TNF-α在强直性脊柱炎患者血清中的表达

肿瘤坏死因子一仅（TNF-α）是一种具有杀伤肿瘤细胞功能的促炎细胞因子,主要由活化的单核巨噬细胞产生,具有多种生物学功能,在炎症反应、免疫调节中起重要作用。在免疫病理发病机制的研究中发现,强直性脊柱炎（AS）的发病与促炎细胞因子表达的上调有关,其中较为重要并为多数学者所公认的细胞因子是TNF-α。     

依那西普抑制博来霉素诱导的小鼠肺纤维化

目的：观察肿瘤坏死因子α(TNF-α)拮抗剂依那西普对博来霉素诱导的肺纤维化小鼠的抑制纤维化作用,并探讨依那西普治疗肺纤维化的可能机制。方法：将45只SPF级雌性昆明小鼠随机分为3组：对照组（气管内雾化生理盐水）、纤维化组（气管内博来霉素3mg/kg溶于100μL生理盐水内雾化）和依那西普干预组（气管内雾化博来霉素后,4mg/kg依那西普溶于100μL生理盐水内腹腔注射,每3d注射1次）。处理后第28d收集样本,小鼠左肺置于10%中性甲醛固定,石蜡包埋切片后行HE与Masson染色;右肺碱水解法检测组织羟脯氨酸(HYP)的含量;酶联免疫法检测血清TNF-α和转化生长因子β（TGF-β）的含量;提取肺组织总蛋白,Westernblotting检测磷酸化ERK1/2、JNK和p38的表达。结果：依那西普干预组肺组织病理损伤及气道上皮下胶原沉积较纤维化组减轻,肺叶炎症损伤评分和纤维化评分明显下降（均P<0.01）,肺组织HYP含量显著降低（P<0.05）,血清TNF-α和TGF-β的浓度明显减少（均P<0.01）,肺组织ERK1/2、JNK和p38蛋白的磷酸化水平也显著下降（P<0.01,P<0.05,P<0.01）。结论：依那西普能显著下调TNF-α和TGF-β的水平,从而抑制ERK1/2、JNK和p38的活化,缓解博来霉素诱导的小鼠肺纤维化病变。     

强直性脊柱炎患者血清白细胞介素18检测的意义

目的探讨白细胞介素18(IL-18)在强直性脊柱炎(AS)发病中的作用及其血清水平检测的临床意义。方法采用酶联免疫吸附试验法(ELISA)检测53例活动期AS患者与40例健康对照组血清IL-18及肿瘤坏死因子α(TNF-α)的水平,并动态观察治疗前后IL-18及TNF-α的变化及其与病情活动指标之间的关系。结果AS患者治疗前血清IL-18水平明显高于健康对照组[(415.7±30.4)ng/L比(45.7±10.4)ng/L,P<0.05)],并与TNF-α、Bath强直性脊柱炎病情活动性指数(BASDAI)、晨僵时间、Bath强直性脊柱炎功能指数(BASFI)和Bath强直性脊柱炎脊柱活动测量指数(BASMI)呈正相关(r分别为0.52、0.63、0.48、0.58和0.48,P均<0.01)。治疗12周、24周后AS患者血清IL-18水平分别为(323.6±85.8)和(220.1±15.1)ng/L,均较治疗前明显下降,且治疗24周后下降更明显。结论IL-18可能参与AS发病机制,血清IL-18的检测可作为反映AS病情活动的指标之一。     

强直性脊柱炎患者血清白细胞介素18检测的意义

目的 探讨白细胞介素18(IL-18)在强直性脊柱炎(AS)发病中的作用及其血清水平检测的临床意义.方法 采用酶联免疫吸附试验法(ELISA)检测53例活动期AS患者与40例健康对照组血清IL-18及肿瘤坏死因子α(TNF-α)的水平,并动态观察治疗前后IL-18及TNF-α的变化及其与病情活动指标之间的关系.结果 AS患者治疗前血清IL-18水平明显高于健康对照组[(415.7±30.4)ng/L比(45.7±10.4)ng/L,P＜0.05)],并与TNF-α、Bath强直性脊柱炎病情活动性指数(BASDAI)、晨僵时间、Bath强直性脊柱炎功能指数(BASFI)和Bath强直性脊柱炎脊柱活动测量指数(BASMI)呈正相关(r分别为0.52、0.63、0.48、0.58和0.48,P均＜0.01).治疗12周、24周后AS患者血清IL-18水平分别为(323.6±85.8)和(220.1±15.1)ng/L,均较治疗前明显下降,且治疗24周后下降更明显.结论 IL-18可能参与AS发病机制,血清IL-18的检测可作为反映AS病情活动的指标之一.     

