What is the role of Upadacitinib (Janus kinase inhibitor) in treating patients with moderate to severe Inflammatory Bowel Disease (IBD) who are intolerant or unresponsive to other treatments, such as aminosalicylates, corticosteroids, immunomodulators, or biologics?

Upadacitinib in Inflammatory Bowel Disease

Upadacitinib is a highly effective JAK1 inhibitor approved for moderate-to-severe ulcerative colitis and Crohn's disease in adults who have failed or are intolerant to one or more TNF blockers, ranking among the highest efficacy medications available for IBD. 1, 2

Regulatory Status and Positioning

FDA-Approved Indications

• Ulcerative Colitis: Approved for adults with moderately to severely active UC who have had inadequate response or intolerance to one or more TNF blockers 2
• Crohn's Disease: Approved for adults with moderately to severely active CD who have had inadequate response or intolerance to one or more TNF blockers 2, 3
• Critical FDA Restriction: In the United States, the FDA label specifically recommends use of JAK inhibitors only in patients with prior failure or intolerance to TNF antagonist therapy 1, 4

Comparative Efficacy Rankings

For treatment-naïve UC patients (in countries outside the US where JAK inhibitors can be used first-line), the 2024 AGA guidelines classify upadacitinib as a HIGHER efficacy medication alongside infliximab, vedolizumab, ozanimod, etrasimod, risankizumab, and guselkumab 1, 4

Upadacitinib demonstrates superior efficacy compared to other advanced therapies:

• Induction of clinical remission in UC: 29.1% with upadacitinib vs 3.7% with placebo (RR 7.15,95% CI 4.26-11.99), achieving 615 more remissions per 1000 patients treated 1
• Network meta-analysis findings: Upadacitinib was the most efficacious in inducing clinical remission as first-line treatment, achieving remission in approximately 50% of patients 1
• Superiority over other JAK inhibitors: Both upadacitinib 30 mg daily (RR 2.83) and 15 mg daily (RR 2.32) were superior to risankizumab for maintenance of remission at 1 year 1

Dosing Regimens

Ulcerative Colitis

• Induction: 45 mg once daily for 8-16 weeks 1, 2
• Maintenance: 15 mg or 30 mg once daily 1, 2
• Extended induction: Nearly half (48%) of patients who failed initial 8-week induction responded to an additional 8 weeks of therapy 1

Crohn's Disease

• Induction: 45 mg once daily 2, 3
• Maintenance: 15 mg or 30 mg once daily 2, 3

Dose Adjustments

• Severe renal impairment (CrCl <30 mL/min): Maximum 15 mg daily 4, 2
• Severe hepatic disease (Child-Pugh C): Not recommended 4, 2
• Age ≥75 years: Consider dose reduction to 15 mg daily 4

Clinical Efficacy Data

Ulcerative Colitis Outcomes

Induction (Week 8):

• Clinical remission: 26% vs 5% placebo (treatment difference 22%, 95% CI 16-27%) 2
• Clinical response: 73% vs 27% placebo (treatment difference 46%, 95% CI 38-54%) 2
• Endoscopic improvement: 36% vs 7% placebo (treatment difference 29%, 95% CI 23-36%) 2
• Histologic-endoscopic mucosal improvement: 30% vs 7% placebo (treatment difference 24%, 95% CI 17-30%) 2

Maintenance (Week 52):

• Clinical remission with 15 mg daily: 42.6% vs 12.1% placebo (RR 3.52,95% CI 2.20-5.65) 1
• Clinical remission with 30 mg daily: 51.9% vs 12.1% placebo (RR 4.30,95% CI 2.72-6.81) 1

Efficacy in biologic-experienced patients:

• Prior biologic failure: 18% clinical remission vs <1% placebo 2
• No prior biologic failure: 35% clinical remission vs 9% placebo 2

Real-World Evidence

A 2024 systematic review and meta-analysis demonstrated:

• Clinical remission: 36% in RCTs, 40% in retrospective studies, 55% in cohort studies 5
• Clinical response: 61% in RCTs, 65% in cohort studies 5
• Endoscopic remission: 19% in RCTs, 29% in cohort studies 5

Safety Profile and Monitoring

FDA Boxed Warnings

All JAK inhibitors, including upadacitinib, carry black box warnings for:

• Serious infections (bacterial, fungal, viral, opportunistic) including tuberculosis 2
• Higher all-cause mortality vs TNF blockers (based on tofacitinib data in RA patients ≥50 years with CV risk factors) 2
• Malignancies (higher rates of lymphomas and lung cancers vs TNF blockers) 2
• Major adverse cardiovascular events (MACE) 2
• Thrombosis (pulmonary embolism, venous and arterial thrombosis) 2

Common Adverse Events in UC Trials

Induction phase: Acne, creatine phosphokinase elevation, nasopharyngitis, headache, anemia 6

Maintenance phase: Nasopharyngitis, CPK elevation, UC exacerbation, upper respiratory tract infection, arthralgia, anemia 6

Adverse Events of Special Interest

• Herpes zoster: More frequent with upadacitinib; zoster vaccination should be considered before starting therapy, particularly in patients aged >70 years or >50 years at high risk 1
• Venous thromboembolism: Increased risk, particularly at higher doses 1, 7
• Infections: Increased risk of serious infections requiring hospitalization 2

Mandatory Pre-Treatment Screening

• Tuberculosis screening (latent and active) 4, 2
• Hepatitis B and C serologies 4
• Complete blood count with differential 4
• Liver and renal function tests 4
• Lipid panel 4
• Pregnancy testing 4
• Herpes zoster vaccination (live vaccine must not be given for 3 months after stopping biologics; upadacitinib should not be started for 4 weeks after vaccination) 1

