Therapeutic Drug Monitoring in RA Is of Uncertain Utility

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Physicians interviewed by Rheumatology Advisor recommend using the Clinical Disease Activity Index and to treat-to-target by measuring clinical response and adapting therapy rapidly for patients with rheumatoid arthritis.

Therapeutic drug monitoring is defined as “a clinical decision-making tool that enables dosage regimen adjustments based on clinical and laboratory measurements, typically drug blood concentrations, to reach drug exposure that is associated with the highest possible response.”1 It includes the measurement of serum drug concentrations and antidrug antibodies and has been proposed as a method to optimize treatment in patients with rheumatoid arthritis (RA) who are receiving biological disease-modifying antirheumatic drugs (bDMARDs).1 Some researchers have advocated for the adoption of therapeutic drug monitoring in the clinic to establish whether a flare of disease activity in a patient previously responsive to a bDMARD treatment is transient and likely to resolve, or whether it is indicative of a loss of response that necessitates a change to a different agent.2 Other clinical scenarios in which therapeutic drug monitoring has been proposed include prediction of response after bDMARD initiation, prediction of response to a subsequent bDMARD in patients who have insufficiently responded to the first, and prediction of successful tapering of doses or discontinuation in patients with low disease activity.2 However, the role for therapeutic drug monitoring in routine clinical practice has not yet been established, and researchers have not reached a consensus as to whether its use could enhance therapeutic decision-making.

In recent years, significant reductions in disease severity, extra-articular manifestations, joint surgeries, and radiographic progression have been noted in RA cohorts.3,4 The introduction of bDMARDs, along with a treat-to-target approach involving the regular assessment and adjustment of therapies until treatment goals are reached, has played a large role in these remarkable improvements in patient outcomes. bDMARDs target specific molecules implicated in the pathogenesis of RA, such as tumor necrosis factor (TNF), interleukin 6, CD20, and cytotoxic T-lymphocyte-associated protein-4. TNF inhibitors were the first class of bDMARDs to be approved for patients with RA, and are currently the bDMARD that is most commonly prescribed.5,6 Despite the benefits of TNF inhibitors, a considerable proportion of patients with RA who receive them are subject to treatment failure. A large number of patients with RA are intolerant or insufficiently responsive to the first bDMARD they receive,7 and discontinuation rates up to 27% occur with bDMARDs at 1 year.8 The most frequent reason for the dis­continuation of TNF inhibitors in previously responsive patients is the re‑emergence of RA symp­toms such as synovitis, indicating a loss of clinical response.9 Two types of treatment failure can occur: primary failure, in which patients do not experience any response to therapy from the outset, and secondary failure, in which they initially have a therapeutic response but then experience relapse even when doses are increased or the drug is administered more frequently.10 Immunogenicity, or a molecule’s ability to induce antibodies against itself when it is recognized as foreign by the immune system, can result in the neutralization of drug activity and/or acceleration of the clearance of the drug, and is a frequent factor in secondary failure.10

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In a recent literature review, Alfons Den Broeder, MD PhD, rheumatologist and epidemiologist at the Sint Maartenskliniek, The Netherlands, and colleagues noted that positive conclusions about the use of therapeutic drug monitoring in the clinic were frequently made in several other reviews, but that they stemmed fromfailure to recognize incorrect study designs, false positives because of lack of validation after explorative multiple testing, cherry picking of studies, and incorrect interpretation of test characteristics.”11 The authors pointed out that although antidrug antibodies are prevalent in patients who are receiving TNF-inhibitors and associated with lower response rates, the presence of antidrug antibodies do not predict the ability to stop the drug in patients who continue to exhibit a good clinical response. Moreover, although dose response curves have been established for groups of patients, serum drug levels are highly variable between responders, suggesting that a drug level that produces a good response in one individual may be too high or low for another.11

In an email interview with Rheumatology Advisor, Josef F. Smolen, MD, professor of internal medicine at the University of Vienna and chairman of the Department of Rheumatology at Vienna General Hospital, Austria, stated that although therapeutic drug monitoring provides information on statistical differences, it is not useful for facilitating clinical decision making for an individual patient. “Individual patients may have no response to therapy despite high drug levels, and good response can be obtained despite low drug levels. For me, clinical improvement is what counts. If a patient improves by greater than 50% within 3 months, the chance of having a good response 3 months later are good.”

Dr Smolen also noted that patients benefit from being clinically assessed with the Clinical Disease Activity Index. “Treat-to-target is exactly that: measure clinical response and adapt therapy rapidly.”


1. Dreesen E, Bossuyt P, Mulleman D, Gils A, Pascual-Salcedo D. Practical recommendations for the use of therapeutic drug monitoring of biopharmaceuticals in inflammatory diseases. Clin Pharmacol. 2017;9:101-111.

2. Van Herwaarden N, Van Den Bemt BJF, Wientjes MHM, Kramers C, Den Broeder AA. Clinical utility of therapeutic drug monitoring in biological disease modifying anti-rheumatic drug treatment of rheumatic disorders: a systematic narrative review. Expert Opin Drug Metab Toxicol. 2017;13(8):843-857.

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7. Reynolds A, Koenig AS, Bananis E, Singh A. When is switching warranted among biologic therapies in rheumatoid arthritis? Expert Rev Pharmacoecon Outcomes Res. 2012;12(3):319-333.

8. Jansen JP, Incerti D, Mutebi A, et al. Cost-effectiveness of sequenced treatment of rheumatoid arthritis with targeted immune modulators. J Med Econ. 2017;20(7):703-714.

9. Kalden JR, Schulze-Koops H. Immunogenicity and loss of response to TNF inhibitors: implications for rheumatoid arthritis treatment. Nat Rev Rheumatol. 2017;13(12):707-718.

10. Prado MS, Bendtzen K, Andrade LEC. Biological anti-TNF drugs: immunogenicity underlying treatment failure and adverse events. Expert Opin Drug Metab Toxicol. 2017;13(9):985-995.

11. den Broeder AA, van Herwaarden N, van den Bemt BJF. Therapeutic drug monitoring of biologicals in rheumatoid arthritis: a disconnect between beliefs and facts. Curr Opin Rheumatol. 2018;30(3):266-275.