Evaluating the benefit-risk profile of upadacitinib in IBD

Across phase 2b/3 trials of patients with Crohn’s disease and ulcerative colitis, the oral, reversible Janus kinase inhibitor upadacitinib consistently outperformed placebo in induction and maintenance, regardless of cardiovascular risk, age, or treatment history, a post hoc analysis showed. Improvements were seen in clinical remission, endoscopic outcomes, symptom scores, and patient-reported outcomes.

“Our findings suggest the favorable benefit-risk profile of upadacitinib for the treatment of moderately to severely active Crohn's disease and ulcerative colitis in general, and for the specific subgroups evaluated,” corresponding author Edward Loftus, Jr., of the Mayo Clinic, Rochester, Minn., and colleagues wrote in the study, which was published in the Journal of Crohn’s and Colitis.

The findings come from a pooled analysis of phase 2b/3 induction and maintenance trials in Crohn's disease and ulcerative colitis. Induction used upadacitinib 45 mg daily for 8 weeks (ulcerative colitis) or 12 weeks (Crohn's disease), with induction responders re-randomized to upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 52-week maintenance.

The analysis looked at 1,021 patients with Crohn's disease and 1,097 with ulcerative colitis during the induction phase, and 673 patients with Crohn's disease and 746 with ulcerative colitis during maintenance.

Upadacitinib 30 mg showed numerically higher efficacy than 15 mg in nearly every subgroup examined. This pattern was observed in Crohn's disease (AI remission, endoscopic endpoints) and ulcerative colitis (clinical and endoscopic remission, maintenance of response). This reinforces the practical approach of reserving 30 mg for patients requiring sustained, deeper disease control, especially younger patients or those with prior biologic failure.

In terms of safety, across subgroups, rates of MACE, VTE, malignancy (excluding NMSC), NMSC, and GI perforation were low and comparable between upadacitinib and placebo during both the induction and maintenance phases. The authors noted that this is clinically important given concerns about JAK inhibitor safety derived from rheumatoid arthritis. The IBD population in this analysis, which was generally younger and with different comorbidity profiles, showed no signal for increased MACE or VTE risk.

Herpes zoster incidence was higher with upadacitinib across most subgroups, especially with the 30 mg dose and in Crohn's disease. This pattern was consistent across cardiovascular risk categories, biologic-experience subgroups, and younger age groups (<50 years) in Crohn's disease. Ulcerative colitis showed similar trends, though the magnitude was somewhat lower.

Considering the low baseline zoster vaccination rates in the study population, the findings reinforce existing practice guidelines that zoster vaccination should be strongly considered before initiating upadacitinib.

A modest numerical increase in serious infections was observed with upadacitinib 30 mg versus placebo during Crohn's disease maintenance, particularly in non-bio-IR patients, though absolute rates remained low. This pattern was not seen in ulcerative colitis to the same extent. Clinically, the authors noted, this supports vigilance in patients with additional infection risk factors, particularly when using the higher maintenance dose.

The authors acknowledged certain limitations of their analysis, including the lack of predefined endpoints and small patient numbers in the subgroups. “The results should be considered exploratory, warranting further research,” they wrote.

Cuckoo Choudhary, MD, a spokesperson forAGA and Professor of Medicine at Thomas Jefferson University, Philadelphia, who was not involved in the work, said that the post hoc analysis provides several actionable conclusions:

• Upadacitinib demonstrates consistent efficacy across key patient subgroups, “supporting its use regardless of cardiovascular risk, age, or prior biologic exposure,” she said.

• Upadacitinib 30 mg delivers the strongest maintenance efficacy, “appropriate for patients with more refractory or aggressive disease.”

• Safety signals observed in RA populations were not reproduced in IBD, “except for expected increases in herpes zoster and mild increases in serious infections (mainly Crohn's disease, upadacitinib 30 mg),” Choudhary said.

• Zoster vaccination should be prioritized, “particularly in younger patients and those starting 30 mg,” she added.

• For patients aged 65 and older, data are reassuring but limited. “Individualized decision-making and shared discussion of uncertainties remain important,” she said.

The bottom line is that, across multiple IBD trials, “upadacitinib consistently outperforms placebo with a generally favorable safety profile across diverse patient subgroups. These findings support its role as a flexible, potent therapeutic option in moderate to severe Crohn's disease and ulcerative colitis and can help guide dosing and risk-mitigation strategies in everyday practice,” noted Choudhary.

The study was supported by AbbVie, which designed the trials. Loftus disclosed that he has served as a consultant for AbbVie and for several other pharmaceutical companies. He also holds shares in Exact Sciences and Moderna. Choudhary reported having no disclosures.