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1、研阿维A 治疗斑块型银屑病的疗效及作用机制的研究张红婧吉林大学分类号：R751.05 单位代码：10183研究生学号：2018744089 密级：公开 吉林大学硕士学位论文（专业学位）阿维A治疗斑块型银屑病的疗效及作用机制的研究The efficacy and mechanism of Acitretin in the treatment of plaque psoriasis作 者 姓 名：张红婧类 别：临床医学硕士领 域（方向）：皮肤病与性病学指 导 教 师：夏建新 教授培 养 单 位：吉林大学第二医院2021年04月阿维A治疗斑块型银屑病的疗效及作用机制的研究The efficacy a

2、nd mechanism of Acitretin in the treatment of plaque psoriasis作 者 姓 名：张红婧领 域（方向）：皮肤病与性病学指 导 教 师：夏建新 教授类 别：临床医学硕士答 辩 日 期：2021年04月吉林大学硕士学位论文原创性声明 本人郑重声明：所呈交学位论文，是本人在指导教师的指导下，独立进行研究工作所取得的成果。除文中已经注明引用的内容外，本论文不包含任何其他个人或集体已经发表或撰写过的作品成果。对本文的研究做出重要贡献的个人和集体，均已在文中以明确方式标明。本人完全意识到本声明的法律结果由本人承担。 学位论文作者签名：日期： 年 月

3、 日关于学位论文使用授权的声明 本人完全了解吉林大学有关保留、使用学位论文的规定，同意吉林大学保留或向国家有关部门或机构送交论文的复印件和电子版，允许论文被查阅和借阅；本人授权吉林大学可以将本学位论文的全部或部分内容编入有关数据库进行检索，可以采用影印、缩印或其他复制手段保存论文和汇编本学位论文。 （保密论文在解密后应遵守此规定） 论文级别：硕士 博士 学科专业：临床医学硕士（皮肤病与性病学） 论文题目：阿维A治疗斑块型银屑病的疗效及作用机制的研究作者签名： 指导教师签名： 年 月 日 作者联系地址（邮编）；作者联系电话：中文摘要阿维A治疗斑块型银屑病的疗效及作用机制的研究银屑病是一种由免疫因

4、素介导的慢性、复发性、炎症性、系统性疾病，临床表现分为寻常型、脓疱型、关节病型和红皮病型，其中寻常型占97.06%，银屑病病因复杂，且发病机制尚未完全清楚，治疗方法多种多样，阿维A作为第二代芳香维甲酸依曲替酯的代谢产物，是目前国内外公认的一线用药，对治疗中、重度脓疱型及红皮病型银屑病，疗效显著，在斑块型银屑病的治疗上，我们常选择阿维A联合用药，单独应用阿维A治疗斑块型银屑病的研究相对不多，其单独治疗的有效性仍需更多科学、可靠的证据；通常认为阿维A的作用机制主要建立在表皮细胞维A酸受体的基础上, 而与银屑病相关细胞因子这种非受体的研究仍相对不足。为了研究阿维A治疗斑块型银屑病的疗效及作用机制，本

5、文选取了80例口服阿维A治疗的斑块型银屑病患者，通过调查问卷、定期随访、电话回访的方式全面了解患者的患病情况，观察患者应用阿维A治疗的临床疗效，同时研究其可能的作用机制。目的：为了探索阿维A单一用药治疗斑块型银屑病的临床疗效及可能的作用机制。方法：1、选取符合临床诊断的80例斑块型银屑病患者，给予单独口服阿维A系统治疗，20mg/d与午餐同服，体重70kg者给予30mg/d，最大剂量不超过50mg/d，并根据患者皮损情况给予保湿剂外用。对斑块型银屑病患者进行BSA评分、DLQI、PASI评分，根据PASI评分的下降指数、皮损面积及患者生活质量的改善程度，综合分析阿维A药物的临床疗效。2、对80

