开放科学(资源服务)标识码(OSID)的开放科学计划以二维码为入口,提供丰富的线上扩展功能,包括作者对论文背景的语音介绍、该研究的附加说明、与读者的交互问答、拓展学术圈等。读者“扫一扫”此二维码即可获得上述增值服务。
风湿性疾病(rheumatic disease,RD)是一组因不明原因导致结缔组织受累的自身免疫性疾病,包括类风湿关节炎(rheumatoid arthritis,RA)、强直性脊柱炎(ankylosing spondylitis,AS)、银屑病关节炎(psoriatic arthritis,PsA)、系统性红斑狼疮(systemic lupus erythematosus,SLE)、骨关节炎(osteoarthritis,OA)和痛风性关节炎(gouty arthritis,GA)等[1-2],其病因至今未完全明确,共同特点是免疫功能紊乱,风湿性疾病患者会出现调节性T淋巴细胞(regulatory T lymphocyte,Treg)功能缺陷和程序性死亡受体-1(Programmed death-1,PD-1)表达异常,这是加速风湿性疾病进展的原因之一[3-4]。PD-1分子表达异常还会增加风湿性疾病患者结核分枝杆菌(Mycombacterium tuberculosis, MTB)感染或复发的概率[3]。此外,风湿性疾病患者常使用糖皮质激素、免疫抑制剂、生物制剂等药物,使人体处于免疫紊乱状态,机体对免疫复合物的清除能力减弱,此时容易出现结核分枝杆菌潜伏感染(latent tuberculosis infection,LTBI)的激活,还可能导致结核分枝杆菌出现播散或达到难以控制的程度,增加结核病的治疗难度。因此,如何管理LTBI逐渐成为管控结核病的一大重点和难点,故笔者将对风湿性疾病合并LTBI作一综述,为加强高危人群LTBI筛查和预防性治疗提供参考。
一、风湿性疾病患者LTBI的易感机制
风湿性疾病的主要发病机制为机体免疫功能受损,出现B淋巴细胞异常激活和T淋巴细胞异常反应,增加MTB的感染概率。由于疾病本身或使用糖皮质激素、免疫抑制剂、生物制剂治疗,抑制了淋巴细胞、单核巨噬细胞和嗜酸性粒细胞的功能,使LTBI发展为活动性结核病的风险明显增加[5-6]。肿瘤坏死因子-α(tumour necrosis factor-α,TNF-α)在宿主的免疫应答中起关键作用,在MTB感染的病灶中,TNF-α可以增加巨噬细胞的吞噬能力并促进细胞内细菌的死亡,也可以促进病灶周围肉芽肿的形成并维持肉芽肿结构的完整性,进而防止MTB的进一步扩散。风湿性疾病患者在使用肿瘤坏死因子抑制剂(tumour necrosis factor inhibitors,TNFi)阻断TNF-α后肉芽肿内MTB会恢复生长,甚至导致肉芽肿结构的崩解从而出现MTB的扩散[7]。除了TNF-α,白细胞介素-12(interleukin-12,IL-12)/γ-干扰素(interleukin-γ,IFN-γ)通路在防御结核病中也是十分重要的一环,当IL-12/IFN-γ出现通路特异性下调时,会诱发系统性Th1缺陷,导致结核病的出现[8]。
二、风湿性疾病患者合并LTBI的流行病学
我国作为全球结核病高负担国家,目前尚未获得LTBI流行的系统数据。《全国结核分枝杆菌潜伏感染率估算专家共识》[15]中估算2013年我国5周岁及以上人群LTBI率为18.1%(95%CI: 13.7%~22.4%),≥15岁人群LTBI率为20.3%(95%CI:15.6%~25.1%),感染率随年龄增长而升高。国内也有部分单中心的小样本研究,邱可为等[16]对广东省第二人民医院371例风湿性疾病患者行结核感染T细胞斑点试验(T-SPOT.TB)检测,其阳性率为18.9%,显著高于健康体检组(6.2%,P<0.01)。黄安芳等[17]对四川大学华西医院759例风湿性疾病患者进行筛查,发现LTBI率为27.27%,高于健康体检者(10.53%)。邓国防等[18]对深圳市1218例风湿性疾病患者进行LTBI筛查,发现LTBI率最高(21.3%),其次是非活动性结核病(2.2%)和活动性结核病(1.1%)。从以上资料可以看出,我国风湿性疾病患者LTBI率约为18.1%~27.27%。但目前我国尚缺乏系统性大范围的流行病学研究数据,风湿性疾病患者LTBI的流行病学现状还需进一步研究探讨。
三、风湿性疾病合并LTBI的诊断方法
(一)结核菌素皮肤试验(tuberculin skin test,TST)
