5-year data from the PROFILE trial, presented by Nuru Noor (Cambridge, UK), suggest that the course of Crohn’s disease can be modified with early, effective treatment. Previously published data from week 48 of the trial, in which patients with newly diagnosed active Crohn’s disease were randomly assigned to top-down infliximab plus an immunomodulator or conventional step-up care, indicated a significant benefit in sustained steroid-free and surgery-free remission with the top-down approach. After 48 weeks of protocolised care, participants returned to the local standard of care. For this new analysis, data were available for 180 (93%) of the 193 participants in the top-down group and 177 (92%) of the 193 patients in the step-up group. After a median follow-up of 5 years from diagnosis, 28 patients in the step-up group had needed abdominal surgery compared with just six in the top-down group (risk ratio 4·33, 95% CI 1·82–10·29). The risk of disease progression was also higher in participants initially managed via a step-up approach than in those managed with a top-down approach (2·50, 1·33–4·54), as was the risk of hospitalisation due to Crohn’s disease (1·64, 1·13–2·40).

Ontunisertib, an oral gut-restricted ALK5 inhibitor that blocks signalling of the profibrotic TGFβ pathway, showed preliminary activity in patients with fibrostenosing Crohn’s disease, according to data from the STENOVA phase 2a trial presented by Florian Rieder (Cleveland, OH, USA). Adults with symptomatic fibrostenosing Crohn’s disease with at least one ileal stricture confirmed by magnetic resonance enterography (MRE) were randomly assigned to receive either ontunisertib 200 mg twice daily, 100 mg once daily, or placebo for 12 weeks. Treatment-emergent adverse events were reported by 21 (62%) of 34 participants in the 200 mg group (of which four were serious), 22 (65%) of 34 in the 100 mg group (none serious), and 25 (71%) of 35 in the placebo group (four serious). Pharmacokinetic data indicated that there was low systemic exposure to the drug, supporting gastrointestinal absorption and liver metabolism. Exploratory efficacy endpoints suggested a measurable effect on disease activity, with 10 (29%) participants in the 200 mg group, four (12%) in the 100 mg group, and four (11%) in the placebo group having an endoscopic response (assessed by Simple Endoscopic Score for Crohn’s disease) at 12 weeks, and in MRE-assessed stricture features (eg, stricture length).

Dan Turner (Jerusalem, Israel) presented results from the PIONIR trial, which explored whether a whole-food diet could improve biomarkers of inflammation in first-degree relatives of patients with Crohn’s disease who were at high risk of developing Crohn’s. In the study, 331 healthy first-degree relatives were screened for elevated faecal calprotectin concentrations, of whom 42 with two or more tests of >70 μg/g underwent panenteric capsule endoscopy or ileocolonoscopy. Nine individuals with Crohn’s-related mucosal changes were excluded. Of the remaining 33 eligible individuals, deemed to be in a potential pre-Crohn’s stage, 29 were randomly assigned to either the Tasty & Healthy diet or to continue their habitual diet for 8 weeks, followed by crossover to the alternate diet for a further 8 weeks. Faecal calprotectin was measured every 4 weeks. An adjusted generalised estimating equations analysis, combining both treatment phases, showed that there was a 38% decrease from baseline in faecal calprotectin with the habitual diet (likely reflecting the placebo effect), while there was a 61% decrease with the Tasty & Healthy diet (ratio 0·63, 95% CI 0·51–0·81; p<0·001).

Use of RNA-derived biomarkers to inform therapy guidance for patients with inflammatory bowel disease commencing infliximab improved clinical outcomes according to data from the GUIDE-IBD trial, presented by Florian Tran (Kiel, Germany). Patients with either Crohn’s disease or ulcerative colitis who were starting treatment with infliximab were randomly assigned to 52 weeks of either best care or molecular medicine care. No treatment algorithm was predetermined in the study, but a treat-to-target approach was followed for all patients, with infliximab dose adjustments, co-medications, and switching to alternative advanced therapies permitted. Decisions on changes to treatment were made at multiple timepoints throughout the trial in multidisciplinary team meetings using structured longitudinal case presentations, with those assigned to the molecular medicine care group also receiving structured molecular reports that integrated findings from mRNA markers from blood and intestinal tissue and pharmacokinetic modelling data to inform treatment decisions. At week 52, 14 (25%) of 55 individuals in the best care group and 22 (46%) of 48 in the molecular medicine care group had achieved disease control, defined as a combination of clinical and endoscopic remission and biomarker normalisation (adjusted odds ratio 2·53, 95% CI 1·09–5·86; p=0·031).