Therapeutic Drug Monitoring Not Ready for Prime Time in Rheumatology
Common sense might dictate that, in maintaining health and wellness, being proactive is generally better than being reactive. But the practice of medicine often demands more than just common sense — it demands data and evidence to support clinical decision making. The discussion of therapeutic drug monitoring for biologic therapies hinges on this conundrum. Proactive monitoring appears to be the common-sense approach, but the data supporting its use have not yet closed the case.
In specialties such as gastroenterology, clinicians have been clamoring for increased use of proactive therapeutic drug monitoring (TDM) over the reactive protocols they currently use: A patient develops symptoms on a therapy, and the clinician assesses drug concentrations and antibody levels to help determine the next best step, whether increasing the dose of the drug or switching therapies.
Although some biologic therapies may bridge the rheum-GI specialties, the rheumatology community has not issued similar calls for greater TDM use, with some skeptics noting that the benefit does not yet outweigh the formidable costs.
“Rheumatologists do a lot less monitoring than gastroenterologists,” Daniel Aletaha, MD, chair of rheumatology in the department of medicine at MedUni Vienna/Vienna General Hospital in Austria, told Healio Rheumatology. “In gastroenterology, you may have two or three drugs for any given indication, and you have to use them wisely and based on all possible evidence. In rheumatology, we are far ahead of many other disciplines because of the number of drugs available. This allows us to cycle through therapies using a treat-to-target approach.”
Alfons A. den Broeder, MD, PhD, a rheumatologist-epidemiologist in the department of rheumatology at Sint Maartenskliniek and Radboud University Medical Center Nijmegen, in The Netherlands, added that while he believes that the idea of TDM in rheumatology is “attractive,” there are many hurdles to clear before it becomes standard practice. “The data do not show that it contributes to improved outcomes or quality of life, and there is a long turnaround time to get lab results, which can result in high costs,” he said. “Also, sensitivity and specificity outcomes remain very low.”
Indeed, TDM of any kind requires consideration of a number of variables, including timing of blood sampling to check serum concentrations; the route, dose, and mechanism of action of the drug being monitored; the accuracy of analyzing concentrations; and the clinical status of the patient, to name a few.
Despite these myriad factors, Adam Cheifetz, MD, director of the Center for Inflammatory Bowel Disease at Beth Israel Deaconess Medical Center, remains a strong supporter of proactive TDM. “With biologics in particular, it is critical,” he said, noting that both rheumatology and gastroenterology are increasingly relying on biologic and biosimilar therapies. “If the patient gets too little medication, the drugs are ineffective. Additionally, low drug concentrations are associated with immunogenicity and loss of response.”
At the moment, drugs like infliximab (Remicade, Janssen) and adalimumab (Humira, AbbVie) have been studied to a reasonable extent for TDM outcomes. However, ustekinumab (Stelara, Janssen), vedolizumab (Entyvio, Takeda) and others are only just beginning to undergo rigorous investigation. It is difficult, then, to make any sort of generalizations about the efficacy of TDM in rheumatology.
Moreover, there are disease-specific issues to consider, and factors associated with patient selection, because a one-size-fits-all approach is likely not going to work. Also, some clinicians argue for proactive TDM, which is to monitor drugs immediately upon initiating first-line therapy, while others prefer reactive monitoring, which calls for monitoring levels in second-line treatment, after the patient has failed on one drug.
It is a multifactorial equation with more questions than answers regarding proactive TDM. But if more data supporting its use emerge, that tide may turn.
A watershed moment for proactive TDM was the TAXIT trial, which was conducted by Vande Casteele and colleagues. The 1-year randomized controlled trial included 263 adults with IBD who had stable responses to maintenance infliximab. Researchers aimed to escalate or reduce doses to reach a target trough concentration of 3 g/mL to 7 g/mL in all patients.
Seventy-six patients (91%) with trough concentrations less than 3 g/mL achieved the target trough concentration after dose escalation. This resulted in a higher proportion of patients with Crohn’s disease in remission than before dose escalation (88% vs 65%; P = .02).
