肿瘤坏死因子α介导银屑病脂肪酸去饱和酶2低表达

【摘要】 目的 探讨脂肪酸去饱和酶2（FADS2）在银屑病皮损中的表达变化及其影响因素。方法 通过Gene Expression Omnibus（GEO）数据集GDS4602统计分析银屑病患者皮损FADS2的表达变化。取5只咪喹莫特诱导的C57BL/6小鼠银屑病模型背部皮肤,并取收集于上海市皮肤病医院的人正常对照皮肤和银屑病患者英夫利西单抗治疗前及10周后的皮损组织标本各4份以及司库奇尤单抗治疗前及12周后的皮损组织标本各3份,免疫组化染色检测表皮中FADS2的表达。体外培养的人永生化角质形成细胞HaCaT用50 ng/ml肿瘤坏死因子α（TNF-α）刺激0、6、12或24 h,用200 ng/ml白细胞介素17A（IL-17A）刺激0、6、12 h;用TNF-α单独或联合NF-κB通路抑制剂BAY 11-7082（5 μmol/L）刺激6 h。处理完成后,实时荧光定量PCR（qPCR）、Western印迹法分别检测FADS2 mRNA和蛋白的相对表达量。采用单因素方差分析法和t检验进行统计分析。结果 GDS4602统计结果显示,与人正常皮肤对照组FADS2基因表达水平（2.035 ± 1.226）相比,银屑病皮损（0.656 ± 0.475）及非皮损（1.503 ± 1.062）组织中显著降低,F值分别为55.17、3.07,P值分别＜0.001、 = 0.012,并且皮损处显著低于非皮损处（F = 26.27,P＜0.001）。Western印迹和免疫组化染色显示,与正常对照组小鼠皮肤FADS2蛋白表达（灰度值比值：1.000;荧光强度：30.720 ± 6.850）相比,咪喹莫特组小鼠皮损表达显著降低（灰度值比值：0.463 ± 0.172,t = 7.00,P = 0.002;荧光强度：21.840 ± 3.125,t = 3.15,P = 0.035）。银屑病患者使用英夫利西单抗治疗10周后,皮损中FADS2蛋白表达（43.775 ± 3.342）较未治疗时（27.950 ± 1.218）显著升高（t = -6.95,P = 0.006）;而使用司库奇尤单抗治疗12周后的银屑病患者皮损处FADS2 蛋白表达（28.667 ± 3.402）与治疗前（31.933 ± 2.987）比较没有显著升高（t = 2.72,P = 0.113）。qPCR显示,与HaCaT细胞TNF-α 0 h组相比,TNF-α 6 h组、12 h组FADS2 mRNA相对表达量显著降低（P值分别为0.002、0.003）;与IL-17A 0 h组相比,IL-17A 6 h组、12 h组相对表达量变化无统计学意义（P值分别为0.849、0.961）。与HaCaT细胞对照组（正常培养基培养,1.000）相比,TNF-α 6 h组FADS2 mRNA相对表达量显著降低（0.682 ± 0.132,t = 4.82,P = 0.017）;与TNF-α 6 h组相比,TNF-α + BAY 11-7082 6 h组显著升高（1.541 ± 0.525,t = -3.58,P = 0.037）。Western印迹显示,与HaCaT细胞TNF-α 0 h组相比,TNF-α 24 h组FADS2蛋白相对表达量降低（F = 6.24,P = 0.013）。结论 FADS2在银屑病皮损中表达下降,其表达下调可能与TNF-α有关。     

英夫利西单抗治疗重度斑块状银屑病的疗效和安全性及其对PD-1、PD-L1表达的影响

目的:探讨英夫利西单抗治疗重度斑块状银屑病的疗效和安全性及其对银屑病皮损组织中程序性死亡蛋白1（PD-1）及程序性死亡蛋白配体1（PD-L1）表达的影响。方法:2019年2-4月收集就诊于上海市皮肤病医院的17例重度斑块状银屑病患者,在第0、2、6、14、22、30、38、46周给予5 mg/kg英夫利西单抗静脉滴注治...     

