Abstract Background Consistent alterations in DNA methylation in peripheral blood are reported at Inflammatory Bowel Disease (IBD) diagnosis1,2; the ‘IBD methylome’. These data provide new insights into disease mechanisms and potential for biomarker discovery. Biological age can be accurately measured by DNA methylation clocks, and compared with chronological age to derive epigenetic age acceleration (EAA). Previous studies demonstrate EAA in patients with active inflammation. We studied EAA in two well-characterised cohorts of adult Crohn’s disease (CD) patients in sustained remission on combination infliximab and immunomodulator therapy whilst evaluated for treatment withdrawal. Methods STORI3 was a multicentre study (France/Belgium; n = 115) of patients after infliximab withdrawal. SPARE4 was a multicentre trial (seven European countries; n = 211) comparing therapy continuation vs infliximab- or immunomodulator withdrawal. Baseline blood DNA methylation was profiled on the Illumina Infinium MethylationEPIC v1.0 array. Epigenetic age was estimated using Levine’s DNAm PhenoAge clock (92 STORI; 170 SPARE). EAA was obtained by regressing DNAm PhenoAge on chronological age, adjusting for cell counts. Clinical variables included age at diagnosis, disease duration, smoking status, C-reactive protein (CRP), CD Activity Index (CDAI), CD Endoscopic Index of Severity (CDEIS), and relapse after infliximab withdrawal. Results In both cohorts, chronological age strongly correlated with DNAm PhenoAge (STORI: R = 0.76, p 2.2 × 10⁻¹6, Figure 1A; SPARE: R = 0.85, p 2.2 × 10⁻¹6). Median EAA was 0.08 years (STORI) and 0.09 years (SPARE). A proportion of patients showed marked biological ageing. In STORI, 8.7% exhibited 5–10 years EAA and 6.5% 10 years; in SPARE, 14.7% and 4.7%. In search of the drivers of EAA, no significant associations were found between EAA and age at diagnosis, disease duration, smoking status, baseline CRP, CDAI, or CDEIS. EAA did not differ between patients who relapsed and those who remained in remission on follow-up (STORI: W = 1187, p = 0.18, Figure 1B; SPARE: W = 2001, p = 0.73). Conclusion Across two independent CD cohorts, median biological age was highly correlated with chronological age. However, 15-20% patients had age acceleration of 5 years even in long-term remission. These data complement previous studies1,2, adding to the interest in the factors driving age acceleration in IBD, and its potential prognostic importance. We will extend these analyses in search of the drivers of accelerated biological ageing in these patients. In addition, we will extend epigenetic analyses with genetic and proteomic studies, to identify biomarker profiles predictive of infliximab withdrawal outcomes, which may be suitable for clinical translation. References: 1. Ventham NT, Kennedy NA, Adams AT, et al. Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease. Nat Commun. Nov 25 2016;7:13507. doi:10.1038/ncomms13507 2. Noble A, Adams A, Nowak J, et al. The Circulating Methylome in Childhood-Onset Inflammatory Bowel Disease. J Crohns Colitis. Mar 5 2025;19(3). doi:10.1093/ecco-jcc/jjae157 3. Louis E, Mary JY, Vernier-Massouille G, et al. Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology. Jan 2012;142(1):63-70 e5; quiz e31. doi:10.1053/j.gastro.2011.09.034 4. Louis E, Resche-Rigon M, Laharie D, et al. Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn’s disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial. Lancet Gastroenterol Hepatol. Mar 2023;8(3):215-227. doi:10.1016/S2468-1253(22)00385-5 Conflict of interest: Dr. Ramsteijn, Anouschka: No conflict of interest Noble, Alexandra: Grants from Girdlers’ New Zealand Health Research Council Fellowship (24/389). Antunes, Catia: No conflict of interest Flores, Belén Morón: No conflict of interest Glapa-Nowak, Aleksandra: No conflict of interest Cabras, Silvia: No conflict of interest Meuwis, Marie-Alice: No conflict of interest Laharie, David: Personal Fees: Board, consulting and lecture fees from Abbvie, Alfasigma, Amgen, Biocon, Celltrion, Ferring, Fresenius-Kabi, Johnson & Johnson, Lilly, MSD, Pfizer, Sandoz and Takeda Colombel, Jean-Frédéric: Grant: AbbVie, Janssen Pharmaceuticals, Takeda, Prometheus and Bristol Myers Squibb Lectures from: AbbVie, Roche and Takeda Other: AbbVie, Amgen, AnaptysBio, Allergan, Apini, Arena Pharmaceuticals, Astellas, Boehringer Ingelheim, Bristol Myers Squibb, candidrx Celgene, Celltrion, Clearview Curogen, Eli Lilly, Envision Pharma Ferring Pharmaceuticals, Galmed Research, Glaxo Smith Kline, Roche, Janssen Pharmaceuticals, Kaleido Biosciences, Immunic, Iterative Scopes, Landos, Microba Life Science, Merck, Mirador, Novartis, Otsuka Pharmaceutical, Owkin, Pfizer, Protagonist Therapeutics, Sanofi, Sun Pharma, Takeda, Teva, TiGenix, and is holding stock options in Intestinal Biotech Development Louis, Edouard: Education and Reserach Grants for my department: Abbvie, Takeda, Johnson and Johnson, Pfizer, Fresenius-Kabi, Celltrion, EG pharma, Sandoz, Falk Personal Fees for conferences, advisory boards and consultancy: Abbvie, Takeda, Ferring, Pfizer, Johnson and Johnson, Lilly, Galapagos, Celltrion, Arena, BMS, Falk, Biokuris, Fresenius-Kabi, Thabor Satsangi, Jack: Grant: Grants to Oxford University from Helmsley Trust & European Community.
Ramsteijn et al. (Thu,) studied this question.