Cheifetz believes these findings are extremely encouraging, but he also understands that other experts may have reservations. “They took patients with Crohn’s or [ulcerative colitis] who were in remission or stable clinical response and then checked drug concentrations,” he said. “It was only after they put everybody in a therapeutic window that they randomized them to proactive or reactive TDM. This design issue is why the study did not reach its primary endpoint. However, despite this flaw, many secondary endpoints favored continued proactive TDM.”
In short, because patients in the cohort were already in stable condition, it may be difficult to draw the conclusion that proactive TDM is clearly superior to reactive.
Another key data set cited by TDM proponents is the PANTS cohort study, conducted by Kennedy and colleagues, which demonstrated that week 14 infliximab levels greater than 7 µg/mL and adalimumab drug levels greater than 12 µg/mL were associated with clinical remission at weeks 14 and 54.
The proportion of patients who developed anti-drug antibodies was 62.8% for infliximab and 28.5% for adalimumab. For both therapies, suboptimal week 14 drug concentrations predicted immunogenicity, and the development of anti-drug antibodies predicted subsequent low drug concentrations.
“Though most of the data to date are in the maintenance phase, proactive TDM is most important during induction and post-induction,” Cheifetz said. “That is when patients are sickest and have the highest drug clearance. This is when patients are most likely to have sub-therapeutic drug concentrations.”
Aline Charabaty, MD, director of the Inflammatory Bowel Disease Center and clinical director of the division of gastroenterology at Johns Hopkins Sibley Memorial Hospital, agrees that, “early post-induction is likely the best time to get drug levels, so that therapy can be optimized early and effectively to maximize chances of achieving and maintaining remission.”
Given the encouraging results of these trials, it is not hard to imagine that more trials with similar outcomes will emerge in the coming years. Meanwhile, clinicians must try to make sense of retrospective analyses and review articles showing that higher drug levels early after induction and during maintenance were associated with clinical, biologic and endoscopic remission. Of concern for rheumatologists is that many of these studies can be somewhat less encouraging.
One such paper was published by den Broeder and colleagues, who performed an exhaustive review of TDM in rheumatoid arthritis. They found that available published data sets were rife with poor study designs, false positives due to lack of validation, “cherry picking” of trials and faulty interpretation of test characteristics.
“On the basis of current evidence, therapeutic drug monitoring of biologicals cannot be recommended in the treatment of rheumatoid arthritis patients,” they wrote.
“I reviewed all the reviews, and the evidence is not there,” den Broeder said, noting that the group found zero trials looking at TDM of any kind vs. currently approved standard of care in a head-to-head matchup. “Most reviews conclude that there is no evidence in favor of TDM.”
Clinical trial design is very complicated, den Broeder acknowledged. “But many of these trials conclude that TDM should be used, regardless of the study design or what the data are saying,” he said. “These conclusions are flawed.”
In a review by Van Herwaarden and colleagues, in which den Broeder was also an investigator, biologic DMARDs in RA and the spondyloarthropathies underwent analysis. They concluded that the limited available evidence frequently fails to report diagnostic information such as sensitivity and specificity. “In most clinically relevant scenarios, predictive value of serum (anti-) drug levels is absent, therefore the use of TDM of [biologic] DMARDs cannot be advocated,” they wrote. “Well designed prospective studies should be done to further investigate the promising scenarios to determine the place of TDM in clinical practice.”
For Marla C. Dubinsky, MD, chief of pediatric gastroenterology and hepatology and co-director of the Susan and Leonard Feinstein IBD Clinical Center at Mount Sinai Hospital, drug-specific questions also must be answered, and they must be answered for every therapy on the market. “TDM, in theory, can be done for all biologics and agnostic to any previous exposure,” she said. “But getting the dosage right is critical for all biologics. We have the most exposure response data for the anti-TNF drugs. More work needs to be done to understand the exposure response for non-TNF biologics.”
The frequency with which drug levels should be checked during the maintenance phase after the patient is in clinical and/or endoscopic remission is another question that remains unanswered. The research community is zeroing on answers to some of these questions for infliximab and adalimumab, but if there is another central argument against proactive TDM, it is that few studies have been conducted in other drugs.
Beyond Infliximab, Adalimumab
Waqqas Afif, MD, associate professor of medicine in the division of gastroenterology at McGill University Health Center and GI Site Director at Montreal General Hospital, aimed to rectify the shortage of data for drugs other than infliximab and adalimumab. His group published a review article on the available data on TDM with ustekinumab and vedolizumab.