TST是采用结核菌素纯蛋白衍生物(purified protein derivative,PPD)为抗原的一种基于细胞免疫的试验,具有价格较低、检测方便的特点,对LTBI的诊断具有重要的参考意义。PPD包含200多种蛋白,是从MTB中粗提的非特异性抗原混合物,其中很多是非结核分枝杆菌(non-tuberculous mycobacteria,NTM)及卡介苗的共同抗原成分,易导致卡介苗接种者出现假阳性,也不能鉴别MTB感染和NTM感染。部分风湿性疾病患者由于使用免疫抑制剂,在免疫力低下时TST可能会出现假阴性结果,故朱翠云[19]经研究后提出,在风湿性疾病患者CD4+ T淋巴细胞计数升至200个/μl以上时有必要再次行TST检查,以防止出现假阴性结果。
(二) 新型结核菌素皮肤试验(creation tuberculin skin test,C-TST)
(三)γ-干扰素释放试验(interferon-gamma release assay,IGRA)
IGRA可以检测MTB抗原刺激后致敏T淋巴细胞中INF-γ的释放,从而判断人体是否存在MTB感染。与TST相比,IGRA不易被卡介苗所影响,具有高敏感度和高特异度,但是无法区分LTBI与活动性结核病。我国常用的两种IGRA试剂盒是QFT-GIT和T-SPOT。有研究发现,IGRA诊断LTBI的特异度>95%[21],最近的新型QFT-Plus的检测性能与QFT-GIT相当,总体敏感度为87.9%[22-23]。赵静等[24]研究发现T-SPOT.TB的诊断效能在风湿性疾病患者中并不理想,既往结核病史、吸烟史和部分并发症会影响T-SPOT.TB的诊断准确性。许敏殷等[25]发现将血清细胞白介素-6测定与IGRA相结合可提高IGRA诊断活动性肺结核的特异性,这2种检测方法通过患者外周血样本即可完成检测,样本获取相对简单,并且具有可行性。
(四)胸部X线摄片
TST和胸部X线摄片(chest X-ray,CXR)是20世纪LTBI诊断过程中的重要方法,至今仍被广泛应用,特别是在结核病负担较高的低收入国家。可以通过检测CXR发现患者可能存在的陈旧性结核病或对活动性结核病进行排除,以辅助发现LTBI。Wang等[26]提出,当怀疑风湿性疾病患者合并LTBI时,CXR可作为IGRA的一种补充性检查,尤其是在IGRA阴性但是既往存在结核病史的风湿性疾病患者中,可以使用CXR筛查LTBI有无激活。
四、风湿性疾病患者LTBI激活的危险因素
在风湿性疾病患者LTBI激活的相关高危因素中,Long等[10]对1788例风湿性疾病患者展开研究,发现低体质量指数、系统性红斑狼疮、免疫抑制剂的使用和合并症是其主要的危险因素,其中合并症如恶性肿瘤、糖尿病、慢性肾衰竭和矽肺等都是LTBI激活的高危因素。
随着近年来对药物的深入研究,人们对部分免疫抑制剂的MTB感染风险有了新的认识。Chung等[27]检索了1994年2月至2019年6月中国香港医院管理局临床管理中心的1099例类风湿关节炎患者和2489例非特异性腰痛(nonspecific back pain,NSBP)患者,发现类风湿关节炎患者的结核病发病率是NSBP患者的2.53倍。排除使用改善病情抗风湿药(disease-modifying anti-rheumatic drugs,DMARDs)的类风湿关节炎患者后,无服用DMARDs的类风湿关节炎患者其MTB感染风险与NSBP患者相似(HR=2.72,P=0.11),这一结果提示类风湿关节炎患者MTB感染风险的上升并非完全由类风湿关节炎患者疾病本身所致,更多是由DMARDs的使用而造成的。与此同时,有学者对合并有脊柱关节炎(spondyloarthritis,SpA)的结核病患者展开了另外一项类似的研究,发现除服用DMARDs之外,吸烟、饮酒、慢性肺病、既往结核病史以及TNFi的使用也是LTBI激活的危险因素[27-28]。
非受体酪氨酸激酶(janus kinase inhibitors,JAK)是一个细胞因子家族,可介导造血、自身免疫、炎症反应等多种生物进程,JAK-信号转导转录活化因子(STAT)途径是类风湿关节炎进展的关键[37]。随着免疫药物的发展,越来越多的非受体酪氨酸激酶抑制剂(Janus kinase inhibitors,JAKi)被用于风湿性疾病的治疗[35]。常用的JAKi包括托法替尼、巴瑞替尼和乌帕替尼,JAKi主要用于血液系统疾病、肿瘤、类风湿关节炎及银屑病的治疗[38]。Cantini等[35]对使用JAKi的类风湿关节炎患者结核风险进行研究,有发现托法替尼可能会增加LTBI激活的风险。也有研究发现在给予10mg每天2次的托法替布治疗后有6例患者罹患结核病(0.5/100 患者年)[39]。此外有研究发现,JAKi不单单只会为类风湿关节炎患者带来负面的影响,当类风湿关节炎患者对MTB有过强的免疫反应时,特别是对于那些炎症水平较高、组织损伤较重的结核病患者,托法替尼治疗此类合并结核病的类风湿关节炎患者效果较好[35]。