6、例斑块型银屑病患者进行自然情况的统计、分析。3、于治疗前、中、后检测肝肾功、血常规、尿常规、血糖、血脂，评估阿维A的不良反应及安全性。4、通过电话回访了解患者停药后3个月内的复发情况。5、观察患者血清细胞因子 IL-8、IL-22、IL-36于治疗前、后的表达水平。结果：1、80例患者治疗前PASI评分1.557.0，平均10.088.48，用药疗程10天8个月，起效时间7天35天，平均21.277.76天。治疗后有67例（83.8%）患者皮损得到改善，其中，痊愈4例（5%），显效37例（46.3%），好转26例（32.5%），无效13例（16.2%），治疗有效率为51.3%。使用SPSS 2

7、5.0对80例患者治疗前、治疗8W后的PASI评分、BSA评分、DLQI分别进行Wilcoxon秩和检验，结果显示治疗前、后的PASI评分、BSA评分及DLQI均存在显著性差异（P0.01），即应用阿维A治疗后患者皮损及生活质量显著改善；将疗效指数与用药疗程进行Spearman等级相关系数分析，结果P0.01，r=0.357，即用药疗程越长，疗效也越好。2、不良反应：共60例（75%）患者出现不良反应，多数患者同时伴有两种或两种以上的不良反应，口唇粘膜干燥者42例（52.5%），皮肤干燥、瘙痒25例（31.3%），脱发者13例（16.3%），皮肤发红者7例（8.8%），胃部不适及血脂异常者各4

8、例（分别占5.0%），疲惫乏力者5例（6.3%），肝功异常者3例（3.8%），关节痛者1例（1.3%），针对以上出现的不良反应，给予相应的对症治疗及阿维A减量后，不良反应均得到缓解。3、复发情况：在41例治疗有效（痊愈+显效）的患者中，对其中38例已停药的患者进行电话回访，结果有11例（28.9%）患者于停药后出现复发，其中7例（63.6%）患者于停药后3个月内复发，4例（36.4%）患者于停药后半年复发，对于复发后继续选择口服阿维A治疗者，其疗效仍确切。4、患者自然情况：80例研究对象中男性54例，女性26例，男女大致比例2.1：1，患者年龄在18岁74岁，平均39.715.3岁，病程15天

9、50年，首次发病年龄为6岁74岁，其中18岁45岁者最多50例（62.5%），69岁者2例（2.5%）；首发部位为头皮者20例（25.0%），下肢20例（25%），躯干11例（11.3%），上肢8例（10.0%），肘膝关节4例（5.0%），面部3例（3.7%），同时发生多个部位者13例（16.3%），部位不详者3例（3.7%）；冬季首次发病者最多24例（30.0%），其次为秋季18例（22.5%），冬季病情加重者最多31例（38.8%），夏季加重者最少4例（5.0%）；有同形反应者7例，甲损害者6例，有关节症状者1例，合并高血压、冠心病、糖尿病、乙肝、梅毒、过敏性疾病、肿瘤及其他系统疾病者15

10、例（18.8%），因疾病反复发作不能痊愈而严重焦虑者4例；有家族史者29例（36.3%），其中含一级亲属者8例；59例（73.8%）患者此次就诊为再次发病；患者发病诱因与精神压力、熬夜或休息不好、饮酒及辛辣刺激性食物、感冒、手术及外伤、食用海鲜或牛羊肉、进食油腻食物、环境潮湿有关，其中因饮酒或食用辛辣食物者而发病者最多15例（18.8%），因手术外伤发病者最少2例（2.5%），平时精神压力较大者28例（35.0%），因精神压力诱发疾病者6例（7.5%），未见明显诱发因素者39例（48.8%）；患者多存在吸烟、喝酒、熬夜、节食等不良生活习惯，有吸烟史者35例（43.8%），且发病期间仍有吸烟者3

