What are the next treatment options for a patient with moderate-to-severe plaque psoriasis who has failed Skyrizi (risankizumab) after an adequate trial?

Treatment Options After Skyrizi Failure

Switch to an alternative biologic with a different mechanism of action—specifically, consider IL-17 inhibitors (ixekizumab, secukinumab, bimekizumab, or brodalumab) or IL-12/23 inhibitor (ustekinumab) as your next-line therapy. 1, 2

Algorithmic Approach to Biologic Selection

When risankizumab (Skyrizi, an IL-23p19 inhibitor) fails, the British Association of Dermatologists and AAD-NPF guidelines provide clear direction: any currently licensed biologic can be used after first biologic failure 1, 2. The key principle is that failure of one biologic does not preclude successful response to another, even within the same class 1.

Primary Considerations for Drug Selection:

1. Presence of Psoriatic Arthritis:

• If present: Prioritize adalimumab or ustekinumab (both have strong evidence for joint disease) 1, 2
• Secukinumab is also an option for psoriatic arthritis 2

2. High-Impact Area Involvement:

• Genital or scalp psoriasis: Consider continuing with another IL-23 inhibitor or switching to IL-17 inhibitors, which show excellent efficacy in these areas 1
• Palmoplantar involvement: Ustekinumab 90 mg (for patients >100 kg) showed 67% clearance versus 9% with 45 mg 1
• Nail psoriasis: Ustekinumab demonstrated median NAPSI improvement of 100% by week 40 1

3. Speed of Response Needed:

• Faster onset required: IL-17 inhibitors (ixekizumab, secukinumab, bimekizumab) have more rapid onset than IL-23 inhibitors 3
• Sustained long-term control: Consider ustekinumab or another IL-23 inhibitor (guselkumab) 1

Specific Drug Recommendations by Efficacy

Based on the most recent network meta-analysis 4, the hierarchy for PASI 90 achievement at week 16 is:

1. Bimekizumab (IL-17A/F inhibitor): OR 170.04 vs placebo
2. Risankizumab (IL-23p19): OR 95.01 vs placebo
3. Guselkumab (IL-23p19): OR 82.25 vs placebo
4. Secukinumab (IL-17A): OR 75.01 vs placebo
5. Ixekizumab (IL-17A): Comparable to secukinumab 5
6. Ustekinumab (IL-12/23): OR 26.68 vs placebo
7. Adalimumab (TNF-α): OR 30.07 vs placebo

Practical Selection Strategy:

First choice after Skyrizi failure:

• Bimekizumab or ixekizumab if maximum efficacy is the priority and no psoriatic arthritis 5, 4
• Ustekinumab if psoriatic arthritis is present, or if patient has high-impact area involvement (palmoplantar, nail) 1

Dosing for ustekinumab:

• Patients ≤100 kg: 45 mg at weeks 0,4, then every 12 weeks
• Patients >100 kg: 90 mg at weeks 0,4, then every 12 weeks
• Consider dose escalation (90 mg instead of 45 mg, or every 8 weeks instead of 12) for inadequate response 1

Important Caveats

Before switching:

1. Rule out modifiable factors: Obesity, poor adherence, and inadequate adjunctive therapy can contribute to apparent biologic failure 2
2. Consider dose escalation first: If the patient is obese or experiencing end-of-cycle flares, dose escalation may restore response before switching 2
3. Timing of switch: Discontinue risankizumab approximately 3-4 half-lives before starting the new biologic if clinically stable; otherwise, direct switch is acceptable 1

Combination therapy options with ustekinumab (if selected):

• High-potency topical corticosteroids ± vitamin D analogue (Level C recommendation) 1
• Methotrexate (Level B recommendation—may improve drug survival) 1
• Narrowband UVB phototherapy (Level B recommendation) 1

Safety monitoring:

• Screen for tuberculosis before initiating any new biologic 6
• All biologics carry infection risk; counsel patients on infection symptoms 6
• Avoid live vaccines during biologic therapy 1

The evidence consistently shows that switching to a different mechanism of action after IL-23 inhibitor failure is both rational and effective 1, 5. The choice between IL-17 inhibitors and IL-12/23 inhibition (ustekinumab) should be guided by the presence of psoriatic arthritis, specific anatomic involvement, and patient preference regarding injection frequency.