Deep resolution of clinical, cellular, and transcriptomic inflammatory markers during 52 weeks of IL-17A inhibition by secukinumab

Abstract

Background: Secukinumab, an anti-IL-17A monoclonal antibody, induces histological and molecular resolution of psoriatic plaques by 12 weeks. However, the long-term effects of secukinumab on molecular resolution of psoriatic inflammation remain unknown.

Objective: To investigate the molecular resolution of psoriasis following 52-weeks of secukinumab treatment.

Methods: NCT01537432 was a two-part Phase 2, randomised, double-blinded, placebo-controlled, 52-week study of patients with moderate to severe psoriasis receiving secukinumab 300 mg. Psoriatic lesional and non-lesional skin biopsies were obtained at baseline, Week 12, and Week 52, and the composition of the residual disease genomic profile (RDGP, i.e., "molecular scar") of biopsies from secukinumab-responders was analysed.

Results: After 52 weeks of treatment, 14/24 enrolled patients were considered clinical responders (≥75% improvement in Psoriasis Area and Severity Index [PASI]; PASI75), 4/24 were considered non-responders (<PASI75), and 6/24 patients were lost to follow-up; both histological and transcriptomic profiles of PASI75 responders improved from Week 12-52. RDGP transcripts of histological responders only partially overlapped between Week 12 and 52, despite similar number of transcripts in each RDGP; specifically, four novel transcript subsets showed distinct expression dynamics between Week 12 and 52 (slow-resolving, recurring, persistent, and resolved), with anti-inflammatory and immunomodulatory genes (e.g., SOCS1, CD207, IL-37) notably restored at Week 52. Shorter disease duration prior to secukinumab treatment coincided with greater transcript improvements at Week 12 and Week 52.

Conclusions: Secukinumab improves the histological and molecular phenotype of psoriatic lesional skin up to 52 weeks of treatment; these results suggest possible mechanisms that drive long-term control of psoriasis.