Professor of Pediatrics & Biochemistry and Molecular Medicine
Department of Pediatrics, Gastroenterology, Hepatology and Nutrition
USC Keck School of Medicine
Children's Hospital Los Angeles
Los Angeles, California
D. Brent Polk, MD, AGAF, has no real or apparent financial relationships to disclose.
At the 2019 Crohn’s & Colitis Congress in Las Vegas, Nevada, exciting new data on disease and drug monitoring were presented in a session reviewing reactive vs proactive approaches. Here, I discuss both this important session and real-world experience from the accompanying poster program.
In Crohn’s disease, evidence suggests that markers of inflammation—C-reactive protein (CRP) and fecal calprotectin (FC)—are elevated prior to relapse. In ulcerative colitis, an increase in FC is also a strong predictor of relapse.
Can these biomarkers guide treatment decisions? The recent CALM study examined this. It compared management by clinical symptoms alone, where TNF inhibitor dose escalation was based on CDAI and steroid use, to a treat-to-target approach, where dose escalation was based on clinical symptoms and levels of CRP and FC. After 48 weeks, the treat-to-target approach was associated with a higher percentage of patients meeting the primary endpoint (CDEIS < 4 and no deep ulcerations), suggesting that using disease monitoring with CRP and FC levels to guide treatment decisions can improve outcomes.
Proactive vs Reactive Therapeutic Drug Monitoring
For adults treated with anti-TNF agents, the American Gastroenterological Association (AGA) recommends reactive therapeutic drug monitoring (TDM) (ie, in patients with active IBD) to guide treatment changes, yet they make no recommendation regarding the use of proactive TDM (ie, in patients in remission), identifying this as an area without evidence. To address this knowledge gap, randomized studies of proactive TDM vs standard of care (reactive TDM) are needed.
Current evidence supporting the use of reactive TDM for managing patients with IBD is based on studies of anti-TNF therapies. Higher trough drug levels are associated with higher remission rates, and drug levels may be influenced by the presence of antidrug antibodies. In patients with low or no detectable antibodies, increases in drug dosing following TDM has been associated with higher response rates. Therefore, measuring drug levels and anti-TNF antibodies has been incorporated into the practice of many clinicians.
In the TAXIT study in patients with stable response on maintenance anti-TNF therapy, using a proactive TDM approach to optimize doses in those with subtherapeutic anti-TNF levels led to better control of Crohn’s disease. Other studies suggest that, compared with adults, pediatric patients may have a greater need for such dose intensification. Furthermore, findings reported at DDW 2018 suggest that proactive induction optimization is superior to postinduction drug optimization.
Personally, in order to recommend proactive TDM for all patients receiving biologics, or even just those receiving anti-TNF therapy, I would need to see demonstrated benefit in randomized, controlled trials where patients were matched for disease features. These studies would have to be long enough to discern the clinical, psychosocial, and financial impact compared with the standard reactive approach. Ideally, there would also be real-world demonstration that any benefits translated beyond highly selective clinical trials.
Real-World Experience With TDM
Although AGA recommendations on reactive TDM come from evidence with anti-TNFs, data on TDM with IL-12/23 inhibitors and integrin inhibitors are lacking. I was, therefore, glad to see 2 posters at the Crohn’s & Colitis Congress reporting results of TDM in the real-world setting for newer therapies: the IL-12/23 inhibitor ustekinumab (N = 46 patients with Crohn’s disease) and the integrin inhibitor vedolizumab (N = 49 patients with IBD).
Using a reactive TDM approach, more than half of the drug levels drawn were identified as low in each study. However, using a proactive approach, 90% of drug levels were identified as low in the ustekinumab study, and 38% of drug levels were identified as low in the vedolizumab study.
In both studies, higher trough levels of drug (> 5 μg/mL in the ustekinumab study and > 20 μg/mL in the vedolizumab study) were associated with lower markers of inflammation (erythrocyte sedimentation rate and CRP). In the vedolizumab study, these higher trough levels were also associated with higher endoscopic plus histologic remission rates.
These results suggest that TDM may have utility in optimizing drug levels and improving outcomes for patients receiving either of these newer therapies.
When do you use markers of inflammation to guide treatment and when do you use reactive or proactive TDM in your patients with ulcerative colitis or Crohn’s disease? Do you have experience with TDM in IL-12/23 inhibitors or integrin inhibitors? Share your thoughts in the Comments section below.