五、风湿性疾病合并LTBI筛查的重要性
对伴有高危因素的风湿性疾病患者而言,定期筛查十分重要。Mohamed等[40]对200例系统性红斑狼疮患者进行为期1年的随访,发现系统性红斑狼疮患者发生感染的比例高达55%,其中10%的患者出现了多重感染,TB感染率为2%。Lao等[41]对中山大学附属第一医院收治的1108例患者进行了回顾性研究,发现合并活动性结核病的系统性红斑狼疮患者共59例(5.3%),其中41例为肺结核,约1/3(35.6%)的患者发展为播散性结核病。淋巴细胞减少和糖皮质激素的累积剂量与狼疮患者的MTB感染有关,尤其在播散性结核病中[42]。中国香港公立医院使用TNFi治疗之前,临床医生对结核病需要进行常规的筛查评估与预防性治疗,发现LTBI激活的风险依旧增加[27]。这说明采用筛选评估和预防性治疗相结合的方法也难以降低LTBI激活的风险。Alaşan等[43]的研究发现即使接种了卡介苗并服用异烟肼进行预防性治疗,也不能提供充分的保护。这也说明目前对LTBI患者的筛查、预防标准还存在诸多不足,需要进一步研究以加强对LTBI患者的管理。
Goel等[31]为了评估TNFi的使用对LTBI激活的风险以及对筛查策略的影响,在美国结核病发病率较高的河滨县3个健康中心中收集了2010年1月至2017年1月符合要求的217例使用TNFi至少1年的类风湿关节炎患者,发现对于使用TNFi的类风湿关节炎患者,应该实行每年一次的常规普查以加强MTB感染的筛选管理。虽然这种方法可以有效的诊断和治疗LTBI,但是并不是一种经济有效的方法,所以作者将研究结果与其他地区的结核病发病率进行对比,发现利用部分地区的结核病发病率来制定筛查策略,其效益会更高。
Rotar等[2]通过研究发现,斯洛文尼亚对风湿性疾病患者执行规范的LTBI筛查策略和预防性治疗方案后,使用TNFi的风湿性疾病(类风湿关节炎、强直性脊柱炎和银屑病关节炎)患者结核病发病率虽然高于该国普通人群的发病率(SIR=7~9),但是与非结核病流行国家的结核病发病率相当。此外,Rotar等[2]还注意到1例完成预防性抗结核治疗的风湿性疾病患者出现LTBI激活的情况。这些都说明强制性筛查LTBI和预防性抗结核治疗虽然可以减少结核病的出现,但不能完全预防,可见在筛查手段和选择预防性抗结核治疗人群这两方面还有待进一步研究。其次,Rotar等[2]发现在该使用TNFi的风湿性疾病患者中需要预防性抗结核治疗的例数少于1/10,提示如何准确的筛选出需要预防性治疗的风湿性疾病患者显得十分重要。法国结核病发生率和接种卡介苗的情况与斯洛文尼亚相似,用IGRA的筛查手段代替TST可以使接受预防性抗结核治疗的患者比例减半,提高了筛查的精准度的同时减少了医疗资源的浪费[2]。
六、风湿性疾病合并LTBI的预防性抗结核治疗
对于使用免疫抑制剂的风湿性疾病患者,目前有两套主要的预防性抗结核治疗方案,由2018年WHO和2020年美国疾病预防控制中心发布的指南[44-45]在预防性抗结核治疗的主流治疗方案上有相似之处,但也存在差异。其中有4种预防性抗结核治疗方案是2篇指南共同推荐的:(1)异烟肼(isonia zide,INH,简称“H”)单药疗法:即每日服用剂量为0.3g的INH,疗程持续6~9个月。有研究发现该方法在治疗后的第一年保护作用最强,可以减少60%的LTBI激活概率,是WHO推荐的首选方案和美国疾病预防控制中心推荐的备选方案,也是目前使用最广泛的方案[44-45]。该方案的缺点是治疗时间长,治疗完成率和依从性较低[46]。(2)利福平(rifampicin,RFP,简称“R”)单药疗法:即每日服用剂量为0.45~0.6g的RFP,疗程持续3~4个月。其优点是疗效与INH单药疗法相似,但毒性较小,是WHO推荐的备选方案,同时也是美国疾病预防控制中心强推荐的首选方案。有研究表明在矽肺患者中,RFP单药疗法与其他疗法相比更为有效,建议矽肺患者首选该方案。该方案的缺点是药物相互作用较多,与华法林、抗HIV逆转录药物和唑类抗真菌药等联用易出现药物相互作用而影响疗效,特别是在利福平联用托法替尼时会降低托法替尼的疗效。所以存在使用利福平的禁忌时,可以改用利福喷丁(rifapentine,Rft,简称“P”),使用INH+Rft方案[45,47]。