BOSTON — Higher doses of JAK and interleukin (IL)-23 inhibitors led to greater remission rates in ulcerative colitis patients over 6 months compared to lower doses, according to a retrospective analysis reported by researchers from the Cleveland Clinic. The analysis included outcomes for 14,962 patients who initiated JAK or IL-23 inhibitors between 2018 and 2024.

Patients receiving higher-dose therapy achieved greater rates of remission at 6 months across all types of these inhibitors (P<0.01). For upadacitinib, 59% of patients on 30 mg daily achieved remission, compared to 48% on 15 mg daily. Tofacitinib saw 45% of patients on 10 mg twice-daily achieve remission, while 36% on 5 mg twice-daily reached remission.

Among IL-23 inhibitors, 48% of patients on 360 mg every 8 weeks of risankizumab achieved remission, compared to 40% on 180 mg every 8 weeks. For guselkumab, 39% of patients on 200 mg every 4 weeks achieved remission, whereas 33% on 100 mg every 8 weeks did. The Cleveland Clinic analysis also indicated that higher doses were associated with greater improvements in inflammation markers. By 12 months, patients on higher doses experienced lower rates of therapy changes, hospitalization, or colon surgery.

JAK and IL-23 inhibitors are used in routine care for ulcerative colitis, with several drugs receiving FDA approval in the past 2 to 4 years. Pivotal trials for these inhibitors were not powered to compare different doses against each other. Rahul Dalal, a gastroenterologist at Brigham and Women's Hospital and Harvard Medical School, stated, "The unresolved question is: Which patient actually needs the higher maintenance dose? Is it the patient with severe endoscopic disease, extensive colitis, prior advanced therapy failure, steroid dependence, high fecal calprotectin, or only a partial induction response?"

Dalal prefers the higher, every-4-week dosing regimen for guselkumab from the onset. He also noted, "For risankizumab [Skyrizi], we also use the higher-dose regimen of 360 mg every 8 weeks for most patients and often consider escalating further to every 6- or every 4-week dosing for those with partial response or loss of response." He added, "Higher maintenance doses may be more effective, particularly for those with refractory disease or recent acute severe colitis, but they also raise more safety concerns."

The FDA requires a boxed warning on JAK inhibitors due to an increased risk of serious heart-related events, cancer, venous thromboembolism, and death. Dalal said, "These drugs can be extremely effective and fast-acting, but I would assess age, cardiovascular risk, VTE history, smoking, malignancy history, infection risk, and other comorbidities before committing to higher-dose regimens for a prolonged period of time." Higher doses of IL-23 inhibitors are linked to a greater risk of shingles. The Cleveland Clinic study did not analyze adverse effects.

Dalal stated, "Real-world data can be influenced by how sick patients were to begin with and regional differences in prescribing habits." JAK and IL-23 inhibitors are expensive, but insurers have covered them at various on-label doses. Some higher-dose regimens require more frequent administration, which may be more burdensome for patients.