The use of biologic agents in the management of uveitis

The uveitides are a heterogenous group of ocular inflammatory disorders that account for the third highest cause of blindness worldwide, responsible for 5–10% of visual impairment globally. Up to 35% of patients with uveitis can suffer significant vision loss. To prevent irreversible structural damage and blindness, it is important that the diagnosis and commencement of appropriate therapy occurs promptly. Management includes topical and systemic corticosteroid therapy and conventional immunomodulatory agents, including methotrexate, azathioprine, mycophenolate mofetil and cyclosporin. Significant progress has been made in the past decade in our understanding of the immunopathological pathways that drive intraocular inflammation, allowing the development of targeted therapy with biologic agents. These include TNF‐α inhibitors, such as infliximab, adalimumab and etanercept; interleukin blockers, such as tocilizumab and daclizumab; and other targeted therapies, such as rituximab and abatacept. The efficacy of these agents has been studied in cases of severe uveitis that are refractory to conventional immunomodulatory agents and provide exciting results that have revolutionised uveitis management. Though the biologic era has provided a large armamentarium to treat uveitis, ongoing challenges and cases of recalcitrant uveitis remain, posing a challenge to internal medicine physicians. This comprehensive review aims to construct an updated summary on the existing evidence pertaining to the use of biologic agents in the treatment of uveitis. Methods include a systematic search for studies between 2000 and 2018 using PubMed, EMBASE, Ovid MEDLINE and Cochrane libraries.     

Therapy with biologic agents in SLE

The revolution of biologic targeted therapy for autoimmune disease is underway. While anticytokine treatment (anti‐TNF‐α and anti‐IL‐1Ra) are proving beneficial in such diseases as rheumatoid arthritis and spondyloarthropathies, the road to successful treatment in systemic lupus erythematosus (SLE) is more complex, and perhaps because the mechanisms of disease remain unelucidated. The aims of novel therapies in SLE are to target the autoimmune disease at different points: B‐cell depletion (Lymphostat‐B, Rituximab), inhibition of T–B interaction (IDEC‐131), blockade of cytokines (anti‐IL‐10 antibodies), manipulation of idiotypes (IVIG), tolerance induction to DNA and to Ig‐peptides and peptide therapy (Riquent). We review the current knowledge on biologic agents in SLE patients. We utililized MEDLINE for relevant information from 2000 to 2003. Since biologic agents in this disease are at preliminary stages, we include information from abstracts, open trials, as well as phase I, II, and III studies. Anecdotal reports are not included. B‐cell depletion therapy is promising.     

Clinical guidelines to diagnose smear-negative pulmonary tuberculosis in Pakistan, a country with low-HIV prevalence

OBJECTIVES: To develop and validate clinical guidelines for diagnosis of smear-negative pulmonary tuberculosis (TB) in developing countries with low-HIV prevalence. METHODS: We developed diagnostic guidelines for smear-negative TB. Clinical diagnoses based on these guidelines were compared with sputum culture, chest X-rays and reports of an expert panel. RESULTS: The guidelines achieved a sensitivity of 0.59 [confidence interval (CI) 0.46-0.66] and a specificity of 0.86 (CI 0.84-0.88) in diagnosing smear-negative TB. A total of 6.8% of patients who initially improved after a course of antibiotics were later confirmed to have TB. Clinicians detected an abnormal chest X-ray in 92% (CI 88-96%) and radiological signs of pulmonary TB in 98% (CI 94-100%) of cases. CONCLUSIONS: Our experience highlights a number of dilemmas faced in developing, testing and implementing diagnostic guidelines in poorly resourced conditions. Using radiological criteria for TB and appropriate training can help in improving the diagnostic skills of primary care clinicians working in low-HIV settings with access to X-ray facilities. But a significant number of apparently smear-negative TB cases may in fact be smear positive and TB programmes should focus on improving the quality of direct acid-fast bacilli microscopy. The value of an antibiotic trial is questionable due to the relatively large number of false negatives generated by this approach.     

Fusion proteins of biologic agents in the treatment of rheumatoid arthritis (RA): A network meta-analysis

Background:To evaluate the efficacy of fusion proteins biologics (Etanercept (ETN), Anakinra (ANA), and Abatacept) combinations in the treatment of rheumatoid arthritis (RA) using network meta-analysis to rank those according to their performance medicines. The performance of these processes is ranked according to the results of the analysis and an explanatory study of the possible results is carried out.Methods:Multiple databases including PubMed, EMBASE, and Cochrane Library were used to identify applicable articles and collect relevant data to analyze using STATA (14.0) software. The literature included in this study was divided into a combination of a placebo, methotrexate (MTX), and an observation group (1 of the 3 drugs). The last search date was December 12, 2019.Results:A total of 19 eligible randomized controlled trials of fusion proteins biologics were identified, a total of 1109 papers were included, and the results showed that the ETN + MTX had the highest probability of being the most clinically efficacious intervention, with a surface under the cumulative ranking curve of 91.6, was significantly superior (P < .05). Patients who had received ETN or ETN + MTX or ANA had effective compared with patients who had received placebo (95% CI 1.28%–8.47%; 1.92%–19.18%; 1.06%–10.45%).Conclusions:1. The combination of ETN and MTX had the highest probability of optimal treatment compared to other drugs and 2. ENT, ENT + MTX, and ANA were effective in the treatment of RA compared to placebo.     

