The Effect And Mechanism Of IL-17A Inhibitor Ixekizumab In Thetreatment Of Chronic Severe Plaque Psoriasis

Psoriasis is a chronic recurrent inflammatory systemic disease characterized by erythema and scales.Up to now,the clear cause and pathogenesis are not completely clear.Due to its prolonged illness,and serious cases can involve the heart,kidney,liver,joints and other organs,the quality of life and mental health of patients has a great impact.In recent years,with the in-depth study of immune molecular mechanism in psoriasis,biological agents have opened a new field of treatment of psoriasis.Among them,Ixekizumab(IXE)can specifically bind IL-17 A to achieve the goal of rapid treatment of psoriasis.In order to investigate the efficacy and mechanism of IXE in the treatment of chronic severe plaque psoriasis,this study selected part of a randomized,placebo-controlled trial to observe the clinical efficacy of IXE in 30 patients with severe chronic plaque psoriasis and to investigate its possible mechanism of action.Objective:To investigate the clinical effect and possible mechanism of Ixekizumab single drug on chronic severe plaque psoriasis.Methods:1.According to the diagnostic criteria of chronic severe plaque psoriasis,all 30 patients were clearly diagnosed.Of the 30 patients,5 received placebo treatment(subcutaneous(SC)injection in 2 doses)at week 0.From week 2 to week 10,these 5 patients received single subcutaneous administration every 2 weeks.Then,at week 12,the experimental drug(IXE 80mg)was administered twice,and from week 16 to week 56,IXE 80 mg was administered subcutaneously once every 4 weeks(Q4W).The remaining 25 patients received IXE treatment of 80mg×2(divided into 2 subcutaneous injections)at week 0,and were subsequently divided into groups A and B.Group A received single subcutaneous administration of 80mg(Q2W)every 2 weeks from week 2 to week 10,and group B received Q4 W.At week 12,11 of the 25 patients received placebo twice and 14 received IXE 80 mg twice.From week 16 to week 56,the above 14 patients continued to receive IXE 80 mg Q4W,and the above 11 patients were given IXE 80 mg if there was recurrence(sPGA score ?3),or placebo if there was no recurrence.PASI scores of patients with psoriatic lesions were obtained before treatment and at week 12,week 16 and week 28,respectively,and the improvement rate of PASI scores was calculated to evaluate the efficacy of IXE on chronic severe plaque psoriasis.Meanwhile,the patients were followed up to 2020.03 to observe the recurrence time(skin lesions)and the time when sPGA reached 3 after drug withdrawal.2.Blood routine,blood sugar,liver function,urine routine,ions,blood lipid,kidney function,blood pressure monitoring were detected before,during and after treatment,and adverse reactions of IXE were evaluated.3.The expression levels of serum cytokines IL-17?IL-23?TNF-a and IL-8were observed before and after treatment.,as well as the correlation between serum concentrations of cytokines IL-17?IL-23?TNF-a and IL-8 before treatment and PASI score were observed.4.The relationship between BMI(Body Mass Index)and patients' itch score(NRS)before treatment and the difference in NRS levels before and after 12 weeks of treatment were compared.The relationship between DLQI(Dermatology Life Quality Index)and PASI score before treatment,and the difference between levels of DLQI before and after treatment in 22 patients with 0 PASI at 52 weeks were compared.Results:1.PASI score of 30 patients before treatment was 12-55.8 points,with an average of 27.19 points.The proportions of 30 patients who received PASI75,PASI90 and PASI100 at week 12 were 96.7%,86.7% and 46.7%,respectively.Among the 19 patients who had not stopped the drug,the proportion of patients who received PASI75,PASI90 and PASI100 at week 16 were 100%,89.5% and 57.9%,respectively.At week 28,100%,94.7% and 78.9% of patients received PASI75,PASI90 and PASI100,respectively.Relapses of 11 patients who were discontinued after 12 weeks: 3 patients had skin lesions at 1 month,4 patients at 2 months,and 1 patient at 3,4,5,and 6 months respectively.There were 3 patients with sPGA?3 at 2 months,2 patients with sPGA?3 at 3 months,2 patients with sPGA?3 at 4 months,2 patients with sPGA?3 at 7 months,and 1 patient with sPGA?3 at 9 months.Relapse status of 19 patients with drug withdrawal after 52 weeks(followup to 2020.03.20): 2 patients reached sPGA?3 at 3 and 4 months,respectively,1 patient used other biological agents when the skin lesions