Abstract Background Dual-targeted therapy (DTT) is a treatment paradigm that involves combining medications which target different inflammatory pathways in the management of immune-mediated conditions. Here we describe our tertiary centre experience of adding guselkumab (GUS) to upadacitinib (UPA) in patients with medically complex CD. Methods We performed a retrospective case series of adult patients with active CD (symptomatic, biochemical, radiographic, endoscopic and/or extraintestinal) despite treatment with UPA and then received GUS between March 25 and October 30, 2025. Disease activity was prospectively recorded. We examined one or more of the following outcomes: clinical response defined as a decrease in Harvey-Bradshaw Index (HBI) of 3, clinical remission (HBI 5), biochemical response (50% reduction in baseline CRP or fecal calprotectin), radiographic or endoscopic improvement of inflammation based on physician assessment, activity of extra-intestinal manifestations (EIMs), and steroid-free remission. Results We identified 10 adult patients with ileocolonic CD who had GUS added to UPA over a median follow-up of 3 months (IQR 3) (Table 1). 5 patients had perianal disease, and 8 had B2 or B3 behaviour. All had active disease at the time of DTT. Of 7 patients with EIMs, 4 had suboptimal EIM control. The median number of advanced therapies prior to DTT was 5 (IQR 2.25) and half of patients had previously received DTT. The median duration of UPA use was 21.5 months (IQR 8.8) before initiating GUS. All patients received subcutaneous (SC) induction loading of GUS (400mg SC on week 0, 4, and 8) with a maintenance dose of 200mg SC every 4 weeks. After starting DTT, 3 patients achieved clinical response (Table 2). 6 patients maintained clinical remission, of which 3 had biochemical response and 1 also had radiographic improvement. 1 patient did not achieve clinical response nor remission and is planned for surgery. Of the 4 patients who started DTT for EIMs, 2 had improvement of arthropathy, and 1 had partial healing of orofacial granulomatosis. 9 patients were in steroid-free remission at the end of follow-up. Adverse events included minor facial skin irritation (n = 1) and fatigue (n = 1) which coincided with starting UPA prior to adding GUS. One patient was hospitalized for a bowel obstruction 2 weeks after starting DTT and required an ileal resection for stricturing CD. All patients remain on combination UPA and GUS at the end of follow-up. Conclusion Adding GUS to UPA in patients with medially complex CD resulted in a 30% clinical response rate and improvement of EIMs in 75% of affected patients. DTT with GUS should be considered in appropriate patients with CD who have evidence of active inflammation or EIMs despite monotherapy with UPA. Reference: Solitano V, Ma C, Hanžel J, Panaccione R, Feagan BG, Jairath V. Advanced combination treatment with biologic agents and novel small-molecule drugs for inflammatory bowel disease. Gastroenterol Hepatol (NY). 2023;19(5):251-263. Conflict of interest: Dr. Natt, Navneet: No conflict of interest Shafrir, Asher: No conflict of interest Choi, David: No conflict of interest Cleveland, Noa Krugliak: Consultant for Abbvie, Johnson & Johnson, GE, Samsung, Sanofi. Board of directors of IUSCAN Cohen, Russell: Personal Fees: Abbvie, Celgene, Eli Lilly, Hospira, Janssen, Pfizer, Sandoz Biopharma, Takeda, UCB Pharma Non-financial Support: Abbvie Rubin, David T.: Grant support: Takeda Pharmaceuticals Consultant: Abbvie, Abivax SA, Altrubio, Athos Therapeutics, Inc, Bristol-Myers Squibb, Celltrion, Connect BioPharma, Eli Lilly & Co., Genentech (Roche) Inc., Iterative Health, Janssen Pharmaceuticals, Johnson & Johnson, Merck & Co., Mirador, Odyssey Therapeutics, Pfizer, Sanofi, Spyre, Takeda Pharmaceuticals, Vedanta Biosciences, and Ventyx.
Natt et al. (Thu,) studied this question.