Modeling the 5‐year cost effectiveness of treatment strategies including tumor necrosis factor‐blocking agents and leflunomide for treating rheumatoid arthritis in the Netherlands

Objective

To determine the cost effectiveness of treatment strategies for rheumatoid arthritis patients satisfying the indication for tumor necrosis factor (TNF)‐blocking treatment.

Methods

A Markov model study was performed. The following treatment strategies were considered: 1) usual treatment; 2) treatment with leflunomide, in the case of nonresponse after 3 months, switch to usual treatment; 3) TNF‐blocking treatment, in the case of nonresponse after 3 months, switch to usual treatment; 4) treatment with leflunomide, in the case of nonresponse, switch to TNF‐blocking treatment, in the case of nonresponse to TNF‐blocking treatment, switch to usual treatment; 5) TNF‐blocking treatment, in the case of nonresponse, switch to leflunomide treatment, in the case of nonresponse to leflunomide, switch to usual treatment. Expected patient‐years in the different Markov states, costs, and quality‐adjusted life years (QALYs) were compared between the treatment strategies; incremental cost‐effectiveness ratios (ICERs) were calculated.

Results

Over the 5‐year period, the expected effect on disease activity and QALYs was better for treatment strategies that included TNF‐blocking treatment than for the other treatment strategies. The greater effectiveness of these treatment strategies reduced medical and nonmedical costs compared with usual treatment by about 16% and 33%, respectively, omitting the costs of medication. When the costs of medication were included, the costs of strategies that started with TNF‐blocking treatment were higher than those of the other treatment strategies. Treatment strategy 4 had the most favorable ICER of the treatment strategies that included TNF‐blocking treatment: €163,556/QALY compared with usual treatment.

Conclusion

Among strategies that include TNF‐blocking agents, one starting with leflunomide and, in the case of nonresponse, switching to TNF‐blocking treatment probably results in the most favorable ratio between incremental costs and effects.

     

中国社区肺结核主动筛查循证指南

为实现终止结核病流行策略目标,迫切需要实施更强有力的措施来改善结核病患者的发现和治疗管理,而主动筛查作为实现目标的重要组成部分,旨在确保结核病患者的早期诊断。中国防痨协会结核病控制专业分会和老年结核病防治专业分会与《中国防痨杂志》编辑委员会共同组织专家,在解读吸收世界卫生组织2021年最新指南证据和建议的基础上,补充了后续新发表的文献和我国国内的相关文献和研究证据,结合中国结核病防治实践和研究结果制订了本指南。本指南系统总结了症状筛查、胸部影像学检查、C反应蛋白检测等筛查技术的特点,提出了在肺结核患者密切接触者、既往结核病患者、HIV/AIDS者、老年人、糖尿病患者和高疫情地区的一般人群等社区人群中开展肺结核主动筛查的方式,为国家和各地完善和优化重点人群肺结核主动筛查策略提供循证依据。     

Anti‐tumor necrosis factor therapy: the Australian experience

Anti‐tumor necrosis factor (TNF) therapy for the management of rheumatic diseases has been reimbursed in Australia progressively per agent and disease indication since 2003. Initial projections of uptake were grossly overestimated. In this article the anti‐TNF experience in Australia is reviewed, including results of an eligibility study, Australian Rheumatology Association guidelines, anti‐TNF registry, and a report of adverse effects. These observations may assist APLAR countries currently coming to terms with anti‐TNF drug registration and funding.     

终止结核病流行须加强结核分枝杆菌潜伏感染高危人群筛查和预防性治疗的管理

当前,全球结核病发病率下降缓慢,给实现终止结核病目标带来了严峻的挑战。2020年估算全球结核分枝杆菌潜伏感染人群近20亿,在无预防性治疗干预情况下,其中有5%~10%的感染者在一生中会发展为活动性结核病,在结核病高危人群中发病率更高。世界卫生组织在全球范围内号召推广结核分枝杆菌潜伏感染(LTBI)的预防干预,以实现结核病发病率快速下降的目标。笔者就LTBI流行和预防性治疗的现状、高危人群发病风险、筛查方法、干预和管理建议等进行论述,为制定我国LTBI干预和管理策略及措施提供参考。     

Use of interferon-gamma release assay for latent tuberculosis infection screening in older adults exposed to tuberculosis in a nursing home

