Integreted Olink Proteomics And Transcriptomics Analysis Reveals Anti-IL-17 Treatment-related Pathways And Biomarkers In Chinese Psoriasis Patients

Background: Psoriasis is a chronic,immune-mediated disease.Its pathogenesis is likely to be multifactorial.There is growing evidence that interleukin（IL）-17 plays a critical role in the pathophysiology of psoriasis.IL-17 cytokines produced by T cells and other cell types effectively activate keratin-forming cells,thereby promoting inflammation in the feed-forward circulation.Given this key pathogenic role of the IL-17 pathway in autoimmune and inflammatory diseases,it has been the focus of therapeutic targeting.the inflammatory effects of IL-17 can be targeted directly by blocking cytokines or their receptors,or indirectly by blocking cytokines upstream of IL-17 producing cells.Psoriasis has been a major success story for anti-IL-17 agents,and they have been shown to be more effective than other indications.Although secukizumab is designed to block IL-17 activity,its mechanism of action in psoriasis remission remains incompletely understood at the molecular level.Methods: Thirteen adult patients with moderate to severe psoriasis were recruited for this study and were injected with secukizumab,300 mg in 2 subcutaneous doses of 150 mg at weeks 0,1,2,3,4,8,and 12.This dose was then maintained every 4 weeks for a treatment cycle of at least 16 weeks.Patients were clinically evaluated before and during treatment using the Psoriasis Area Severity Index（PASI）score.Blood from patients with psoriasis before and after 12 weeks of treatment was taken for Olink proteomics and transcriptomics analysis.Results:（1）All patients treated with secukizumab achieved PASI 75 at week 12 and all patients at week 16 achieved PASI 90,with two patients experiencing adverse events during follow-up,manifesting as local injection reactions.（2）Secukinumab treatment resulted in increased expression of IL-17 A and decreased expression of IL-17 C in the plasma of patients with psoriasis.（3）We identified 145 differentially expressed genes（DEGs）before and after secukinumab treatment.Among them,106 up-regulated differentially expressed genes and 39 down-regulated differentially expressed genes.Through differentially expressed gene enrichment analysis,we identified 20 pathways in which inflammatory and immune responses are the primary pathways in the therapeutic response to secukinumab.Conclusion: Sikucizumab showed sustained long-term efficacy and good safety profile in13 patients with psoriasis,and its remission mechanism may be related to AGE-RAGE signaling pathway,NF-kappa B signaling pathway,TLR signaling pathway and TNF signaling pathway in diabetic complications,and IL-17 C,IL1B,FN1,JUN,CXCL8,and MMP2 may be key targets for anti-IL-17 therapeutic response in psoriasis.