As in many other fields of medicine, valiant efforts are being directed towards personalizing medical therapy for individual patients with inflammatory bowel disease (IBD). The holy grail of personalized medicine in IBD would be to have a test that could identify the predominant pathways contributing to disease activity for an individual patient. That test would then determine the optimal treatment regimen for that patient and thereby increase that patient’s chance of controlling their IBD without unnecessarily exposing them to ineffective treatments or their adverse effects. Alas, we are not there yet.
In fact, we don’t really have any good predictors of relative response to our existing IBD treatments. Markers of inflammation, such as CRP and calprotectin, can assess a patient’s inflammatory burden and help identify those who may benefit from treatment, but they do not inform the decision about which specific treatment is best for an individual patient. Research investigating serogenetic markers, T-cell gene expression profiles and a variety of –omics for the prediction of treatment response is underway, but this knowledge gap remains.1 So, for now, we must choose drugs for individual patients through the complex synthesis of a patient’s clinical characteristics as well as published guidelines, clinical trial data, observational studies of real-world outcomes, our own clinical experience, insurance formulary mandates and— perhaps most importantly — discussions with our patients about their preferences.
The holy grail of personalized medicine in IBD would be to have a test that could identify the predominant pathways contributing to disease activity for an individual patient.
Society guidelines provide well-referenced reviews of treatment options for the different subtypes and severities of IBD. For mild IBD, these recommendations have not changed significantly recently; however, guidelines for the management of moderate to severe disease can become outdated quickly given the rapid pace of drug development and evolution of data regarding clinical management. In the absence of data from head-to-head trials comparing different agents in different scenarios, observational comparative effectiveness studies can help us choose. Observational studies serve to define real-world effectiveness, which may differ from efficacy estimates from randomized controlled trials. For instance, several recent studies using administrative claims and national registry cohorts have indicated that using infliximab as a first line anti-TNF agent may achieve better outcomes than adalimumab for both Crohn’s disease and ulcerative colitis (UC).2,3 Based on these data, coupled with its rapid onset of action and dosing flexibility, infliximab remains our anti-TNF of choice, when available, in those with the most severe disease.
Prospective studies comparing agents with new mechanisms of action, such as vedolizumab, ustekinumab, and tofacitinib, to anti-TNF agents are either underway, or remain to be done. In the meantime, synthesis of the available data may allow comparison of these drug classes. For example, a recent network meta-analysis demonstrated that, for moderate to severe UC, infliximab or vedolizumab should be considered first-line therapies as opposed to other biologic agents.4 This aligns with our own clinical experiences as well, employing vedolizumab as a first-line therapy in those with moderate disease or comorbidities that may increase the risks of anti-TNF therapy. Similar analyses in Crohn’s disease demonstrate that both infliximab and adalimumab are ideal first line therapies, while ustekinumab should be considered for second-line therapy.5
Beyond incorporating available data on efficacy and effectiveness, it is essential to consider our patients’ preferences and specific circumstances. Taking the time to discuss data as well as their priorities and concerns will very often identify an ideal option. For example, if they are frequently travelling, infusion-based therapies may be more challenging than injection-based agents. Do they have a family history of lymphoma and fear this potential outcome more than anything else? Then perhaps choosing ustekinumab or vedolizumab monotherapy for their Crohn’s disease instead of combination therapy with an anti-TNF agent and azathioprine is the right option for them.
In addition to such data-driven and patient-centered decision-making, there are several clinical scenarios for which certain treatments are conceptually preferable, although supporting data remains to be accumulated for some of these recommendations:
- For patients with other serious systemic comorbidities, such as a recent malignancy or infections, vedolizumab may be preferable given its gut-specific mechanism of action.
- For patients with problematic extraintestinal manifestations of IBD, vedolizumab may not be the best option given it is a gut-specific mechanism of action.
- For younger patients (under 25 years of age) and older patients (65 or older), we generally avoid the use of thiopurines due to increased baseline risks of lymphoproliferative diseases.
- Tofacitinib is generally reserved as a second-line agent for UC at this time, particularly in light of a possible association with thromboembolic events. Further research is required in this regard.
In summary, the armamentarium of available medications for the treatment of IBD is rapidly expanding. With these new options comes increasing complexity in selecting the right drug for the right patient. While we await predictive tools that enable truly personalized medication selection, data from observational studies as well as clinical experience can be applied to both maximize the effectiveness of our existing therapies while minimizing their potential risks.
- Clinical tools to predict treatment response are lacking.
- Observational comparative effectiveness studies and network meta-analyses can help to inform decisions between different treatments for IBD.
- Patients’ priorities and concerns will often guide ultimate treatment decisions.
Disclosures: Dr. Gerich has no conflicts to disclose. Dr. Scott has participated in advisory boards (one-time engagements) for Merck, Janssen. Dr. Scott has received investigator-initiated grants from Takeda Pharmaceuticals and Janssen Pharmaceuticals.
1. Weersma R.K., Xavier R.J., Consortium IBDMO, Vermeire S., Barrett J.C. Multiomics analyses to deliver the most effective treatment to every patient with inflammatory bowel disease. Gastroenterology. 2018;155(5):e1-e4.
2. Singh S., Andersen N.N., Andersson M., Loftus E.V., Jr., Jess T. Comparison of infliximab and adalimumab in biologic-naive patients with ulcerative colitis: A nationwide Danish cohort study. Clinical Gastroenterolology Hepatology. 2017;15(8):1218-1225.
3. Singh S., Heien H.C., Sangaralingham L.R., et al. Comparative effectiveness and safety of anti-tumor necrosis factor agents in biologic-naive patients with Crohn’s disease. Gastroenterology. 2016;14(8):1120-1129.
4. Singh S., Fumery M., Sandborn W.J., Murad M.H. Systematic review with network meta-analysis: First- and second-line pharmacotherapy for moderate-severe ulcerative colitis. Gastroenterology. 2018;47(2):162-175.
5. Weersma R.K., Xavier R.J., Consortium IBDMO, Vermeire S., Barrett J.C. Systematic review and network meta-analysis: first- and second-line biologic therapies for moderate-severe Crohn’s disease. Ailment Pharmacol Ther. 2018;48(4):394-409.