Adalimumab (ADM), a fully human monoclonal antibody that neutralizes tumor necrosis factor-α (TNF-α), was initially approved for the treatment of moderate to severe rheumatoid arthritis (RA) in 2002 (Rau, 2002). Since then, it has been found to be effective in treating a variety of other conditions, such as ankylosing spondylitis, psoriasis, Crohn’s disease (CD), ulcerative colitis (UC), uveitis, and juvenile idiopathic arthritis, making it the most widely used agent.

Therapeutic drug monitoring (TDM) is a practical method used to monitor the drug concentration and their metabolites in the blood, which can help guide clinical medication decisions, enhance drug effectiveness, prevent drug toxicity, and establish personalized treatment schedules. Recently, TDM has become essential in biological therapy due to the impact of drug concentrations of TNF-α inhibitors on clinical outcomes (Pouw et al., 2015; Rinawi et al., 2021). Anti-drug antibodies (ADA) play a significant role in the inter-individual variability of drug clearance, leading to insufficient drug exposure and treatment failure, such as primary non-response (PNR) and loss-of-response (LOR) (Bartelds et al., 2011; Baert et al., 2016; Ding et al., 2020). Reactive TDM refers to measure biological concentration and ADA in patients experiencing treatment failure. This approach is endorsed by the American Gastroenterological Association and expert consensus statements to understand treatment failure (Feuerstein et al., 2017; Mitrev et al., 2017; Cheifetz et al., 2021; Krieckaert et al., 2023), despite the limited quality of evidence. The supported evidence comes primary from studies involving infliximab therapy. It is not yet clear how many benefits of TDM can bring to the clinical application of ADM. However, the use of proactive TDM, which involves scheduled testing and adjusting dosages to achieve predefined target concentrations, lacks consistent recommendations (Feuerstein et al., 2017; Cheifetz et al., 2021). There are persistent uncertainties surrounding the most effective use of TDM in clinical settings. Specifically, the evidence supporting the use of TDM to guide dose reduction or discontinuation in patients achieving deep remission has not been reviewed.

To systematically review the value of TDM in optimizing ADM therapy, three key questions throughout the entire drug treatment process were considered: 1) Could routine proactive TDM assist in improving outcomes in patients receiving ADM? 2) Could reactive TDM assist in guiding subsequent treatment strategies for patients PNR or LOR to ADM? 3) Could TDM assist in informing dose reduction or discontinuation in patients with low disease activity or in remission treated with ADM?

In clinical setting, TDM typically involves adjusting the dosage based on blood concentrations and using pharmacometrics model to ensure that the concentration falls within the desired range to achieve optimal efficacy and avoid adverse reaction. The clinical implementation of TDM of ADM is intricate, mainly due to the need to adjust treatment plans based on different clinical scenarios and TDM results. Our study outlines the benefits of TDM in the entire clinical process of ADM treatment for various diseases. The comprehensive clinical scenarios and evidence are demonstrated in Figure 4.

