An increasing number of medications can be used to treat patients with inflammatory bowel disease (IBD). Newer agents include the anti-tumor necrosis factor (TNF)-α (adalimumab, infliximab [IFX]) class, an integrin inhibitor (vedolizumab [VDZ]), and an interleukin (IL)-12/23 inhibitor (ustekinumab [USK]). Outside of these biologic agents, additional options that are also sometimes used as monotherapy or in combination with biologics are immunomodulators (6-mercaptopurine, azathioprine) and a Janus kinase inhibitor (tofacitinib).
Once on medication, patients with IBD will typically undergo routine monitoring using a combination of testing that includes the following: C-reactive protein and fecal calprotectin, radiographic imaging (computed tomography or magnetic resonance imaging), and endoscopic procedures, such as colonoscopy. As many of the available agents have complex pharmacokinetic (PK) and pharmacodynamic properties, there has been a great deal of research interest in their monitoring over recent years.
In 2017, the American Gastroenterological Association (AGA) published a guideline for therapeutic drug monitoring (TDM) in patients with IBD.1 Therapeutic drug monitoring can be performed either proactively (when patients are considered to be in remission) or reactively (when there is a concern that a patient is not responding to treatment). For the most part, the AGA guidelines favor reactive TDM, with less evidence to support routine proactive TDM.
Therapeutic drug monitoring can help indicate if a medication is not working secondary to multiple mechanisms, including mechanistic failure and PK failure (nonimmune and immune).1,2 In mechanistic failure (≤~30%), the patient will have a therapeutic drug trough concentration with either detectable or undetectable antibodies (Abs).2 In this scenario, it is usually recommended to switch out of that therapeutic class, as that specific patient’s pro-inflammatory state may be primarily driven by another pathophysiologic pathway.
In non–immune-mediated PK failure (~51%), patients have subtherapeutic trough concentrations with undetectable Abs, which is consistent with rapid clearance of the medication.2 In this case, gastroenterologists can consider increasing the dose or decreasing the dosing interval.
Finally, in immune-mediated PK failure (~19%), there are detectable levels of Abs and subtherapeutic trough concentrations. In this situation, a dose increase can be considered if the Ab levels are low, or a change within the drug class with the addition of an immunomodulator in those patients with high Ab levels.
The 2017 AGA guidelines do provide goal trough concentrations for certain classes, such as anti–TNF-α agents. Examples include IFX trough levels >5 ug/mL and adalimumab trough levels ≥7.5 ug/mL. No trough level goals are provided for VDZ or USK. Therefore, it is important to note that not all medications used in IBD have TDM available. Even if TDM is available, there can still be barriers to access according to cost (especially if not covered by insurance) and availability of sites that conduct such testing. As the trough level is a critical component of TDM, the timing of samples has to be relatively precise, which may be difficult to coordinate with certain patients.
In addition, even if TDM is an option for a medication, there are often barriers with respect to insurance coverage that may make it challenging for patients to achieve. Therapeutic drug monitoring also can require that a patient obtain a trough level; therefore, the specific timing may also represent a barrier to routine use.
Although TDM has had a significant effect on IBD management, there are a lack of similar options that may assist in predicting which medication may be best for a patient and/or may be considered a responder. Being able to determine if a patient has a high risk for either a mechanistic or PK failure before starting a medication such as IFX would represent a significant improvement in overall patient care.
One area of research that may help advance this concept resides within the gut microbiome. The gut microbiome is complex within IBD, and its disruption may be one of the potential contributing factors in the pathogenesis of IBD.3 Using the patient’s gut microbiome to help choose the best medication could potentially help avoid complications and unnecessary testing, limit costs, and, most importantly, improve patient outcomes. Choosing the best medication for a patient is challenging, as anywhere between 40% and 50% of patients with IBD may not respond to medications such as IFX and/or lose their response over time.3 Some research indicates that the gut microbiome could be used in a predictive, as well as monitoring, role within IBD.
A group led by Ventin-Holmberg recently evaluated the effect of IFX on the gut microbiome and whether it could be used to predict response.3 The study was conducted in a prospective fashion at a single site in Helsinki, Finland. Researchers followed a total of 72 patients prospectively (47 with ulcerative colitis and 25 with Crohn disease) and analyzed stool samples for both bacterial and fungal species. They evaluated gut microbiome before IFX initiation, as well as at 2 weeks, 6 weeks, 12 weeks, and 1 year. Investigators measured “response” to IFX at 12 weeks, using colonoscopy as well as clinical findings.
At week 12, a total of 44 patients (62.9%) were responders, 12 (17.1%) were partial responders, and 14 (20%) were nonresponders (NRs); 52 patients (72.2%) were able to be evaluated at 52 weeks, with 15 patients discontinuing IFX between weeks 12 and 52. When compared with responders, patients in the NR group had significantly lower amounts of short chain fatty acid-producing bacteria, including Clostridia and higher amounts of pro-inflammatory species such as Candida. Responders were also more likely to have less variation in their microbiome. There was more variation in the microbiome composition in response groups in patients with Crohn disease compared against patients with ulcerative colitis.
Use of the gut microbiome both as “TDM” and/or a predictive model for safety and efficacy will certainly be a focus of future gastroenterology research. The study by Ventin-Holmberg et al does raise several important observations. If the gut microbiome can assist in choosing which patients may respond best to medications to IFX, it could become a routine part of a pretreatment algorithm that already includes labs, procedures, imaging, and stool studies. It will be interesting to see whether certain patients who are expected to be NRs to a medication could potentially be converted to responders by having their microbiomes altered with antibiotics and/or probiotics.
If responders eventually become NRs, the role of fecal microbiota transplantation could be evaluated in attempts at “salvaging” the medication and potentially avoiding costly and time-consuming changes to other medications.
The practicality of these specific stool tests may be limited to academic centers/tertiary care facilities that conduct research and may have limited access to the actual patient. Patients may also find it challenging to submit one more additional test, but if combined with other routine stool tests, the process may become less arduous. Costs of these highly specialized stool tests may also be prohibitive for many patients if not covered by insurance, which will likely be the case until literature supports more routine use. As the study by Ventin-Holmberg and colleagues only evaluated IFX, similar studies will need to evaluate medications in additional therapeutic classes, such as VDZ and USK.
1. Feuerstein JD, Nguyen GC, Kupfer SS, Falck-Ytter Y, Singh S. American Gastroenterological Association Institute guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterol. 2017;153(3):827-834.
2. Vande Casteele N, Herfarth H, Katz J, Falck-Ytter Y, Singh S. American Gastroenterological Association Institute technical review on the role of therapeutic drug monitoring in the management of inflammatory bowel diseases. Gastroenterol. 2017;153(3):835-857.e6.
3. Ventin-Holmberg R, Eberl A, Saqib S, et al. Bacterial and fungal profiles as markers of infliximab drug response in inflammatory bowel disease. J Crohns Colitis. Published online December 10, 2020. doi: 10.1093/ecco-jcc/jjaa252