Guselkumab efficacy after withdrawal is associated with suppression of serum IL-23-regulated IL-17 and IL-22 in psoriasis: VOYAGE 2 study

Abstract Background Guselkumab selectively inhibits interleukin (IL)-23 and in psoriasis, produces high clinical responses including durable maintenance following treatment withdrawal in some patients. The relationships between IL-23 blockade, serum markers downstream of IL-23 signaling, and withdrawal were explored with guselkumab in VOYAGE 2. Methods At week 28, patients with ≥90% Psoriasis Area and Severity Index improvement from baseline (PASI 90) were re-randomized to withdrawal and received placebo (n=182), or maintenance therapy (n=193). The guselkumab withdrawal group reinitiated guselkumab upon loss of ≥50% of week 28 PASI improvement or by week 72. Cytokines changes associated with psoriasis recurrence (serum IL-17A, IL-17F, IL-22, and IL-23) following withdrawal were evaluated. Results Efficacy in the guselkumab maintenance group was sustained through week 72, while efficacy diminished in the guselkumab withdrawal group (PASI 90: 86.0% vs. 11.5%). After 20 weeks of retreatment, 80.4% of guselkumab withdrawal patients achieved PASI 90 responses versus baseline. Maintenance of response following withdrawal was associated with suppression of IL-17A, IL-17F and IL-22. Increases in cytokine levels had poor predictive power for psoriasis reoccurrence as these increases lagged behind increases in PASI scores Conclusion Upon guselkumab withdrawal, most patients lost clinical response and regained responses with retreatment. Correlation of IL-23 signaling serum cytokines increased with disease recurrence, supporting the role of IL-23 in expansion and maintenance of CD4+ Th17, Th22, and related CD8+ Tc cell subsets producing IL-17A, IL-17F, and IL-22.