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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与人体免

4、疫系统密切相关的疾病，当人体内的免疫系统出现障碍后，人体很容易患上银屑病。银屑病是一种慢性疾病，它的治愈复发率很高，患者在患病后往往表现为全身系统性的炎症反应。临床上将它分为四类，包括寻常型，还有脓疱型，还有关节病型，以及红皮病型。其中寻常型是临床最常见的类型，它的病例占比达97.06%。银屑病的治病因素目前还不清楚，同时，对它的发病机制也不明确。治疗方法多种多样，阿维A是目前临床用于治疗银屑病的首选药，这是国内外临床医师所认同的。它与芳香维甲酸依曲替酯有密切联系，是它的代谢产物。阿维A对两种类型的银屑病疗效明显，分别是红皮病型，还有中、重度脓疱型。面对斑块型银屑病，我们常选择阿维A联合用药，

5、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；阿维A的作用机制如下，作用与表皮细胞，细胞表面的维A受体从而产生作用。关于银屑病的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，本文选取了80例口服阿维A治疗的斑块型银屑病患者，采用三种方式了解患者的信息，有调查问卷，还有定期随访，还有电话回访。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，给患者进行只用阿维A治疗，剂量为20mg/d，时间为午

6、餐后服用，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。评价患者的疗效采用三种评价体系，包括BSA评分，还有DLQI评分，以及PASI评分。根据PASI的得分，以及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例斑块型银屑病患者进行自然情况的统计、分析。3、在治疗的前期、中期、后期检测下列指标，有肝肾功能，还有血常规，还有尿常规，以及血糖血脂水平。通过这些指标确保患者的安全性，同时，研究阿维A所带来的副反应。4、采用电话回访的方式，统计收集治愈患者的复发情况，时间期限为3个月内。5、在用药期间，记录患者的血清细胞因子浓

7、度变化，这些因子包括IL-8，还有IL-22，以及IL-36。比较前后的浓度变化。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。完全痊愈4例，占比5%，有明显改善37例，占比46.3%，有疗效26例，占比32.5%，没有疗效13例，占比16.2%。药物的有效率为51.3%。利用统计学软件SPSS25.0，对收集到的PASI评分，还有BSA评分，以及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

8、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

9、应均得到缓解。3、复发情况：在41例应用药物有效的案例中，(包括完全治愈，还有明显改善)，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，7位患者在治愈后3个月内复发，占比63.6%。4位患者在治愈的半年后复发，占比36.4%。对于复发后继续选择口服阿维A治疗者，其疗效仍确切。4、患者信息：80位患者中男性有54位，女性26位，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

10、例（25%），躯干11例（11.3%），上肢8例，占比10.0%，肘膝关节4例，占比5.0%，面部3例，占比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1位患者出现关节问题，有高血压，还有冠心病，还有糖尿病，还有乙肝，以及梅毒、过敏性疾病、肿瘤及其他系统疾病者15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

11、.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，还有饮酒，还有食用辛辣刺激性食物，还有感冒，还有手术外伤，以及食用海鲜或牛羊肉、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%）；患者有许多坏的生活习惯，包括吸烟，还有喝酒，还有熬夜，以及节食等不良习惯。有吸烟史者35例（43.8%），且发病期间仍有吸烟者34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

12、，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、记录患者的血清细胞因子浓度变化，这些因子包括IL-8，还有IL-22，以及IL-36。结果显示患者体内的含量远高于正常人，差异具有统计学差异。在用阿维A治疗后，患者体内两种因子含量减少，分别是IL-8，以及IL-22，差异有统计学意义。患者体内的IL-36含量无明显变化，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，用药后，药物的有效率为51.3%。患者的皮肤改善情况良好，生活质量显著提高。同时，药物的安全性高，副反应可控。患者的疗效指数与用药疗程存在正相关性，药物作用显著

13、，可以用于斑块型银屑病的治疗用药，建议作为首选药物。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，对于复发的患者，继续采用阿维A治疗，疗效依然明显。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的作用机制体现在抑制相关的炎症因子，例如，抑制因子IL-8。同时，还会阻断TH22因子通路，改善患者免疫系统功能。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

14、Acitretin in the 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

15、 vulgaris patients 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

16、in the treatment 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

17、Acitretin single 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 t

18、o understood them 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 psor

19、iasis that are 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,

20、 DLQI, PASI scores 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 pa

21、tients with plaque 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 mont

22、hs after stopping 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

23、days, with an 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

24、 51.3%. Using 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 ski

25、n lesions and 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 efficac

26、y.2、Adverse reactions: 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

27、 redness (8.8%), 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、Recurr

28、ence: Among 41 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, an

29、d 4 patients (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 fro

30、m 18 to 74 years 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

31、.5%) are older 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 site

32、s at the same 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 nai

33、l damage, 1 case 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 famil

34、y history, including 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 gr

35、easy food, and 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 o

36、bvious predisposing 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

37、of drinking (1 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 sho

38、wed that the levels 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 statistica

39、lly significant. 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 var

40、ying degrees. 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 treatm

41、ent of plaque 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 Aci

42、tretin was applied 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

43、 IL-22 related 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

44、.92.2.1 患者自然情况.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TNF