A multicenter retrospective study evaluating the effectiveness and safety of ustekinumab combined with low-dose upadacitinib in patients with refractory Crohn's disease.

This is a multicenter, retrospective, real-world observational study conducted at several inflammatory bowel disease centers in China. The study is designed to evaluate the effectiveness and safety of ustekinumab (UST) combined with low-dose upadacitinib (UPA; 15 mg/day or 30 mg/day) in patients with moderate-to-severe active refractory Crohn's disease. Eligible patients received combination therapy between July 1, 2023 and December 31, 2025. Patients were required to have previously failed, been intolerant to, or experienced adverse events with anti-tumor necrosis factor therapy, followed by an inadequate response or intolerance to UST monotherapy or UPA 45 mg/day administered for 12 weeks. The combination regimen consisted of intravenous re-induction with UST and oral low-dose UPA at 15 mg/day or 30 mg/day for 12 weeks. Clinical response and clinical remission are assessed at weeks 12 to 16, while endoscopic response and endoscopic remission are assessed between weeks 12 and 24. Maintenance treatment after the initial 12-week combination period and safety outcomes through week 24 are also evaluated. Data are obtained retrospectively from existing medical records, and no study-specific intervention is assigned to participants.

Inclusion Criteria:

• Aged 18 to 65 years.
• Patients with a confirmed diagnosis of Crohn's disease according to the European Crohn's and Colitis Organisation (ECCO) criteria.
• Patients with prior failure, loss of response, intolerance, or contraindication to anti-TNF therapy, who subsequently had inadequate response to ustekinumab or upadacitinib monotherapy between July 1, 2023 and May 31, 2025.
• Active Crohn's disease defined by Harvey-Bradshaw Index (HBI) >4, or endoscopic disease activity with at least one segment having an SES-CD ulcer subscore ≥2. Postoperative endoscopic recurrence was defined as modified Rutgeerts score ≥i2b. For patients in whom the small bowel anastomosis could not be reached endoscopically, disease activity was assessed by the treating physician based on clinical symptoms, elevated inflammatory markers, and imaging findings.
• Patients who required dose reduction during full-dose upadacitinib treatment because of adverse events, or who had persistent clinical symptoms, elevated C-reactive protein, active endoscopic disease, postoperative recurrence, or active disease on imaging despite upadacitinib treatment.
• Patients with inadequate response or loss of response to ustekinumab treatment, defined by persistent clinical symptoms, elevated C-reactive protein, active endoscopic disease, postoperative recurrence, imaging evidence of active disease, or recurrence after initial response during maintenance therapy.
• Availability of inflammatory markers and imaging results within 3 months before initiation of combination therapy.

Exclusion Criteria:

• Patients receiving upadacitinib in combination with biologics other than ustekinumab.
• Patients receiving full-dose upadacitinib 45 mg/day in combination with ustekinumab.
• Patients with contraindications to upadacitinib, including hypersensitivity to the active substance or excipients, active tuberculosis or severe infection, malignancy, thromboembolic events, or severe hepatic impairment.
• Patients with severe infection, malignancy, pregnancy, or lactation.
• Patients with severe intestinal stricture, perforation, or intra-abdominal abscess that might require surgery and interruption of drug therapy during the study period.
• Patients considered unsuitable for the above treatment by the treating physician.
• Patients with incomplete data, inability to complete follow-up, or loss to follow-up.

Adult patients with refractory Crohn's disease from multiple inflammatory bowel disease centers in China who had prior anti-TNF therapy failure, intolerance, or contraindication and inadequate response to ustekinumab or upadacitinib monotherapy. Eligible patients received low-dose upadacitinib in combination with ustekinumab in routine clinical practice between July 1, 2023 and May 31, 2025, and were included in this retrospective real-world cohort study.