Introduction

The natural history of coeliac disease (CD) is still unknown. Clinically, CD appears both in childhood and adulthood, but whether CD can be acquired in adulthood is unknown. In addition, spontaneous normalization in serological tests has been observed in adults with initially positive serology. The aim of the present study was to assess serological signs of CD in pre-diagnostic samples of individuals from the general population with a subsequent CD diagnosis.

Aims & Methods

The study was based on the Trøndelag Health Study (HUNT). The HUNT study has been conducted in four comprehensive surveys inviting all adult inhabitants (>20 years of age) of Nord-Trøndelag County, Norway: HUNT1 (1984-1986), HUNT2 (1995-1997), HUNT3 (2006-2008) and HUNT4 (2017-2019). Blood samples were drawn from the participants during HUNT2, 3 and 4, and sera were aliquoted and stored at -80° Celsius at HUNT Biobank for future analyses. Of about 56,000 participants in HUNT4, 26,000 had participated in HUNT2 and 34,000 had participated in HUNT3, corresponding to approximately 20 and 10 years of follow-up, respectively.
Sera from participants in HUNT4 have were analysed for CD using a newly developed serological assay for detection of anti- transglutaminase 2 (anti-TG2) IgA. All seropositive participants were invited to a clinical validation study with upper endoscopy and tissue sampling to confirm the diagnosis histologically using the Marsh criteria. Available historical sera from HUNT2 and HUNT3 from seropositive participants in HUNT4 were analysed with the same serological assay.

Results

Of 686 seropositive participants in HUNT4 with available historical samples, 564 serum samples collected in HUNT2 and 594 serum samples collected in HUNT3 were analysed. Of the seropositive participants in HUNT4, 38% (215/564) and 24% (143/594) were seronegative in HUNT2 and HUNT3, respectively. Of 472 seropositive participants in HUNT4 with available historical sera from both HUNT2 and HUNT3, 19% (91/472) were seronegative in both surveys and 22% (104/472) were seronegative in one of the surveys. Hereof, 87 were negative in HUNT2, but positive in HUNT3. The remaining 17 were positive in HUNT2, but negative in HUNT3.
Of the 686 seropositive participants in HUNT4, 438 individuals have participated in the clinical validation study by March 2022. Of these, 62% (272/438) received a subsequent CD diagnosis and 8% (34/438) had already a biopsy-verified CD diagnosed before HUNT4.
Of 267 previously seronegative participants in HUNT2 and/or HUNT3 that participated in the clinical validation study, 3% (8/267) received a CD diagnosis before HUNT4 and 52% (139/267) received a subsequent CD diagnosis after HUNT4. Of 17 seropositive participants in HUNT2 with negative seroconversion in HUNT3, 2 participants received a subsequent CD diagnosis after HUNT4.

Conclusion

Our study demonstrates that CD may occur at any age, also in adulthood. In addition, a significant proportion of CD individuals may have lived with undiagnosed CD for several decades. Some individuals with negative serology, even with high IgA TG2 titres, can test negative later. Individuals with previous elevation of CD serology and conversion to negative serology are still be at risk of a subsequent CD diagnosis.

Introduction

Treatment goals in inflammatory bowel disease (IBD) have evolved beyond symptom control to include mucosal healing, prevention of disease-related complications, improvement of health-related quality of life, and reduction of long-term disability, as outlined by the STRIDE II initiative¹. Despite significant progress in the development of advanced therapies (ADTs), up to 50% of IBD patients fail to respond to currently available treatments, underscoring the urgent need for new therapies, which are investigated in randomized clinical trials (RCTs). However, stringent eligibility criteria in RCTs limit the inclusion of real-world IBD patients, potentially compromising the generalizability of trial findings to daily clinical practice.

Aims & Methods

The aim of this study was to evaluate the proportion of real-life IBD patients who would be eligible for ongoing RCTs and to assess the representativeness of this population. Moreover, we aimed to identify the most frequently unmet eligibility criteria leading to patient exclusion and to characterize the clinical profiles that differentiate eligible from ineligible patients.
This prospective, observational, multicenter study was conducted between October 2023 and October 2024 at 2 tertiary IBD referral centers: the Fondazione Policlinico Universitario “A. Gemelli” in Rome, Italy, and the Crohn’s & Colitis Center at the University of Miami, USA. Consecutive patients with IBD indicated for a new ADT were enrolled. Each patient was systematically screened for inclusion and exclusion criteria across all actively recruiting phase 2b and 3 RCTs available at each center at the time of evaluation (6 RCTs in Rome: 4 UC and 2 CD; 5 RCTs in Miami: 3 UC and 2 CD).

Results

A total of 166 IBD patients (69 UC and 97 CD) were enrolled, with 129 patients from the Italian cohort and 37 from the American cohort. Among UC patients, only 16 (23.2%) met the eligibility criteria for at least 1 RCT, whereas 53 (76.8%) were deemed ineligible (p<0.001). In the CD group, just 10 patients (10.3%) were eligible for at least 1 RCT, compared to 87 (89.7%) who were not (p<0.001). The most common reasons for ineligibility among UC patients included: Modified Mayo score not within the required range of 5–9 (50.7%), absence of bowel urgency (63.8%), Mayo Endoscopic Subscore <2 (39.1%), failure to comply with ADT washout requirements (56.5%), insufficient number of prior ADT failures (39.0%), and recent use of topical 5-ASA or steroids within 4 weeks prior to screening (62.3%).
In CD patients, the most frequently unmet criterion was a CDAI between 220 and 450 (92.8%), followed by insufficiently liquid stool frequency (≥4 very soft or liquid stools/day; 75.3%), SES-CD<6 (39.2%), and the presence of CD-related complications such as strictures or fistulas (13.1%).

Conclusion

The majority of real-life IBD patients, particularly those with CD, are ineligible for participation in current RCTs—primarily due to relatively mild disease activity or ongoing need for concomitant therapies that are not permitted by trial protocols. Importantly, many real-world CD patients initiate new ADTs based on radiologic signs of disease activity, the presence of disease complications, or as prophylaxis for post-surgical recurrence, rather than clinical activity scores alone. Similarly, UC patients may require ADTs even in the context of corticosteroid dependence and low-grade disease activity. These findings underscore the need to revisit and broaden eligibility criteria in future RCTs to ensure greater external validity and alignment with the heterogeneity of real-life IBD population.

References

1. Turner D, Ricciuto A, Lewis A, D'Amico F, Dhaliwal J, Griffiths AM, Bettenworth D, Sandborn WJ, Sands BE, Reinisch W, Schölmerich J, Bemelman W, Danese S, Mary JY, Rubin D, Colombel JF, Peyrin-Biroulet L, Dotan I, Abreu MT, Dignass A; International Organization for the Study of IBD. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology. 2021 Apr;160(5):1570-1583. doi: 10.1053/j.gastro.2020.12.031. Epub 2021 Feb 19. PMID: 33359090.