类风湿性关节炎是一种主要引起炎症的慢性自身免疫性疾病,关节疼痛和僵硬。患有严重疾病的人可以使用生物疾病缓解抗风湿药进行治疗,包括肿瘤坏死因子-α抑制剂,但是抗药物抗体的存在阻碍了这些药物的功效。监测对这些治疗的反应通常涉及使用反应标准的临床评估。如28个关节的疾病活动评分或欧洲抗风湿病联盟。酶联免疫吸附测定也可用于测量血液中的药物和抗体水平。这些测试可以告知是否需要调整治疗或帮助临床医生了解治疗无反应或失去反应的原因。
进行了系统评价,以确定报告使用酶联免疫吸附测定法测量药物和抗药物抗体水平以监测对肿瘤坏死因子-α抑制剂的反应的临床有效性和成本效益的研究[阿达木单抗(Humira®;AbbVie,Inc.,北芝加哥,IL,美国),依那西普(Enbrel®;辉瑞,Inc.,纽约,NY,美国),英夫利昔单抗(Remicade®,默克夏普和多姆有限公司,Hoddesdon,英国),塞托珠单抗pegol(Cimzia®;UCB制药有限公司,Slough,UK)和golimumab(Simponi®;MerckSharp&DohmeLimited)]在达到治疗目标(缓解或低疾病活动)或显示原发性或继发性对治疗无反应的类风湿性关节炎患者中。一系列书目数据库,包括MEDLINE,EMBASE和CENTRAL(Cochrane中央控制试验登记册),从成立到2018年11月进行了搜索。使用CochraneROBINS-1(非随机研究中的偏倚风险-干预)工具评估非随机研究的偏倚风险,进行适当的调整。进行了基于决策树模型的阈值和成本效用分析,以估计将治疗药物监测添加到标准护理的经济结果。从NHS和个人社会服务的角度考虑了成本和资源使用。由于经济分析采用的短期时间范围为18个月,因此没有对成本和效果进行折扣。在许多临床上合理的敏感性分析中探讨了测试和治疗策略变化对结果的影响。
确定了两项研究:(1)一项非随机对照试验,INGEBIO,将标准护理与使用Promonitor®测定的治疗药物监测进行比较[ProgenikaBiopharmaSA(Grifols-Progenika公司),Derio,西班牙]在接受阿达木单抗的西班牙患者中,患者已达到缓解或低疾病活动;和(2)历史对照研究。经济分析由INGEBIO提供。INGEBIO的不同结果在阈值和成本效用分析中都产生了不一致的结果。治疗药物监测的成本效益各不相同,从干预占主导地位到每获得质量调整生命年164,009英镑的增量成本效益比。然而,当测试的频率被假定为每年一次,并且静脉切开术的费用被排除在外,治疗药物监测主导了标准护理。
在类风湿关节炎患者中使用基于酶联免疫吸附测定的测试进行治疗药物监测的临床有效性和成本效益方面,相关研究证据有限,并且存在许多不确定性。INGEBIO在国家健康与护理卓越研究所的范围方面有严重的局限性:只有三分之一的参与者患有类风湿性关节炎,这些分析大多不是通过意向治疗进行的,随访时间仅为18个月.此外,结果可能无法推广到NHS.
根据现有证据,对于英格兰和威尔士的治疗药物监测的成本效益,尚不能得出确切的结论.
需要进一步的对照试验来评估使用酶联免疫吸附试验监测类风湿性关节炎患者抗肿瘤坏死因子的影响。
本研究注册为PROSPEROCRD42018105195。
该项目由国家卫生研究所(NIHR)卫生技术评估计划资助,并将在《卫生技术评估》中全文发表。25号8.有关更多项目信息,请参阅NIHR期刊库网站。
类风湿性关节炎是导致疼痛的长期病症,关节肿胀和僵硬。患有严重疾病的人可以用称为肿瘤坏死因子-α抑制剂的药物治疗[阿达木单抗(Humira®;AbbVieInc.,北芝加哥,IL,美国),依那西普(Enbrel®;辉瑞,Inc.,纽约,NY,美国),英夫利昔单抗(Remicade®;默克夏普和多姆有限公司,Hoddesdon,英国),塞托珠单抗pegol(Cimzia®;UCB制药有限公司,Slough,英国)和戈利木单抗(Simponi®;默克夏普和多姆有限公司)]。一些服用这些药物的人发现他们的疾病有所改善,而其他人对治疗没有反应或最初改善,然后经历反应丧失。失去反应的一个原因是个体产生针对药物的抗体(即保护性蛋白质),这阻碍了治疗的效果。已经开发了各种测试来测量患者血液样品中的药物和针对这些药物的抗体的水平。这种监测将允许根据测试结果调整治疗,以优化患者的利益。并帮助临床医生更好地了解缺席或失去治疗反应的原因。这项研究的目的是找出使用这些测试来监测药物和抗体水平是否具有临床效果(即对患者有益)和成本效益(即良好利用NHS资源),作为评估控制的类风湿性关节炎患者的治疗反应的一种手段,没有回应或失去回应。系统评价的结果表明,由于证据有限且质量差,试验的临床有效性存在很大的不确定性.一个简单的数学模型借鉴了一项报道不佳的研究的证据,得到了其他研究数据和专家建议的大量补充。该模型的结果尚无定论,表明测试的成本效益存在相当大的不确定性。因此,这里提出的结果应谨慎考虑.需要进一步的研究来评估肿瘤坏死因子检测对类风湿关节炎患者的影响。
Rheumatoid arthritis is a chronic autoimmune disease that primarily causes inflammation, pain and stiffness in the joints. People with severe disease may be treated with biological disease-modifying anti-rheumatic drugs, including tumour necrosis factor-α inhibitors, but the efficacy of these drugs is hampered by the presence of anti-drug antibodies. Monitoring the response to these treatments typically involves clinical assessment using response criteria, such as Disease Activity Score in 28 joints or European League Against Rheumatism. Enzyme-linked immunosorbent assays can also be used to measure drug and antibody levels in the blood. These tests may inform whether or not adjustments to treatment are required or help clinicians to understand the reasons for treatment non-response or a loss of response.