During maintenance therapy for ustekinumab, drug concentrations of greater than 1µg/mL were associated with improved outcomes, while for vedolizumab there was an association of improved outcomes with concentrations of 5 µg/mL to 11 µg/mL.
“From the pivotal clinical trials of [ustekinumab] and [vedolizumab], we know that during maintenance treatment there is an association between drug concentrations and clinical and endoscopic remission,” Afif said in an interview. “It is important to note that these concentrations are just associations and not an absolute threshold concentration of drug that clinicians should target.”
In the setting of loss of response, dose optimization when concentrations are lower may be of benefit, Afif added. “What is important to note is that the rates of antibody formation with these newer biologic medications are much lower — approximately 10% for vedolizumab and less than 5% for ustekinumab — than we see with anti-TNF medications like infliximab and adalimumab, so TDM testing to detect antibodies for ustekinumab and vedolizumab may be less important,” he said.
In another key data set involving these two drugs, Plevris and colleagues found that a post-induction vedolizumab trough level more than 18 µg/mL was associated with mucosal healing within the first year of therapy. A post-induction ustekinumab trough greater than 3.3 µg/mL was associated with clinical remission.
Regarding therapies such as golimumab (Simponi, Janssen) and certolizumab (Cimzia, UCB), Afif said that the data are limited. “Tofacitinib is a small molecule medication and there is no antibody formation,” he added. “Drug clearance is stable across patients, so TDM will not be helpful.”
Barriers to TDM
The lack of convincing data supporting TDM in many drugs in the rheumatology armamentarium is not the only barrier to uptake. “TDM is an area where experts interpret the available evidence differently and, therefore, disagree on whether proactive TDM should be broadly applied,” Michael J. Rosen, MD, medical director of the Schubert-Martin Inflammatory Bowel Disease Center at Cincinnati Children’s Hospital Medical Center, told Healio Rheumatology. “So, the lack of consensus in the field is an obstacle to uptake.”
Insurance coverage can also be problematic, both for clinical and administrative reasons. “For some reason, proactive monitoring is listed by insurance carriers as ‘experimental’ for most patients despite the cost savings associated with precision dosing,” Dubinsky said.
Although Rosen stated he routinely uses proactive TDM in his own practice, he acknowledged it may add to the administrative workload for many clinicians. “It is simply more work to order, interpret and respond to levels on many patients on a regular basis,” he said.
But there are solutions to this particular set of challenges, according to Dubinsky. “It is a matter of educating third party payers to benefits in outcomes,” she said. “Specifically, they need to understand that proactive monitoring keeps patients on drug longer and requires less health care utilization.”
However, whether monitoring truly keeps patients on drug longer is a question mark for Aletaha. “If a patient is nonadherent to one drug, they are likely to be nonadherent to the next one,” he said. “This is a problem that must be dealt with on its own and monitoring alone does not necessarily help.”
Cost of TDM laboratory analysis was at the top of Charabaty’s list of obstacles, along with wait time to get results. “This limits the ability to make immediate, quick decisions regarding drug optimization in our sicker patients,” she said.
This brings the discussion to patient-level questions that remain unanswered. “Most studies looked at the optimal drug level during induction or early maintenance, when the disease is active,” Charabaty said. “Would that be the same drug level we need to keep once the patient is in endoscopic remission for more than a year? Do we need a lower drug level to maintain remission in patients in stable remission?”
At the heart of the issue is that there is no consensus on what exactly makes a therapeutic drug level, according to Charabaty. “We know that our target drug levels are different during induction and early maintenance, for luminal Crohn’s and perianal disease” she said. “It could also vary between early maintenance and long-term maintenance. In addition, target drug level could vary between individuals, and might be different in a patient who is on their first biologic vs. a patient with history of loss of response to several therapies.”
Target drug level might also be different based on disease behavior, severity and phenotype, and it might be different in patients at higher risk for disease progression and surgery, according to Charabaty. “Overall, we need more data on what a personalized target level should be, at different times of the disease process, before we can justify having proactive TDM standard of practice,” she said.
For Aletaha, the utility of TDM hinges on the nature of inflammation. “Gastroenterologists are often dealing with diseases with a lot of variability in the target site occurrence,” he said. “If you have a bowel with a large mass of inflammation, a standard dose may not lead to a response, regardless of the body weight of the patient.”
