肿瘤坏死因子-α拮抗剂治疗中国汉族人群强直性脊柱炎369例不良反应初步研究

目的 旨在评价接受了肿瘤坏死因子(TNF)-α拮抗剂治疗的中国汉族人群强直性脊柱炎(AS)患者的不良反应,为生物制剂的临床治疗提供参考依据.方法 本研究纳入在我科接受了TNF-α拮抗剂治疗的369例中国汉族人群AS患者,未完全跟踪随访给药1011次.所有患者均评估了用药后2h出现的不良反应,对其中126例长期用药患者进行了第8、12、52、104周的随访.观察患者用药后2h的短期不良反应和长期不良反应.采用Fisher确切概率法进行统计分析.结果 接受TNF-α拮抗剂治疗的369例AS患者,随访用药后2h共计发生30次不良反应.英夫利西单抗和重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白(rhTNFR:Fc)引起的短期不良反应发生率差异无统计学意义(分别为3.8％,2.6％,P=0.31).126例患者分别依次进行了第8、12、52、104周的随访,共计39例发生不良反应,长期应用英夫利西单抗和rhTNFR:Fc不良反应发生率差异无统计学意义(分别为49％,51％,P=0.69).结论 中国汉族人群AS患者在接受TNF-α拮抗剂治疗时应注意上述不良反应的发生,尤其应注意第3、4次接受英夫利西单抗治疗患者的不良反应.接受英夫利西单抗和rhTN FR:Fc治疗的患者用药后2h内和长期(≥2年)治疗的不良反应发生相当.     

肿瘤坏死因子拮抗剂治疗风湿性疾病安全性的短期临床观察

目的 描述肿瘤坏死因子(TNF)-α拮抗剂治疗风湿性疾病发生的不良反应,评价临床应用的安全性和耐受性.方法 对2007年1月至2008年10月使用TNF-α拮抗剂的患者从临床症状、体征及实验室检查方面记录使用过程中发生的不良反应及程度和最终结局.结果 78例患者中35%(27/78)为类风湿关节炎(RA),41%(32/78)为强直性脊柱炎(AS),17%(13/78)为银屑病关节炎(PsA),6%(5/78)为未分化脊柱关节病(uSpA).59例患者使用依那西普,7例(12%)发生注射局部反应、上呼吸道感染及结核病等不良反应.19例患者使用英夫利西单抗,3例(16%)发生不良反应,1例(AS)为上呼吸道感染,1例(AS)前两次均在输注完24 h内出现伞身红色丘疹及心悸,1例(RA)输注4次后出现不明原因发热.部分不良反应可自行消失,其余经适当处理后痊愈.结论 证实依那西普和英夫利西单抗治疗风湿性疾病具有较好的安全性和耐受性,发生的不良反应是温和的,经适当处理可痊愈.     

风湿性疾病的T细胞γ干扰素释放分析诊断潜伏性结核分枝杆菌感染

风湿性疾病患者的机体处于免疫抑制状态,而其中接受肿瘤坏死因子α(tumor necrosis factor α,TNF-α)拮抗剂治疗的患者更可能存在结核(tuberculosis,TB)复燃的风险.T细胞γ干扰素释放试验(interferon-γ release assays,IGRA)对于潜伏性结核感染(laten...     

依那西普治疗降低强直性脊柱炎外周血T细胞活性

目的 研究肿瘤坏死因子(TNF)-α抑制剂依那西普(Etanercepl)对强直性脊柱炎(AS)患者外周血T细胞活性的影响.方法 10例健康志愿者,40例活动性AS患者,随机给予依那西普(50 mg,皮下注射,每周1次)或安慰剂治疗,治疗前后分离外周血单个核细胞(PBMC),酶联免疫斑点法(ELISPOT)分别检测分泌TNF-α、白细胞介素(IL)-2、干扰素(IFN)-γ的细胞数量.WST-1法检测T细胞增殖.结果 依那西普治疗后,分泌TNF-α的单核细胞数量减少;抗CD3和抗CD28抗体刺激后,分泌IL-2和IFN-γ的T细胞数量减少.CD4+/CD8+T细胞增殖没有明显变化.结论 抗TNF-α的治疗降低了AS患者外周血T细胞的活性,改善了AS患者病情.     

