What is the role of ixekizumab (interleukin-17A inhibitor) and tofacitinib (Janus kinase inhibitor) in the treatment of patients with psoriatic arthritis, particularly those who have failed or have contraindications to traditional disease-modifying antirheumatic drugs (DMARDs) or biologic agents?

Ixekizumab and Tofacitinib in Psoriatic Arthritis

Both ixekizumab (IL-17A inhibitor) and tofacitinib (JAK inhibitor) are effective second-line agents for psoriatic arthritis after csDMARD failure, with ixekizumab preferred when significant skin involvement is present, and tofacitinib reserved for patients who have failed or cannot tolerate biologics.

Treatment Algorithm for Peripheral Arthritis

After csDMARD Failure (First Biologic)

• Start with a biologic DMARD (bDMARD) after inadequate response to at least one csDMARD 1
• When clinically relevant skin involvement exists, prefer IL-17 inhibitors (including ixekizumab) or IL-12/23 inhibitors over TNF inhibitors 1
• Ixekizumab demonstrated comparable efficacy to adalimumab across all musculoskeletal domains and superior psoriasis outcomes in head-to-head trials 2

After Biologic Failure (Role of Tofacitinib)

• Tofacitinib should be considered in patients with inadequate response to at least one bDMARD, or when a bDMARD is not appropriate, taking safety considerations into account 1
• The 2023 EULAR guidelines notably removed the requirement for csDMARD failure before initiating JAK inhibitors, allowing their use after a single bDMARD failure 1
• Tofacitinib 5 mg or 10 mg twice daily achieved ACR20 response rates of 50% and 61% respectively at 3 months in csDMARD-inadequate responders, compared to 33% with placebo 3

Efficacy Across Disease Domains

Ixekizumab Performance

• Achieves ACR20 response in 58% of biologic-naïve patients at 24 weeks with 80 mg every 4 weeks dosing 4
• Effective for peripheral arthritis, enthesitis (73% achieving sPGA 0/1 for genital psoriasis), and psoriasis 4
• Demonstrates efficacy in both TNF-naïve and TNF-experienced populations 4

Tofacitinib Performance

• Pooled analysis of 710 patients showed significant improvements in peripheral arthritis, psoriasis, enthesitis, and dactylitis at 3 months 5
• HAQ-DI improvements of -0.35 (5 mg BID) and -0.40 (10 mg BID) versus -0.18 with placebo at 3 months 3
• Efficacy maintained through 12 months with both dosing regimens 3

Axial Disease Considerations

• For clinically relevant axial disease with inadequate NSAID response, consider IL-17A inhibitors, TNF inhibitors, IL-17 A/F inhibitors, or JAK inhibitors 1
• This represents an important update from 2019 guidelines that primarily recommended TNF inhibitors for axial disease 1
• Ixekizumab is specifically approved for axial spondyloarthritis and demonstrates similar pharmacokinetics across PsA and axial disease indications 4

Safety Profile Comparison

Ixekizumab Safety

• Injection site reactions occur in 9.5-10.6% with ixekizumab versus 3.2-3.5% with adalimumab (p<0.01) 2
• Serious adverse events significantly lower than adalimumab: 4.2% versus 12.4% at 52 weeks (p<0.01) 2
• Allergic reactions in 6.2% versus 1.8% with placebo 2

Tofacitinib Safety

• Adverse event rates through 12 months: 66% (5 mg BID) and 71% (10 mg BID) versus 72% with adalimumab 3
• Four cases of cancer, three serious infections, and four cases of herpes zoster reported in tofacitinib-treated patients 3
• Increased risk of serious infections, malignancy, and laboratory abnormalities requires monitoring 6

Critical Safety Considerations for Tofacitinib

The 2023 EULAR guidelines explicitly state that JAK inhibitors should be used "taking safety considerations into account" 1. This reflects emerging cardiovascular and malignancy concerns with JAK inhibitors in older populations with cardiovascular risk factors. Consider the following contraindications:

• Age ≥65 years with cardiovascular risk factors
• History of malignancy (particularly within 5 years)
• Current smokers or significant smoking history
• Patients at high risk for venous thromboembolism

Switching Within and Between Classes

• Switching to another bDMARD or JAK inhibitor should be considered with inadequate response or intolerance, including one switch within a class 1
• When switching from IL-17 inhibitor failure, ACR/NPF guidelines conditionally recommend TNF inhibitors over different IL-17 inhibitors, though IL-17 inhibitors may be considered with severe psoriasis or TNF contraindications 1

Common Pitfalls to Avoid

• Do not delay biologic therapy in patients with polyarthritis or poor prognostic factors (structural damage, elevated acute phase reactants, dactylitis, nail involvement) 1
• Do not use tofacitinib as first-line therapy after csDMARD failure when biologics are appropriate 1
• Do not ignore skin disease severity when selecting between agents—ixekizumab provides superior psoriasis control compared to TNF inhibitors 2
• Do not overlook cardiovascular and malignancy risk factors before initiating tofacitinib 1

Monitoring Requirements

• Ixekizumab: Screen for tuberculosis before initiation; monitor for injection site reactions and infections 4
• Tofacitinib: Baseline and periodic monitoring of complete blood count, lipid panel, liver enzymes; tuberculosis screening; assess cardiovascular risk factors 6