Real-World Efficacy of IL-23 Inhibitors in Psoriasis Affecting High-Impact Areas: Indirect Comparison of Tildrakizumab 200 mg, Risankizumab, and Guselkumab-IL PSO (Italian Landscape Psoriasis)

Introduction: Psoriasis involving special or high-impact areas (scalp, nails, palms/soles, genitalia) is associated with a disproportionate functional and psychological burden that is often underestimated by conventional severity scores and remains challenging to treat effectively. This study compared the real-world efficacy and safety of three interleukin (IL)-23p19 inhibitors—risankizumab, guselkumab, and tildrakizumab 200 mg—in patients with moderate-to-severe plaque psoriasis with involvement of high-impact sites. Methods: This multicenter retrospective study included 670 patients treated for at least 52 weeks across 37 Italian dermatology centers. Patients received risankizumab (n = 254), guselkumab (n = 177), or tildrakizumab 200 mg (n = 239) according to approved regimens. Effectiveness was assessed using Psoriasis Area Severity Index (PASI) and site-specific Physician’s Global Assessment (PGA) scores (scalp, nails, palms/soles, genitalia) at weeks 4, 16, 36, and 52. Safety was evaluated through reported adverse events. Results: Risankizumab demonstrated the fastest and most pronounced reduction in PASI, achieving PASI90 and PASI100 responses in 89.6% and 82.1% of patients at week 52, respectively. Tildrakizumab 200 mg showed a slower onset but comparable long-term efficacy, particularly in nail and palmoplantar psoriasis. At week 52, complete nail clearance (fn-PGA = 0) was achieved in 90.0% of patients treated with risankizumab, 76.7% with tildrakizumab, and 66.7% with guselkumab. Palmoplantar and genital psoriasis showed near-complete resolution across all treatment groups by week 52. Scalp involvement improved markedly with all agents, with lower residual disease observed with risankizumab. All treatments were well tolerated, with infrequent and predominantly mild adverse events and no major safety concerns. Conclusion: In real-world clinical practice, IL-23p19 inhibitors provide high and sustained efficacy in psoriasis affecting high-impact sites. Risankizumab offers faster and deeper responses, while tildrakizumab 200 mg represents an effective long-term option, particularly in patients with higher BMI or more treatment-resistant disease. These findings support a personalized approach to biologic selection based on disease localization, patient characteristics, and therapeutic goals.