Background and Aims

Several advanced therapies for ulcerative colitis (UC) have more than one U.S. Food and Drug Administration-approved dosing strategy, yet comparative real-world data to guide dose selection are lacking. We compared the effectiveness and safety of higher-dose versus standard-dose regimens for upadacitinib, tofacitinib, risankizumab, and guselkumab.

Methods

Using a U.S. federated electronic health record network (>90 million patients), we identified adults with UC who initiated therapy between January 1, 2018 and December 31, 2024 and had ≥12 months of follow-up. Regimens included upadacitinib 30 mg vs 15 mg daily; tofacitinib 10 mg vs 5 mg twice daily; risankizumab 360 mg vs 180 mg every 8 weeks; and guselkumab 200 mg every 4 weeks vs 100 mg every 8 weeks.

The primary outcome was steroid-free clinical remission at 6 months. Secondary outcomes included changes in fecal calprotectin and C-reactive protein, therapy switching, UC-related hospitalization, and colectomy. Propensity-weighted logistic and Cox models adjusted for demographics, disease extent, baseline biomarkers, prior biologic exposure, corticosteroid use, and comorbidities.

Results

Among 14,962 patients (upadacitinib 4,995; tofacitinib 5,308; risankizumab 3,702; guselkumab 2,957), higher-dose therapy was consistently associated with greater remission at 6 months: upadacitinib 58.7% vs 48.2%; tofacitinib 44.9% vs 36.4%; risankizumab 47.8% vs 40.1%; guselkumab 38.9% vs 32.7% (all p≤0.002).

Biomarker improvement favored higher doses across all agents, with larger reductions in fecal calprotectin and C-reactive protein (all p<0.001). At 12 months, higher-dose regimens were associated with lower rates of therapy switching, hospitalization, and colectomy. In adjusted analyses, higher-dose therapy demonstrated superior effectiveness across all agents, including upadacitinib (adjusted odds ratio [aOR] for remission 1.48; adjusted hazard ratio [aHR] for hospitalization 0.62; for switching 0.58), tofacitinib (aOR 1.36; aHR for hospitalization 0.68), risankizumab (aOR 1.32), and guselkumab (aOR 1.29).

Conclusions

Across all studied mechanisms, higher-dose regimens within approved labeling were associated with superior clinical remission, greater biomarker improvement, and reduced healthcare utilization compared with standard dosing. These findings provide large-scale real-world evidence supporting dose optimization as a strategy to improve outcomes in ulcerative colitis and highlight the importance of individualized treatment escalation within approved dosing ranges.

Ahmed Salem

Appearances