Laboratory Monitoring Requirements

Avoid initiation or interrupt therapy if:

• Absolute lymphocyte count <500 cells/mm³ 2
• Absolute neutrophil count <1000 cells/mm³ 2
• Hemoglobin <8 g/dL 2

Ongoing monitoring:

• CBC with differential at baseline and after initiation/dose escalation 4
• Liver enzymes at baseline and periodically 4
• Lipids at 12 weeks after initiation 4
• Active TB monitoring during treatment, even in patients with initial negative latent TB test 2

High-Risk Populations Requiring Special Consideration

Cardiovascular Risk

Do not use upadacitinib as first-line therapy in patients ≥65 years with cardiovascular risk factors when TNF inhibitors remain viable options 4

Risk factors requiring enhanced monitoring:

• Age >65 years 4, 2
• Current or previous long-term smokers 4
• History of cardiovascular disease 4
• History of venous thromboembolism 4

Stable coronary artery disease is not an absolute contraindication but requires enhanced cardiovascular monitoring 4

Thromboembolic Risk

The European Medicines Agency advises that high-dose JAK inhibitors should not be used in patients at increased risk of pulmonary embolism, including those with:

• Heart failure 1
• Malignancy 1
• Impending/recent surgery 1
• Inherited coagulation disorders 1
• Previous thromboembolism 1
• Combined contraceptive therapy or HRT 1

Other Contraindications

• Active serious infection 2
• Severe hepatic impairment (Child-Pugh C) 4, 2
• Pregnancy or breastfeeding (limited data available; animal studies suggest potential adverse effects) 4

Treatment Algorithm and Positioning

For Ulcerative Colitis

Step 1: Biologic-Naïve Patients

• In the US: Must fail or be intolerant to at least one TNF blocker before upadacitinib 1, 4
• Outside the US: Upadacitinib can be considered as first-line advanced therapy in select cases, classified as HIGHER efficacy medication 1

Step 2: After TNF Blocker Failure

• Primary non-response to TNF blocker: Upadacitinib is recommended as a swap to different mechanism of action 1
• Secondary non-response or intolerance: Consider dose escalation of TNF blocker, switch to another TNF blocker, or swap to upadacitinib 1

Step 3: Maintenance Therapy

• Approximately 29% of patients de-escalated from 10 mg twice daily tofacitinib to 5 mg twice daily required dose re-escalation, with only 63% recapturing response 1
• A subset of patients, particularly those with severe disease, may require maintenance at higher doses (30 mg daily for upadacitinib) 1
• Monitor carefully for adverse effects (shingles, VTE) at higher maintenance doses 1

For Crohn's Disease

• Upadacitinib is the first and only JAK inhibitor approved for CD, providing a novel oral treatment option 3
• Approved for adults with moderately to severely active CD who have failed or are intolerant to one or more TNF blockers 2, 3
• May change current treatment algorithms for CD, though further real-world studies and head-to-head comparisons are needed 3

For IBD-Associated Spondyloarthritis

Active axial SpA with active IBD:

• Anti-TNF agents remain first-line treatment 1
• In case of primary non-response to one anti-TNF, swapping to JAK inhibitors (upadacitinib or tofacitinib) is recommended 1
• Upadacitinib and tofacitinib have proven efficacy for ankylosing spondylitis, unlike filgotinib 1

Active axial SpA with IBD in remission:

• TNF inhibitors remain preferred 1
• In case of primary non-response to one anti-TNF, swapping to JAK inhibitors is recommended 1

Combination Therapy Restrictions

Upadacitinib is NOT recommended in combination with:

• Other JAK inhibitors 2
• Biologic therapies for IBD 2
• Potent immunosuppressants (azathioprine, cyclosporine) 2

Permitted concomitant medications:

• Stable doses of oral aminosalicylates 2
• Methotrexate (though limited use in UC) 2
• Oral corticosteroids up to 30 mg/day prednisone equivalent 2
• UC-related antibiotics 2

Emerging Data and Special Scenarios

Acute Severe Colitis

A 2024 retrospective study evaluated upadacitinib as rescue therapy for acute severe colitis in 12 hospitalized patients:

• Five patients (42%) met the primary composite endpoint (surgery, inability to withdraw steroids, or readmission within 90 days) 8
• Four patients required surgery 8
• Most patients who avoided surgery achieved clinical remission within 90 days with decreased partial Mayo scores 8
• Upadacitinib may be effective salvage therapy for acute severe colitis, but larger controlled trials are required 8

Advantages Over Biologics

• Oral administration (no infusion reactions or injection site reactions) 1
• No immunogenicity concerns as a small molecule 1
• Rapid onset of action 7
• Efficacy in biologic-experienced patients, including those who failed multiple biologic classes 2, 6

Critical Clinical Pitfalls to Avoid

1. Do not use upadacitinib as first-line therapy in the US without documented TNF blocker failure or intolerance (FDA restriction) 1, 4

2. Do not initiate upadacitinib in patients ≥65 years with multiple cardiovascular risk factors unless no suitable alternatives exist 4

3. Do not ignore smoking status—current or past smokers with cardiac disease represent the highest-risk population 4

4. Do not start therapy without completing TB screening and treating latent TB if present 2

5. Do not administer live vaccines within 3 months after stopping biologics or within 4 weeks before starting upadacitinib 1

6. Do not automatically de-escalate maintenance doses in patients with severe disease—approximately 25-29% cannot maintain remission on lower doses 1

7. Do not combine with other JAK inhibitors, biologics, or potent immunosuppressants 2

8. Do not use in patients at high risk for thromboembolism without careful risk-benefit assessment and enhanced monitoring 1