Proactive therapeutic drug monitoring relies on laboratory testing of antibodies and other markers

Tumor necrosis factor (TNF) inhibitors and other biologic agents have improved outcomes for common chronic immune-mediated inflammatory diseases such as ulcerative colitis and Crohn’s disease. But treatment failures after initial response are common, and they often result in organ damage and disability.

To prevent this, some clinicians try therapeutic drug monitoring (TDM). Reactive TDM involves measuring serum drug levels and the presence of anti-drug antibodies (ADAs) in response to evidence of active disease. In contrast, proactive TDM aims to optimize drug concentrations through scheduled assessments of serum drug levels and ADAs. While reactive TDM is included in clinical guidelines, multiple studies have found no benefit for proactive TDM.

The recent Norwegian Drug Monitoring (NORDRUM) trial, however, shows that proactive TDM for maintenance infliximab better sustains control of multiple immune-mediated inflammatory diseases than standard therapy (JAMA 2021;326:2375-84). “This paper is the first to show you can improve patient outcomes by doing proactive TDM,” said Maria Alice Willrich, PhD, DABCC, FAACC, consultant and associate professor of laboratory medicine and pathology at Mayo Clinic in Rochester, Minnesota. If findings are replicated, labs could see increased demand for this biologics testing.

Experts say proactive TDM involves tackling several factors, including choice of quantitative assay, trough level testing, and difficulty measuring ADAs, which are associated with increased risk of infusion reactions and decreased duration of response.

New Data in Focus

The recent study details the second NORDRUM trial of proactive TDM. The first trial examined proactive TDM during infliximab induction and found it did not significantly improve remission rates over 30 weeks (JAMA 2021;325:1744-54). The more recent paper examined rates of sustained control during maintenance therapy in 458 patients with autoimmune diseases at 20 hospitals in Norway. These conditions were ulcerative colitis, Crohn’s disease, rheumatoid arthritis, spondylarthritis, psoriatic arthritis, and psoriasis.

The proactive TDM group had dose and interval adjustments based on an algorithm of serum drug levels and ADAs measured by immunoassay. The standard therapy was based on clinician judgement and discretion.

The sustained disease control rate was 73.6% in the proactive TDM group, compared with 55.9% in the standard therapy group. The estimated hazard ratio of disease worsening was 2.1 for standard therapy, compared with TDM. Fifteen percent of standard therapy patients and 9.2% of TDM patients developed significant levels of ADAs, defined as 50 μg/L or more. Rates for discontinuing infliximab and adverse events were similar in
both groups.

“We recommend proactive TDM at least for infliximab in maintenance phase. We’re not sure if it’s a beneficial approach for other drugs. It should be tested in proper trials before making it standard of care,” said study coauthor Nils Bolstad, PhD, senior consultant and attending physician at Oslo University Hospital. He noted that proactive TDM already is a popular approach for Crohn’s disease, ulcerative colitis, and certain rheumatological and dermatological conditions in Norway, which he said has the necessary lab services widely available at low cost.

The second NORDRUM trial’s findings are not applicable beyond TDM for maintenance therapy with infliximab to other biologics, noted an editorial by Zachary S. Wallace, MD, MSc, and Jeffrey A. Sparks, MD, MMSc.

In an interview, Wallace called for further study of proactive TDM during maintenance of remission with infliximab in specific disease subgroups and TDM involving other biological disease-modifying antirheumatic drugs.

Another View

While reactive TDM is recommended in multiple national and international inflammatory bowel diseases (IBD) guidelines, only those from the Australian Inflammatory Bowel Diseases Consensus Working Group and the U.S.-based gastroenterology research group BRIDGe currently recommend the proactive approach. No rheumatology organization has taken a position on TDM, perhaps because its clinicians have more treatment options and can detect diseases’ damage more easily, Willrich noted.

Hans Herfarth, MD, PhD, professor of medicine and codirector of the UNC Multidisciplinary IBD Center at the University of North Carolina in Chapel Hill, does not believe the second NORDRUM paper will spur more proactive TDM for infliximab and other biologics. He noted the paper showed no difference in infliximab trough levels between the two study arms and involved a population with a mixture of autoimmune diseases.

