There was no need. Multiple consultations with specialist doctors and nurses, clinical investigations such as scans and colonoscopies, time off work, time off education etc – all have a huge impact on a person’s quality of life.”

Although there are other anti-TNF drugs, such as adalimumab, that work similarly to infliximab and are significantly cheaper, more research is needed to understand whether these will be as clinically effective.

Ruth Wakeman, Director of Services, Advocacy and Evidence at Crohn’s & Colitis UK, said: “Crohn’s disease affects over 200,000 people in the UK and we know that many of them go undiagnosed for a long time. Symptoms remain until then. But a diagnosis is not made. The end of their journey, and the trial and error involved in finding the right treatment, can be difficult and painful.

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

This research was funded by Wellcome and Product Immune Ltd and supported by the NIHR Cambridge Biomedical Research Centre.