11、4例，3支20支/日不等，有饮酒史（每周1次）者9例（11.3%），多为啤酒，少数为低度白酒，有熬夜习惯者7例，节食者2例，周围环境中存在潮湿、蚊虫、花草、噪音等不利因素者33例。5、实验研究结果显示斑块型银屑病患者血清IL-8、IL-22、IL-36水平显著高于正常人，差异有统计学意义；治疗后血清IL-8、IL-22的表达水平显著下降，差异有统计学意义；IL-36的表达水平于治疗前、后差异无统计学意义。结论：1、阿维A治疗斑块型银屑病疗效明显，患者治疗后皮损及生活质量均得到不同程度的改善，治疗有效率达51.3%，且不良反应可逆，有较好的安全性，患者的疗效指数与用药疗程存在正相关性，可以作为治

12、疗斑块型银屑病的一线用药长期服用。2、患者停药后复发时间15天6个月不等，复发时间大多（63.6%）出现在停药后3个月内，少数（36.4%）出现在停药后半年内，复发后再次应用阿维A治疗，效果仍然确切。3、IL-8、IL-22、IL-36可能参与了斑块型银屑病的发病。4、阿维A可以通过抗炎、抑制炎症细胞因子IL-8的产生，并影响TH22细胞及IL-22相关通路的方式来调节银屑病的免疫功能。并且认为作用机制中并不涉及IL-36的调节。关键词：阿维A，斑块型银屑病，IL-8，IL-22，IL-36AbstractThe efficacy and mechanism of Acitretin in t

13、he treatment of plaque psoriasisPsoriasis is a chronic, recurrent, inflammatory, and systemic disease mediated by immune factors. The clinical manifestations are divided into psoriasis vulgaris, psoriasis pustulosa, psoriasis arthropathica and psoriasis erythrodermic, and the psoriasis vulgaris pati

14、ents accounts for 97.06% . The etiology of psoriasis is complicated, and the pathogenesis is not fully understood. There are various treatment methods. As a metabolite of the second generation of aromatic retinoic acid etretinate, Acitretin is currently recognized as a first-line drug in the treatme

15、nt of psoriasis at home and abroad. The treatment of severe psoriasis pustulosa patients and psoriasis erythrodermic patients, the effect of Acitretin is distinct. We often choose Acitretin combination therapy in the treatment of plaque psoriasis, and still fewer researches related to Acitretin sing

16、le drug on the plaque psoriasis. In order to study the efficacy and mechanism of Acitretin in the treatment of plaque psoriasis, this article selected 80 patients with plaque psoriasis treated with Acitretin, and through questionnaires, regular follow-ups, and telephone return visits to understood t

17、hem comprehensively. Including the patients conditions, clinical efficacy. And at the same time study its possible mechanism.Objective: To explore the clinical efficacy and possible mechanism of Acitretin single drug on the plaque psoriasis.Methods:1、Select 80 patients with plaque psoriasis that are

18、 in the clinical diagnosis, and give them oral Acitretin system treatment alone, 20mg/d with lunch, and 30mg/d for those weighing 70kg, with the maximum dose not exceeding 50mg/d . According to the patients skin conditions to give them external use of moisturizer. Calculate BSA scores, DLQI, PASI sc

19、ores of these plaque psoriasis patients, and the clinical efficacy of acitretin drugs was comprehensively analyzed by the decrease index of PASI score, the area of skin lesions and the improvement of the patients quality of life. 2、Statistics and analysis of natural conditions of 80 patients with pl

20、aque psoriasis.3、Test liver and kidney function, blood routine, urine routine, blood sugar, and blood lipids before, during and after treatment to evaluate the adverse reactions and safety of Acitretin.4、Through telephone return visit to understand the patients recurrence within 3 months after stopp

21、ing the drug.5、Observe the expression levels of serum cytokines IL-8, IL-22, and IL-36 before and after treatment.Results:1、The pre-treatment PASI score of 80 patients was 1.557.0, with an average of 10.088.48. The treatment was 10 days to 8 months, and the onset time was 7 days to 35 days, with an