法舒地尔对急性脑梗死患者血清hs-CRP和TNF-α的影响

目的 探讨新型细胞内钙离子拮抗剂法舒第尔对急性脑梗死患者血清hs-CRP和TNF-α的影响及临床疗效.方法 64例脑梗死患者随机分为观察组和对照组,在常规使用阿司匹林肠溶片基础上,观察组静脉滴注盐酸法舒地尔注射液,对照组静脉滴注奥扎格雷钠注射液,均治疗14 d;治疗前及治疗3个月后随访监测血清高敏C反应蛋白(hs-CRP)、肿瘤坏死因子-α(TNF-α)水平,并根据临床神经功能缺损程度评分判定疗效.结果 两组治疗后hs-CRP、TNF-α水平均较治疗前显著降低(p均＜0.05);治疗后观察组hs-CRP、TNF-α水平明显低于对照组(P均＜0.05).观察组临床治疗总有效率显著高于对照组,差异有统计学意义(P＜0.05).结论 新型细胞内钙离子拮抗剂法舒第尔对急性脑梗死具有良好的疗效.     

急性心肌梗死合并类风湿性关节炎患者炎性因子与内皮和血小板功能的相关性

目的:探讨肿瘤坏死因子(TNF)-α拮抗剂对急性心肌梗死合并类风湿性关节炎患者内皮功能和血小板功能的影响。方法:将纳入的104例急性心肌梗死合并类风湿性关节炎患者随机性分为2组,一组给予依那西普(10mg,研究组),另外一组给予安慰剂(0.9%氯化钠,对照组)处理,分别测定2组患者基线和24h后白细胞数量、血浆中细胞因子浓度、血小板活化、外周血管舒缩和纤溶功能。结果:研究组TNF-α拮抗剂治疗后(24h),患者血液中中性粒细胞、淋巴细胞、TNF-α浓度和白细胞介素(IL)-6浓度与治疗前相比差异显著(P0.05);研究组治疗后血小板单核细胞聚集率较治疗前(基线时)相比显著增加[(31.4±5.5)%∶(20.4±4.4)%,t=7.96,P0.001];TNF-α拮抗剂治疗24h后t-PA活性显著性降低[(0.50±0.14)IU/ml∶(0.42±0.09)IU/ml,t=2.45,P=0.009]。结论:抑制急性心肌梗死合并类风湿性关节炎患者炎性细胞因子进而降低系统性炎症,可导致血小板激活而不影响外周血管舒缩功能或纤溶功能,因此抑制炎性细胞因子TNF-α等水平并不能使急性心肌梗死合并类风湿性关节炎患者从中获益。     

TNF-α拮抗剂与炎症性肠病合并肝炎病毒感染的关系

炎症性肠病(IBD)是一类病因不明的慢性肠道非特异性炎性疾病.TNF-α拮抗剂是一种被广泛应用于治疗IBD的生物制剂,可以有效改善患者的病情.有研究发现适当的TNF-α水平在机体感染肝炎病毒时可能起到保护性作用,使用TNF-α拮抗剂可能会升高IBD患者发生肝炎病毒感染和再激活的风险.由于在中国病毒性肝炎的发病率和患病率...     

7例HIV感染者颈背部脂肪聚积的手术治疗并复习文献

目的分析艾滋病病毒(HIV)感染者颈背部脂肪聚积的临床特点及手术治疗效果,结合复习文献,以提高对此类疾患的诊治能力。方法回顾性分析7例HIV感染者颈背部脂肪聚积进行手术切除的病例,综合分析其临床表现、治疗方法以及治疗效果,并通过复习文献,探讨该病的外科治疗方法。结果 7例患者均经手术切除颈背部聚积脂肪组织,术后无重大并发症,3例术后出现伤口并发症(2例血清肿,1例伤口感染)。术后所有患者外形整复满意,颈部活动范围恢复正常,随访8-52个月均无局部复发。复习相关文献,国外有相关手术治疗的少数病例报道,国内尚无相关报道。吸脂及抽吸辅助的脂肪切除也是脂肪聚积症的外科治疗方法。结论脂肪聚积症是长期HIV感染和高强度抗病毒治疗的并发症。局部聚积脂肪切除能有效地恢复患者外形,改善患者的生活质量。     

