What is the role of Upadacitinib (Janus kinase inhibitor) in treating Crohn's disease affecting the small bowel?

Upadacitinib in Crohn's Disease Affecting the Small Bowel

Upadacitinib is conditionally recommended for moderate-to-severe Crohn's disease involving the small bowel, particularly in patients who have failed or are intolerant to anti-TNF therapy, with strong evidence supporting both induction and maintenance efficacy. 1

Regulatory Status and Positioning

• Upadacitinib is FDA-approved for Crohn's disease and represents the first oral agent proven effective for both inducing and maintaining remission in this condition. 1
• The European Crohn's and Colitis Organisation (ECCO) provides a strong recommendation for upadacitinib as induction therapy in moderate-to-severe Crohn's disease with high-quality evidence. 1
• Both FDA and European Medicines Agency labeling restrict JAK inhibitors to patients who have failed or are intolerant to TNF antagonists—they should not be used as first-line therapy in biologic-naïve patients. 2, 3

Efficacy in Small Bowel Crohn's Disease

Induction Therapy (12 weeks)

• Clinical remission rates: 49.5% (U-EXCEL) and 38.9% (U-EXCEED) versus 29.1% and 21.1% with placebo (p<0.001). 4
• Endoscopic response rates: 45.5% (U-EXCEL) and 34.6% (U-EXCEED) versus 13.1% and 3.5% with placebo (p<0.001). 4
• Real-world data demonstrates clinical response in 76.5% and clinical remission in 70.6% by 8 weeks, with responses evident as early as week 2 (56.3% clinical remission). 5

Maintenance Therapy (52 weeks)

• Clinical remission: 37.3% with 15mg and 47.6% with 30mg versus 15.1% with placebo (p<0.001). 4
• Endoscopic response: 27.6% with 15mg and 40.1% with 30mg versus 7.3% with placebo (p<0.001). 4
• In highly refractory real-world cohorts (100% prior anti-TNF exposure, 89.3% with ≥2 prior advanced therapies), 69.7% achieved clinical response and 30.3% achieved clinical remission at last follow-up. 5

Dosing Algorithm

Induction Phase:

• 45mg once daily for 12 weeks 3, 6

Maintenance Phase:

• 15mg or 30mg once daily 3, 6
• The 30mg dose demonstrates superior efficacy (47.6% vs 37.3% remission) but carries higher risk of adverse events. 4
• For patients with mild-to-moderate hepatic impairment: 30mg for induction, 15mg for maintenance. 6

Pre-Treatment Screening Requirements

Before initiating upadacitinib, complete the following mandatory screening:

• Screen for active and latent tuberculosis 1, 3
• Evaluate for viral hepatitis 1
• Update all immunizations 1
• Obtain baseline absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) 1

Safety Monitoring and Contraindications

Black Box Warnings

• Venous thromboembolism (VTE) and major adverse cardiovascular events (MACE) in higher-risk populations 1
• FDA and EMA advise JAK inhibitors should be used only if no suitable alternatives exist in patients who are:
  • ≥65 years of age
  • Current or long-term former smokers
  • History of cardiovascular disease or MACE risk factors 3

Laboratory Monitoring

• Interrupt treatment if ANC <1000 cells/mm³ 1, 3
• Interrupt treatment if ALC <500 cells/mm³ 1, 3

Common Adverse Events

• Herpes zoster infections: 4.0-7.2% on maintenance therapy (more frequent with 45mg and 30mg doses) 1, 4
• Acne: 22.9% in real-world cohorts 5
• Hepatic disorders and neutropenia: more frequent with 30mg maintenance dose 1, 4
• Gastrointestinal perforations: rare but reported (4 patients on 45mg, 1 each on 30mg and 15mg in phase 3 trials) 1, 4

Comparative Positioning

• In biologic-exposed Crohn's disease patients, risankizumab and upadacitinib are favored over ustekinumab, adalimumab, and vedolizumab, with no demonstrated superiority between risankizumab and upadacitinib. 2
• Upadacitinib is effective even in patients with prior tofacitinib exposure, with 77.8% achieving clinical remission by 8 weeks in real-world data. 5

Clinical Pitfalls to Avoid

• Do not use as first-line therapy in biologic-naïve patients—regulatory restrictions mandate prior TNF antagonist failure or intolerance. 2, 3
• Do not overlook cardiovascular and VTE risk stratification—the EMA specifically cautions against use in patients with increased cardiovascular risk, history of VTE, or cancer. 1
• Do not continue therapy without monitoring laboratory parameters—neutropenia and lymphopenia require treatment interruption at specified thresholds. 1, 3
• Consider herpes zoster vaccination before initiating therapy given the 4-7% infection rate. 1, 4