英夫利西单抗长疗程治疗中重度寻常性银屑病的疗效评价

【摘要】 目的 观察长期使用英夫利西单抗治疗中重度寻常性银屑病的疗效。方法 随访分析2016年3月至2018年5月在北京大学第三医院皮肤科应用英夫利西单抗治疗的中重度寻常性银屑病患者,纳入用药超过54周的患者。用药剂量5 mg/kg,总剂量以100 mg为间隔取整数。前两次用药间隔依次为2、4周,然后间隔均为8周。采用Mauchly球性检验法、随机区组的方差分析法及Bonferroni法分析治疗前、治疗2、6、14、22、30、38、46及54周银屑病皮损面积和严重程度指数（PASI）变化,同时记录病情转归及不良反应。结果 12例患者接受治疗,9例持续用药超过54周,遂纳入数据分析。治疗前,9例患者PASI值［M（P25,P75）］为26.3（23.4,27.7）。不同治疗时间点的PASI值不等（F = 7.12,P = 0.0004）,且患者PASI值呈总体下降趋势。治疗30周时,PASI值为4（2.5,5.2）,PASI改善率为86.38% ± 6.98%。其中,改善率达PASI50的患者8例,达PASI75的患者7例,达PASI90的患者2例。治疗54周时,PASI值为8（3.5,8.9）,PASI改善率为64.23% ± 17.32%,8例达PASI50,4例达PASI75,1例达PASI90。Bonferroni法显示,与治疗30周时相比,治疗54周时PASI评分显著升高（t = 3.269,P = 0.0048）,但治疗30周及54周时PASI评分值均显著低于治疗前（30周：t = 18.49,P < 0.0001;54周：t = 5.81,P = 0.0004）。结论 英夫利西单抗治疗中重度寻常性银屑病在长达54周的时间内有显著疗效。     

英夫利西单抗治疗关节病性银屑病进展

关节病性银屑病（PsA）可累及四肢、脊柱等单个或多个关节,是一种慢性炎症过程。70% ~ 85%患者在关节症状出现前有过皮损。约25% ~ 34%银屑病患者并发关节症状［1］。PsA具有较大侵蚀性,严重时可使关节畸形,甚至使患者丧失基本活动能力,具有难治性特点［2-3］。在银屑病的进程中,肿瘤坏死因子α（TNF-α）是占主导作用的炎症细胞因子,可刺激巨噬细胞和T细胞分泌炎症因子如白介素1（IL-1）、IL-6、IL-8,从而导致T细胞活化及增殖;TNFα也促进了破骨细胞的分化和成熟,并刺激成纤维细胞、破骨细胞和软骨细胞释放酶蛋白,从而破坏关节软骨和骨组织［4］。英夫利西单抗是抗TNFα单克隆抗体,系鼠源性抗原结合可变区与人源性免疫球蛋白G 1恒定区组成的生物嵌合体,与体液中或细胞膜表面的TNF-α具有高亲和力,干扰其与受体结合,从而阻断TNF-α的作用［5］……     

英夫利西单抗在银屑病中的应用进展

银屑病为多基因遗传背景的慢性炎症性皮肤病,遗传因素、环境因素及人体免疫等之间复杂多变的相互作用导致银屑病发生。大量研究表明,肿瘤坏死因子α（TNF-α）在角质形成细胞的过度增生、内皮细胞调节及记忆T细胞的募集及效应功能中起重要作用［1］。抗TNF-α制剂在银屑病治疗中显示出理想效果。在过去的十几年间,包括TNF-α抑制剂（依那西普、英夫利西单抗和阿达木单抗）的生物制剂等新的高选择性生物疗法已被批准用于治疗银屑病。英夫利西单抗（infliximab）为美国FDA批准应用于临床的肿瘤坏死因子人鼠嵌合IgG单克隆抗体,其适应证包括类风湿性关节炎、强直性脊柱炎、克罗恩病、银屑病等。本文就英夫利西单抗治疗银屑病的作用机制及临床应用做一介绍……     

