【作者】 李静；

【导师】 李珺莹；

【作者基本信息】 天津中医药大学 ， 中西医结合临床（专业学位）， 2024， 硕士

【摘要】 背景:银屑病的病因和发病机制仍然是当前研究的热点和难点,相关的遗传易感基因和遗传模式也被不断发掘和报道,加之随着多种生物制剂的成功研发和广泛应用,银屑病临床治疗取得里程碑式的突破。既往研究报道发现生物制剂疗效以及安全性受遗传基因、银屑病共病及其他免疫系统疾病等多因素影响,但具体的影响机制和相应结果仍未阐明。基因组学研究发现,HLA-Cw6(Guman Leukocyte Antigen-Cw6,人类白细胞抗原-Cw6)和CARD14(Caspase Recruitment Domain 14,半胱天冬酶募集结构域14)相关变异体的存在与银屑病的发病和治疗密切相关。本研究探讨HLA-Cw6基因和CARD14基因突变与银屑病患者临床特征的相关性和生物制剂疗效方面的差异,以期对银屑病的临床特征和生物制剂疗效预测提供参考依据。体质是人在生长过程中受先天和后天影响所形成的与外界环境相适应的相对稳定的个性特征。多项研究表明,银屑病患者存在体质偏颇。因此,本研究探究中医体质与斑块状银屑病在年龄、性别、病程、顽固皮损分布、上感后银屑病复发情况、新冠病毒感染后银屑病复发情况、复发季节等方面的联系,以期为银屑病患者的个性化治疗和防复提供一定的参考和理论依据。目的:1.探讨HLA-Cw6基因和CARD14基因突变与银屑病患者临床特征的相关性和生物制剂疗效的差异有助于银屑病生物制剂疗效的预测以及生物制剂的精准化选择,提高生物制剂的有效性和安全性,以利于指导生物制剂的个性化用药,也为银屑病的遗传学发病机制提供理论依据,为银屑病生物治疗提供新的思路。2.探究中医体质与斑块状银屑病在年龄、性别、病程、顽固皮损分布、上感后银屑病复发情况、新冠病毒感染后银屑病复发情况、复发季节等方面的联系,遵循中医“治未病”思想,以达到治病求本,未病先防,既病防变,瘥后防复的治疗目的,为银屑病患者的治疗和预后提供依据。方法:1.收集39例银屑病患者的临床资料,使用ORAcollect·DNA工具组采集患者口腔内壁脱落细胞并使用高通量全基因组分型技术,检测HLA-C基因的单倍型分型HLA-Cw6(*06:02)和CARD14 rs11652075 C>T(又名c.2458C>T或p.Arg820Trp)两种基因型。根据基因检测结果分为HLA-Cw6阳性组和阴性组,CARD14 rs11652075阳性组和阴性组,比较同基因两组间在临床特征方面的差异。在0、4、16、28周时随访25例使用乌司奴单抗治疗的银屑病患者并进行PASI(Psoriasis area and severity index,银屑病面积与严重程度指数)评分,比较治疗前后同基因两组间在临床疗效方面的差异。2.收集150例斑块型银屑病患者的临床资料,向患者发放《中医体质量表》,根据《中医体质分类与判定表》判断体质类型并按体质类型分组,分析不同体质的斑块状银屑病患者在年龄、性别、病程、顽固皮损分布、复发情况等方面的差异。结果:1.HLA-Cw6阳性组的银屑病患者携带CARD14 rs11652075的比例明显高于阴性组(P<0.05),HLA-Cw6阳性的银屑病患者头皮皮损发生率高于阴性组(P<0.05),CARD14rs11652075阳性组患者疾病严重程度高于阴性组(P<0.05),在接受乌司奴单抗治疗的银屑病患者中,第4周时,HLA-Cw6阳性组达PASI50的患者比例高于阴性组(P<0.05)。2.中医体质分布:150例斑块状银屑病患者中医体质分布:气郁质36例(24%),阴虚质30例(20%),平和质21例(14%),气虚质15例(10%),阳虚质14例(9.3%),血瘀质11例(7.3%),湿热质9例(6%),痰湿质8例(5.3%),特禀质6例(4%)。3.中医体质与性别:平和质和气郁质在斑块状银屑病患者中存在性别差异,男性平和质多于女性(P<0.05),女性气郁质多于男性(P<0.05)。4.中医体质与顽固皮损分布:在顽固皮损部位为下肢的斑块状银屑病患者中,湿热质、痰湿质患者比例高于其他组(P<0.05)。5.中医体质与病情复发:较偏颇体质,平和质的斑块状银屑病患者复发次数更少。较其他体质,气郁质患者复发频次更多(P<0.05)。气虚质、阳虚质的斑块状银屑病患者上感后复发率更高(P<0.05)。气郁质、气虚质的斑块状银屑病患者在新冠病毒感染后复发率更高(P<0.05)。阴虚质的斑块状银屑病患者更易在秋季出现病情复发(P<0.05)。结论:1.HLA-Cw6基因和CARD14基因突变与银屑病关系密切,HLA-Cw6阳性组的银屑病患者更易携带CARD14 rs11652075,表明PSORS1和PSORS2之间存在遗传联系。携带HLA-Cw6基因的银屑病患者更易累及头皮,且对乌司奴单抗的应答更快,疗效更好,携带CARD14 rs11652075的银屑病患者疾病严重程度更高,HLA-Cw6和CARD14rs11652075可能是银屑病生物治疗的潜在靶点,银屑病相关遗传基因的研究可能成为生物制剂疗效预测的有力工具,为银屑病生物治疗提供新的思路。2.本研究中,气郁质、阴虚质、平和质是斑块状银屑病患者主要的中医体质。气郁质、阴虚质、气虚质为斑块状银屑病的主要偏颇体质。3.平和质和气郁质在斑块状银屑病患者中存在性别差异,男性平和质居多,女性气郁质居多。4.湿热质、痰湿质的斑块状银屑病患者顽固皮损主要分布在下肢。5.在病情复发方面,平和质的斑块状银屑病患者病情更稳定,复发次数更少。气郁质患者复发频次更多。气虚质和阳虚质的斑块状银屑病患者在上感后更易复发。气郁质和气虚质的斑块状银屑病患者在新冠病毒感染后更易复发。阴虚质的斑块状银屑病患者更易在秋季出现病情复发。因此,为达到治病求本,未病先防,既病防变,瘥后防复的治疗目的,应针对不同体质患者采用个性化治疗和防护措施,同时本研究也为不同体质的银屑病患者的预防和治疗提供了新的理论依据。更多还原

【Abstract】 Background:The etiology and pathogenesis of psoriasis is still a hotspot and difficulty in the current research.The related genetic susceptibility genes and inheritance models have been continuously discovered and reported.A large number of studies have reported that the efficacy and safety of biological agents are affected by multiple factors such as genetics,psoriasis comorbidity and other immune system diseases,but the definite mechanisms and corresponding results have not been ascertained.Genomic studies have found that,The presence of variants related to human leukocyte antigen-Cw6(HLA-Cw6)and caspase recruitment domain 14(CARD14)is closely related to the pathogenesis and treatment of psoriasis.The aim of this study is to investigate the correlation between HLA-Cw6 and CARD14 gene mutations and the clinical characteristics of patients with psoriasis and the differences in the efficacy of biological agents,in order to provide a reference for