22、average of 21.277.76 days. After treatment, there were 67 patients (83.8%) with skin lesions were improved. Among them, 4 cases (5%) were cured, 37 cases (46.3%) were markedly effective, 26 cases (32.5%) were improved, and 13 cases (16.2%) were ineffective. The total effective rate was 51.3%. Using

23、SPSS 25.0 to perform Wilcoxon rank sum test on the PASI score, BSA score, and DLQI of 80 patients, before and after 8 weeks of treatment. The results showed that there were significant differences in PASI score, BSA score and DLQI , before and after treatment (P 0.01). The patients skin lesions and

24、quality of life were significantly improved after the application of Acitretin; Spearman rank correlation coefficient was used to analyze the efficacy index and the course of medication. The result was P0.01, r=0.357, that is, the longer the course of medication, the better the efficacy.2、Adverse re

25、actions: A total of 60 patients (75%) had adverse reactions. Most patients had two or more adverse reactions at the same time. There were 42 cases (52.5%) feel mouth and lip mucosa drying, 25 cases (31.3%) feel skin drying and itching, 13 cases with hair loss (16.3%), 7 cases with skin redness (8.8%

26、), 4 cases with stomach upset and dyslipidemia (5.0%), 5 cases feel fatigue (6.3%), 3 cases (3.8%) with abnormal liver function and 1 case (1.3%) with arthralgia. After corresponding symptomatic treatment and the reduction of Acitretin，all the adverse reactions were alleviated.3、Recurrence: Among 41

27、 patients with effective treatment (cured add markedly effective patients), 38 patients who had stopped the drug were interviewed by telephone. As a result, there were 11 patients (28.9%) recurrence after stopping the drug, of which 7 cases (63.6%) patients relapsed within 3 months, and 4 patients (

28、36.4%) relapsed half a year. For those who continue to choose oral Acitretin after recurrence, the effect is still definite.4、Natural conditions of patients: Among the 80 subjects, there were 54 males and 26 females. The ratio of male to female was 2.1:1. The patients ranged in age from 18 to 74 yea

29、rs old, with an average of 39.715.3 years old. The course of disease was 15 days to 50 years. The age of first onset was 6 74 years old, of which 50 cases (62.5%) were 18-45 years old, 16 cases (20.0%) were younger than 18 years old, 12 cases (15.0%) are 46-69 years old, and 2 cases (2.5%) are older

30、 than 69 years; As the first part of disease, 20 cases (25.0%) on the scalp, 20 cases (25%) in the lower limbs, 11 cases (11.3%) in the torso, 8 cases (10.0%) in the upper limbs, 4 cases (5.0%) in the elbow and knee joints, 3 cases(3.7%) in the face, 13 cases (16.3%) with multiple sites at the same

31、time, 3 cases (3.7%) with unknown sites; For the first season, there were 24 cases (30.0%) happened in winter, followed by 18 cases (22.5%) in autumn. And 31 cases (38.8%) worsened in winter, at least, 4 cases (5.0%) in summer; There were 7 cases of homomorphic reaction, 6 cases of nail damage, 1 ca

32、se of joint symptoms. There were 15 cases (18.8%) combined with hypertension, coronary heart disease, diabetes, hepatitis B, syphilis, allergic diseases, tumors and other system diseases. Due to repeated episodes of the disease, 4 cases were severely anxious. 29 cases (36.3%) had family history, inc

33、luding 8 cases of first-degree relatives; 59 cases (73.8%) of the patients were relapsed this time. The triggers of the disease are related by the mental stress, staying up late or poor rest, drinking or spicy food, colds, surgery or trauma, eating seafood or beef and mutton, eating greasy food, and

34、 humid environment. Among them, 15 cases (18.8%) were caused by drinking or eating spicy food, at least, 2 cases (2.5%) were caused by surgical or trauma. 28 cases (35.0%) usually have mental stress, due to the stress, only 6 cases (7.5%) were induced disease. 39 cases (48.8%) had no obvious predisp