Systematic reviews were conducted to identify studies reporting on the clinical effectiveness and cost-effectiveness of using enzyme-linked immunosorbent assays to measure drug and anti-drug antibody levels to monitor the response to tumour necrosis factor-α inhibitors [adalimumab (Humira®; AbbVie, Inc., North Chicago, IL, USA), etanercept (Enbrel®; Pfizer, Inc., New York, NY, USA), infliximab (Remicade®, Merck Sharp & Dohme Limited, Hoddesdon, UK), certolizumab pegol (Cimzia®; UCB Pharma Limited, Slough, UK) and
golimumab (Simponi®; Merck Sharp & Dohme Limited)] in people with rheumatoid arthritis who had either achieved treatment target (remission or low disease activity) or shown primary or secondary non-response to treatment. A range of bibliographic databases, including MEDLINE, EMBASE and CENTRAL (Cochrane Central Register of Controlled Trials), were searched from inception to November 2018. The risk of bias was assessed using the Cochrane ROBINS-1 (Risk Of Bias In Non-randomised Studies - of Interventions) tool for non-randomised studies, with adaptations as appropriate. Threshold and cost-utility analyses that were based on a decision tree model were conducted to estimate the economic outcomes of adding therapeutic drug monitoring to standard care. The costs and resource use were considered from the perspective of the NHS and Personal Social Services. No discounting was applied to the costs and effects owing to the short-term time horizon of 18 months that was adopted in the economic analysis. The impact on the results of variations in testing and treatment strategies was explored in numerous clinically plausible sensitivity analyses.
Two studies were identified: (1) a non-randomised controlled trial, INGEBIO, that compared standard care with therapeutic drug monitoring using Promonitor® assays [Progenika Biopharma SA (a Grifols-Progenika company), Derio, Spain] in Spanish patients receiving adalimumab who had achieved remission or low disease activity; and (2) a historical control study. The economic analyses were informed by INGEBIO. Different outcomes from INGEBIO produced inconsistent results in both threshold and cost-utility analyses. The cost-effectiveness of therapeutic drug monitoring varied, from the intervention being dominant to the incremental cost-effectiveness ratio of £164,009 per quality-adjusted life-year gained. However, when the frequency of testing was assumed to be once per year and the cost of phlebotomy appointments was excluded, therapeutic drug monitoring dominated standard care.
There is limited relevant research evidence and much uncertainty about the clinical effectiveness and cost-effectiveness of using enzyme-linked immunosorbent assay-based testing for therapeutic drug monitoring in rheumatoid arthritis patients. INGEBIO had serious limitations in relation to the National Institute for Health and Care Excellence scope: only one-third of participants had rheumatoid arthritis, the analyses were mostly not by intention to treat and the follow-up was 18 months only. Moreover, the outcomes might not be generalisable to the NHS.
Based on the available evidence, no firm conclusions could be made about the cost-effectiveness of therapeutic drug monitoring in England and Wales.
Further controlled trials are required to assess the impact of using enzyme-linked immunosorbent assays for monitoring the anti-tumour necrosis factors in people with rheumatoid arthritis.
This study is registered as PROSPERO CRD42018105195.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 8. See the NIHR Journals Library website for further project information.
Rheumatoid arthritis is a long-term condition that causes pain, swelling and stiffness in the joints. People with severe disease may be treated with drugs called tumour necrosis factor-α inhibitors [adalimumab (Humira®; AbbVie Inc., North Chicago, IL, USA), etanercept (Enbrel®; Pfizer, Inc., New York, NY, USA), infliximab (Remicade®; Merck Sharp & Dohme Limited, Hoddesdon, UK), certolizumab pegol (Cimzia®; UCB Pharma Limited, Slough, UK) and
golimumab (Simponi®; Merck Sharp & Dohme Limited)]. Some people taking these drugs find that their disease improves, whereas others do not respond to the treatment or improve initially and then experience loss of response. One cause of lost response is that individuals develop antibodies (i.e. protective proteins) against the drug, which hamper the effect of treatment. Various tests have been developed to measure the level of drugs and antibodies against these drugs in patient’s blood samples. This kind of monitoring would allow treatment to be adjusted in response to the test outcomes to optimise benefit for the patient, and help clinicians to better understand the reasons for an absence or a loss of response to treatment. The aim of this study was to find out whether or not it would be clinically effective (i.e. good for patients) and cost-effective (i.e. a good use of NHS resources) to use these tests for monitoring drug and antibody levels, as a means of assessing treatment response in rheumatoid arthritis patients who are controlled, have not responded or have lost response. Results from a systematic
review showed that, because of the limited and poor-quality evidence, there was much uncertainty in the clinical effectiveness of testing. A simple mathematical model drew on evidence from one poorly reported study, which was heavily supplemented by data from other studies and expert advice. Results from the model were inconclusive and suggest that there is considerable uncertainty in the cost-effectiveness of testing. Therefore, the results presented here should be considered with caution. Further studies are needed to assess the impact of tumour necrosis factor testing in patients with rheumatoid arthritis.