In arthritis, however, the target organs — the joints — can be examined clinically, and inflammation can be easily seen. “This makes it much easier to adjust doses without costly monitoring,” Aletaha said.
Regardless of the specialty, the future of TDM is uncertain. For Charabaty, at the current state, it is a matter of patient selection. “I recommend proactive TDM for patients who are likely to clear the drug faster, those with extensive or severe disease burden, with high CRP and low albumin levels,” she said. “Patients who might require higher drug levels to achieve response — such as perianal Crohn’s disease — are also candidates, as are those who have a disease that is difficult to control or who have failed or lost response to more than one biologic.”
The data support many of these recommendations, according to Cheifetz, and he is happy to spread the word. “I do not know what it is going to take to get more widespread use of proactive TDM,” he said. “I will say that I have seen a huge change over the last 5 years. People are talking about it, and when I talk to people about it, it makes sense to them.”
With common sense arguments in mind, Aletaha entertained the idea of TDM with use of synthetic drugs in rheumatology. “Some of these drugs have a poor or unreliable bioavailability, so it could be used to make sure there is a sufficient amount in the bloodstream,” he said. “Testing this noninvasively would be the best approach, but that is not currently possible.”
Ultimately, den Broeder continues to urge clinicians to separate common sense from hard data. “There is a lobby of people who believe in TDM, in good faith, I might add,“ he said “I like the idea of measuring concentration, but as we speak, in the rheumatologic diseases, there is no clear case for any context in which it would say anything about efficacy or side effects in any patients. The contexts in which it could really be helpful are few and far between.” – by Rob Volansky and Ryan McDonald
- den Broeder A, et al. Curr Op Rheum. 2018;doi: 10.1097/BOR.0000000000000487.
- Kennedy NA, et al. Lancet Gastro Hep. 2019;doi:10.1016/S2468-1253(19)30012-3.
- Vande Casteele N, et al. Gastroenterology. 2015;doi:10.1053/j.gastro.2015.02.031.
- Van Herwaarden N, et al. Expert Opinion on Drug Metabolism & Toxicology. 2017;doi:10.1080/17425255.2017.1353602.
- Verdon C, et al. Gastroenterology. 2019;doi:10.1016/S0016-5085(19)39815-4.
- For more information:
- Waqqas Afif, MD, can be reached at 1560 Cedar Ave., C7-200, Montreal, Quebec, Canada H3G 1A4; email: email@example.com.
- Daniel Aletaha, MD, PhD, can be reached at Waehringer Guertel 18-20, 1090 Vienna, Austria; email: firstname.lastname@example.org.
- Aline Charabaty, MD, can be reached at 5255 Loughboro Rd. NW, Washington, DC 20016; email: email@example.com.
- Adam Cheifetz, MD, can be reached at 330 Brookline Ave., Boston, MA 02215; email: firstname.lastname@example.org.
- Alfons A. den Broeder, MD, PhD, can be reached at Hengstdal 3, 6574NA Ubbergen, The Netherlands; email: email@example.com.
- Marla Dubinsky, MD, can be reached at 17 East 102nd St., 5 floor, Area D New York, NY 10029; email: firstname.lastname@example.org.
- Michael J. Rosen, MD, can be reached at 3333 Burnet Ave., MLC 2010, Cincinnati, OH 45229; email: email@example.com.
Disclosures: Afif reports being on the advisory board or speaking for AbbVie, Janssen, Merck, Novartis, Pfizer, and Takeda, and receiving research support from AbbVie, Janssen, Prometheus and Theradiag. Aletaha and den Broeder report no relevant financial disclosures. Charabaty reports being on an advisory board or speaking for AbbVie, Janssen, and Takeda. Cheifetz reports consulting for AbbVie, Grifols, Janssen, Pfizer, Prometheus, and Takeda; research from Inform Diagnostics. Dubinsky reports consulting for AbbVie, Arena, Boehringer Ingelheim, Genentech, Gilead, Janssen, Pfizer, Projections Research, Takeda, and UCB; and being co-founder of Cornerstones Health and MiTest Health. Rosen reports a research collaboration with Prometheus Laboratories Inc.