In scenario A, people hope to obtain the drug concentration and antibody level of ADM to actively intervene and achieve better therapeutic effects. In a meta-analysis of 3 RCTs and 1 retrospective cohort involving 626 IBD patients treated with ADM. Numerically but not statistically significant superiority of proactive TDM over reactive TDM and/or conventional management in achieving and/or maintaining clinical remission was observed. Our results are in line with previous studies on TNF-α inhibitors (Nguyen et al., 2022) which included 9 RCTs (6 for infliximab and 3 for ADM) in patients with IBD. There was no significant difference in the risk of failing to maintain clinical remission in patients who underwent proactive TDM vs. conventional management. Disease duration, concomitant immunomodulators, disease activity at baseline, and optimization of therapy before randomization did not modify this association. Exposure response relationship studies in IBD patients clearly demonstrate that higher anti-TNF drug concentrations are associated with clinical, biochemical, endoscopic, and histological remission (Zittan et al., 2016; Ward et al., 2017; Papamichael et al., 2018). According to reports, proactive TDM is important not only during maintenance therapy but also during induction therapy. Research has shown that ADA can develop as early as the second week in CD patients, leading to unresponsiveness. Proactive TDM can detect low concentrations at the fourth week to avoid immunogenicity and impact patient prognosis (Ungar et al., 2016). However, it seems that we have not obtained the expected evidence of benefits of ADM proactive TDM, but it is worth noting that the included literatures varied in study design, with moderate heterogeneity. The results may be influenced by factors such as patient population, sample size, study time, and detection method, etc. Therefore, more high-quality research is needed to provide additional evidence to clarify benefits of proactive TDM. Proactive TDM may be more important in more severely active patients and those with higher drug clearance rates, such as during induction therapy and in patients with acute severe UC and severe CD. These patients have a high burden of inflammation, increased drug clearance rates, and therefore a higher risk of insufficient drug exposure, immunogenicity, and treatment failure (Brandse et al., 2015; Brandse et al., 2016; Ungar et al., 2016; Battat et al., 2021). Another population with high drug clearance rates is the pediatric population (Jongsma et al., 2020; Winter et al., 2020). Assa et al. conducted relevant studies on pediatric IBD patients and demonstrated that proactive TDM can guide higher frequency treatment strategy adjustments, resulting in higher sustained response rates in the absence of corticosteroids and biological responses (Assa et al., 2019).

In scenario B, reactive TDM is performed when the patient experiencing treatment failure (Krieckaert et al., 2015; Irving and Gecse, 2022; Papamichael et al., 2022). For example, approximately one-third of IBD patients do not respond to TNF-α inhibitors treatment, and among those who initially respond, the LOR is an important clinical issue. In the first year of treatment, up to 40% of patients experience this condition (Colombel et al., 2007). For unresponsive patients, empirical dose escalation therapy may incur significant additional costs, leading to potential ineffective treatment and delaying more effective treatment. In addition, in patients with immune-mediated pharmacokinetic failure (for which ADA was established), additional drug exposure may lead to hypersensitivity reactions. Similarly, excessive drug exposure can lead to a higher risk of drug-related adverse events (such as severe infections). Roblin’s two studies confirmed that different levels of drug and ADA in the IBD population are associated with corresponding treatment adjustment strategies (Roblin et al., 2014; Roblin et al., 2022). Although there was no RCTs to demonstrate superior clinical outcomes of reactive TDM compared to empirical care, the use of TDM can elucidate the mechanism of LOR, whether the lack of response is caused by pharmacokinetic issues, insufficient drug levels, or pharmacological issues of ineffective ADA. TDM provides information for clinical decision-making in unresponsive patients and has intuitive benefits, such as preventing ineffective and potentially dangerous dose escalation in high-titer ADA patients. These results lay the foundation for the guiding the role of TDM in clinical practice and have been introduced in clinical guidelines and expert consensuses to support reactive TDM in ADM treatment (Feuerstein et al., 2017; Khan et al., 2019; Cheifetz et al., 2021; Krieckaert et al., 2023). In addition, Ulijn et al. conducted a study on RA and reported that reactive TDM data cannot predict subsequent biological therapy (TNF-α inhibitors or a non TNF-α inhibitors) responses in patients who failed treatment with ADM (Ulijn et al., 2020). On this issue, current researches have not reached a consistent convincing conclusion. In previous studies, it has been suggested that the measurement of ADM serum levels and/or ADA might be helpful for channeling the right patients to a TNF-α inhibitors or a non TNF-α inhibitors, thus increasing overall response chances (Bartelds et al., 2010; Jamnitski et al., 2011; Plasencia et al., 2013). There may be several reasons for these different results. In Ulijn’s study, samples were not collected at the trough level but were randomly collected after injection of ADM. This might have reduced the association between ADA and response. Second, as this was a retrospective study, serum samples and clinical results were not always available, which may have led to selection bias. In summary, further prospective studies with larger sample sizes are needed to confirm whether drug and ADA levels indeed cannot predict disease activity.

