Background: 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.
Methods: 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.
Results: 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.
Limitations: 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.
Conclusions: Based on the available evidence, no firm conclusions could be made about the cost-effectiveness of therapeutic drug monitoring in England and Wales.
Future work: 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.
Study registration: This study is registered as PROSPERO CRD42018105195.
Funding: 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.
Keywords: ADALIMUMAB; ANTIBODIES; BIOLOGIC; BIOMARKER; CERTOLIZUMAB PEGOL; COST-EFFECTIVENESS ANALYSIS; COST-UTILITY ANALYSIS; DECISION TREE; DRUG MONITORING; ENZYME-LINKED IMMUNOSORBENT ASSAY; ETANERCEPT; GOLIMUMAB; INFLIXIMAB; RHEUMATOID ARTHRITIS; TUMOUR NECROSIS FACTOR-ALPHA.
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.