(3)异烟肼联合利福平每日疗法:即每日服用剂量为0.3g的INH和0.45~0.6g的Rft,疗程持续3~4 个月。该方案与异烟肼单药疗法相比疗效相似,其优点是治疗时间较短、依从性和完成率较高,是WHO推荐的方案,同时也是美国疾病预防控制中心推荐的首选方案之一,其缺点是在HIV阳性患者中两种药物联用可能比单独使用有更高的肝毒性风险[45]。中国香港的一项研究表明,该方案的肝毒性小于异烟肼单药使用12个月的方案,但是大于异烟肼单药使用6~9个月的方案,提示当需要延长异烟肼单药治疗方案时,应该使用INH+Rft方案,以减少肝损害[47]。(4)异烟肼联合利福喷丁每周疗法:WHO在2018年LTBI指南中更新并推荐了该方案,称3HP方案,美国疾病预防控制中心也同样推荐了该方案[44-45],即>14岁的人群每周服用剂量为INH 0.9g和Rft 0.9g,2~14岁的人群每周服用INH 15mg/kg和Rft 0.3~0.75g,疗程持续3个月。有研究表明,3HP方案有较高的治疗完成率[48],疗效较好。该方案的缺点是费用较高,虽然减少了服药次数但是每次服药的药物数量较多。其次有研究表明该方案在老年人中需谨慎评估风险,减少不良事件的发生[49]。
除了以上WHO和美国疾病预防控制中心共同推荐的4个方案之外,WHO在《结核病综合指南(2020版)-模块1:预防》[50]中还推荐了以下方案:(1)异烟肼联合利福喷丁每日疗法:即每日服用INH 0.3g和Rft 0.6g,疗程为28d。(2)左氧氟沙星每日疗法:>14岁人群每日服用0.75~1g的左氧氟沙星,≤14岁人群每日服用剂量为15~20mg/kg,疗程为6个月,该方案是WHO推荐用于预防性治疗耐多药结核病的方案。
七、问题与展望
综上所述,风湿性疾病患者LTBI激活的风险日益增高,已成为管控结核病的关键问题,对LTBI进行早期诊治能够显著降低罹患结核病的风险。目前缺乏直接诊断LTBI的金标准,其筛查策略以高危人群和危险因素为主,具有一定的局限性。在高危因素的筛查策略方面,不同地区和不同类型的TNFi风险不同,建议针对不同地区和类型的TNFi制定与之相适应的筛查方案,以提高筛查的精准度并减少医疗资源的浪费。目前国内对于风湿性疾病合并LTBI治疗方面的相关研究较少,这需要风湿免疫科和结核科共同协作,进行前瞻性研究,以得出更多具有借鉴意义的结果或结论供临床参考。
利益冲突 所有作者均声明不存在利益冲突
作者贡献 陈秋奇:设计撰写、修改;韩婷婷:参与修改;王庆文、邓国防: 指导撰写
参考文献
Incidence of Tuberculosis in Inflammatory Rheumatic Diseases: Results from a Lithuanian Retrospective Cohort Study
Tuberculosis among patients treated with TNF inhibitors for rheumatoid arthritis,ankylosing spondylitis and psoriatic arthritis in Slovenia:a cohort study
不同的风湿免疫性疾病患者免疫功能差异分析
Increased percentages of PD-1 on CD4+ T cells is associated with higher INF-γ production and altered IL-17 production in patients with systemic lupus erythematosus
Programmed death (PD)-1 is a cell death receptor that, upon stimulation, leads to apoptosis. Previous studies have shown alteration of PD-1 expression on T cells and PD-1 genes in patients with systemic lupus erythematosus (SLE). The aim of this study was to assess the expression of this receptor on effector T cells in patients with SLE.In this study we enrolled 32 SLE patients and 31 healthy controls. T cells from peripheral blood were