Thank you for your interest in CCO content. As a guest, please complete the following information fields. These data help ensure our continued delivery of impactful education.
Become a member (or login)? Member benefits include accreditation certificates, downloadable slides, and decision support tools.
Chief of Pediatric Gastroenterology and Nutrition
Co-Director, Susan and Leonard Feinstein IBD Clinical Center
Icahn School of Medicine
Mount Sinai, New York
Marla Dubinsky, MD, has disclosed that she has received consulting fees from AbbVie, Arena, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, F. Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Lilly, Pfizer, Prometheus, Takeda, and UCB; funds for research support from AbbVie, Janssen, Pfizer, and Prometheus; has ownership interest and intellectual property rights in Trellus Health; and has received other financial or material support from Takeda.
Dr. Burrill B. Crohn Professor of Medicine
Chief of the Dr. Henry D. Janowitz Division of Gastroenterology
Mount Sinai Hospital
Chief, Division of Gastroenterology
Mount Sinai Health System
Director, Digestive Disease Institute
Icahn School of Medicine at Mount Sinai
New York, New York
Bruce E. Sands, MD, MS, AGAF, has disclosed that he has received consulting fees from 4D Pharma, Abivax, AbbVie, Alimentiv, Allergan, Amgen, Arena, AstraZeneca, Bacainn, Boehringer-Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Calibr, Capella, Celgene, Celltrion, ClostraBio, Enthera, F. Hoffmann-La Roche, Ferring, Galapagos, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Immunic, Index, Innovation, Ironwood, Janssen, Kaleido, Kallyope, Lilly, MiroBio, Morphic, Oppilan, OSE, Otsuka, Palatin, Pfizer, Progenity, Prometheus, Protagonist, Q32 Bio, Redhill, Rheos, Salix, Seres, Shire, Sienna, Sun Pharma, Surrozen, Takeda, Target PharmaSolutions, Teva, Thelium, Theravance, TLL Pharma, USWM Enterprises, Ventyx, Viela Bio, Vivante, and Vivelix; funds for research support from Janssen, Pfizer, Takeda, and Theravance; and has ownership interest in Ventyx and Vivante.
Among the key tools for therapeutic drug monitoring, particularly for anti‑TNF agents, are clinical assays that measure serum levels of both the drug and antidrug antibodies (ADAs)—but not all assays are the same.
Measuring Drug Levels
From the perspective of measuring anti-TNF drug levels, the assays are more alike than different. From assay to assay, you can look at drug levels and essentially know whether the serum drug concentration is in a good range. They match up pretty well.
Some would say that—the current drug level (typically, at the trough)—is ultimately what you need to know. However, decisions informed by drug levels must be made in the context of other clinical parameters, including inflammation and ADA levels, and measuring ADAs is where these assays differ most.
Measuring ADA Levels
There are different methodologies to measure ADA levels, including enzyme-linked immunosorbent assay (ELISAs), electrochemiluminescence immunoassays (ECLIAs), and homogenous mobility shift assays (HMSAs), but—of importance—some are drug tolerant and others are not. Drug‑tolerant assays can accurately measure ADAs in the presence of drug, whereas drug intolerant assays cannot. It follows that there is intertest variability in what levels of ADAs are considered below a certain threshold. We suggest learning to use 1 or 2 assays well so that, over time, you understand the meaning of the results. However, in practice, you cannot directly translate an ADA concentration readout from one assay to another.
Interpreting Assay Results
Identifying a low titer of ADAs in the presence of detectable drug can be difficult to interpret. There is some evidence that the detection of ADAs, even in the presence of circulating drug, portends a loss of response over time and is associated with high levels of inflammation already present—for example, as measured by C-reactive protein. It could be that the ADA level will rise higher over time and that the drug level could then drop, leading to a loss of response. In that circumstance, you might consider intervening proactively to inhibit the low‑titer ADAs, such as by adding an immunomodulator, adjusting the dosing frequency, or increasing the dose.
On the other hand, the ADAs could be non-neutralizing, such that they do not hinder therapeutic activity of the drug, and presumably they are clinically insignificant. Indeed, in the phase IIIb SEAVUE trial of ustekinumab vs adalimumab in patients with moderate to severe Crohn disease, patients in the adalimumab arm had considerably higher rates of ADAs than those in the ustekinumab arm (>60% vs 2%). Yet, there was no significant difference in the efficacy of the 2 drugs. Hence, the assay used for adalimumab (which was highly sensitive) probably was not detecting neutralizing antibodies. Moreover, regarding ustekinumab, it is worth mentioning that we are uncertain of the role of testing for ADAs with this and other non–anti‑TNF drugs.
Low levels of antibodies detected by non–radio-labeled liquid-phase mobility shift assays merit more exploration. However, if there is measurable drug, the antibodies most likely are not neutralizing.
Do you routinely monitor ADA levels in patients with inflammatory bowel disease who are receiving anti-TNF biologics? Answer the polling question and join the discussion by posting a comment.