Abstract Background Endoscopy is the gold standard for assessing treatment effectiveness in ulcerative colitis (UC) patients, but it is an invasive procedure and therefore frequent repeated procedures are not feasible routine practice. Biochemical measures are used as proxy endpoints alongside clinical parameters. However, discrepancies between clinical and biochemical remission are commonly seen in clinical trials and daily practice. We conducted a large real-world cohort study to assess divergence between clinical and biochemical parameters over time in UC patients starting advanced agents. Methods Data were obtained from the Dutch Initiative on Crohn and Colitis (ICC) Registry. UC patients initiating anti-TNFα agents, vedolizumab, IL-(12/)23 inhibitors, or JAK inhibitors before 1 November 2024 were included; those with colectomy were excluded. Clinical remission was defined as Simple Clinical Colitis Activity Index ≤2, and biochemical remission as faecal calprotectin ≤250µg/g. Divergence was defined as the proportion of patients in either clinical or biochemical remission, divided by those with both measures available at treatment start (week 0), week 12 (±6 weeks), week 24 (±6 weeks), and week 52 (±8 weeks). Differences between the different treatment classes were analysed using Pearson’s χ2 or Fisher’s exact tests. Results A total of 777 patients were included. Availability of data varied over time; both clinical and biochemical data were available for 394 patients (45.7%) and 171 patients (22.0%) at baseline and week 52, respectively. Divergence fluctuated across the different treatment classes and in general (Figure 1), from 20.7% (95%CI 16.7-25.3) at baseline to 29.8% (95%CI 23.2-37.4) at week 52. When divergence occurred, clinical remission was more frequently observed than biochemical remission. Patients on anti-TNF agents were, on average, more likely to exhibit divergent remission outcomes, although differences between medication classes were not statistically significant. Among patients with divergence at baseline, 22/77 (28.6%) showed divergence up to week 12, and one patient showed persistent divergence up to week 52, being in biochemical remission at week 0, 24, and 52, but in clinical remission only at week 12. Conclusion Divergence between clinical and biochemical remission in ulcerative colitis is common, dynamic, and varies across advanced treatment classes. This persistent disconnect highlights that clinical remission alone is an insufficient primary endpoint in therapeutic trials. Robust research into the mechanisms and determinants of this divergence is essential to inform evidence-based, multidimensional endpoints and to refine treatment targets in clinical practice. Conflict of interest: Verleye, Loriane: No conflict of interest Bloemen, Hannah: No conflict of interest Pierik, Marieke: Grant: TKI, MLDS, Galapagos, Janssen-Cilag, Takeda, Pfizer Other: Financial support to institution for consultancy or lectures: Takeda, Janssen-Cilag, BMS, MSD, Abbvie, Galapagos, Ferring Winkens, Bjorn: No conflict of interest Visschedijk, Marijn: Speakers fees from Jansen-Cilag, Abbvie, Ferring, Alfasigma, Takeda. Van der Meulen - de Jong, Andrea Elisabeth: Speaking fees from Alfasigma, Ferring and Abbvie. Advisory board fees from Abbvie, Alfasigma, Ferring, Janssen, Takeda, Vedanta and grant/research support from Alfasigma, Cablon and Norgine. van Schaik, Fiona: FDM van Schaik has received consultancy fees from Takeda, Galapagos and AbbVie, speaker’s honoraria from Galapagos, Lilly, AbbVie and Janssen-Cilag B.V., hospitality fees from Ferring and dr. Falk Farma and an unrestricted research grant from Takeda. Naber, Myrthe: No conflict of interest Löwenberg, Mark: Consultancy/lecture fees from Abbvie, Bristol Myers Squibb, Eli Lilly, Galapagos, Janssen-Cilag, Johnson & Johnson, Medtronic, Pfizer, Takeda, Tillotts. Grants received from Alfasigma, NFU transformation deal, ZonMW and TKI. De Vries, Annemarie C.: Grant: Grants, advisory boards: Pfizer, Galapagos, Takeda, Janssen Bodelier, Alexander: Participation in advisory boards of: Johnson & Johnson, Eli Lilly, Sanofi. Received unrestricted grant from Amphia research fund. Smid, Jael: No conflict of interest Duijvestein, Marjolijn: Grant: Speaking fees from Bristol Meyers Squibb, Takeda, Galapagos, Janssen, Dr. Falk, Advisory board fees from Abbvie, Bristol Meyers Squibb, Celltrion, Galapagos/Alfasigma, Janssen, Takeda Grant/Research support: Pfizer, Bristol Meyers Squibb, Galapagos, Alfasigma, Janssen, Lilly Mujagić, Zlatan: Grants from ZonMw, Niels Stensen Fellowship, Maag Lever Darm Stichting (MLDS), Academische Alliantie Fonds (AAF), Top consortium for Knowledge and Innovation (TKI) and Galapagos, advisory board fees from Johnson & Johnson, Eli Lilly, Pfizer (paid to host institution) and speaker’s fees from Friso – Friesland Campina, Galapagos / Alfasigma, Eli Lilly, Takeda (paid to host institution).
Verleye et al. (Thu,) studied this question.