Upadacitinib Shows Promise for Hard-to-Treat Crohn Disease

Upadacitinib demonstrated effectiveness in achieving clinical and endoscopic remission in patients with Crohn disease (CD), including those with prior advanced therapy exposure, with no new safety signals, according to a real-world study.¹

The Crohn disease subtype of inflammatory bowel disease is estimated to impact 1.01 million Americans (205 cases per 100,000 people). | Image credit: tract_Grispb - stock.adobe.com

This study, published in Clinical Gastroenterology and Hepatology, was conducted to address limitations in current treatments for moderate to severe CD, such as nonresponse, loss of response, and challenges with injection-based biologics that may affect patient adherence. Crohn disease is a subtype of inflammatory bowel disease (IBD).

“Given the heterogeneity found among patients with CD, the fact that [upadacitinib] is currently not approved for first-line use, and prior off-label usage of [tofacitinib] in many patients with CD, we wanted to understand whether prior biologic or [tofacitinib] exposure affected outcomes. Our study indicated that patients with previous [tofacitinib] exposure had similar outcomes with [upadacitinib] compared with those without prior [tofacitinib] exposure, demonstrating its potential as a rescue therapy in patients with refractory CD,” the authors explained.

The age- and sex-standardized incidence of IBD in the US is 10.9 per 100,000 person-years, peaking in the third decade of life.² The standardized prevalence is 721 per 100,000, translating to about 2.39 million Americans with IBD. The CD subtype is estimated to impact 1.01 million Americans (205 cases per 100,000 people).³

Small molecule therapies like Janus kinase (JAK) inhibitors, particularly upadacitinib, offer promising oral alternatives with rapid onset and no risk of immunogenicity.¹ However, real-world evidence for upadacitinib in CD is limited, especially regarding its effectiveness, safety, and optimal use. This study aimed to evaluate upadacitinib's real-world performance and identify predictors of treatment response in patients with active luminal CD across multiple US tertiary IBD centers.

The study was a multicenter retrospective analysis conducted across 9 centers using data from the REBOOT-IBD consortium. It included adults with histologically confirmed CD who were prescribed upadacitinib for active luminal disease and had at least 1 follow-up visit. Data were collected using standardized forms and included clinical, endoscopic, radiographic, and biomarker assessments.

The primary goals were to evaluate clinical remission at 12 weeks and endoscopic remission at 6 months. Secondary outcomes included longer-term clinical response, steroid cessation, and radiographic improvement. Only patients on the 45-mg dose were included in effectiveness analyses, while safety outcomes were tracked for all patients. Adverse events (AEs), including infections, venous thromboembolism, cardiac events, and hospitalizations, were recorded.

This real-world study included 334 patients with CD treated with upadacitinib and a median follow-up of 5 months. The cohort had a median age of 34 years, 44.6% were female, and most had longstanding, refractory disease. Upadacitinib was started in 93.4% due to active disease, with 80% showing confirmed inflammation by colonoscopy. Most (79%) underwent a 12-week induction, 96% of whom followed that with a 30 mg-maintenance dose. Nearly all had prior exposure to advanced therapies (ATs), and almost half had a history of bowel surgery.

At 12 weeks, 52.1% achieved clinical remission, 90.4% of whom were corticosteroid free. At 6 months, remission was maintained in 55.9%, with 94% corticosteroid free. Endoscopic remission at 6 months was 42.7%. Non-White patients had higher 6-month remission rates than White patients (87.3% vs 74.5%; P = .03), and ileum-dominant disease was associated with better outcomes than colon-dominant (67.1% vs 47.1%; P = .02). Longer disease duration, higher body mass index, stricturing/penetrating disease, and prior surgery predicted lower remission, while higher albumin was favorable.

Clinical response was seen in 61.7% at 12 weeks and 66.5% at 6 months. More prior AT exposure reduced remission rates; AT-naïve patients had the best outcomes (97.7% at 6 months). Radiographic improvement occurred in 73.3%, histologic remission in 23.5%, and endohistologic remission in 7.8%. C-reactive protein levels improved, but fecal calprotectin did not. Safety findings included acne (3.3%), herpes zoster (2.4%), and 1 case of venous thromboembolism (0.6%). No malignancies or major cardiovascular events occurred.

Eighteen serious AEs occurred, including 3 cases of herpes zoster and 2 cases of deep venous thrombosis/pulmonary embolism, leading to treatment discontinuation or hospitalization.

The authors concluded, “These findings highlight [upadacitinib's] potential as an effective therapy positioned as a second-line and beyond but also highlights the need for further studies to reevaluate its position to where it may serve as the most effective therapy while balancing the risk of AEs.”

References

1. Real-world effectiveness and safety of upadacitinib in Crohn's disease: a multicenter study. Clin Gastroenterol Hepatol. Published March 8, 2025. doi:10.1016/j.cgh.2025.01.012

2. Leris JD, Parlett LE, Funk MLJ, et al. Incidence, prevalence, and racial and ethnic distribution of inflammatory bowel disease in the United States. Gastroenterology. 2023;165(5):1197-1205.e2. doi:10.1053/j.gastro.2023.07.003

3. Lewis JD, Parlett LE, Jonsson Funk ML, et al. Incidence, prevalence, and racial and ethnic distribution of inflammatory bowel disease in the United States. Gastroenterol. 2023;165(5):1197-1205.e2. doi:10.1053/j.gastro.2023.07.003