35、osing factors. Mostly patients had bad habits, such as smoking, drinking, staying up late, dieting, etc. And there were 35 cases (43.8%) had a history of smoking, among them, 34 cases were still smokers during disease, ranging from 3 to 20 cigarettes/day. 9 cases (11.3%) had a history of drinking (1

36、 time/week), mostly drank beer, fewer drank low-alcohol liquor. 7 cases had the habit of staying up late; 2 cases were on a diet; 33 cases had unfavorable factors such as humidity, mosquitoes, flowers, and noise in the surrounding environment.5、The results of the experimental study showed that the l

37、evels of serum IL-8, IL-22, and IL-36 in patients with plaque psoriasis were significantly higher than those in normal subjects, and the difference was statistically significant. After treatment, the expression levels of serum IL-8 and IL-22 decreased, and the difference was statistically significan

38、t. However, the change of expression level of IL-36 after treatment was not statistically significant.Conclusion:1、Acitretin has obvious curative effect in the treatment of plaque psoriasis. After treatment, the skin lesions and quality of life of the patients have been improved to varying degrees.

39、The effective rate of treatment is 51.3%, and the adverse reactions are reversible. It has good safety and the patients curative effect. There is a positive correlation between the index and the course of medication, and Acitretin can be used as the first-line medication for the treatment of plaque

40、psoriasis for a long term.2、The recurrence time of patients after stopping the drug ranges from 15 days to 6 months. Most of (63.6%) the recurrence time occurs within 3 months after stopping the drug, and a few (36.4%) appear within half a year. After recurrence, the treatment with Acitretin was app

41、lied again, and the effect was still sure.3、IL-8, IL-22, IL-36 may be involved in the pathogenesis of plaque psoriasis.4、Acitretin can regulate the immune function of psoriasis by anti-inflammatory, inhibiting the production of inflammatory cytokine IL-8, and influencing TH22 cells and IL-22 related

42、 pathways. And it is believed that the regulation of IL-36 was not involved in the mechanism of action.Key words:Acitretin，plaque psoriasis，IL-8，IL-22，IL-36目 录引 言第1章 综述.21.1 银屑病流行病学及临床表现.21.2 银屑病合并症.21.3 银屑病病因及发病机制.21.4 阿维A治疗寻常型银屑病.4第2章 临床疗效观察.62.1 对象及方法.62.1.1 研究对象.62.1.2 研究方法.62.2 结果.92.2.1 患者自然情况

43、.92.2.2 临床治疗结果.112.2.3 停药后复发情况.11第3章 实验部分.203.1 材料及方法.20 3.1.1 材料.20 3.1.2 实验方法.20 3.1.3 统计学分析.213.2 结果.21 3.2.1 正常组与病例组血清IL-8、IL-22、IL-36表达水平比较.21 3.2.2 阿维A对斑块型银屑病的血清IL-8表达的影响.21 3.2.3 阿维A对斑块型银屑病的血清IL-22表达的影响.22 3.2.4 阿维A对斑块型银屑病的血清IL-36表达的影响.23第4章 讨论.24第5章 结论.29参考文献.30作者简介及在学期间所取得的科研成果.40致 谢.41英文单词

44、缩写英文缩写英文全称中文名称PASIpsoriasis area severity index银屑病皮损面积和严重程度指数BSAbody surface area受累体表面积DLQIDermatology life quality score皮肤病生活质量评分ELISAenzyme linked immunosorbent assay酶联免疫吸附试验ILinterleukin白细胞介素TNFtumor necrosis factor肿瘤坏死因子HBVhepatitis B virus乙型肝炎病毒HCVhepatitis C virus丙型肝炎病毒Th17T helper cell 17辅助性T细胞17IFNinterferon干扰素IQRinterquartile range四分位数间距Mmedian中位数HPAhypothalamic-pituitary-adrenal下丘脑-垂体-肾上腺轴Th22T helper cell 22辅助性T细胞22IX第一章 综述