尿毒症合并冠心病患者治疗预后的影响因素分析

目的探讨白细胞介素-6(IL-6)和肿瘤坏死因子-α(TNF-α)在尿毒症维持性血液透析合并冠心病经皮冠状动脉介入治疗(PCI)患者中的临床价值。方法选取武汉市汉口医院收治并接受PCI治疗的尿毒症维持性血液透析合并冠心病患者76例,双抗体夹心酶联免疫法检测患者PCI治疗术前最后1次常规血液透析后、术后1h及术后3次常规血液透析后血清IL-6和TNF-α水平。随访2年或发生终点事件,观察住院期间及随访期间的主要不良心脏事件(MACE)发生情况。结果急性心肌梗死(AMI)组血清IL-6和TNF-α水平高于不稳定型心绞痛(UAP)组及稳定型心绞痛(SAP)组(P 0. 05)。术后1h血清IL-6和TNF-α水平高于术前及术后3次透析后,术后3次常规血液透析后血清IL-6和TNF-α水平最低(P 0. 05)。发生MACE患者PCI术后3次常规血液透析后血清IL-6和TNF-α水平明显高于未发生MACE的患者,差异有统计学意义(P 0. 05)。经Logisitc多因素分析显示,IL-6和TNF-α水平是尿毒症维持性血液透析合并冠心病患者经PCI治疗后发生MACE的独立危险因素。结论IL-6和TNF-α在尿毒症维持性血液透析合并冠心病患者中异常升高,且与冠心病的类型密切相关。PCI术后行3次透析后IL-6和TNF-α水平能有效预测远期MACE的发生。     

肿瘤坏死因子α抑制剂治疗强直性脊柱炎停药后的复发与应对策略

在过去的10年中,新的影像技术和治疗手段的应用,使风湿科医生对强直性脊柱炎(AS)的处理策略发生了本质的变化.虽然非甾体消炎药(NSAIDs)和功能锻炼在AS的长期治疗中仍占至关重要的地位[1],但TNFα抑制剂的应用与普及可谓后来居上,已有数以万计的AS患者接受了其治疗,目前常用的有英夫利西单抗、依那西普、阿达木单抗.对多数传统方法治疗效果欠佳的AS患者,TNFα抑制剂能迅速控制关节滑膜炎症,减轻疼痛与僵硬,甚至延缓软骨和骨的破坏,改善患者的生活质量,降低致残率;另外,也有较好的远期治疗的有效性、安全性和耐受性[2].由于其价格昂贵,我国患者多难以承受长期治疗费用,且我国为结核和乙型肝炎的高发区,TNFα抑制剂长期应用后结核和乙型肝炎的发病率有可能上升.从治疗费用与安全性的考虑,当TNFα抑制剂诱导活动性AS获得缓解后,多会改用传统方法维持治疗,但停药后部分获得缓解的AS会在数周至数月内复发.因此,TNFα抑制剂停药后的复发及如何应对成为当前风湿科医师面临的重要课题.     

Risk of tuberculosis in a Chinese registry of rheumatoid arthritis and ankylosing spondylitis for tumour necrosis factor‐α antagonists

Aim: To understand the risk of tuberculosis (TB) infection in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) who required tumour necrosis factor‐α (TNF‐α) antagonist treatment. Methods: Patients with RA and AS who were screened for infliximab and etanercept treatment for up to 6 months were entered in a registry between 2003 and 2005. The purified protein derivative (PPD) test and chest anteroposterior and lateral view X‐ray were performed at screening. The risk of TB infection in theses patients was observed during follow up. Results: Among 67 RA patients screened, a positive PPD reaction was found in one patient. Of the 169 AS patients screened, 23 were positive for the PPD reaction, two had pulmonary TB calcinosis and two were diagnosed as having pulmonary TB. The incidence of PPD positive reaction and pulmonary TB calcinosis or active TB in our screened RA and AS patients was significantly lower than that reported in the recent fourth national TB infection rates and prevalence (P < 0.01). Only one patient with RA developed neck lymph node TB 6 months after completion of infliximab infusion. Conclusion: Patients with AS and RA are not at an increased risk of TB infection if screened properly before short course treatment with anti‐TNF‐α agents.     