analysed by flow cytometry for the expression of PD-1. Interferon (IFN)-γ and interleukin (IL)-17-producing cells were investigated for the expression of this co-stimulatory marker.Percentages of CD4(+) T cells expressing PD-1 were significantly increased in patients with SLE compared to healthy controls. The percentage of PD-1 expression was correlated with the production of INF-γ (r = 0.83, p < 0.0001). We also investigated the production of IL-17 by PD-1(+) CD3(+) T cells. Inactive patients (3.2 ± 1.2% vs. 5.9 ± 3.5%, p = 0.002) and patients without lupus nephritis (LN) (3.2 ± 1.5% vs. 5.9 ± 3.5%, p = 0.005) showed lower levels of IL-17 compared to healthy controls.We have demonstrated increased expression of PD-1 on CD4(+) T cells in SLE patients and an association between PD-1 expression on CD4(+) T cells and IFN-γ expression on CD3(+) T cells. We have also shown that there is an altered subset of PD-1(+) T cells in inactive patients and patients without LN producing lower amounts of IL-17.
Latent tuberculosis infection in patients with rheumatic diseases
Tuberculosis risk and anti-tumour necrosis factor agents in rheumatoid arthritis: a critical appraisal of national registry data
Role of tumour necrosis factor (TNF) in host defence against tuberculosis: implications for immunotherapies targeting TNF
Studies in mouse infection models clearly demonstrate tumour necrosis factor (TNF) to be a critical component of both the antibacterially protective and the inflammatory immune response to Mycobacterium tuberculosis. It is therefore not surprising that treatment of patients-for example, those with rheumatoid arthritis-with biological agents interfering with TNF activity have shown an increased risk of reactivating tuberculosis. However, conceivably, TNF targeting biological agents can be developed that because of their particular mode of action and their specific pharmacodynamics may be less likely to have this side effect.
