What is the recommended approach for using ixekizumab (an interleukin-17A inhibitor) and tofacitinib (a Janus kinase inhibitor) in combination for a patient with psoriatic arthritis who has failed or has contraindications to traditional Disease-Modifying Antirheumatic Drugs (DMARDs) or biologic agents?

Combination Therapy with Ixekizumab and Tofacitinib is NOT Recommended for Psoriatic Arthritis

Combination therapy using ixekizumab (IL-17 inhibitor) and tofacitinib (JAK inhibitor) together is explicitly contraindicated and should never be used in psoriatic arthritis. 1

Explicit Contraindications to Combination Therapy

The FDA label for tofacitinib clearly states: "Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended" for psoriatic arthritis. 1 This prohibition includes all biologic agents, which encompasses ixekizumab.

• EULAR 2020 guidelines similarly emphasize that biologics should not be combined with other biologics or JAK inhibitors due to safety concerns and lack of efficacy data. 2
• The ACR/NPF 2018 guidelines do not support combination biologic therapy in any clinical scenario for psoriatic arthritis. 2

Sequential Treatment Algorithm After csDMARD Failure

When patients fail conventional synthetic DMARDs (csDMARDs), the recommended approach is sequential monotherapy, not combination targeted therapy:

First-Line Targeted Therapy Selection

For patients with significant skin involvement: Initiate an IL-17 inhibitor (ixekizumab) or IL-12/23 inhibitor as first-line biologic therapy, as these demonstrate superior skin efficacy compared to TNF inhibitors. 2

For patients without significant skin involvement: Either TNF inhibitors or IL-17 inhibitors can be used as first-line biologic therapy, with no clear hierarchy established between these classes. 2

• Ixekizumab has demonstrated similar efficacy to adalimumab for musculoskeletal manifestations in head-to-head trials. 2
• IL-17 inhibitors may increase risk of mild localized candidiasis and require monitoring for inflammatory bowel disease. 2

Positioning of JAK Inhibitors (Tofacitinib)

Tofacitinib should only be considered AFTER inadequate response to at least one biologic DMARD, or when a biologic is not appropriate. 2

• The 2023 EULAR update maintains this positioning due to significant safety concerns, including increased cardiovascular events, malignancies, and venous thromboembolism observed in patients ≥65 years with cardiovascular risk factors. 2
• Tofacitinib must be prescribed with methotrexate according to European regulatory approval. 2
• Safety signals include increased herpes zoster infections and deep vein thrombosis, particularly in older patients with cardiovascular risk factors. 2

Sequential Switching Strategy After Biologic Failure

If ixekizumab (IL-17 inhibitor) fails:

• First option: Switch to a different biologic class (TNF inhibitor preferred, or IL-12/23 inhibitor). 2
• The ACR/NPF guidelines conditionally recommend switching to a TNF inhibitor over switching to another IL-17 inhibitor after IL-17 failure. 2
• Consider IL-12/23 inhibitor if patient has concomitant inflammatory bowel disease. 2

If multiple biologics have failed:

• Then consider tofacitinib as a JAK inhibitor option, provided the patient does not have contraindications. 2
• Contraindications include: age ≥65 years, current/past smoking, cardiovascular risk factors, history of malignancy, or venous thromboembolism risk. 2, 1

Critical Safety Considerations for Tofacitinib

The FDA black box warnings for tofacitinib include: 1

• Serious infections: Including tuberculosis, bacterial, invasive fungal, viral, and opportunistic infections leading to hospitalization or death
• Malignancies: Higher rates of lymphomas and lung cancers compared to TNF blockers, with additional risk in current/past smokers
• Major adverse cardiovascular events (MACE): Increased cardiovascular death, myocardial infarction, and stroke in patients ≥50 years with cardiovascular risk factors
• Thrombosis: Including pulmonary embolism, deep venous thrombosis, and arterial thrombosis

Common Pitfalls to Avoid

• Never combine two targeted therapies (biologic + biologic, or biologic + JAK inhibitor) due to excessive immunosuppression risk without proven benefit. 2, 1
• Do not use tofacitinib as first-line therapy after csDMARD failure when biologics are appropriate options. 2
• Do not overlook cardiovascular and malignancy screening before initiating tofacitinib, particularly in older patients and smokers. 2, 1
• Avoid premature switching from ixekizumab—allow adequate trial duration (3 months minimum at target dose) before declaring treatment failure. 3