What is the recommended treatment approach for patients with psoriatic arthritis who have had an inadequate response to previous treatments, considering the use of upadacitinib (Janus kinase inhibitor) and methotrexate (conventional synthetic disease-modifying antirheumatic drug, csDMARD)?

Treatment Approach for Psoriatic Arthritis: Upadacitinib and Methotrexate

For patients with psoriatic arthritis and inadequate response to previous treatments, initiate methotrexate first (especially if clinically relevant skin involvement is present), escalate to a biologic DMARD after inadequate response to at least one csDMARD, and reserve upadacitinib (JAK inhibitor) for patients who fail or cannot tolerate biologics, with careful attention to safety considerations in high-risk populations. 1

Initial Treatment Strategy with Methotrexate

When to Start Methotrexate:

• In patients with polyarthritis, initiate a csDMARD rapidly, with methotrexate preferred when clinically relevant skin involvement is present 1
• In patients with monoarthritis/oligoarthritis who have poor prognostic factors (structural damage, elevated acute phase reactants, dactylitis, or nail involvement), a csDMARD should also be initiated rapidly 1
• Methotrexate can be used alone or in combination with other DMARDs 2

Treatment Target:

• Aim for remission or, alternatively, low disease activity through regular disease activity assessment and appropriate therapy adjustment 1

Escalation to Biologic DMARDs

When Methotrexate Fails:

• After inadequate response to at least one csDMARD (including methotrexate), therapy with a biologic DMARD should be commenced 1
• Preferred biologics include TNF inhibitors, IL-17 inhibitors, IL-17A/F inhibitors, IL-23 inhibitors, or IL-12/23 inhibitors 1, 2
• When clinically relevant skin involvement exists, preference should be given to IL-17A, IL-17A/F, IL-23, or IL-12/23 inhibitors 1

Role of Upadacitinib (JAK Inhibitor)

When to Consider Upadacitinib:

• Upadacitinib may be considered in patients with peripheral arthritis and inadequate response to at least one biologic DMARD, or when a biologic DMARD is not appropriate 1
• Critical change from 2019 guidelines: The 2023 EULAR update removed the requirement for prior csDMARD failure before using JAK inhibitors after biologic failure, streamlining the treatment pathway 1
• The recommended dose is upadacitinib 15 mg once daily for psoriatic arthritis 3

Efficacy Data:

• In biologic DMARD-inadequate responders, upadacitinib 15 mg achieved 56.9% ACR20 response at week 12 versus 24.1% with placebo (p<0.001) 4
• Minimal disease activity was achieved by 25.1% of patients on upadacitinib 15 mg versus 2.8% on placebo at week 24 4
• Efficacy was maintained through 152 weeks of treatment in long-term studies 5
• Upadacitinib demonstrated improvements in dactylitis, enthesitis, and skin manifestations 3, 6

Combination with Methotrexate:

• Combining upadacitinib with methotrexate showed similar efficacy to upadacitinib monotherapy in both biologic-naive and biologic-experienced patients 6
• This suggests methotrexate can be continued or discontinued based on individual patient factors without compromising upadacitinib efficacy 6

Critical Safety Considerations for Upadacitinib

High-Risk Populations Requiring Caution: 1

• Patients aged 65 years or above
• Current or past long-time smokers
• History of atherosclerotic cardiovascular disease or other cardiovascular risk factors
• Other malignancy risk factors
• Known risk factors for venous thromboembolism

Common Adverse Events:

• Upper respiratory tract infection, nasopharyngitis, and increased creatine phosphokinase were most common 7
• Higher rates of herpes zoster compared to adalimumab (though not considered serious adverse events) 6, 7
• Serious infection rates were 0.5% with upadacitinib 15 mg through 24 weeks 4
• Rates of malignancies, major adverse cardiovascular events, venous thromboembolic events, and deaths were similar to adalimumab 7

The 2023 EULAR guidelines introduced a new overarching principle emphasizing that treatment choice should account for safety considerations regarding individual modes of action to optimize the benefit-risk profile 1

Treatment Algorithm Summary

1. First-line: Methotrexate (or other csDMARD like leflunomide or sulfasalazine), preferred with skin involvement 1, 2

2. Second-line: Biologic DMARD after inadequate response to at least one csDMARD 1

3. Third-line: Upadacitinib 15 mg once daily after inadequate response to at least one biologic DMARD or when biologics are not appropriate, with careful safety screening 1

4. Switching: If inadequate response or intolerance to upadacitinib occurs, switching to another biologic DMARD or JAK inhibitor should be considered, including one switch within a class 1

Special Considerations for Axial Disease

• For clinically relevant axial disease with insufficient response to NSAIDs, upadacitinib is an appropriate option alongside IL-17A inhibitors, TNF inhibitors, and IL-17A/F inhibitors 1