银屑病患者抗肿瘤坏死因子α治疗前后血清抗核抗体、抗dsDNA抗体及抗ENA抗体的变化

目的：观察银屑病患者接受抗肿瘤坏死因子α制剂治疗后抗核抗体（ANA）、抗dsDNA抗体和抗可提取性核抗原（ENA）抗体的变化。方法回顾分析32例银屑病患者,其中13例使用英夫利西单抗治疗,19例使用依那西普治疗。英夫利西单抗组第0、2、6周各用药1次,此后每隔8周用药,于每次用药前检测患者ANA、抗dsDNA抗体及ENA的情况和临床症状的变化。依那西普组每周用药2次,每3~6个月检测患者ANA、抗dsDNA抗体及ENA的情况和临床症状的变化。采用银屑病皮损面积和严重度指数（PASI）75、疾病活动评分（DAS）28评估临床疗效,间接免疫荧光法检测血清ANA水平,免疫印迹法和ELISA法检测抗dsDNA抗体水平,免疫印迹法检测抗ENA抗体水平。结果32例银屑病患者临床症状有不同程度缓解。32例抗TNF?α治疗的患者中有7例（21.9%）出现自身抗体,其中英夫利西单抗组中4例治疗（8.3±5.1）个月后出现自身抗体,3例ANA阳性,3例ENA阳性;依那西普组中3例治疗（9.0±3.0）个月后出现自身抗体,3例ANA阳性,1例ENA阳性。结论部分银屑病患者接受抗肿瘤坏死因子α制剂治疗后可出现自身抗体。     

英夫利西单抗治疗17例中重度寻常性银屑病北大核心CSCD

银屑病是一种在多基因遗传因素与环境因素相互作用的基础上,由T淋巴细胞介导的免疫性慢性炎症性皮肤病,可并发多种系统性疾病,也可严重影响患者心理健康。目前认为肿瘤坏死因子（α（TNF-α）等前炎症因子在银屑病的发病机制中发挥了作用。英夫利西单抗是一种针对TNF—α的人鼠嵌合型单克隆抗体,可以阻断TNF—α与免疫活性细胞表面的TNF—α受体结合,抑制机体的炎症反应,达到控制病情的目的。我们观察英夫利西单抗治疗寻常性银屑病的疗效和安全性。     

MTX对关节病型银屑病患者血清TNF-α影响的研究

目的：研究肿瘤坏死因子α（TNF-α）在关节病型银屑病发病中的作用及MTX对其调节作用，探讨MTX治疗关节病型银屑病的机制。方法：应用双抗体夹心酶联免疫吸附法（ELISA），检测15例关节病型银屑病患者经MTX治疗前后外周血清中TNF-α的水平。结果：MTX治疗前血清中。的水平显著高于治疗后及正常人对照组（P〈0．001）。结论：TNF—α在关节病型银屑病致病中可能起重要作用。MTX治疗关节病型银屑病的机制可能是通过抑制TNF-α的分泌而达到治疗作用。     

英夫利西单抗治疗中重度斑块状银屑病患者生活质量的研究

目的研究英夫利西单抗治疗中重度斑块状银屑病患者生活质量的影响因素。方法对31例中重度斑块状银屑病患者予以英夫利西单抗治疗,观察患者在治疗前,治疗后2、6、14周时的银屑病皮损面积和严重度指数(PASI)和皮肤病生活质量指数(DLQI)评分。结果在英夫利西单抗治疗前,患者PASI评分为(18.48±5.08)分,治疗14周后,患者PASI评分降为(3.03±2.65)分;皮肤病生活质量指数(DLQI)评分治疗前为(14.74±4.67)分,治疗14周后降为(1.87±1.82)分,治疗前后差异有统计学意义(P 0.05)。通过对患者生活质量的相关因素:性别、年龄、文化程度、病程、PASI评分进行逐步多元线性回归分析,PASI评分和病程进入回归方程有统计学意义(P 0.05)。结论中重度斑块状银屑病在英夫利西单抗治疗后,病情得到快速控制,低生活质量得以改善。PASI评分和病程是影响患者生活质量的主要因素,PASI评分越低,病程越短,中重度斑块状银屑病患者生活质量越好。     