Reactivation of latent tuberculosis with TNF inhibitors: critical role of the beta 2 chain of the IL-12 receptor
Tumor necrosis factor (TNF) inhibitors have improved a lot the treatment of numerous diseases, with the well-known example of rheumatoid arthritis (RA). In the early 2000s, postmarketing data quickly revealed an alarming number of severe tuberculosis (TB) under such treatment. These findings were consistent with previous results in mice where TNF is essential for lymph node formation and granuloma organization. The effects of TNF inhibition on RA synovium structure are very similar to those on granuloma, with changes in cellular interactions, cytokine, and chemokine production. In addition to the role of TNF in granuloma, the interleukin (IL)-12/interferon (IFN)-γ pathway is required for an efficient host defense against TB. Primary and secondary immunodeficiencies affecting this pathway lead to severe bacillus Calmette-Guérin (BCG) reaction or full TB. Any chronic inflammation as in RA induces a systemic Th1 defect that predisposes to TB through specific downregulation of the IL-12Rß2 chain. When TNF inhibitors are initiated, this transiently increases this risk of TB, through effects on cellular interactions in a latent TB granuloma. At a later stage, when a better control disease activity is obtained, the risk of TB is reduced but not abrogated. Given the clear benefit from TNF inhibition, latent TB infection screening at baseline is essential for an optimal safety.
Latent tuberculosis infection and tuberculosis in patients with rheumatic diseases treated with anti-tumor necrosis factor agents
The introduction of biological agents, especially the tumor necrosis factor inhibitors (anti-TNF), for the treatment of rheumatic diseases increased the risk of developing tuberculosis (TB). Screening for latent TB infection (LTBI) is strongly recommended before starting therapy with anti-TNF agents. The objective of this study was to identify the prevalence of LTBI and TB among patients with rheumatic diseases on anti-TNF agents. This is a cross-sectional study. The electronic medical records of all adult patients (≥18 years old) undergoing anti-TNF treatment were reviewed. Every patient underwent tuberculin skin test (TST) before starting anti-TNF treatment. In total, 176 patients were included; the mean age was 51.9 ± 12.4 years, 34.7% were males, and 90.9% were white. The underlying diseases were rheumatoid arthritis (RA) in 50.6% (N = 89), ankylosing spondylitis (AS) in 27.8% (N = 49), and psoriatic arthritis (PsA) in 17.6% (N = 31). The prevalence of positive TST was 29.5%. Household contact with TB was significantly associated with a positive TST (p = 0.020). RA patients had lower TST reactions than AS patients (p = 0.022). There were six cases of TB (3.4%) diagnosed during anti-TNF therapy. We demonstrated a high prevalence of positive TST (29.5%) among patients with rheumatic diseases in a region with high TB prevalence. Our data corroborates the ACR's recommendation that patients who live in high TB incidence settings should be tested annually for LTBI.
High risk of activation of latent tuberculosis infection in rheumatic disease patients
Tuberculosis in biologic users for rheumatic diseases: results from the South African Biologics Registry (SABIO)
To evaluate the rate of tuberculosis (TB) in biologic users for rheumatic diseases in South Africa, the effectiveness of our latent TB infection (LTBI) programme, risk factors and outcome.TB cases were collected from the South African Biologics Registry (SABIO), rheumatologists and pharmaceutical companies. Demographics, LTBI screening and treatment, biological and disease modifying antirheumatic drug (DMARD) therapies, TB diagnosis and outcomes were recorded.96 TB cases were collected from 1999 to June 2017: rheumatoid arthritis 55, ankylosing spondylitis 27, psoriatic arthritis 4, and juvenile inflammatory arthritis 10. The TB rate was 1240/100 000 person years for biologic users (n=96) versus the biologic naive cohort of 0/100 000 years with an incidence rate difference of 0.0124 (p<0.0001). 60/96 had pulmonary and 36/96 had extra-pulmonary TB. Reactivation TB occurred in 45/96 cases. TB occurred in all biologics licenced in South Africa, the majority in monoclonal inhibitors (1683/100 000 person years) compared with etanercept (861/100 000 person years) and non-tumour necrosis factor (TNF) inhibitors (681/100 000 person years). The incidence rate ratio for monoclonal inhibitors compared with etanercept was 1.96 (p=0.005) and 2.47 (p=0.002) compared with non-TNF inhibitors with no significant difference between non-TNF inhibitors and etanercept (p=0.336). From those (12.9%) who screened LTBI positive, 14 developed TB, while the majority (77) screened LTBI negative. Black race, male sex, younger age and residence in the Western Cape were statistical risk factors. Two drug resistant TB cases and six deaths occurred.Reactivation and new onset TB is a significant risk for all biologics users in SA. Screening for LTBI is an imperative preventative strategy.© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.