抗肿瘤坏死因子治疗关节病中出现银屑病加重或新发二例并文献复习

目的 探讨抗肿瘤坏死因子(TNF)治疗关节病的疗效以及加重或新发银屑病的原因.方法 分析2例使用TNF治疗过程中出现银屑病加重和新发银屑病的关节病[1例为银屑病关节炎(PsA),1例为强直性脊柱炎(AS)]的临床特点,并复习有关文献.结果 1例PsA患者在使用抗TNF过程中出现银屑病皮损加重,停药后缓解,加用后再次出现皮损加重;1例确诊的AS使用抗TNF过程中出现新发银屑病,停药后皮损消失,再次使用后皮损再次出现.结论 抗TNF是治疗脊柱关节病(SpA)等关节病的有效药物,但在治疗过程中可能出现银屑病皮损,停药后可以减轻,具体机制尚不清楚.     

我国部分地区肿瘤坏死因子拮抗剂使用人群的结核病预防性治疗情况分析

目的 了解中国部分地区应用肿瘤坏死因子(tumor necrosis factor,TNF)拮抗剂治疗的患者结核病预防性治疗情况。方法 搜集2014年3月至2016年2月中国东、中、西部13家三级甲等综合医院接诊的应用依那西普或英夫利西单抗治疗的类风湿关节炎(rheumatoid arthritis,RA)或强直性脊柱炎(ankylosing spondylitis,AS)患者作为研究对象,共981例。收集研究对象的性别、年龄、激素和免疫抑制剂使用情况、并发基础疾病情况、结核病既往史、结核分枝杆菌潜伏感染(LTBI)筛查情况、胸部X线摄片(简称“胸片”)或胸部CT扫描结果、结核病预防性治疗情况。分析应用TNF拮抗剂的RA或AS患者筛查LTBI和非活动性肺结核的比例,进行结核病预防性治疗的比例以及采用的治疗方案。结果 981例研究对象中应用依那西普者779例(79.4%),应用英夫利西单抗者202例(20.6%)。仅有25.7%(252/981)的研究对象进行LTBI筛查,阳性率为18.3%(46/252)。2.8%(27/981)的研究对象诊断为非活动性肺结核,其中,有结核病既往史者19例。712例(72.6%)研究对象进行了胸片检查和(或)胸部CT扫描,报告非活动性肺结核者13例(1.8%)。共15例研究对象进行了结核病预防性治疗;并发LTBI者中有6例(13.0%,6/46)进行结核病预防性治疗;诊断为非活动性肺结核者均未进行结核病预防性治疗。进行结核病预防性治疗者中,应用异烟肼单药预防方案者9例(60.0%,9/15),疗程1~18个月不等。结论 中国部分地区目前应用TNF拮抗剂治疗的RA或AS患者的LTBI筛查比例低,进行结核病预防性治疗比例低,预防对象选择标准不一且预防方案不规范。     

Does anti-tumor necrosis factor-α therapy affect risk of serious infection and cancer in patients with rheumatoid arthritis?: a review of longterm data

Given the important role tumor necrosis factor-α (TNF-α) antagonists play in managing rheumatoid arthritis and the concern for safety during longterm therapy, we reviewed the latest evidence regarding longterm risk of infection and malignancy with TNF-α antagonists. Our objective was to provide clinicians with information that can be used to counsel and monitor patients who may be candidates for biologic therapy for rheumatoid arthritis (RA). Risk is examined in the context of background infection and malignancy rates in RA. Randomized controlled trial (RCT) data and observational studies summarizing the risk of infection and/or malignancy in RA and specific risks associated with the use of anti-TNF-α biologic agents (adalimumab, infliximab, and etanercept) were identified through a PubMed search. Overall, patients with RA appear to have an approximately 2-fold increased risk of serious infection compared to the general population and non-RA controls, irrespective of TNF-α antagonist use. Although data on infection rates with TNF-α antagonist use are contradictory, caution is merited. Recent analyses suggest that the risk of infection is highest within the first year. Regarding malignancy risk, RCT and observational data are also conflicting; how ever, caution is warranted regarding lymphoproliferative cancers in children and adolescents.     