中药熏蒸联合温泉浴治疗关节病性银屑病的疗效观察

【摘要】 目的 观察中药熏蒸联合温泉浴治疗关节病型银屑病的疗效和安全性。方法 将48例关节病型银屑病患者随机分为两组,均采用温泉浴治疗,1次/d,30min/次,治疗组同时采用中药熏蒸治疗,1次/d,20min/次。两组疗程均为6周。在治疗后3、6周根据PASI评分和关节症状积分评估疗效。结果 治疗3周时,在皮损消退和关节症状缓解方面治疗组PASI评分和关节症状评分下降值均显著高于对照组（P﹤0.01）。疗程结束时,治疗组在关节症状缓解方面有效率为84. 00%,对照组有效率为47. 83%,两组比较差异有统计学意义（P﹤0.05）。在皮损消退方面治疗组和对照组有效率分别为92. 00%和60.87%,两组差异比较有统计学意义（P﹤0.05）。疗程结束时,两组疗法都未出现系统不良反应。结论 中药熏蒸联合温泉浴治疗关节病型银屑病安全有效。     

重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白治疗红皮病性银屑病的疗效观察

目的 评价重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白(rhTNFR:Fc)治疗红皮病性银屑病的疗效.方法 红皮病性银屑病患者23例,给予rhTNFR:Fc 25 mg皮下注射,每周2次,首剂加倍,疗程12周,之后随访至2年.以治疗中不同时间的银屑病面积与严重度指数(PASI)评分达PASI50、PASI75和PASI90的患者比例、肿瘤坏死因子α(TNF-α)值及不良反应等情况为观察指标.用SPSS 19.0版统计软件进行非参数Friedman检验和重复测量方差分析.结果 23例红皮病性银屑病患者PASI评分从治疗前57.35±3.45降至12周时5.57±3.60(P＜0.01),PASI50、PASI75、PASI90改善例数至12周时分别为23例(100％)、22例(95.65％)和14例(60.87％)(均P＜0.01),TNF-α值从治疗前(62.87±15.23) ng/L降至12周时(4.57±2.99) ng/L(P＜ 0.01).未发现不良反应.第24个月随访时,PASI评分与12周时比较差异无统计学意义;PASI50改善例数为23例,PASI75为20例,PASI90为15例;TNF-α值[(3.37±1.62) ng/L]低于12周时(P＜0.05).结论 rhTN FR:Fc是控制红皮病性银屑病急性期炎症的一个有效的药物.     

Chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab) in psoriasis

BACKGROUND: Insights into the pathogenesis of psoriasis have provided opportunities to target key steps in the disease process. Tumor necrosis factor-alpha (TNF- alpha) being crucial to the pathogenesis of psoriasis, monoclonal antibodies against this cytokine have proved useful in its treatment. AIM: To study the efficacy of chimeric monoclonal antibody to TNF- alpha (infliximab) in Indian patients with recalcitrant psoriasis vulgaris. MATERIALS AND METHODS: Three patients with recalcitrant psoriasis vulgaris were studied. Baseline haemogram, biochemical parameters, chest radiograph and Mantoux skin test were performed. A loading dose regimen of 5 mg/kg infliximab was administered at weeks 0, 2 and 6. PASI assessment, adverse drug event monitoring and laboratory assessments were carried out at 2-week intervals until week 10. Patients were followed up until week 22 for relapse. RESULTS: Infliximab was well tolerated. The mean PASI was 25.4 at presentation and declined to 5.5 at 10 weeks. PASI 75 was attained at a mean of 9.6 weeks. Relapse occurred at a mean of 18.6 weeks after the first infusion. CONCLUSIONS: This study on Indian patients brings out the importance of cytokine-based therapies in psoriasis. Indigenous production could make these therapies a viable therapeutic option for psoriasis patients in the near future.     