While the study showed no differences in mean and median trough levels in the two study arms, the proactive TDM group had less variation in infliximab levels, which “were more focused in the assumed therapeutic range,” Bolstad said.

Herfarth remarked that a recent study comparing proactive and reactive TDM demonstrated no significant differences in drug persistence or overall maintenance of clinical remission (J Crohns Colitis 2022;16:199-206). Others that compared reactive TDM to dosing based on clinical symptoms or biomarkers found the proactive approach did not improve remission rates (Gastroenterology 2018;154:1343-51; Gastroenterology 2015;148:1320-9).

The pediatric PAILOT (Pediatric Crohn's Disease Adalimumab Level-based Optimization Treatment Trial) reported lower frequency of mild flares and less steroid exposure in its proactive TDM arm over 1 year, compared with its reactive TDM arm, but no difference in drug persistence or overall clinical remission (Gastroenterology 2019;157:985-96).

However, certain subgroups of patients on anti-TNF therapy may benefit from proactive TDM, Herfarth said. These include patients with an HLA-DQ1*05 allele that confers risk of developing low anti-TNF levels or ADAs, patients on a second anti-TNF therapy after loss of response to the first one, or patients on anti-TNF therapy in combination with thiopurines or methotrexate, who de-escalate to anti-TNF monotherapy.

Using TDM

Willrich suggested ways labs can encourage proper utilization of TDM tests. These include taking trough samples, providing timely test results to enable patient management decisions shortly after the draw for reactive TDM, offering interpretation to clinicians, and using reflex testing approaches when appropriate.

Willrich added that all U.S. tests for drug quantitation and ADAs are lab developed and require high complexity environments. While drug quantitation can be done via immunoassays or mass spectrometry, she prefers mass spectrometry. Unlike immunoassays, mass spec does not require creating an antidrug monoclonal antibody to be used as a capture or detection antibody as an additional reagent. For large labs that have the proper instrumentation and a high test volume, mass spec can be a cost-effective approach if they have access to the drug as a calibrator.

Europe has CE-marked ELISAs, so ELISA testing for drug quantitation is more common there, Willrich said. She also noted that ELISAs are easier to automate and compare very well if there is access to the drug as a calibrator. For smaller U.S. labs, label-free immunoassay strategies such as surface plasmon resonance and interferometry with similar accuracy claims may be an option for both drug quantitation and ADAs. Label-free technologies detect the change of physical parameters caused by antibody–antigen interaction rather than the signal from a reporter, resulting in real-time immunometric measurement.

Bolstad prefers immunoassays to mass spec, which requires anti-idiotype antibody or the drug target to isolate the active/unbound drug, lest the test detect inactive drug either bound to the drug target or neutralized by an anti-drug antibody.

Comparing ADA assays is very difficult because of variation in patients and lack of reference materials, Willrich and Bolstad agreed. Each lab uses different standards and units, so only qualitative comparison of ADA tests is possible. Bolstad recommends ADA assays that measure only antibodies that neutralize the drug.

In an interview, Wallace urged laboratorians to think about how to achieve a quick return of results to guide clinician decisions about infliximab because clinicians want to act on TDM test results quickly and then adjust the dose of the next infusion. Meeting this goal requires coordination between labs and decisions about how to interpret the results of drug levels measured at certain time points in a patient’s treatment cycle.

While Wallace also noted that providers may want to assess a level at a random point during a treatment cycle and might need help interpreting results, Willrich said that non-trough data assessment for biologics is different from and far more complex than for small molecule drugs that undergo liver and kidney metabolism.

Laboratorians must keep in close dialogue with clinicians using TDM of biologics and think about their complexities, Bolstad said. “Remember that biologics are different from most drugs. They are big, complicated molecules and are associated with adverse reactions, side effects, and complications related to measurements in the lab. Know the properties and limitations of assays in detail.

Deborah Levenson is a freelance writer in College Park, Maryland. Email: [email protected]