the clinical characteristics of psoriasis and the prediction of the efficacy of biological agents.Constitution is a relatively stable personality characteristic which is formed by innate and acquired influences in the process of growth and ADAPTS to the external environment.A number of studies have shown that psoriasis patients have constitutional bias.Therefore,this study explores the relationship between TCM constitution and plaque psoriasis in terms of age,gender,course of disease,distribution of refractory skin lesions,recurrence after infection,recurrence after COVID-19 infection,and recurrence season,in order to provide certain reference and theoretical basis for the personalized treatment and prevention of psoriasis patients.Objective:1.To explore the correlation between HLA-Cw6 gene and CARD14 gene mutations and the clinical characteristics of patients with psoriasis and the differences in the efficacy of biological agents,which is helpful to predict the efficacy of biological agents and the precise selection of biological agents,improve the efficacy and safety of biological agents,and guide the personalized medication of biological agents.It also offers the theoretical basis for the genetic pathogenesis of psoriasis,and provides new ideas for the biological treatment of psoriasis.2.To explore the relationship between TCM constitution and plaque psoriasis in terms of age,gender,course of disease,distribution of refractory skin lesions,recurrence after infection,recurrence after novel coronavirus infection,and recurrence season.Follow the concept of TCM "preventive treatment",so as to achieve the treatment of the root cause,prevent the disease before it occurs,prevent the disease from changing,and prevent the recovery after it,and provide a basis for the treatment and prognosis of psoriasis patients.Methods:1.Clinical data of 39 patients with psoriasis were collected.ORAcollect·DNA was used to collect the exfoliated cells from the oral lining of patients and high-throughput whole-genotyping technique was used.Two genotypes of HLA-Cw6(*06:02)and CARD14rs11652075 C>T(also known as C.2458 C >T or p.Arg820Trp)of HLA-C gene were detected.2.The clinical data of 150 patients with plaque psoriasis were collected,and the TCM Constitution Scale was distributed to the patients.According to the TCM Constitution Classification and Determination Table,the constitution types were judged and grouped according to the constitution types.The differences in age,gender,course of disease,distribution of refractory skin lesions,and recurrence of patients with plaque psoriasis with different constitutions were analyzed.Results:1.The proportion of psoriasis patients with CARD14 rs11652075 in HLA-Cw6 positive group was significantly higher than that in negative group(P<0.05).The incidence of scalp lesions in HLA-Cw6 positive patients was higher than that in HLA-Cw6 negative patients(P<0.05);Patients with positive CARD14 rs11652075 had higher disease severity than those with negative CARD14 rs11652075(P<0.05).At week 4,more patients in the HLA-Cw6-positive group than in the HLA-Cw6-negative group reached PASI50(P<0.05).2.TCM constitution distribution: The distribution of TCM constitution of 150 patients with plaque psoriasis is shown as follows: 36 cases(24%)of Qi-stagnation constitution,30cases(20%)of yin-deficiency constitution,21 cases(14%)of gentleness constitution,15cases(10%)of Qi-deficiency constitution,14 cases(9.3%)of yang-deficiency constitution,11cases(7.3%)of