Treatment effect of adalimumab and infliximab in Japanese psoriasis patients: results in a single community-based hospital

Because adalimumab and infliximab were approved in Japan for psoriasis treatment only 1 year ago, therapeutic efficacy of these agents is not well studied in a Japanese psoriasis population. Moreover, the evaluation of scalp psoriasis treated with biologics has never been reported in these subjects. In this study, 21 patients with moderate to severe plaque psoriasis were assigned to receive adalimumab 40 mg every other week with an initial loading dose of 80 mg (n = 11), or infliximab 5 mg/kg at weeks 0, 2, 6, 14 and 22 (n = 10). The treatment efficacy was evaluated by the proportion of patients who achieved at least 75% improvement in Psoriasis Area and Severity Index (PASI 75) and Psoriasis Scalp Severity Index score (PSSI 75) from baseline at weeks 4, 8, 16 and 24. A patient selection bias existed between the two groups in body surface area and PASI (44.0 ± 24.7 vs 30.2 ± 13.5, P = 0.12 and 22.2 ± 9.3 vs 15.6 ± 7.75, P = 0.09, respectively). At week 16, 81.8% of adalimumab-treated patients and 60.0% of infliximab-treated patients achieved PASI 75 response, but no statistically significant difference was found between these response rates. There was a tendency toward a reduced PSSI 75 response rate in the adalimumab-treated group compared to the infliximab-treated group (54.5% vs 90% at week 16, P =0.15). In conclusion, both of the tumor necrosis factor-α inhibitors demonstrated good therapeutic response similar to that in the previously reported randomized controlled trials, without any severe adverse reactions. Treatment response in scalp lesions tended to be lower in adalimumab-treated patients, possibly because of delayed treatment onset of adalimumab.     

司库奇尤单抗治疗中重度斑块状银屑病20例临床观察

目的:观察司库奇尤单抗注射液治疗中重度斑块状银屑病的临床疗效及安全性.方法:纳入20例中重度斑块状银屑病患者,给予司库奇尤单抗注射液皮下注射治疗,300 mg/次,分别于第0、1、2、3、4周注射1次,随后每4周1次,于第4、8、12周时记录患者银屑病皮损面积和严重度指数(PASI)、中性粒细胞和淋巴细胞比值(NLR)...     

关节病型银屑病患者外周血中血管内皮生长因子(VEGF)水平的动态观测

目的：检测关节型银屑病患者外外周血中VEGF水平的改变，探讨其与PASI评分、治疗前后的关系。方法：采用双抗体夹心酶联免疫技术（ELISA）检测23例关节病型银屑病患者治疗前、中、治疗后血清中VEGF水平。另检测了23例正常人血清中的VEGF水平作为对照组。结果：关节病型银屑病患者血清中VEGF水平较正常对照组显著增高（P〈0．001），治疗前后患者血清中VEGF水平有显著差异（P〈0．05）。结论：VEGF在关节病型银屑病发病机制中起重要作用。     

沙利度胺治疗关节病型银屑病疗效评价及对血浆VEGF水平的影响

目的：评价沙利度胺治疗关节病型银屑病的临床疗效以及对患者外周血中VEGF水平的影响。方法：30例关节病型银屑病患者口服沙利度胺治疗,150mg,每日1 次,疗程 12周;采用PASI评分标准及关节症状评分评价疗效。采用酶联免疫吸附试验（ELISA）测定患者治疗前后血清VEGF水平。结果：患者治疗后皮损和关节炎均较治疗前得到明显改善;血清中VEGF水平治疗后为(578.38±169.05) pg/L较治疗前（1045.56±289.28pg/L）明显下降。结论：沙利度胺治疗关节病型银屑病安全有效,其作用机制可能与抑制患者血浆VEGF有关。     

Long-term study of infliximab in Japanese patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma

The efficacy and safety of infliximab in patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis (excluding localized type) and psoriatic erythroderma were assessed in clinical practice. Without washout of the existing treatment of psoriasis, treatment was switched to infliximab, which was given at a dose of 5 mg/kg at weeks 0, 2 and 6 and then every 8 weeks up to week 46. The primary end-points were 75% improvement in Psoriasis Area and Severity Index score (PASI 75 response rate) for plaque psoriasis, 20% improvement in American College of Rheumatology criteria (ACR 20 response rate) for psoriatic arthritis, and global improvement in pustular psoriasis and psoriatic erythroderma. The PASI 75 response rate in plaque psoriasis was 72.2% at week 10 and 53.6% at week 50. The ACR 20 response rate in psoriatic arthritis was 66.7% at week 14 and 80.0% at week 46. The response defined as global improvement in pustular psoriasis was between 66.7% and 100.0% during the 2–50-week period. The response defined as global improvement in psoriatic erythroderma was between 75.0% and 100.0% during the week-2–50 period. There were 14 discontinued patients. The most frequently reported reason for discontinuation was the development of adverse events. However, there were no serious respiratory diseases, infections or infusion reactions. In patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma, infliximab was well tolerated, regardless of prior treatment, and also showed superior efficacy over a period of approximately 1 year.     

开玄解毒法干预斑块型银屑病皮损部位肿瘤坏死因子-α、白细胞介素-8,P物质含量的动态变化

目的观察“开玄解毒法”治疗斑块型银屑病过程中，皮损部位肿瘤坏死因子（TNF-α）、白细胞介素-8（IL-8）、P物质（SP）含量的动态变化情况，进而探讨该方法治疗斑块型银屑病的作用机制。方法对12例斑块型银屑病患者采用“开玄解毒法”（口服“开玄解毒方”结合刺络放血疗法）连续治疗3周，以银屑病皮损面积和严重程度（PASI）评分进行疗效评价；每次刺络放血疗法后（共5次）采集患者治疗过程中皮损部位释放出的末梢血，用ELISA双抗体夹心法检测TNF-α、IL-8、SP的含量，分别绘制每例患者治疗过程皮损部位TNF-α、IL-8、SP含量的变化曲线图，了解“开玄解毒法”对斑块型银屑病皮损处TNF-α、IL-8、SP的干预作用。结果“开玄解毒法”治疗斑块型银屑病的总有效率为66．67％，治疗后PASI评分较治疗前显著下降（P=0．005）；治疗过程中皮损PASI评分、TNF-α与IL-8在皮损部位的含量呈逐渐下降趋势；但SP在皮损部位的含量无显著变化。结论“开玄解毒法”治疗斑块型银屑病有效，可能与降低皮损处TNF-α与IL-8含量有关，但尚不能认为该法可以降低皮损部位SP的含量。     

Efficacy of infliximab for severe recalcitrant psoriasis after 6 weeks of treatment

Infliximab treatment has been shown to be effective for moderate-to-severe psoriasis in several large clinical trials. Nonetheless, experience with this new treatment is still needed to evaluate its efficacy and tolerance in everyday practice. In this follow-up study, we report our experience with infliximab for recalcitrant psoriasis. Nineteen patients with recalcitrant psoriasis were treated between July 2004 and December 2006 with 5 mg/kg infliximab i.v. at weeks 0, 2 and 6 followed by maintenance every 8 weeks. In three patients resistant to treatment, methotrexate was added at a 15-25 mg dose weekly after the sixth week of infliximab therapy. Pretreatment evaluations included chest X-ray, tuberculin test (5 units), full blood count, kidney and liver function tests, antinuclear antibodies and patient weight. Response to treatment, using the Psoriasis Area and Severity Index (PASI) score, and adverse effects were prospectively assessed at weeks 0, 6 and 22. At week 6, after only two infusions, 78.9% (15/19) of patients showed at least 75% improvement in baseline PASI (PASI 75). At week 22, 73.6% (14/19) patients had reached PASI 75. Three patients had a relapse. Four developed adverse effects that required suspension of infliximab therapy. No tuberculosis or lymphoproliferative disease was observed. Four patients (21%) showed apparition of positive antinuclear antibody during the course of treatment and 57.8% (11/19) of patients showed an increase in weight at week 22. Our experience shows that infliximab is a very rapidly effective treatment of severe, treatment-resistant psoriasis as soon as the sixth week of treatment.