D Turner et al. . Gut 2025;0:1–7. doi:10.1136/gutjnl-2025-336368. Preclinical stages of Crohn’s disease defined by faecal calprotectin in asymptomatic first-degree relatives: screening framework for prevention trial

Methods: “Faecal calprotectin was measured in asymptomatic FDRs aged 6–38 years; those with persistent elevation, defined as >70 µg/g in at least two separate tests, were offered panenteric video capsule endoscopy or ileocolonoscopy”

Population: 331 (35%) first-degree relatives (FDRs) (from a group of 950) agreed to be screened: 63 (19%) had persistently elevated calprotectin, of whom 42 underwent further evaluation

Key findings:

• From the initial screened cohort of 331 patients, nine (2.7%) had endoscopic appearance compatible with presymptomatic CD, and 22 (6.6%) had non-specific macroscopic mucosal changes
• Median calprotectin was significantly higher in those with presymptomatic CD (772µg/g (IQR 279–1685)) compared with others (31µg/g (IQR 30–61), p<0.0001)
• Calprotectin >225 µg/g predicted presymptomatic CD (area under the receiver operating
  characteristic curve 0.97 (95% CI 0.94 to 1.0; p<0.001; sensitivity 89%, specificity 94%)

Discussion Points:

• “There is no universally accepted definition for preclinical stages of CD, and
  the distinction between these stages remains partly subjective.”
• “The lack of longitudinal follow-up is also a limitation, but this will be completed as part of the PIONIR trial.”

My take (borrowed in part from the authors):

1. Identification of pre-symptomatic CD “can facilitate designing targeted interventions and defining inclusion criteria for prevention trials.” The disease may be more modifiable in the early stages of disease.
2. This trial suggests the calprotectin threshold of >70 is too low to target screening. For specificity, the study showed that persistent elevation above 225 merits investigation; though, it has been our practice to use a threshold of >150 for children older than 5 years.
3. Approximately 5% of asymptomatic FDRs of CD patients have evidence of pre-symptomatic CD and approximately 10% more have non-specific mucosal changes when evaluated

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