blood-stasis constitution,9 cases(6%)of damp-heat constitution,and 8 cases(5.3%)of phlegm-dampness constitution.Six cases(4%)were idiopathic constitution.3.TCM constitution and gender: there were gender differences in gentleness and qi-stagnation constitution in patients with plaque psoriasis,and gentleness constitution in males was significantly higher than that in females(P<0.05),and the qi-depression trait of females was significantly more than that of males(P<0.05).4.TCM constitution and distribution of stubborn skin lesions: In the patients with plaque psoriasis of lower limbs,the proportion of patients with damp heat and phlegm was higher than that of other groups(P<0.05).5.Chinese medicine constitution and disease recurrence: patients with plaque psoriasis with biased constitution and gentleness constitution had fewer recurrences.Patients with Qi-stagnation constitution had more recurrence frequency than those with other constitutions(P<0.05).Patients with plaque psoriasis of qi deficiency and Yang deficiency have a higher recurrence rate after sensitization(P<0.05).Patients with plaque psoriasis of qi stagnation and qi deficiency have a higher recurrence rate after COVID-19 infection(P<0.05).Patients with plaque psoriasis of Yin deficiency are more likely to have disease recurrence in autumn(P<0.05).Conclusions:1.HLA-Cw6 gene and CARD14 gene mutations are closely related to psoriasis.Psoriasis patients in the HLA-CW6-positive group were more likely to carry CARD14rs11652075,suggesting a genetic link between PSORS1 and PSORS2.Patients with HLA-Cw6 gene are more likely to have scalp involvement,and respond faster and better to ustekinumab.HLA-Cw6 and CARD14 rs11652075 may be potential target of psoriasis.The study of psoriases-related genetic genes may become an effective tool for predicting the efficacy of biological agents,and provide new ideas and opportunities for biotherapy of psoriasis.2.In this study,Qi-stagnation constitution,yin-deficiency constitution,and gentleness constitution were the main TCM constitutions of patients with plaque psoriasis.Qi-stagnation constitution,yin-deficiency constitution and Qi-deficiency constitution are the main abnormal constitution of plaque psoriasis.3.There are gender differences in the gentleness and qi-depression constitutions in patients with plaque psoriasis.The gentleness constitution is more common in males,and the Qi-depression constitution is more common in females.4.Patients with plaque psoriasis with damp-heat and phlegm-dampness lesions were mainly distributed in the lower limbs.5.In terms of disease recurrence,patients with mild plaque psoriasis are more stable and have fewer relapses.Qi-depression patients have more recurrence frequency.Plaque psoriasis patients with qi deficiency and Yang deficiency are more likely to relapse after upper sensation.Plaque psoriasis patients with qi stagnation and qi deficiency are more likely to relapse after COVID-19 infection.Patients with plaque psoriasis of Yin deficiency are more likely to relapse in autumn.Therefore,personalized treatment and protective measures should be adopted for patients with different constitutions in order to achieve the purpose of curing the disease,preventing the disease before it develops,preventing the disease from changing,and preventing the disease after it develops.At the same time,this study also provides a new theoretical basis for the prevention and treatment of psoriasis patients with different constitutions.更多还原