Therapeutic drug monitoring does not improve remission for patients starting infliximab

November 06, 2020

ATLANTA -- New research presented at ACR Convergence, the American College Rheumatology's annual meeting, showed that patients with rheumatic diseases whose infliximab treatment was individually assessed and adjusted with a new strategy called therapeutic drug monitoring did not achieve remission at higher rates compared to those who received standard care. (ABSTRACT #2029)

Tumor necrosis factor inhibitors (TNFi) are drugs approved for treatment of rheumatoid arthritis, psoriatic arthritis and other inflammatory conditions. They are part of a class of drugs called biologic disease-modifying anti-rheumatic drugs, or biologics. TNFi drugs may help patients lower their disease activity, relieve debilitating symptoms, and manage their condition long term.

Some patients experience a lack or loss of response to TNFi, possibly due to low serum drug levels and or the formation of anti-drug antibodies. Therapeutic drug monitoring is one proposed strategy to prevent loss of response and to optimize TNFi effectiveness. It is an individualized strategy that includes regular assessments of a patient's serum drug levels. This personalized monitoring can be time-consuming and costly, and it is unclear whether it actually improves clinical outcomes. To learn more, researchers in Norway launched the first open-label, multi-center, randomized, controlled trial to assess its effectiveness in achieving remission in patients with several inflammatory diseases.

"Based on observational data showing associations between serum drug levels and effectiveness, we believed that individual treatment, with optimizing drug levels and early identification of anti-drug antibodies, would optimize the efficacy, safety and cost effectiveness of TNFi therapy," says the study's principal author, Silje Watterdal Syversen, MD, PhD, a rheumatologist at Diakonhjemmet Hospital in Oslo, Norway.

Adults with rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, ulcerative colitis, Crohn's disease and psoriasis who were starting infliximab therapy were recruited for the study. Patients were randomly assigned to receive infliximab either with or without therapeutic drug monitoring. They were examined at each infusion visit. The study's primary endpoint was remission at week 30. The study included 411 patients from 21 medical centers between January 2017 and December 2018: 80 with rheumatoid arthritis, 42 with psoriatic arthritis, 117 with spondyloarthritis, 80 with ulcerative colitis, 57 with Crohn's, and 22 with psoriasis. The researchers included 198 patients in the therapeutic drug monitoring arm and 200 patients were included in the control group. Researchers also recorded any adverse events the patients experienced, such as infections or infusion reactions.

According to their results, therapeutic drug monitoring was not superior to standard treatment for achieving disease remission at 30 weeks in people with a range of rheumatic diseases. In the study's therapeutic drug monitoring arm, 100 or 53% of patients achieved remission, while 106 or 54% of the patients in the standard treatment group also achieved remission. The study also found that 10% of patients who had therapeutic drug monitoring and 15% of patients receiving standard treatment developed significant levels of anti-drug antibodies. Adverse events were similar for both treatment groups as well, but infusion reactions were less frequent in patients who received therapeutic drug monitoring.

"Our study does not support therapeutic drug monitoring be applied as a general treatment strategy during induction of infliximab. Despite a lack of clinical trial data and diverging guidelines, proactive therapeutic drug monitoring has already been adopted in clinical practice across different specialities. This study highlights the need for thorough evaluation of monitoring tools and treatment strategies before their implementation in clinical care," says Dr. Syversen. "We feel that our results put to rest a long-standing debate on the merits of using therapeutic drug monitoring in all patients starting TNFi."

Future research should explore if more targeted applications of therapeutic drug monitoring, such as assessment of serum drug levels in treatment failures, could be a useful clinical tool, she adds.
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About ACR Convergence

ACR Convergence, the ACR's annual meeting, is where rheumatology meets to collaborate, celebrate, congregate, and learn. Join ACR for an all-encompassing experience designed for the entire rheumatology community. ACR Convergence is not just another meeting - it's where inspiration and opportunity unite to create an unmatched educational experience. For more information about the meeting, visit https://www.rheumatology.org/Annual-Meeting, or join the conversation on Twitter by following the official hashtag (#ACR20).

About the American College of Rheumatology

The American College of Rheumatology (ACR) is an international medical society representing over 7,700 rheumatologists and rheumatology health professionals with a mission to empower rheumatology professionals to excel in their specialty. In doing so, the ACR offers education, research, advocacy and practice management support to help its members continue their innovative work and provide quality patient care. Rheumatologists are experts in the diagnosis, management and treatment of more than 100 different types of arthritis and rheumatic diseases.

ABSTRACT:

Therapeutic Drug Monitoring Compared to Standard Treatment of Patients Starting Infliximab: Results from a Multicenter Randomized Controlled Trial of 400 Patients

Background/Purpose:

A lack or loss of response to TNFα inhibitors (TNFi) has been associated with low serum drug levels and formation of anti-drug antibodies (ADAb). Therapeutic drug monitoring (TDM), an individualized treatment strategy based on regular assessments of serum drug levels, has been suggested to optimize efficacy of TNFi. It is still unclear if TDM improves clinical outcomes, and the value of TDM has recently been included in the research agenda across different specialties. This first randomized controlled trial on the effectiveness of TDM in a range of immune mediated inflammatory diseases including rheumatic diseases, the NORwegian DRUg Monitoring trial part A (NOR-DRUM (A)) focus on the induction period of infliximab (INX) treatment and aim to assess if TDM is superior to standard treatment in order to achieve remission.

Methods:

In the investigator-initiated, randomized, open-label, multicenter NOR-DRUM (A) study, adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), spondyloarthritis (SpA), ulcerative colitis (UC), Crohn's disease (CD) and psoriasis (Ps) starting INX therapy were randomly assigned administration of INX according to a treatment strategy based on TDM (TDM arm) or to standard administration of INX without TDM (control arm). Study visits were conducted at each infusion. The primary endpoint was remission at week 30. In the TDM arm, the dose and interval were adjusted according to INX trough levels to reach the therapeutic range (Figure 1). If the patient developed significant levels of ADAb, INX was terminated. To guide the investigators, the TDM strategy was integrated in an interactive eCRF. The primary endpoint was analysed by mixed effect logistic regression in the full analyses set (FAS), adjusting for diagnoses. Infections and infusion reactions were specified as adverse events (AEs) of special interest.

Results:

We enrolled 411 patients at 21 study centers between January 2017 and December 2018. 398 patients (RA 80, PsA 42, SpA 117, UC 80, CD 57, Ps 22) received the allocated strategy and were included in the FAS population. Demographic and baseline characteristics were comparable in both arms. TDM was not found to be superior to standard treatment with regard to the primary outcome. Remission at week 30 was reached in 100 (53%) and 106 (54%) of the patients in the TDM and control arm, respectively (adjusted difference, 1.5%; 95% confidence interval (CI), -8.2 to 11.1, p=0.78) (Figure 2). Consistent results were shown for all the secondary endpoints (Figure 3) and in the sensitivity analyses. Twenty patients (10%) in the TDM arm and 30 patients (15%) in the control arm developed significant levels of ADAb. The number of adverse events (AE) was similar in both groups, however infusion reactions were less frequent (5 patients (2.5%) vs 16 patients (8.0%)) in the TDM arm (difference 5.5% (95% CI 1.1, 9.8%))

Conclusions:

NOR-DRUM (A) is the first randomized trial to address effectiveness of TDM in rheumatic diseases. In this study, TDM was not superior to standard treatment in order to achieve remission. Although improved safety is indicated by a reduction in infusion reactions, implementation of TDM as a general strategy in the induction period of INX is not supported by the NOR-DRUM (A) study.

American College of Rheumatology

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