In an adult patient with newly active ankylosing spondylitis and no history of serious infection, malignancy, cardiovascular disease, or thrombosis, how do the risk‑benefit profiles of etanercept (Embrel) and upadacitinib (Rinvoq) compare?

Risk/Benefit Comparison: Etanercept vs Upadacitinib for Ankylosing Spondylitis

For a newly active AS patient without contraindications, etanercept (Embrel) is the preferred initial biologic therapy over upadacitinib (Rinvoq) based on ACR/SAA guidelines, which conditionally recommend TNF inhibitors over JAK inhibitors due to greater long-term safety experience and a more established evidence base. 1

Guideline-Based Treatment Hierarchy

The 2019 ACR/Spondylitis Association of America guidelines establish a clear treatment preference order for active AS despite NSAIDs 1:

• TNF inhibitors (including etanercept) are strongly recommended as first-line biologic therapy 1
• JAK inhibitors (including upadacitinib/tofacitinib) are conditionally recommended below TNF inhibitors 1
• The panel explicitly stated that TNF inhibitors should be used over tofacitinib (the JAK inhibitor class representative at guideline publication) given their larger evidence base and familiarity with long-term safety 1

Efficacy Profile Comparison

Etanercept Efficacy

• ASAS20 response rate of 57% vs 22% placebo at 24 weeks in active AS 2
• Demonstrated efficacy in 24 randomized controlled trials with improvements in patient-reported outcomes, composite response criteria, and MRI inflammation 1
• Significantly improves quality of life across multiple domains including physical functioning, bodily pain, and vitality 2

Upadacitinib Efficacy

• ASAS40 response rate of 45% vs 18% placebo at week 14 in biologic-refractory patients 3
• In biologic-naive patients, ≥70% achieved ASAS40 at week 64 4
• Notably, upadacitinib trials enrolled biologic-refractory populations, making direct efficacy comparison to first-line etanercept inappropriate 5, 3

The higher absolute response rates with upadacitinib reflect different trial populations (biologic-experienced vs biologic-naive) rather than superior efficacy 4, 5, 3.

Safety Profile Comparison

Etanercept Safety

• Generally well tolerated with few serious adverse events 2
• Most common adverse events: injection-site reactions and minor upper respiratory tract infections 2
• Lower tuberculosis risk compared to infliximab 1
• Decades of post-marketing safety data in multiple rheumatologic conditions 1

Upadacitinib Safety Concerns

• FDA boxed warning requiring prior TNF inhibitor failure or contraindication before JAK inhibitor use 1
• This warning stems from a postmarketing surveillance study in rheumatoid arthritis patients aged ≥50 years with cardiovascular risk factors showing increased risks of major adverse cardiovascular events, malignancy, thrombosis, and serious infections with JAK inhibitors compared to TNF inhibitors 1
• Through week 64 in AS trials: no major adverse cardiovascular events, venous thromboembolic events, gastrointestinal perforation, or deaths reported 4
• However, the ORAL Surveillance study demonstrated tofacitinib (same drug class) was inferior to TNF inhibitors regarding adverse events 6

Critical Clinical Decision Points

For your newly active AS patient without contraindications:

1. Start with etanercept 25 mg subcutaneously twice weekly 2

   • This aligns with ACR strong recommendation for TNF inhibitors as first-line biologic therapy 1
   • No particular TNF inhibitor is preferred over another for typical patients 1

2. Reserve upadacitinib for specific scenarios:

   • Primary non-response to first TNF inhibitor (consider IL-17 inhibitors first per guidelines) 1
   • Secondary non-response after trying a second TNF inhibitor 1
   • Contraindication to TNF inhibitors 1

3. Assess response at 12-24 weeks 1, 2

   • Adequate trial = lack of response to at least 2 different NSAIDs at maximal doses over 1 month before starting biologics 1

Important Caveats and Pitfalls

Avoid these common errors:

• Do not use upadacitinib as first-line therapy in biologic-naive AS patients - this violates FDA labeling and ACR guidelines 1
• Do not assume higher response rates in upadacitinib trials indicate superior efficacy - these trials enrolled biologic-refractory populations 5, 3
• Do not overlook the cardiovascular/thrombotic risk signal with JAK inhibitors - while not yet demonstrated in AS-specific trials, the class-wide FDA warning applies 1, 6
• Consider etanercept over other TNF inhibitors if patient has high tuberculosis exposure risk - infliximab carries higher TB and infection risk 1

Special populations requiring modified approach:

• Recurrent uveitis: avoid etanercept, use TNF monoclonal antibodies (adalimumab/infliximab) 1
• Coexistent IBD: avoid etanercept, use TNF monoclonal antibodies 1
• Coexistent ulcerative colitis with TNF contraindication: consider upadacitinib over IL-17 inhibitors 1

The evidence strongly supports etanercept as the appropriate first-line biologic for your patient, with upadacitinib reserved for later-line therapy after TNF inhibitor experience 1.