Screening for latent tuberculosis infection among patients with rheumatoid arthritis in the era of biologics and targeted synthetic disease-modifying anti-rheumatic drugs in India, a high-burden TB country: The importance of Mantoux and Quantiferon-TB Gold tests
To test the validity of an augmented tuberculosis skin test (a-TST) combined with Quantiferon TB-gold (QFTG) test for the screening of latent tuberculosis infection (LTBI) in patients with rheumatoid arthritis (RA) being considered for treatment with biologic disease-modifying anti-rheumatic drugs or targeted synthetic disease-modifying anti-rheumatic drugs.Standard TST using 1 tuberculin unit (TU) of purified protein derivative (PPD, RT23 strain) was carried out. If the positivity was less as compared to the general population, then a-TST using 10 TU PPD was employed. Simultaneously, QFTG test was also performed.Using standard TST, 6/44 (13.6%), patients were positive compared to the reported figures of ~ 40% of the general population; 38 of the remaining TST-negative patients were then given an a-TST with 10 TU PPD; eight of them dropped out. Of the remaining 30 patients, eight (26.6%) were positive. Another 70 patients tested directly with a-TST; 22 (31.4%) were found positive. Thus, of a total of 100 patients tested with a-TST, 30 (30%) were positive. In 54 a-TST negative patients, QFTG was done; seven (13%) were positive. Thus, in combined a-TST with QFTG, 43% of the RA patients were found positive, suggestive of the presence of LTBI.Combined a-TST with QFTG testing gave 43% positivity among RA patients, which is close to the reported ~ 40% Mantoux positivity in the general population. Therefore, this method for the screening of LTBI in Indian patients with RA being considered for tumor necrosis factor alpha treatment could be satisfactory for offsetting TB flare. It may apply to other high-burden TB countries around the world.© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.
Efficacy of Treatment for Latent Tuberculosis in Patients Undergoing Treatment with a Tumor Necrosis Factor Antagonist
The conversion rate of tuberculosis screening tests during biological therapies in patients with rheumatoid arthritis
全国结核分枝杆菌潜伏感染率估算专家共识
T细胞酶联免疫斑点法对风湿病患者感染结核分支杆菌的诊断价值
风湿病患者合并潜伏性结核感染的分析
风湿免疫性疾病并发结核感染的临床特征分析
对人类免疫缺陷病毒感染者潜伏性结核感染的筛查和干预
重组结核杆菌融合蛋白(EC)临床应用专家共识
Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update
Interferon-γ release assays for active pulmonary tuberculosis diagnosis in adults in low- and middle-income countries: systematic review and meta-analysis
TB对风湿免疫病患者活动性肺结核诊断准确性的影响因素分析
γ干扰素释放试验联合IL-6检测对活动性肺结核的诊断价值
Chest roentgenography is complementary to interferon-gamma release assay in latent tuberculosis infection screening of rheumatic patients
A retrospective study on the risk of tuberculosis in patients with rheumatoid arthritis
Tuberculosis (TB) is an important preventable infection in patients with rheumatoid arthritis (RA). To determine the risk of TB in patients with RA by comparing with those with non-specific back pain (NSBP), and to identify the risk factors in the RA group. Medical data were retrieved from a centralized electronic database. A total of 1099 patients with RA and 2489 patients with NSBP were identified. Clinical data, comorbidities, and use of individual disease-modifying anti-rheumatic drugs (DMARDs) were retrieved. Risks of TB in patients with RA and NSBP were compared by propensity score (PS) adjusted analysis with known or potential risk factors for TB. Risk factors of TB were also determined in patients with RA. There were 14 cases of TB in RA group and 25 cases in NSBP group. Median duration of follow-up were 11.3 (0.1-21.9) years in RA group and 15.4 (0.1-24.4) years in NSBP group. The risk of TB in patients with RA was 2.53 times higher (HR 2.53; 95% CI 1.29, 4.94; p < 0.01) than in patients with NSBP. After excluding patients on DMARDs, the risk became similar (HR 2.72; 95% CI 0.81, 9.14; p = 0.11). Independent risk factors found were etanercept (HR 7.16; 95% CI 1.41, 36.30; p = 0.02), and previous TB infection (HR 25.23; 95% CI 6.99, 91.09; p < 0.001). The risk of extrapulmonary involvement between RA and NSBP groups was similar (HR 1.21; 95% CI 0.22, 6.57; p = 0.83). The risk of TB was increased in patients with RA. Anti-TNF therapy was an identified risk factor.