肿瘤坏死因子-α 5 旁侧基因多态性与强直性脊柱炎相关性

目的探讨肿瘤坏死因子α基因多态性与强直性脊柱炎(AS)发生的易感关系。方法采用序列特异引物PCR方法(SSP-PCR)检测了136例AS患者和127例正常人的TNF-α5旁侧-857C/T,-863C/A和-1031T/C三个基因多态性位点,并比较了部分不同地区人群之间的基因型与等位基因频率。结果AS患者TNF-α-857基因型(CC,TC和TT)分布频率分别是64.0%,35.3%和0.7%;TNF-α-863基因型(CC,CA和AA)分布频率分别是68.4%,30.0%和1.5%;TNF-α-1031基因型(TT,TC和CC)分布频率分别是66.2%,32.4%和1.5%;TNF-α-857等位基因频率C和T分别是81.6%和18.8%;TNF-α-863等位基因频率C和A分别是83.5%和16.5%;TNF-α-1031等位基因频率T和C分别是:82.4%和17.6%;正常对照者TNF-α-857基因型(CC,TC和TT)分布频率分别是70.9%,27.6%和1.6%;TNF-α-863基因型(CC,CA和AA)分布频率分别是68.5%,29.9%和1.6%;TNF-α-1031基因型(TT,TC和CC)分布频率分别是69.3%,29.1%和1.6%;TNF-α-857等位基因频率C和T分别是84.6%和15.4%;TNF-α-863等位基因频率C和A分别是83.5%和16.5%;TNF-α-1031等位基因频率T和C分别是:83.9%和16.1%;AS患者和正常对照者之间的基因型分布和等位基因频率比较差异无显著性,(P>0.05);本文中国汉族人TNF-α-857(C/T),-863(C/A),-1031(T/C)位点基因多态性分布同亚洲的日本、韩国人群基本一致,差异无显著性;-863(C/A),-1031(T/C)位点基因多态性分布同欧洲的英国、荷兰、瑞典人群比较差异也无显著性,但欧洲人群的TNF-α-857T的等位基因频率明显高于亚洲人群,差异有显著性(P<0.05)。结论TNF-α-857,-863和-1031三个基因多态性位点可能不是中国人患AS的主要易感位点基因。     

强直性脊柱炎患者血清Dickkopf-1蛋白水平分析

目的:分析强直性脊柱炎(AS)患者血清Dickkopf-1蛋白(DKK-1)水平变化并探讨其临床应用价值。方法:选取2016-12—2018-06我院诊治的50名AS患者[AS组,其中21例患者使用肿瘤坏死因子-α(TNF-α)抑制剂治疗(使用TNF-α抑制剂治疗组),29例患者未使用TNF-α抑制剂治疗(未使用TNF-α抑制剂治疗组)],另选取同期50名健康体检者为健康对照(对照组)。检测两组患者血清DKK-1、红细胞沉降率(ESR)和C-反应蛋白(CRP)水平。比较AS组患者治疗前后疾病活动度BASDAI、DKK-1、ESR及CRP水平变化。同时分析AS患者DKK-1与BASDAI、ESR及CRP的相关性。结果:AS组患者血清DKK-1水平明显低于对照组(P<0.01)。治疗6个月后,AS患者各亚组BASDAI、ESR及CRP水平较治疗前明显下降(P<0.01),且使用TNF-α抑制剂治疗组较未使用TNF-α抑制剂治疗组下降更明显(P<0.01);两组DKK-1水平与治疗前差异均无统计学意义(P>0.05)。AS患者各亚组血清DKK-1与BASDAI、ESR和CRP水平均无明显相关性。结论:DKK-1可能参与AS的新骨形成。TNF-α抑制剂可能对AS新骨形成无阻止作用。     