In scenario C, due to the considerable interindividual variability in ADM concentrations and the existing exposure-response relationship, a considerable number of patients may experience overtreatment, leading to a higher risk of infection and increased costs. It is crucial in clinical practice to taper the dose to the lowest effective level, considering cost-effectiveness and potential adverse reactions. For patients who have achieved remission, sufficient ADM concentrations (≥6.4 μg/mL) can support successful ADM dose reduction (halving the dose to 40 mg monthly) (Chen et al., 2016). This approach has been validated by a RCT (l’Ami et al., 2018), RA patients with ADM concentrations >8 μg/mL can potentially prolong dosing interval to once every 3 weeks without loss of disease control, leading to reduced drug costs. While other biomarkers, involving patient, treatment, disease activity, and laboratory and imaging measurements, have not shown predictive value for successful dose reduction (Tweehuysen et al., 2017). It is hypothesized that patients who have achieved LDA and have undetectable drug concentrations may be considered for discontinuation of ADM, as the maintenance of LDA may be independent of the drug. However, data from the POET study (Chen et al., 2016) revealed that a significant proportion of patients (48%) experienced disease flare even with low or undetectable ADM concentrations, indicating that drug concentrations alone may not be sufficient to guide discontinuation decisions. Alternative strategies, such as disease activity-guided dose reduction and withdrawal or step-down approaches, may also be worth considering (van Herwaarden et al., 2015; Fautrel et al., 2016).

Our systematic review and meta-analysis summarized the benefits of TDM in the entire clinical process of ADM treatment for various diseases. However, there are some limitations to consider. In terms of data sources, limitations in data collection methods or sources may affect the reliability and universality of research results. Grey literature, as an important source of information, plays an indispensable role in literature search. Unlike traditional commercial publications, gray literature is usually published by institutions, enterprises, government agencies, professional conferences, and individuals. Its uniqueness makes it important, such as providing comprehensive information, reflecting practical experience and policy advocacy, timely grasping the latest research results, and eliminating publication bias. However, in our study, we only manually searched the trial registry and the list of references included in the trial, which made our search for grey literature incomplete and needed improvement in future research. Secondly, the included literatures varied in study design and quality. The results may be influenced by factors such as patient population, sample size, study time, and experimental environment, etc. as we excluded studies for which we were unable to extract individual ADM data; consequently, studies related to certain diseases, such as psoriasis and ankylosing spondylitis, were not included. Although evidence of benefits, including CD, UC, and RA, was ultimately included, the patient population, research perspectives, and outcome indicators of these studies were not the same, making it difficult to quantitatively summarize and perform meta-analyses for all literature results. Thirdly, it should be noted that assays used in TDM are varied and not yet standardized and may explain the deviation in results from different studies. Finally, our results are mainly based on the Western population, which means that it is difficult to generalize globally. However, within the scope of the currently published research, this article provides the latest results on the benefits of TDM in the entire process of clinical use and management of ADM.

The systematic review highlights the current evidence of TDM in ADM treatment. We addressed three clinical concerns regarding the benefits of TDM throughout the ADM treatment process. Current evidence suggests that proactive TDM is numerically but not statistically significant superiority over reactive TDM and/or conventional management in achieving and/or maintaining clinical remission. For patients experiencing treatment failure, reactive TDM can aid in understanding the reasons for treatment failure and developing subsequent treatment schedule. For patients reaching LDA or remission, monitoring drug concentrations can help identify and reduce overtreatment, while it cannot inform the successful drug discontinuation. Evidence was observed across various populations, including those with CD, UC, and RA. They encompass optimizing treatment strategies, enhancing clinical outcomes, improving drug utilization, and reducing treatment costs. However, existing clinical trials are limited and of varying quality. More well-designed, high-quality clinical studies are needed to clarify the role of TDM in different clinical settings.