Risk of tuberculosis in patients with spondyloarthritis:data from a centralized electronic database in Hong Kong
Anti-TNF biosimilars in rheumatology:the end of an era
Tuberculosis and targeted synthetic or biologic DMARDs, beyond tumor necrosis factor inhibitors
Screening for acquired latent tuberculosis in rheumatoid arthritis patients on tumor necrosis factor inhibition therapy in Southern California
Drug Survival of Biologics in Treating Ankylosing Spondylitis:A Systematic Review and Meta-analysis of Real-World Evidence
Infection risk in patients undergoing treatment for inflammatory arthritis:non-biologics versus biologics
Association of Secukinumab Treatment With Tuberculosis Reactivation in Patients With Psoriasis,Psoriatic Arthritis,or Ankylosing Spondylitis
Systematic review on tuberculosis risk in patients with rheumatoid arthritis receiving inhibitors of Janus Kinases
Risk of tuberculosis reactivation associated with traditional disease modifying anti-rheumatic drugs and non-anti-tumor necrosis factor biologics in patients with rheumatic disorders and suggestion for clinical practice
JAK-STAT inhibitors: Immersing therapeutic approach for management of rheumatoid arthritis
JAK-Inhibitors for the Treatment of Rheumatoid Arthritis:A Focus on the Present and an Outlook on the Future
Incidence and risk of infection in egyptian patients with systemic lupus erythematosus
Active tuberculosis in patients with systemic lupus erythematosus from Southern China: a retrospective study
Higher risk of tuberculosis reactivation when anti-TNF is combined with immunosuppressive agents:a systematic review of randomized controlled trials
Treatment with tumour necrosis factor antagonists (anti-TNF) has been recognized as a risk factor for tuberculosis (TB) reactivation. Our aim was to evaluate risk of TB reactivation in rheumatologic and non-rheumatologic diseases treated with the same anti-TNF agents with and without concomitant therapies.We searched for randomized controlled trials (RCTs) evaluating infliximab, adalimumab, and certolizumab in both rheumatologic and non-rheumatologic diseases until 2012. Results were calculated as pooled rates and/or pooled odd ratios (OR).Overall, 40 RCTs with a total of 14,683 patients (anti-TNF: 10,010; placebo: 4673) were included. TB reactivation was 0.26% (26/10,010) in the anti-TNF group and 0% (0/4673) in the control group, corresponding to an OR of 24.8 (95% CI 2.4-133). TB risk was higher when anti-TNF agents were combined with methotrexate or azathioprine as compared with either controls (24/4241 versus 0/4673; OR 54; 95% CI 5.3-88) or anti-TNF monotherapy (24/4241 versus 2/5769; OR 13.3; 95% CI 3.7-100). When anti-TNF was used as monotherapy, TB risk tended to be higher than placebo (2/5769 versus 0/4673; OR 4; 95% CI 0.2-15.7).TB risk with anti-TNF agents appeared to be increased when these agents were used in combination with methotrexate or azathioprine as compared with monotherapy regimen. TB risk seemed to be higher than placebo, even when monotherapy is prescribed.
Should isoniazid prophylaxis be prescribed to the patients under tumor necrosis factor-alpha antagonists independent of tuberculin skin test
?.
Latent tuberculosis infection-Updated and consolidated guidelines for programmatic management
Treatment of Latent Tuberculosis Infection
A double-blind placebo-controlled clinical trial of three antituberculosis chemoprophylaxis regimens in patients with silicosis in Hong Kong. Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council
Isoniazid-Rifapentine for Latent Tuberculosis Infection: A Systematic Review and Meta-analysis
New short regimens for latent tuberculosis treatment:safety first!
京公网安备11010202007215号