A new study has found that proactive therapeutic drug monitoring (TDM) with maintenance infliximab is more effective than standard therapy in sustaining control of immune-mediated inflammatory diseases.
The findings from the trial, published December 21 in JAMA, called Norwegian Drug Monitoring B (NOR-DRUM B), provide greater support to the usefulness of TDM in proactively monitoring serum drug levels and antidrug antibodies to infliximab, which has been previously shown to have benefit in patients with inflammatory bowel disease, but leave the benefits of proactive vs reactive monitoring and the cost-effectiveness of the approach in individual immune-mediated inflammatory diseases still open to questioning.
TDM Is “‘Not the Holy Grail,” and That’s OK
“This is an important milestone in the field of TDM with biologics for immunoinflammatory diseases,” Niels Vande Casteele, PharmD, PhD, of the University of California, San Diego, told Medscape Medical News. He was not involved in the study.
Dr Niels Vande Casteele
“When you read through the study, you can see the authors used the TAXIT trial results to inform their study design and the sample size,” he added, referencing his 2015 study on infliximab guide dosing for patients with inflammatory bowel disease, “the first-ever randomized, controlled trial of proactive TDM with any biologic.”
For the TAXIT study’s primary outcome of clinical and biochemical remission at 1 year, “continued concentration-based dosing was not superior to clinically based dosing for achieving remission.” But in regard to their secondary outcome of sustained remission, their results were quite similar to the results of NOR-DRUM B.
“If anything, we already showed a benefit of proactive TDM in 2015,” he said, “but I’m very glad that the authors looked at the trial design and teased out where TDM could be the most important and have the biggest impact, which is to maintain that sustained disease remission over a prolonged period.”
As for next steps, Vande Casteele noted that TDM isn’t a one-size-fits-all upgrade for drug treatments. But that doesn’t mean it won’t be very useful in many patients.
“What the paper is saying, and what we’ve been finding all along, is that TDM is not the holy grail,” he said. “But it is a tool in the physicians’ toolbox to optimize treatments and maximize efficacy, and there are some patients who truly benefit from it.”
To determine if proactive TDM with infliximab led to more sustained disease control than standard therapy, first author Silje Watterdal Syversen, MD, PhD, of Diakonhjemmet Hospital in Oslo, Norway, and co-authors conducted a 52-week, randomized, parallel-group, open-label trial. From 20 Norwegian hospitals, they recruited 458 patients with rheumatoid arthritis (n = 80), spondyloarthritis (n = 138), psoriatic arthritis (n = 54), ulcerative colitis (n = 81), Crohn’s disease (n = 68), or psoriasis (n = 37) who were undergoing maintenance therapy with the biologic.
Dr Silje Watterdal Syversen
The 454 patients who received at least one randomly allocated dose of infliximab were treated with one of two strategies: TDM (n = 227) or standard therapy (n = 227). The TDM group received dose and interval adjustments based on an algorithm that factored in serum drug levels and antidrug antibodies. The standard therapy group was treated on the basis of clinical judgment and physician discretion. The average age across groups was roughly 45 years, and just under 50% were women.
Overall, sustained disease control without worsening was achieved in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group, with an estimated adjusted difference of 17.6% (95% CI, 9.0% – 26.2%; P < .001). The estimated hazard ratio of disease worsening was 2.1 (95% CI, 1.5 – 2.9) for standard therapy, compared with TDM. A total of 27 patients (15%) in the standard therapy group and 21 patients (9.2%) in the TDM group developed significant levels of antidrug antibodies, defined here as 50 μg/L or more.
Thirty-four patients discontinued infliximab in each group; in the TDM group, most discontinued because of antidrug antibody formation, while the main reason for discontinuing in the standard therapy group was disease worsening. Adverse events were reported in 137 patients (60%) in the TDM group and 142 patients (63%) in the standard therapy group.
Removing Barriers to TDM
It’s not clear that proactive TDM will benefit treatment with all biologic disease-modifying antirheumatic drugs (bDMARDs), but the findings from Syversen and colleagues state the clear value of using drug monitoring to guide maintenance therapy with infliximab, Zachary S. Wallace, MD, and Jeffrey A. Sparks, MD, write in an accompanying editorial.
Dr Zachary Wallace
“The relatively large sample size and rigorous study design…helped to overcome some limitations of previous observational studies and small clinical trials that yielded conflicting results regarding TDM,” they add, noting that these findings contrasted somewhat with the NOR-DRUM A trial in which TDM did not improve remission induction in patients initiating infliximab therapy.
Dr Jeffrey Sparks
Along those lines, they recognized that TDM appears to have a greater effect in patients on maintenance infliximab compared with those just starting the drug, surmising ― among several explanations ― that achieving remission in someone beginning treatment is a more difficult outcome to achieve than controlling disease in a patient already in remission.
For now, more clinical trials assessing specific diseases and involving other bDMARDs are needed; Wallace and Sparks state that it’s time to remove barriers to implementing TDM ― including the need for medical insurance preauthorization before increasing drug doses ― and potentially “introduce a new era in treatment approach to maintenance therapy for patients with immune-mediated inflammatory diseases.”
The authors acknowledge their study’s limitations, including disease worsening being measured in part by patient-physician consensus and thus potentially subject to bias. In addition, they did not have the statistical ability to test TDM effectiveness in each of the six disease groups, noting that “these diseases have inherent differences, and findings may not be completely generalizable across groups.”
The study was funded by grants from the Norwegian Regional Health Authorities and the South-Eastern Norway Regional Health Authorities. The authors reported numerous potential conflicts of interest, including receiving personal fees and grants from various pharmaceutical companies. Wallace and Sparks also reported receiving research support and fees from pharmaceutical companies. Vande Casteele reported receiving research grants and personal fees from multiple pharmaceutical companies, all outside of the reviewed work.
JAMA. 2021 Dec 21. doi: 10.1001/jama.2021.21316.
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