What is the preferred initial treatment between tofacitinib (Xeljanz) and upadacitinib (Rinvoq) for patients with similar disease severity?

Upadacitinib vs Tofacitinib: Treatment Selection

For patients with moderate-to-severe ulcerative colitis, upadacitinib is the preferred JAK inhibitor over tofacitinib based on superior efficacy, though both agents demonstrate comparable safety profiles. 1

Efficacy Comparison

Ulcerative Colitis

Upadacitinib demonstrates significantly higher efficacy than tofacitinib across all treatment phases:

• Induction therapy: Upadacitinib achieves clinical remission in 29.1% of patients versus 18.9% with tofacitinib (relative risk 7.15 vs 3.23 compared to placebo), representing 615 more patients per 1000 achieving remission with upadacitinib versus 223 more per 1000 with tofacitinib 1

• Maintenance therapy: Upadacitinib 30 mg daily achieves 51.9% clinical remission versus 40.6% with tofacitinib 10 mg twice daily, with upadacitinib 15 mg daily achieving 42.6% remission 1

• Quality of evidence: Upadacitinib has high certainty evidence (⨁⨁⨁⨁) for induction, while tofacitinib has moderate certainty (⨁⨁⨁) 1

• Efficacy classification: The 2024 AGA guidelines classify upadacitinib as a "HIGHER efficacy medication" while tofacitinib is classified as "INTERMEDIATE efficacy" for biologic-naïve patients 1

Network Meta-Analysis Findings

• Upadacitinib was superior to tofacitinib in direct network comparisons for moderate-to-severe UC 1

• In biologic-exposed patients, upadacitinib, tofacitinib, and ustekinumab all demonstrated superiority over vedolizumab, but upadacitinib showed the greatest magnitude of benefit 1

• The greater JAK selectivity of upadacitinib (preferential JAK-1 inhibition) may allow for better dosing profiles without compromising safety, contributing to superior efficacy 1

Rheumatoid Arthritis Data

• In RA populations, upadacitinib 15 mg and 30 mg with methotrexate ranked highest for efficacy (SUCRA = 0.820,0.762), followed by tofacitinib 10 mg (SUCRA = 0.623) and tofacitinib 5 mg (SUCRA = 0.424) 2

• Upadacitinib demonstrated superiority to adalimumab in head-to-head trials using ACR70 response rates 3

Safety Comparison

Comparable Safety Profiles

Both agents demonstrate similar safety profiles with no significant differences in serious adverse events:

• In acute severe UC, tofacitinib and upadacitinib showed comparable adverse event frequencies in real-world comparative studies 4

• Network meta-analyses in RA found no significant differences in serious adverse events between tofacitinib + MTX, upadacitinib + MTX, and other comparators 2

• Real-world UC/CD experience with upadacitinib showed acne as the most common adverse event (22.9%), with overall favorable safety profile 5

Class-Specific Safety Concerns

Both agents share JAK inhibitor class warnings that require careful patient selection:

• Venous thromboembolism (VTE): Both tofacitinib (especially 10 mg twice daily) and upadacitinib carry increased VTE risk, particularly in patients >50 years with cardiovascular risk factors, high BMI, prior thromboembolism history, or hormone replacement therapy 1

• Herpes zoster: Increased risk with both agents, with tofacitinib showing dose-dependent increases (greater at 10 mg twice daily) 1, 6

• Serious infections: Both agents associated with increased infection risk compared to placebo, though magnitude is small for most UC patients 1

• FDA restrictions: Both agents restricted to patients with prior TNF antagonist failure or intolerance in the United States 1

• European restrictions: EMA recommends cautious first-line use in patients ≥65 years, current/previous smokers, history of cardiovascular disease, or history of cancer 1

Clinical Decision Algorithm

When to Choose Upadacitinib

Upadacitinib should be selected in the following scenarios:

• Biologic-naïve patients requiring maximum efficacy (classified as HIGHER efficacy agent) 1

• Biologic-exposed patients, including those with prior tofacitinib exposure (77.8% achieved remission by 8 weeks in real-world data) 5

• Patients requiring rapid response (clinical remission rates of 36% at week 2 in UC) 5

• Patients without high-risk features for VTE or cardiovascular events who meet regulatory criteria 1

When to Choose Tofacitinib

Tofacitinib remains appropriate in specific contexts:

• Patients already responding well to tofacitinib who do not require switching 1

• Cost or access considerations where upadacitinib is unavailable or unaffordable 1

• Patients with INTERMEDIATE efficacy needs who meet safety criteria 1

Contraindications for Both Agents

Avoid both JAK inhibitors in:

• Patients ≥65 years with cardiovascular risk factors (current/former smokers, cardiovascular disease history) 1

• Active serious infections or history of recurrent serious infections 1

• History of VTE without adequate anticoagulation strategy 1

• Patients with malignancy history (use with extreme caution) 1

Dosing Considerations

Maintenance Dose Optimization

• Tofacitinib: 29% of patients de-escalated from 10 mg twice daily to 5 mg twice daily required dose re-escalation, with only 63% recapturing clinical response 1

• Patients with severe disease may require maintenance at higher doses (tofacitinib 10 mg twice daily), necessitating careful monitoring for VTE and herpes zoster 1

• Upadacitinib: Standard maintenance dosing is 15 mg or 30 mg daily, with 30 mg showing higher remission rates (51.9% vs 42.6%) 1

Real-World Effectiveness

Acute Severe UC Setting

• In hospitalized patients with acute severe UC, both agents showed similar effectiveness when used as salvage therapy (tofacitinib n=35 vs upadacitinib n=31) 4

• Colectomy-free survival at days 98 and 182 was comparable: tofacitinib (79% and 75%) versus upadacitinib (80% and 78%), P=0.99 4

• Upadacitinib showed greater early response rates between days 3-7 (84% vs 54%, P=0.02), but response/remission was comparable by day 98 and 182 4

Heavily Pre-Treated Populations

• In real-world UC/CD cohorts where 100% had prior anti-TNF exposure and 89.3% had ≥2 advanced therapies, upadacitinib achieved 81.5% clinical remission at 8 weeks in UC 5

• Among tofacitinib-exposed UC patients switching to upadacitinib, 77.8% achieved clinical remission by 8 weeks, demonstrating efficacy despite prior JAK inhibitor exposure 5

Monitoring Requirements

Both agents require identical monitoring strategies:

• Baseline screening for tuberculosis, hepatitis B/C, and complete blood count 1

• Prophylactic-dose anticoagulation should be considered in high-risk patients 1

• Monitor for herpes zoster (consider vaccination before initiation if not contraindicated) 1, 6

• Avoid concomitant use with tocilizumab or other IL-6 inhibitors 1

• Regular assessment for skin changes (acne common with both agents) 5

1, 4, 2, 5