停用依那西普后强直性脊柱炎病情复发相关因素分析及骨灵汤对其病情复发的影响

目的探讨停用依那西普后强直性脊柱炎（AS）病情复发情况及其相关因素,评价骨灵汤对病情复发的影响。方法 60例活动性AS随机分为两组,治疗1组（骨灵汤合依那西普组）30例,治疗2组（依那西普组）30例,基线均合用一种非甾体类抗炎药。治疗12周后达到ASAS20改善的患者,停用依那西普,基线药物继续使用,每2～4周定期随访,直至病情复发或至9个月。采用Cox比例风险模型评价与复发有关的因素,Log-rank检验比较两组之间的复发情况。结果 12周后共53例患者达到了ASAS20改善标准并进入随访研究。其中治疗1组28例,治疗2组25例,两组人口统计学资料、基线及12周时病情特征比较差异无统计学意义（P〉0.05）。至研究结束时,有81.1%的患者病情复发。治疗1组复发率为71.4%,复发时间中位数为20周;治疗2组复发率为92.0%,复发时间中位数为14周,两组差异有统计学意义（P〈0.05）。Cox回归模型分析显示,基线BASDAI和CRP高及髋关节受累是病情复发的危险因素（P〈0.05）,治疗方法为保护因素（P〈0.05）。结论 AS停用依那西普后维持原药物治疗多数患者病情会复发,基线高BASDAI、CRP和髋关节受累是疾病复发的不利因素。早期联合使用骨灵汤能够有效维持疗效,延缓复发。     

强直性脊柱炎患者外周血中Th17细胞水平研究

目的建立流式细胞术检测外周血Th17的方法,并探讨强直性脊柱炎患者外周血Th17变化的意义。方法采用四色流式细胞术检测16例AS患者(AS组)和16例健康志愿者(对照组)外周血Th17细胞比例。结果用流式细胞仪结合不同荧光素标记的CD3、CD8、CD45和IL-17A单克隆抗体可准确检测外周血中Th17细胞的数量。对照组中Th17的检测结果分别为(1.58±1.09)%;AS患者组中分别为(3.06±2.24)%,AS患者外周血中Th17细胞显著高于对照组(P=0.004)。结论患者外周血中Th17细胞数量与对照组比较显著升高,该种细胞可能参与了AS的发生和发展。     

湖南地区强直性脊柱炎患者TNFRⅡ基因多态性研究

目的 通过对湖南地区强直性脊柱炎(AS)汉族患者及健康人群DNA中肿瘤坏死因子受体(TNFR)Ⅱnt587位点的多态性分析,研究TNFRⅡnt587位点基因多态性与强直性脊柱炎发病的相关性.方法 采用聚合酶链反应-限制性片段长度多态性法(PCR-RFLP)对100例AS患者和100名健康对照TNFRⅡnt587位点进行基因分型检测.数据经SPSS处理,分析两组中基因型、等位基因频率差异.结果 100例患者中TNFRⅡn687位点T/T型43例(43.0％),T/G型32例(32.0％),G/G型25例(25.0％);100例健康对照中TNFRⅡnt587位点T/T型56例(56.0％),T/G型34例(34.0％),G/G型10例(10.0％),AS患者中TNFRⅡnt587 G频率(41.0％)较正常对照(27.0％)明显增高(x2=8.734,P=0.003).与对照组相比,AS患者TNFRⅡnt587位点基因型为G/G时比数比(OR=3.256)明显高于T/G型(OR=1.226)和T/T型(OR=1).结论 湖南地区汉族人群中TNFRⅡnt587位点多态性与AS发病具有相关性,且G/G基因型在AS发病中具有高风险性.     

