Therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal disease: a systematic literature review informing EULAR points to consider

Abstract

The objectives of this review were to collect and summarise evidence on therapeutic drug monitoring (TDM) of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases and to inform the EULAR Task Force for the formulation of evidence-based points to consider. A systematic literature review (SLR) was performed, covering technical aspects and (clinical) utility of TDM, to answer 13 research questions. MEDLINE, Embase and Cochrane were searched until July 2020. American College of Rheumatology and EULAR abstracts were also considered for inclusion. Data were extracted in evidence tables and risk of bias assessment was performed. For the search on technical aspects, 678 records were identified, of which 22 papers were selected. For the clinical utility search, 3846 records were identified, of which 108 papers were included. Patient-related factors associated with biopharmaceutical blood concentrations included body weight, methotrexate comedication and disease activity. The identification of a target range was hampered by study variability, mainly disease activity measures and study type. Evidence was inconsistent for multiple clinical situations in which TDM is currently applied. However, for some particular scenarios, including prediction of future treatment response, non-response to treatment, tapering and hypersensitivity reactions, robust evidence was found. There is currently no evidence for routine use of proactive TDM, in part because published cost-effectiveness analyses do not incorporate the current landscape of biopharmaceutical costs and usage. This SLR yields evidence in favour of TDM of biopharmaceuticals in some clinical scenarios, but evidence is insufficient to support implementation of routine use of TDM.

Assessing Immunogenicity of Biologic Drugs in Inflammatory Joint Diseases: Progress Towards Personalized Medicine

“…Assays may have widely differing capture and detection principles and some assays include elaborate sample pre-treatment steps. As a consequence, test results from different assays are rarely comparable, and clinicians should be familiar with the properties of the assay provided by their laboratory [10,11]. Perhaps the most important factor to consider is whether the assay specifically measures neutralizing antibodies or also measures non-neutralizing antibodies (as discussed below).…”

“…The number of studies and study populations, the indications for use, as well as dosing regimens and use of concomitant immunomodulators differ among drugs and diagnoses. Importantly, the use of different assays for ADAb detection undoubtedly influences the results [10,11] (as discussed in detail below).…”

“…Reactive TDM has been applied in clinical practice by many rheumatologists, based on empirical and observational data. The recent EULAR PtC state that reactive TDM, including both ADAb and drug concentrations, should be considered to understand clinical non-response, but this statement is based on limited data [10,11]. Clinical trials addressing the effectiveness of reactive TDM strategies in the case of a suspected treatment failure are warranted.…”

“…To achieve this, however, several barriers must be overcome. High-quality clinical trials of TDM within rheumatology are lacking, except for the NOR-DRUM trials [11]. This knowledge gap is underlined by the EULAR PtC research agenda [10].…”

“…While TDM has shown promise and may be an effective strategy in personalizing treatment decisions in IJDs, there are also several challenges. While different methods used for drug measurements usually give comparable results, and published data on therapeutic drug concentrations may be relevant for laboratories and clinicians worldwide, this is not the case for ADAb [10,11]. A plethora of assay formats, with widely differing properties, is currently used for measuring ADAb [12,13].…”