Interleukin-23 (IL-23) inhibitors represent a major advance in the management of moderate-to-severe plaque psoriasis, grounded in the central pathogenic role of the IL-23/Th17 axis. By selectively targeting the p19 subunit, guselkumab, risankizumab, and tildrakizumab effectively suppress disease-driving inflammation while preserving IL-12-mediated host defence. Pivotal randomized trials have demonstrated high levels of skin clearance, durable efficacy, and favourable safety profiles. Nevertheless, such trials only partially reflect the heterogeneous and medically complex populations treated in everyday practice. Against this background, this narrative review focuses on the expanding body of real-world evidence, which has provided novel insights into the long-term durability, drug survival, performance in difficult-to-treat anatomical sites, and safety of IL-23 inhibitors in special and comorbid populations. Real-world studies consistently confirm high effectiveness in elderly patients, individuals with multiple comorbidities, and those with extensive prior biologic exposure, as well as in challenging disease localisations such as scalp, nails, palmoplantar, genital, and pretibial psoriasis. Across large observational cohorts, IL-23 inhibitors show excellent treatment persistence, largely driven by sustained efficacy and low rates of discontinuation for adverse events. Reassuring safety profiles have also been documented in patients with a history of malignancy, latent infections, or cardiometabolic disease, together with improvements in quality of life and systemic inflammatory burden. By integrating evidence from randomized trials with large real-world cohorts, this narrative review provides a clinically oriented synthesis of the efficacy, safety, and therapeutic positioning of IL-23 inhibitors in psoriasis. Although all three agents demonstrate high and durable effectiveness, real-world data suggest subtle intraclass differences, with guselkumab and risankizumab often achieving faster or deeper early responses, and tildrakizumab offering greater dosing flexibility with comparable long-term persistence in selected patient profiles. Overall, IL-23 blockade has evolved from a highly effective trial-based strategy into a versatile and reliable long-term therapeutic approach capable of addressing unmet needs in routine clinical practice.
