Study redefines early treatment of Crohn’s disease and improves outcomes

1st March 2024

Top-down treatment with infliximab plus an immunomodulator substantially improves outcomes for patients with newly diagnosed Crohn’s disease compared with accelerated step-up therapy, UK research finds.

Previous trials had supported earlier use of anti-tumour necrosis factor therapy, usually in combination with an immunomodulator, researchers wrote in The Lancet Gastroenterology and Hepatology.

However, the most common strategy in the UK and globally was an accelerated step-up approach, where treatment is escalated until the tendency to relapse is controlled, they said.

The multi-centre PROFILE trial enrolled 386 patients aged 16-80 years with newly diagnosed, active Crohn’s disease, who had raised C-reactive protein, calprotectin of 200 μg/g or more, plus active inflammation on ileo-colonoscopy.

Patients were stratified based on a blood-based biomarker previously found to correlate with the need for future treatment escalation and then randomised to either top-down therapy or the accelerated step-up approach.

Over 48 weeks off follow-up, the biomarker did not show any clinical utility.

However, 79% of patients achieved sustained steroid-free and surgery-free remission in the top-down group, compared with 15% in the conventional therapy group, a 64-percentage point difference, they reported.

‘Top-down treatment also showed greater efficacy in achieving endoscopic remission, improved quality of life, and reduced number of flares requiring treatment escalation,’ they wrote.

It was also safer than conventional therapy for Crohn’s disease, with fewer adverse and serious adverse events and no increased rate of infection. 

A reduced need for urgent abdominal surgery was also found, with one person in the top-down group requiring surgery for complications, compared with 10 people in the step-up group, they added. 

‘These findings are potentially transformative for the management of Crohn’s disease,’ the study authors concluded. 

‘While PROFILE did not identify a clinically useful biomarker, it has provided clear evidence with regards to optimal treatment strategy from diagnosis.’

First author Dr Nuru Noor, of the Department of Medicine at the University of Cambridge, said the study findings redefined what should be considered as early treatment for Crohn’s disease.

‘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”,’ he said.

‘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.’

Chief investigator Professor Miles Parkes, who is director of the NIHR Cambridge Biomedical Research Centre, said the study showed clinicians could prevent most adverse outcomes for Crohn’s disease, including need for urgent surgery, with a treatment strategy that was safe and becoming increasingly affordable.

‘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,’ he said.

In February 2023, the Medicines and Healthcare products Regulatory Agency approved upadacitinib for use in patients with moderate to severely active Crohn’s disease who have had either an inadequate response, or were intolerant to, conventional therapy or a biological agent.

Infliximab attenuates COVID-19 antibody response

29th March 2021

Immunosuppressant therapy affects an individual’s immune response but how this impacts on the COVID-19 antibodies is uncertain.

The production of an effective immune response after infection with COVID-19 is of paramount importance in preventing further bouts of infection. Moreover, biologicals such as infliximab, which target tumour necrosis factor (TNF), are known to impair protective immunity following a number of viral infection vaccinations including influenza, viral hepatitis and pneumococcus, thereby increasing the risk of serious infection. Hence in the early part of the COVID-19 pandemic, patients prescribed immunosuppressant therapy were advised to shield. Fortunately, information derived from international registry data indicates that the rates of severe infection among patients prescribed immunosuppressants are similar to the background population rates. However, whether anti-TNF drugs actually impair the immune response in those who have already been infected with COVID-19 is uncertain. This prompted a team from the Department of Gastroenterology, Royal Devon and Exeter Trust, UK, to examine the subsequent immune response in those with inflammatory bowel disease (IBD) after infection with COVID-19 and treated with infliximab. In an effort to test whether the immune response was blunted, the team retrospectively compared antibody responses in those treated with either infliximab or vedolizumab, a gut selective anti-integrin alpha4beta7 monoclonal antibody, for at least 6 weeks. Consecutive patients at the hospital were recruited when attending their infusion appointments and those who had participated in any of the COVID-19 vaccine trials were excluded. The primary outcome was the proportion of patients with a positive COVID-19 test and a secondary outcome was the magnitude of the antibody response between the two treatment groups, in those who tested positive. The team collected several additional pieces of information including demographics as well as information on IBD disease activity and mental health wellbeing and anxiety assessment and used this to construct multivariate logistic regression analysis.

Findings
A total of 6935 patients were included in the analysis of whom, 67.6% were prescribed infliximab with a mean age of 37.1 years (45.5% female). The majority of those prescribed infliximab had Crohn’s disease (66.6%) or ulcerative colitis (31.1%). In contrast, most of those (60.1%) prescribed vedolizumab had ulcerative colitis. There were a similar proportion of patients in both groups who either reported COVID-19 symptoms (8.3% vs 8.9%, infliximab vs vedolizumab) or tested positive (5.2% vs 4.3%) or who were hospitalised (0.2% vs 0.2%) because of their infection. Overall, the prevalence of COVID-19 antibodies was 4.3% but this was significantly lower in those using infliximab (3.4% vs 6%, p < 0.0001). Additionally, among those with PCR confirmed COVID-19 infection, seroconversion was observed in fewer patients treated with infliximab (48% vs 83%).

In a discussion of their findings, the authors noted how infliximab appeared to attenuate the subsequent serological response to the virus despite a similar level of rates of either symptoms or positive tests. They also described how as the action of TNF is to stimulate B cells, the effect of infliximab was biologically plausible.

They concluded that their work had important implications for vaccinating those prescribed infliximab and called for serological surveillance to detect suboptimal vaccine responses.

Citation
Kennedy NA et al. Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab. Gut 2021