Etanercept: in ankylosing spondylitis

Etanercept is a dimeric fusion protein based on the p75 tumor necrosis factor (TNF) receptor. It binds to TNFalpha and blocks its biological activity. Subcutaneous etanercept is effective in the treatment of rheumatoid arthritis, psoriatic arthritis, and polyarticular-course juvenile rheumatoid arthritis. More recently, etanercept has shown efficacy in the treatment of adults with ankylosing spondylitis. In randomized, double-blind, placebo-controlled trials, subcutaneous etanercept 25mg twice weekly for 6-24 weeks significantly reduced disease activity in patients with active ankylosing spondylitis. In the largest trial, etanercept produced a response rate of 57% compared with 22% for placebo after 24 weeks (response was determined via the validated ASAS 20 response criteria developed by the Assessments in Ankylosing Spondylitis [ASAS] Working Group). Etanercept therapy significantly improved health-related quality of life in patients with ankylosing spondylitis compared with placebo. The greatest improvements in a 16-week study were seen in the domains of physical functioning, physical role, bodily pain, vitality, and social functioning. Etanercept was generally well tolerated, with few serious adverse events or treatment withdrawals. The most common adverse events were injection-site reactions and minor upper respiratory tract infections.     

The treatment of ankylosing spondylitis

Ankylosing spondylitis is an inflammatory disorder affecting the axial skeleton and periphery. Symptoms can often be debilitating. Current therapy for the disease include physical therapy, non-steroidal anti-inflammatory drugs (NSAIDS, anti-rheumatic disease modifying drugs (DMARDS), and the newly developed biologic agents targeting tumor necrosis factor alpha (TNF-α). This paper will provide a comprehensive review of these treatments which focusing on evidence based medicine for the daily clinical practice of rheumatology. Received: 31 December 2002 / Accepted: 15 January 2003 Correspondence to J.C. Davis Jr.     

Ixekizumab for the treatment of ankylosing spondylitis

ABSTRACT

Introduction

Ixekizumab (IXE) is a high affinity IgG4 approved for the treatment of ankylosing spondylitis (AS). Recently, two phase III randomized clinical trials (COAST-V, COAST-W) showed significant and sustained improvements in signs and symptoms of AS as evaluated by ASAS40 response. Areas covered: The authors performed a comprehensive literature search on this topic, by a review of published articles to date. The authors introduced the structure and the mechanism of action of IXE, and critically reviewed data from clinical trials, concerning its efficacy and safety in AS.Expert opinion: IXE proved dramatic efficacy and tolerable safety in patients with AS, in particular, patients with intolerance or insufficient response to TNFi, which provides an alternative and breakthrough for the treatment options of AS. IXE might not work in AS with IBD and uveitis involvement. Patients treated with IXE should be aware of candida infection in long term application.     

Individual characterization of stably expanded T cell clones in ankylosing spondylitis patients

Ankylosing spondylitis (AS) is commonly characterized by clonal expansions of T cells. However, these clonal populations are poorly studied and their role in disease initiation and progression remains unclear. Here, we performed mass sequencing of TCR V beta libraries to search for the expanded T cell clones for two AS patients. A number of clones comprising more than 5% of the corresponding TCR V beta family were identified in both patients. For the first time, expanded clones were shown to be stably abundant in blood samples of AS patients for the prolonged period (1.5 and 2.5 years for two patients, correspondingly). These clones were individually characterized in respect to their differentiation status using fluorescent cell sorting with CD27, CD28, and CD45RA markers followed by quantitative identification of each clone within corresponding fraction using real time PCR analysis. Stable clones differed in phenotype and several were shown to belong to the proinflammatory CD27 ? /CD28 ? population. Their potentially cytotoxic status was confirmed by staining with perforin-specific antibodies. Search for the TCR V beta CRD3 sequences homologous to the identified clones revealed close matches with the previously reported T cell clones from AS and reactive arthritis patients, thus supporting their role in the disease and proposing consensus TCR V beta CDR3 motifs for AS. Interestingly, these motifs were also found to have homology with earlier reported virus-specific CDR3 variants, indicating that viral infections could play role in development of AS.     

