What are the guidelines for using Upadacitinib (Rinvoq) in adult patients with active spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, who have had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biologic disease-modifying antirheumatic drugs (bDMARDs)?

Upadacitinib in Spondyloarthritis: Guideline-Based Recommendations

Upadacitinib 15 mg once daily is recommended for adult patients with active spondyloarthritis (including ankylosing spondylitis, non-radiographic axial spondyloarthritis, and psoriatic arthritis) who have had an inadequate response or intolerance to at least one biologic DMARD, with important safety considerations required for patients ≥65 years, smokers, and those with cardiovascular risk factors. 1, 2

FDA-Approved Indications for Spondyloarthritis

Upadacitinib is FDA-approved for three distinct spondyloarthritis conditions 2:

• Ankylosing Spondylitis: Adults with active disease who have had inadequate response or intolerance to one or more TNF blockers, dosed at 15 mg once daily 2
• Non-radiographic Axial Spondyloarthritis: Adults with active disease and objective signs of inflammation who have had inadequate response or intolerance to TNF blocker therapy, dosed at 15 mg once daily 2
• Psoriatic Arthritis: Adults and pediatric patients ≥2 years with active disease who have had inadequate response or intolerance to one or more TNF blockers 2

Treatment Algorithm by Disease Manifestation

For Peripheral Arthritis (Psoriatic Arthritis)

Step 1: Initiate conventional synthetic DMARDs (csDMARDs) rapidly, with methotrexate preferred if clinically relevant skin involvement is present 1

Step 2: If inadequate response to at least one csDMARD, commence biologic DMARD therapy 1

Step 3: Upadacitinib may be considered after inadequate response to at least one bDMARD, or when a bDMARD is not appropriate, taking safety considerations into account 1

• This represents Level 1b evidence with Grade B recommendation and 9.1/10 expert agreement 1
• JAK inhibitors (including upadacitinib and tofacitinib) are positioned after bDMARD failure in the 2023 EULAR guidelines 1

For Axial Disease (Ankylosing Spondylitis, Non-radiographic Axial Spondyloarthritis, or Axial PsA)

Step 1: NSAIDs as first-line therapy for insufficient response 1

Step 2: For clinically relevant axial disease with insufficient response to NSAIDs, therapy with an IL-17A inhibitor, TNF inhibitor, IL-17A/F inhibitor, or JAK inhibitor should be considered 1

• This represents Level 1b evidence with Grade B recommendation and 9.4/10 expert agreement 1
• Upadacitinib is explicitly included as an option alongside biologics for axial manifestations in the 2023 EULAR update 1

For Enthesitis

If unequivocal enthesitis with insufficient response to NSAIDs or local glucocorticoid injections, therapy with a bDMARD should be considered first 1

Critical Safety Considerations

Mandatory safety precautions for JAK inhibitors, including upadacitinib 1:

• Age ≥65 years: Exercise caution due to increased risk of adverse events 1
• Current or past long-time smokers: Increased risk profile requires careful consideration 1
• History of atherosclerotic cardiovascular disease or cardiovascular risk factors: Higher rate of major adverse cardiovascular events (MACE) observed with JAK inhibitors versus TNF blockers 1, 2
• Malignancy risk factors: Increased consideration needed 1
• Known risk factors for venous thromboembolism: Thrombosis has occurred in patients treated with JAK inhibitors, with increased incidence of pulmonary embolism and venous/arterial thrombosis versus TNF blockers 1, 2

Efficacy Data Supporting Use

Ankylosing Spondylitis (Biologic-Refractory)

In patients with active AS and inadequate response to 1-2 bDMARDs (TNF or IL-17 inhibitors) 3:

• 45% achieved ASAS40 at week 14 versus 18% with placebo (p<0.0001) 3
• Statistically significant improvements in all multiplicity-controlled secondary endpoints including ASDAS, MRI spine inflammation, pain measures, BASFI, and BASMI 3
• Sustained efficacy through 52 weeks with 66% achieving ASAS40, 57% achieving ASDAS low disease activity, and 26% achieving ASDAS inactive disease 4

Non-radiographic Axial Spondyloarthritis

In patients with active disease and objective signs of inflammation 5:

• 45% achieved ASAS40 at week 14 versus 23% with placebo (p<0.0001) 5
• Treatment difference of 22% (95% CI 12-32%) 5

Psoriatic Arthritis (Biologic-Refractory)

In patients with inadequate response or intolerance to at least one biologic DMARD 6:

• 56.9% (15 mg) and 63.8% (30 mg) achieved ACR20 at week 12 versus 24.1% with placebo (p<0.001) 6
• 25.1% (15 mg) and 28.9% (30 mg) achieved minimal disease activity at week 24 versus 2.8% with placebo (p<0.001) 6

Dosing Specifications

Standard dosing for all spondyloarthritis indications: 15 mg once daily orally 2

Do not use in combination with 2:

• Other JAK inhibitors
• Biologic DMARDs
• Potent immunosuppressants (azathioprine, cyclosporine)

Positioning Relative to Other Therapies

When to Choose Upadacitinib Over Other Options

For axial manifestations: Upadacitinib is positioned as an equal option alongside IL-17 and TNF inhibitors after NSAID failure, representing a significant advancement from prior guidelines that reserved JAK inhibitors for later lines 1

For peripheral arthritis: Upadacitinib is positioned after bDMARD failure or when bDMARDs are not appropriate 1

For inflammatory bowel disease comorbidity: JAK inhibitors (including upadacitinib) may be preferred over IL-17 inhibitors, as anti-TNF monoclonal antibodies, IL-23 inhibitors, IL-12/23 inhibitors, or JAK inhibitors are recommended for IBD 1

Common Pitfalls to Avoid

Do not use upadacitinib as first-line therapy before trying NSAIDs in axial disease or csDMARDs in peripheral arthritis 1, 2

Do not overlook safety screening: Prior to treatment, update immunizations and evaluate for active/latent tuberculosis, viral hepatitis, hepatic function, and pregnancy status 2

Do not initiate or continue if: Absolute lymphocyte count <500 cells/mm³, absolute neutrophil count <1000 cells/mm³, or hemoglobin <8 g/dL 2

Do not ignore extra-articular manifestations: For uveitis, prefer anti-TNF monoclonal antibodies over JAK inhibitors; for significant skin involvement in PsA, IL-17 or IL-23 pathway inhibitors may be preferred over JAK inhibitors 1

Do not combine with other immunosuppressants: Upadacitinib should not be used with other JAK inhibitors, biologic DMARDs, or potent immunosuppressants 2