Differential efficacy of medical therapies for ulcerative colitis according to disease extent: patient-level analysis from multiple randomized controlled trials

Sudheer K Vuyyuru; Christopher Ma; Tran M Nguyen; Guangyong Zou; Laurent Peyrin-Biroulet; Silvio Danese; Parambir Dulai; Neeraj Narula; Siddharth Singh; Vipul Jairath

doi:10.1016/j.eclinm.2024.102621

Differential efficacy of medical therapies for ulcerative colitis according to disease extent: patient-level analysis from multiple randomized controlled trials

EClinicalMedicine. 2024 May 4:72:102621. doi: 10.1016/j.eclinm.2024.102621. eCollection 2024 Jun.

Authors

Sudheer K Vuyyuru¹, Christopher Ma^{2

3}, Tran M Nguyen⁴, Guangyong Zou⁵, Laurent Peyrin-Biroulet⁶, Silvio Danese⁷, Parambir Dulai⁸, Neeraj Narula⁹, Siddharth Singh¹⁰, Vipul Jairath^{1

4

5}

Affiliations

¹ Department of Medicine, Division of Gastroenterology, Schulich School of Medicine, Western University, Canada.
² Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, AB, Canada.
³ Departments of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
⁴ Lawson Health Research Institute, London Health Sciences Center, London, ON, Canada.
⁵ Department of Epidemiology and Biostatistics and Robarts Research Institute, Western University, London, ON, Canada.
⁶ University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France.
⁷ Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
⁸ Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁹ Department of Medicine, Division of Gastroenterology, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.
¹⁰ Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.

Abstract

Background: Disease extent in Ulcerative Colitis (UC) has prognostic implications for disease course. It is unclear whether the efficacy of medical therapies for moderate to severely active UC vary according to disease extent at enrollment.

Methods: We analyzed patient level data from 11 Phase 2 and 3 clinical trials of advanced therapies in patients with moderate-to-severe UC to assess modifications of advanced therapy effects by disease extent. Primary outcome was clinical response and secondary outcomes were clinical remission, endoscopic response/remission and endoscopic improvement, and Mayo clinic subscore for both induction and maintenance studies. Binary and continuous outcomes were analyzed using the modified Poisson regression model and the mixed-effects model, respectively, adjusting for age, sex, disease duration, concomitant steroid use and prior anti-TNF use. Effect modifications with binary outcomes were quantified by ratios of risk ratio for left-sided to that for extensive colitis while effect modifications with the Mayo subscores were quantified by differences of the differences between mean scores of the left-sided and extensive colitis. Results were presented with point estimates and 95% confidence intervals as well as p-values.

Findings: Eleven clinical trials enrolling 5450 UC patients (infliximab = 2, adalimumab = 2, golimumab = 2, vedolizumab = 2, tofacitinib = 3) were included. In induction trials, there was evidence to suggest effect modification by disease extent for clinical response with tofacitinib (the ratio of RRs 0.67, 95% CI [0.45, 0.99], p = 0.049) and clinical remission with infliximab (ratio of RRs 0.33, 95% CI [0.13, 0.85], p = 0.020) favoring patients with extensive colitis. There was no evidence to suggest effect modification for endoscopic improvement and clinical outcomes. There was evidence to suggest effect modification by disease extent for clinical remission with tofacitinib (ratio of RRs 0.44, 95% CI [0.22, 0.89], p = 0.020) favoring patients with extensive colitis. For symptom subscores from the Mayo Clinic score, tofacitinib was associated with a greater reduction in both stool frequency (difference of differences 0.37, 95% CI [0.08, 0.65], p = 0.012) and rectal bleeding scores (difference of differences 0.25, 95% CI [0.03, 0.47], p = 0.026) in patients with extensive colitis compared to left sided.

Interpretation: These findings underscore the possibility of differential efficacy of medical therapies according to disease distribution. These results warrant further exploration in forthcoming trials to better inform treatment strategies and consideration of disease distribution as a baseline stratification factor in clinical trials.

Funding: This study did not receive any financial support.

Keywords: Biologics; Distribution; Extent.