did not recur,so the specific recurrence time could not be calculated.The sPGA score of the remaining 16 patients did not reach 3 points:Three patients reached sPGA2 at 3 months,4 months and 4 months,respectively;nine patients reached sPGA1 at 4 months,3 months,3 months,2 months,2 months,2 months,2 months,2 months and 1 month,respectively;four patients had no recurrence,and the drug was discontinued for 55 days,89 days,96 days and 130 days,respectively.2.The onset time is 3-30 days,with an average of 8.1 days.3.adverse reactions: 18 cases of upper respiratory tract infection(all recovered).Hyperuricemia(3 cases cured),hyperlipidemia(7 cases cured)and liver injury(5 cases mild,2 cases moderate,1 case severe,and 7 cases cured except 1 case severe)were 8 cases each.Urinary tract infection occurred in 7 cases(6 cases recovered).There were 5 cases of hypertension(1 case recovered)and 5 cases of neutropenia(3 cases recovered).There were 4 cases of pharyngeal pain(3 cases recovered).Urticaria(2 cases cured),increased leukocyte(2 cases cured),diabetes(2 cases cured),and itchy skin were 3 cases each.Injection site reaction,thrombocytopenia(1 case recovered),insomnia(all recovered),diarrhea(all recovered),gastrointestinal influenza(all recovered),myocardial ischemia,herpes simplex(1 case relapsed,not cured;Another case recovered)were 2 cases each.Hyperbilirubinemia(recovery),mild kidney injury(recovery),hypokalemia,choking sensation,abdominal distension,viral blepharitis(recovery),mild jaundice,chest tightness,myocardial injury(recovery),oral ulcer and pulpitis(recovery)were1 case each.All the above adverse reactions were considered to be related to IXE,and most of them were significantly improved after symptomatic treatment.4.There was no significant difference in the onset time and PASI improvement rate of the experimental drugs in 30 patients,so the serum cytokines of 30 patients were tested and compared together.Experimental results showed that after Ixekizumab treatment,serum IL-17?IL-23?TNF-? and IL-8 levels in patients with chronic severe plaque psoriasis were all decreased compared with those before treatment,with statistically significant decreases in IL-17 ? IL-8 and TNF-?.There was no significant difference in IL-23 serum concentration before and after treatment.5.Spearman correlation analysis was conducted on BMI and NRS of 30 patients before treatment with SPSS25.0.The results showed that itch score was not correlated with BMI(P=0.269 > 0.05,r=-0.208).The paired sample t test of NRS(6.23±2.93)before medication and NRS(1.13±1.94)after 12 weeks of medication were conducted in 30 patients.The result was P < 0.01,indicating that the NRS level of patients after 12 weeks of medication was significantly lower than that before medication.6.Linear regression analysis was conducted on the DLQI and PASI scores of 30 patients before treatment with SPSS25.0.The results showed that F=9.643,P=0.004 < 0.05,that is,there was a linear correlation between DLQI and PASI scores before treatment.Adjusted R =0.23,it is understood that PASI score can explain 23% variation of DLQI.Paired sample t test was conducted for levels of DLQI(13.59±4.87)before treatment and DLQI(0.77±2.0)after treatment in 22 patients with PASI score of 0 at 52 weeks.The result was P < 0.01,indicating that the level of DLQI before treatment was significantly higher than that after treatment.Conclusions:1.There was no significant difference in the onset time and PASI improvement rate between groups A and B,that is,there was no significant difference in the clinical efficacy between IXE Q4 W and Q2 W.2.Ixekizumab has a significant effect in the treatment of chronic severe plaque psoriasis,with relatively few and mild adverse reactions.3.The mechanism of Ixekizumab in the treatment of chronic severe plaque psoriasis may be related to the down-regulation of IL-17?IL-23?TNF-? and IL-8,especially the decrease of IL-17?IL-8 and TNF-?.4.Before treatment,there was a linear correlation between DLQI and PASI scores.The more severe the skin lesion,the higher the DLQI,and the greater the impact on patients' quality of life.The level of DLQI after treatment was significantly lower than that before treatment,and the patients' quality of life was greatly improved with the improvement of skin lesions.5.IXE was discontinued in patients with PASI75 at 12 weeks and psoriasis recurred.The recurrence time was 1-6 months(mean 2.6 months);The time to reach sPGA3 was 2-9 months,with an average of 4.6 months.