Update on the Japanese guidelines for the use of infliximab and etanercept in rheumatoid arthritis

Abstract

Application of biological agents targeting tumor necrosis factor-α (TNF-α) caused a paradigm shift in the treatment of rheumatoid arthritis (RA). The introduction of infliximab in 2003 and etanercept in 2005 in Japan had a significant impact on both Japanese rheumatologists and RA patients, although serious adverse effects such as bacterial pneumonia, tuberculosis and Pneumocystis jiroveci pneumonia are significant concerns. Based on the data from post-marketing surveillance in Japan and accumulating evidence worldwide, the Internal Medicine Rheumatology Study Group of the Ministry of Health, Labor and Welfare (MHLW), Japan, has updated the guidelines for the use of anti-TNF-α agents for RA, which were subsequently approved by the Board of Japan College of Rheumatology (JCR). In the present revised guidelines, we combined the guidelines for use of each of infliximab and etanercept together with some modifications and precautions, paying special attention to serious adverse reactions. Although it is still controversial whether the use of TNF-α blocking agents per se increases the risk of infection or not, bacterial pneumonia, regardless of the pathogens, is the most frequent complications in RA. The risk factors associated with pneumonia identified in the post-marketing surveillance of infliximab in Japan are presented in this guideline. The diagnostic algorithm is also designed for early diagnosis and treatment of pulmonary lesions seen during the treatment of biological agents. Preventive measures and precautions against tuberculosis, another frequent and significant complication in Japan, are also described. Furthermore, risk factors for developing Pneumocystis pneumonia, which uniquely occurs at 30- to 50-fold frequency under TNF-α blockade therapy in Japan, are described here and its preventive measures are discussed. It is stressed that secondary-care rheumatologists should be better familiarized with the proper use of TNF-α blocking agents and be alert to any adverse events for a better management of RA patients.     

TNF-α antagonist use and risk of hospitalization for infection in a national cohort of veterans with rheumatoid arthritis

Medications used to treat rheumatoid arthritis (RA) may confer an increased risk of infection. We conducted a retrospective cohort study of veterans with RA followed in the United States Department of Veterans Affairs health care system from October 1998 through September 2005. Risk of hospitalization for infection associated with tumor necrosis factor (TNF)-α antagonists therapy was measured using an extension of Cox proportional hazards regression, adjusting for demographic characteristics, comorbid illnesses, and other medications used to treat RA. A total of 20,814 patients met inclusion criteria, including 3796 patients who received infliximab, etanercept, or adalimumab. Among the study cohort, 1465 patients (7.0%) were hospitalized at least once for infection. There were 1889 hospitalizations for infection. The most common hospitalized infections were pneumonia, bronchitis, and cellulitis. Age and several comorbid medical conditions were associated with hospitalization for infection. Prednisone (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.88-2.43) and TNF-α antagonist use (HR, 1.24; 95% CI, 1.02-1.50) were associated with hospitalization for infection, while the use of disease-modifying antirheumatic drugs (DMARDs) other than TNF-α antagonists was not. Compared to etanercept, infliximab was associated with risk for hospitalization for infection (HR, 1.51; 95% CI, 1.14-2.00), while adalimumab use was not (HR, 0.95; 95% CI, 0.68-1.33). In all treatment groups, rate of hospitalization for infection was highest in the first 8 months of therapy. We conclude that patients with RA who are treated with TNF-α antagonists are at higher risk for hospitalization for infection than those treated with other DMARDs. Prednisone use is also a risk factor for hospitalization for infection.     

