Therapeutic drug monitoring not superior to standard of care in achieving remission
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Therapeutic drug monitoring, in which treatments were individually assessed and reviewed, failed to improve remission for patients with a variety of rheumatic diseases who started infliximab, according to a speaker at ACR Convergence.
“The clinical utility of therapeutic drug monitoring — or TDM — for biological drugs is a current debate,” Silje Watterdal Syversen, MD, PhD, of Diakonhjemmet Hospital, in Oslo, Norway, said during a press conference at the virtual meeting. “Infliximab and TNF inhibitors have revolutionized the treatment of a number of chronic immune-mediated inflammatory diseases, including rheumatic disease such as rheumatoid arthritis, spondyloarthritis and psoriatic arthritis, but also inflammatory bowel disease and skin psoriasis. Clinical remission has, as you all know, been an achievable treatment goal.”
“Still, there is a significant proportion of patients who either do not respond or lose their response to therapy, and this failure to achieve disease control has had a major impact on patients’ quality of life, and put them at risk of developing damage and disability,” she added. “So, strategies to optimize treatment with TNF inhibitors are still needed. In addition, observational data indicate a considerable individual variation in serum drug levels with infliximab and other TNF inhibitors, suggesting that patients are both over- and under-dosed; there are associations between serum drug levels and effectiveness.”
According to Syversen, an individualized treatment strategy based on therapeutic drug monitor has been proposed as an approach to optimize efficacy as well as the safety and cost effectiveness of TNF inhibitors.
“Proactive TDM, namely dosing of the drug according to regular assessments of serum drug levels, as to some extent been adopted into clinical practice across specialties,” she said. “However, to date, there have been no studies showing that TDM is really improving clinical outcomes. And in this era of increased use of TNF inhibitors, recommendations for the use of proactive TDM differ considerably.”
To analyze the effectiveness of therapeutic drug therapy in achieving remission among patients with a range of rheumatic diseases, Syversen and colleagues launched the open-label, multi-center, randomized, controlled NOR-DRUM Part A trial. Between January 2017 and December 2018, the researchers enrolled 411 adult participants from 21 centers, including 80 with rheumatoid arthritis, 42 with psoriatic arthritis, 117 with spondyloarthritis, 80 with ulcerative colitis, 57 with Crohn’s disease and 22 with psoriasis. All participants started the induction period with infliximab (Remicade, Janssen).
Patients were randomly assigned to receive infliximab in accordance with either therapeutic drug monitoring strategies or the standard of care. Doses and intervals in the therapeutic drug monitoring arm were adjusted according to infliximab trough levels, to reach the therapeutic range. Treatment was terminated if the patients developed significant levels of anti-drug antibodies. Study visits were performed at each infusion. The primary endpoint was remission at week 30. The researchers used mixed-effect logistic regression to analyze the primary endpoint in the full analyses set, adjusting for diagnoses.
According to the researchers, 53% of patients who received therapeutic drug monitoring achieved remission at week 30, compared with 54% of those in the standard administration group (adjusted difference = 1.5%; 95% CI, –8.2 to 11.1). In all, 10% of participants in the therapeutic drug monitoring arm, and 15% of those in the standard care group, developed significant levels of anti-drug antibodies. The number of adverse events was similar in both groups. However, infusion reactions were less frequent in the therapeutic drug monitoring group — 2.5% compared with 8% (difference = 5.5%; 95% CI, 1.1% to 9.8%).
“The NOR-DRUM Part A is to our knowledge the first randomized trial to address the effectiveness of TDM in rheumatic diseases,” Syversen said. “This study shows that TDM during induction of infliximab is not superior to standard treatment. Although the study indicates improved safety, by a reduction in infusion reactions, implementation of TDM as a general strategy in the induction period of infliximab is not supported by the data. We feel these results put stress on the longstanding debate about the merits of using therapeutic drug monitoring in all patients starting a TNF inhibitor.”
“Despite the lack of clinical trial data and diverging guidelines, TDM has already been adopted in clinical practice, and this study highlights that angle, so that, not only for drugs but also for monitoring tools and treatment strategies, the clinical utility needs to be thoroughly validated before it is implemented in clinical care,” she added. We are also running a second study — Part B of the NOR-DRUM — which is still ongoing, which is assessing TDM during the maintenance phase of infliximab therapy, and I believe these results will be even more applicable to TNF inhibitors that do not have an induction period.”
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Syversen SW. Abstract 2029. Presented at: ACR Convergence 2020; November 5-9, 2020 (virtual meeting).
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