Clinical Efficacy And Safety Analysis Of Secukinumab In The Treatment Of Moderate-to-severe Plaque Psoriasis And Serum Metabolomics Study

Background Psoriasis is a common chronic inflammatory recurrent disease.More and more studies show that IL-17 A plays an important role in the pathogenesis of psoriasis.In recent years,it has been widely used in many fields,such as disease diagnosis,pathogenesis research,individualized administration and drug development.The metabolism of patients with psoriasis is abnormal,accompanied by a variety of endogenous metabolic disorders,and is closely related to cardiovascular disease,diabetes and metabolic syndrome(such as hypertension,obesity,etc.).Secukinumab is a recombinant,high-affinity,fully human immunoglobulin G1? monoclonal antibody that selectively binds and neutralizes interleukin-17 A.Secukinumab has been shown to be highly effective in the treatment of moderate to severe psoriasis and psoriatic arthritis with a sustained effect and a favourable safety profile.Real-world data pertaining to this is limited in China.A series of oxidative metabolites produced by polyunsaturated fatty acids play an important role in the body's inflammatory response,immune defense,endocrine regulation,and oxidative stress.It is not completely clear to what extent these metabolites are involved in the pathophysiology of psoriasis and related metabolic dysfunction.Objective(1)Systematic evaluation of the clinical efficacy and safety of Secukinumab in patients with psoriasis with or without psoriatic arthritis.(2)To further determine the baseline factors related to the efficacy response.(3)Preliminary exploration of biomarkers of metabolic abnormalities in patients with psoriasis using metabolomics technology.(4)Evaluate the effect of Secukinumab on the metabolic profile of patients with psoriasis.Methods Clinical research:(1)Through the treatment of 112 patients with moderate or severe psoriasis with or without psoriatic arthritis,subcutaneous injection of 300 mg / week at 0,1,2,3,4,8,12,the patients were followed up for 16 weeks,and the baseline data of 112 patients with psoriasis were collected and the PSAI score was recorded after each treatment.Among them,those with nail psoriasis and psoriatic arthritis also needed Perform Nail Psoriasis Severity Index(NAPSI)score,joint swelling and tenderness,Health Assessment Questionnaire–Disability Index(HAQ-DI)score,a patient's global assessment of disease,a physician's global assessment of disease,and a patient's assessment of pain,Dermatology Life Quality Index(DLQI).Record any adverse events that occur during treatment for safety assessment.(2)Multiple logistic regression analysis was employed to examine whether the PASI response was associated with gender,age,age of onset,duration,BMI,Ps A,scalp involvement,nail involvement,hypertension,diabetes,smoking,and drinking.Experimental study:(1)Analysis of serum samples from 22 patients with psoriasis and 20 healthy controls based on targeted liquid chromatography-tandem mass spectrometry(LC-MS-MS)serum metabolomics,and 22 patients peripheral serum metabolites were detected before and after 16 weeks of Secukinumab treatment,and grouped according to factors such as PASI,BMI.The test results were analyzed by principal component analysis(PCA)and supervised OPLS-DA for modeling.The VIP value of the model(?1)combined with fold change(fold change)? 2 or fold change ? 0.5 and P value <0.05 to find the difference expression of metabolites,and determine the related metabonomic pathways.Results Clinical research :(1)A total of 112 patients with psoriasis were included in this study.At week 12,89.3%(100/112)of the patients on secukinumab achieved at least a PASI 75 from baseline,and 95.5% of patients achieved this at week 16.At week 4,a PASI 75,PASI 90,and PASI 100 were reached in 39.3%,7.1%,and 0% of patients,respectively.By week 8,PASI 75,PASI 90,and PASI 100 were achieved in 81.7%,50.8%,and 13.4% of patients,respectively.DLQI mean baseline scores changed to 2.1 at week 16.Regarding absolute PASI values,the mean(± SD)PASI-scores at 4,8,12,and 16 weeks were9.8±5.3,13.2±6.7,14.1±6.2 and 15.3±8.1,respectively.DLQI score from baseline 15.5±7.1 to 1.9±0.8 at week 16.For patients with nail psoriasis,the NAPSI score decreased from 43.5 ± 14.6 to 24.6 ± 12.5 after 16 weeks,which was statistically significant before and after treatment(P <0.01);8 patients with psoriatic arthritis achieved ACR20,the PASI score,joint tenderness,a patient's global assessment of disease,a physician's global assessment of disease,and a patient's assessment of pain,and HAQ-DI score were all improved from baseline(P <0.05).(2)Multivariate logistic regression revealed that PASI improvement was related to BMI,age,and comorbid arthritis,and had a negative correlation with efficacy.(3)During the 16-week treatment,41.9%(47/112)of patients had at least one adverse event,and the most common adverse reaction was pruritus 25%(28/112).Experimental study:(1)In 22 patients with psoriasis and 20 healthy controls,7 differential metabolites were found between the two groups,of which 4 elevated,which are PGE-2,5,6-EET,LBT-4,9,10-Ep OME,3 decreased,which are,12-HEPE,PDX,and 13-oxo ODE.(2)In patients with psoriasis,the differential metabolites before and after treatment with Secukinumab were mainly concentrated in the oxidative metabolites downstream of arachidonic acid(AA)and linoleic acid(LA).Among them,5 kinds of metabolites are elevated after treatment: 14,15-EET,11,12-EET,5-oxo ETE,13-oxo ODE,8,9-EET.(3)In addition,this research had studied 10 patients whose PSAI<10,defined as a light group,and 12 patients whose PASI ?10,defined as a severe group,and it was found that the differences between two groups of metabolites including 4 species.11 cases of normal weight group(18.5 ? BMI <24.0),and 11 cases of overweight obesity group(BMI ? 24.0)before treatment,6 species differences metabolites were found.Conclusion(1)Data of clinical application of Secukinumab in patients with psoriasis in China show that the drug treatment can effectively improve skin lesions,nail symptoms and joint symptoms in a short time,and some baseline factors of the patient,such as BMI index,age and the concomitant presence of Ps A may have an impact on the treatment effect of Secukinumab.Overall,all of the reported adverse events were mild-to-moderate in severity,and none of the patients abandoned treatment due to adverse events.(2)Through the application of metabolomics,the discovery of differential metabolites between patients with psoriasis and healthy controls and the severity of the disease will help further reveal the pathogenesis of the disease and reveal the therapeutic effect of Secukinumab,and it can be used as a marker for clinical evaluation and the establishment of pharmacodynamic indexes in the future,providing a basis for subsequent personalized medicine.