OBJECTIVES: To assess the additive value of a newly marketed interferon‐gamma release assay, QuantiFERON‐TB Gold In‐Tube (QFT‐GIT), to a single tuberculin skin test (TST) for the detection of latent tuberculosis infection (LTBI) in older adults who have been exposed to TB in a nursing home. DESIGN: Contact tracing included clinical examination, chest radiography, TST, and QFT‐GIT in TST‐negative people (TST<5 mm). SETTING: A private nursing home. PARTICIPANTS: Seventy‐seven individuals (63 elderly residents, 14 young employees) who had been exposed to an active TB case in a private nursing home. MEASUREMENTS: Comparison of TST and QFT‐GIT in older adults who have been exposed to TB. RESULTS: For the TST, the positive response rate was 31.7% (n=20) of elderly residents and 43% (n=6) of staff. Positive QFT‐GIT results were obtained in seven (16.3%) elderly residents with negative TST, six of whom were aged 80 and older. QFT‐GIT increased the percentage of possible LTBI in this group from 31.7% to 42.9%. CONCLUSION: QFT‐GIT has a significant additive value to single TST for detecting LTBI in institutionalized older adults, identifying infected subjects anergic to the TST.     

Efficacy and safety of the anti-TNF biologic agents

The last decade has seen a marked increase in the elucidation of cellular and molecular factors involved in chronic inflammatory processes that contribute to the pathogenesis of rheumatoid arthritis (RA). Multiple lines of evidence have demonstrated a critical role for the proinflammatory cytokine tumor necrosis factor (TNF) in the perpetuation of inflammatory synovitis and the subsequent destruction of cartilage and bone that leads to the functional disability observed in RA. In the light of these discoveries, new therapeutics have been developed to target TNF. The consistent efficacy demonstrated by these agents for the treatment of RA has validated TNF as an important mediator of the chronic inflammatory events and structural damage that occur with the disease. Three of these agents (etanercept, infliximab, and adalimumab) have been approved by the United States Food and Drug Administration (FDA) over the last 5 years for treatment of moderately to severely active RA. This article will first explain the role of TNF in inflammation and RA, and then compare and contrast the mechanisms of action, efficacy, and safety profiles of the various FDA-approved TNF inhibitors, as well as offer potential explanations for the clinical differences observed between these agents, especially with regard to safety.     

Efficacy and safety of the anti-TNF biologic agents

Abstract

The last decade has seen a marked increase in the elucidation of cellular and molecular factors involved in chronic inflammatory processes that contribute to the pathogenesis of rheumatoid arthritis (RA). Multiple lines of evidence have demonstrated a critical role for the proinflammatory cytokine tumor necrosis factor (TNF) in the perpetuation of inflammatory synovitis and the subsequent destruction of cartilage and bone that leads to the functional disability observed in RA. In the light of these discoveries, new therapeutics have been developed to target TNF. The consistent efficacy demonstrated by these agents for the treatment of RA has validated TNF as an important mediator of the chronic inflammatory events and structural damage that occur with the disease. Three of these agents (etanercept, infliximab, and adalimumab) have been approved by the United States Food and Drug Administration (FDA) over the last 5 years for treatment of moderately to severely active RA. This article will first explain the role of TNF in inflammation and RA, and then compare and contrast the mechanisms of action, efficacy, and safety profiles of the various FDA-approved TNF inhibitors, as well as offer potential explanations for the clinical differences observed between these agents, especially with regard to safety.     

组学方法筛选结核病生物标志物的应用进展

结核病目前仍然是世界范围内最严重的传染病之一。现有结核病诊断方法不能有效区分潜伏感染和活动性结核病例,延误后续的干预治疗。生物标志物含量在结核病潜伏感染、活动性结核等不同阶段存在差异,有望在感染早期做出预警。因此,筛选新的潜在结核病生物标志物,建立有效、快速、灵敏的诊断方法,有助于更早发现并及时采取结核病防治干预措施。随着基因组、转录组、蛋白组、代谢组等组学方法的发展,高通量筛选结核病生物标志物成为可能。交叉组学的应用还能够进一步提高生物标志物筛选的可靠性。本文就组学方法筛选结核病生物标志物的应用进行介绍,以期为新型结核病诊断方法研发提供线索。     

联用环丝氨酸在耐多药肺结核治疗中的疗效及安全性研究

目的探讨环丝氨酸联合抗结核药物治疗耐多药肺结核(multi-drug resistant tuberculosis,MDR-TB)的疗效及安全性。方法选择2012年5—1 1月广西南宁市第四人民医院纳入第五轮中国全球基金耐多药结核病防治项目的MDR-IB患者98例,将其分为试验组(n=50)和对照组(n=48)。2组患者均接受标准MDR-IB治疗方案,在此基础上试验组加用环丝氨酸,对照组加用对氨基水杨酸。分别对2种不同治疗方法的疗效和不良反应进行比较。结果 2组治疗第3、6、9、12、24月末痰菌阴转率差异无统计学意义(P0.05)。试验组中枢神经系统不良反应和周围神经病变发生率高于对照组,而对照组胃肠道反应及药物性肝损伤的发生率远高于试验组,差异有统计学意义(P0.01)。结论环丝氨酸和对氨基水杨酸在治疗MDR-T3方面效果相当,但可引起诸多不良反应,值得深入研究。