单节段经椎弓根椎体截骨术治疗强直性脊柱炎

目的总结单节段经椎弓根椎体截骨术治疗强直性脊柱后凸畸形的临床疗效。方法 2005~2010采取单节段经椎弓根椎体截骨术治疗20例强直性脊柱炎后凸畸形患者。术前、术后均行胸腰椎X线检查,评定胸腰段Cobb角矫正情况、植骨愈合情况、临床疗效、内固定位置及手术并发症。结果无术中死亡及术后感染,术中2例患者硬膜破裂,术后1例患者麻痹性肠梗阻,2例出现短暂不全瘫。随访15~60个月,后凸畸形均获明显矫正,胸腰段Cobb角平均矫正35.6°,矫正前后有显著性差异﹙<0.05﹚。末次随访无内固定断裂、脱出,均达骨性融合。结论单节段经椎弓根椎体截骨术治疗强直性脊柱脊柱后凸畸形,矫形效果及临床疗效满意。     

Genetics of ankylosing spondylitis

Ankylosing spondylitis (AS) is a chronic inflammatory arthritis that affects the spine and sacroiliac joints. It causes significant disability and is associated with a number of other features including peripheral arthritis, anterior uveitis, psoriasis and inflammatory bowel disease (IBD). Significant progress has been made in the genetics of AS have in the last five years, leading to new treatments in trial, and major leaps in understanding of the aetiopathogenesis of the disease.     

Higher prevalence of peripheral arthritis among ankylosing spondylitis patients

This study was performed to define the clinical spectrum and disease manifestations of ankylosing spondylitis (AS) in a referral hospital setting. We identified the differences in clinical manifestations according to the sex, the age at onset, the presence of peripheral arthritis and the presence of HLA B27. A total 412 patients (357 males, 55 females) were recruited. Eighty-seven percent were men and 155 out of 412 patients (35%) were juvenile-onset. HLA B27 was detected in 385 patients (93%). Peripheral joint involvement was noted in 287 of total AS cases (juvenile- onset ankylosing spondylitis (JOAS), 82%; adult-onset ankylosing spondylitis (AOAS), 61%), and was more common than those reported in other studies. A greater portion of patients with JOAS had peripheral arthritis and peripheral enthesitis than the patients with AOAS. The patients with peripheral arthritis showed a younger age at onset and an increased tendency of having enthesitis and trauma history. The natural history of Korean AS appears largely similar to those seen in Europe and North America, except a few differences. JOAS was quite common and AS was about nine times more common in men than in women. In addition, the HLA B27 antigen frequency was 93%, which is higher than those reported in other studies.     

Ultrasonographic evaluation of enthesitis in patients with ankylosing spondylitis

The aim of this study was to assess sensitivity and responsiveness of power Doppler ultrasound (PDUS) in detecting enthesitis for ankylosing spondylitis (AS) patients compared to clinical examinations. Twenty AS patients initiating etanerceptunderwent clinical and PDUS examinations of six bilateral entheseal sites at baseline and after 1, 2 and 3 months of treatment. Clinical and PDUS examinations identified at least one entheseal lesion in nine (45%) and 19 (95%) patients, respectively. Furthermore, of 240 entheseal sites examined in these 20 patients, PDUS detected 123 entheseal lesions (51.3% of sites), compared with only 47 entheseal lesions (19.6%) detected by clinical examination (P < 0.05). The entheseal lesions found on PDUS were most commonly identified by calcification (33.3%), tendon edema (29.2%), abnormal blood flow (25.8%), a thickened tendon (22.1%), cortical irregularity (12.9%), bony erosions (9.6%) and bursitis at the tendon insertion to the bone cortex (7.1%). Improvements in clinical symptoms and laboratory parameters, and significant decreases in PDUS scores were observed following treatment with etanercept. Improvements in PDUS scores continued during follow-up in patients who entered remission following treatment. In conclusion, PDUS improve detection of structural and inflammatory abnormalities of the enthesis in AS compared to physical examination. In addition, PDUS may be useful inascertaining medications.     

强直性脊柱炎患者气道管理分析

目的分析强直性脊柱炎患者的气道管理。方法对2004年1月至2014年12月在北京协和医院因强直性脊柱炎行骨科手术的171名患者的气道管理资料进行回顾性分析。结果 96.5%患者选择全麻手术。Macintosh喉镜和Glidescope喉镜声门暴露Cromack分级Ⅲ-Ⅳ级分别占9.6%和6.6%。90.9%的患者首次插管成功。9例患者需要更换插管工具,并有2例出现困难通气。5例患者选择椎管内麻醉,其中1例因效果不佳而改为全身麻醉。结论强直性脊柱炎患者由于脊柱和关节受累,属于困难气道高危,术前应充分评估和准备,选择最佳麻醉方案,减少并发症的发生。