Trajectory-based profiling of 52-week secukinumab response reveals baseline clinical and transcriptomic differences in plaque psoriasis.

Background: Response to secukinumab in psoriasis varies over time and is not fully captured by single timepoint endpoints. Baseline features associated with long-term response trajectories remain unclear. Objective: To identify 52-week secukinumab response trajectories and examine baseline clinical and peripheral blood mononuclear cell (PBMC) transcriptomic features associated with divergent trajectories. Methods: We analyzed 485 secukinumab-treated patients with plaque psoriasis from the Shanghai Psoriasis Effectiveness Evaluation CoHort (SPEECH). Latent class mixed models were used to derive 52-week Psoriasis Area and Severity Index (PASI) trajectories. Baseline factors associated with the suboptimal trajectory were assessed by logistic regression. In an exploratory subset of 27 patients, paired PBMC samples collected at baseline and week 4 underwent bulk RNA sequencing. Results: Two PASI trajectories were identified: an optimal trajectory (432/485, 89.1%) with rapid, sustained improvement and a suboptimal trajectory (53/485, 10.9%) with higher disease activity. Higher baseline PASI, body mass index (BMI), prior biologic exposure, multi-seasonal flare pattern, and infection-triggered flare history were independently associated with the suboptimal trajectory. Week 4 PASI improvement showed moderate discrimination between the two groups. Baseline PBMC transcriptomes also differed, with the optimal trajectory showing a more prominent mature low-density neutrophil signature and a greater reduction in that signature from baseline to week 4. Conclusion: Long-term response to secukinumab followed two distinct trajectories. Baseline PASI, BMI, prior biologic exposure, patient-reported flare history, and the mature low-density neutrophil signature may help identify patients with different long-term response patterns.