Effect of TNF-α Blockade in Gingival Crevicular Fluid on Periodontal Condition of Patients with Rheumatoid Arthritis

Background: Periodontitis and rheumatoid arthritis (RA) share a number of clinical and pathologic features, one of which is the presence of the tumor necrosis factor alpha (TNF-α)-induced bone resorption that is involved in the pathogenesis of both. Objectives: To investigate the effect of TNF-α blockade on periodontal conditions in patients with active RA. Method: The periodontal statuses of 36 patients (26 females, 10 males) diagnosed with active RA were evaluated both before and after anti-TNF-α therapy. Gingival index, bleeding on probing (BOP), probing pocket depth (PPD), oral hygiene index (OHI), and levels of TNF-α in gingival crevicular fluid (GCF) were measured at the baseline and 6 weeks after the treatment. Wilcoxon signed ranked test was used for statistical analyses. Results: Based on OHI (p=0.860), the level of plaque control did not change during the study period, but there was a significant reduction in gingival inflammation based on the mean BOP (p=0.049) and GI (p=0.036) before and after 6 weeks of anti-TNF-α therapy. The mean PPD index did not significantly differ at the baseline and 6 weeks after treatment (p=0.126). Conclusion: Anti-TNF-α therapy might have a desirable effect on periodontal conditions and might reduce TNF-α level in GCF of patients with RA.     

Exacerbation of adult-onset Still's disease, possibly related to elevation of serum tumor necrosis factor-alpha after etanercept administration

Adult-onset Still's disease (AOSD) is a systemic inflammatory disease of unknown etiology. A 44-year-old male patient presented with AOSD complicated by macrophage activation syndrome after etanercept therapy. His serum tumor necrosis factor-α (TNF-α) level was increased dramatically after etanercept therapy. The clinical course of this case suggests that the increased TNF-α level by etanercept administration might cause macrophage activation syndrome in this case.     

Hypersensitivity reaction against influenza vaccine in a patient with rheumatoid arthritis after the initiation of etanercept injections

Abstract

A 58-year-old Japanese woman with rheumatoid arthritis (RA) suffered from high fever triggered by administration of an influenza vaccine after a 4-month-long effective treatment course with the TNF-α inhibitor etanercept. Influenza vaccine had been previously administrated safely to the patient before initiation of etanercept therapy. The fever occurred without other symptoms soon after vaccine administration, progressed to high fever 1 day later, and spontaneously resolved the second day. The clinical course appears to be compatible with drug fever closely associated with immediate hypersensitivity (in particular, late-phase type I allergic reaction), in which T helper (Th) 2 cells play a crucial role. Etanercept can strongly suppress Th1-mediated reactions; therefore, Th2 activity may be augmented by etanercept treatment in aspect of antagonism between Th1 and Th2 mechanisms. In RA patients who receive treatment with TNF-α inhibitor such as etanercept, activation of Th2-mediated immune responses such as immediate hypersensitivity may be a necessary side effect for those who receive vaccinations.     

Development of sarcoidosis 6-month post discontinuation of etanercept: coincidence or real association?

There have been numerous reports of granulomatous diseases developing in patients receiving anti-tumour necrosis factor (TNF) therapy. Herein, we report a patient who developed sarcoidosis 6?months after discontinuation of etanercept. To date, all reported cases have occurred in patients undergoing ongoing treatment with TNF blockers with resolution on its discontinuation. A 47-year-old man was diagnosed with seropositive rheumatoid arthritis (RA) in 2003. He was initially treated with methotrexate and corticosteroids. In 2005, adalimumab was added due to ongoing disease activity. However, he had persistent low-grade synovitis of bilateral wrist joints and remained oral glucocorticoids dependent. In October 2008, adalimumab was switched to etanercept with marginal benefit; however, etanercept was continued until March 2009. Rituximab was discontinued due to an immediate allergic reaction. In September 2009, he developed bilateral ankle synovitis with erythema nodosum. Further investigations (chest X-ray and CT scan of thorax) revealed new development of bilateral hilar lymphadenopathy and interstitial nodular changes typical of sarcoidosis. His baseline therapy of methotrexate was continued. His recent repeat chest X-ray and CT scan of thorax (March 2010) has shown significant spontaneous resolution of his mediastinal lymphadenopathy and pulmonary nodules. Apart from the initial brief course of NSAIDs, his sarcoidosis resolved spontaneously without requiring any further therapy. For his rheumatoid arthritis, he has been recently commenced on abatacept and his baseline therapy of methotrexate has been continued. It remains speculative as to whether the concurrence of RA and sarcoidosis is purely serendipitous, or is related to an immunodysregulatory state attributable to TNF blockade.