Monotherapy Vs Combination Therapy: Thinking Beyond Traditional Treatment Approaches for Pediatric IBD

Maintenance therapy with infliximab—an anti-tumor necrosis factor agent—is standard treatment for moderate to severe pediatric inflammatory bowel disease (IBD). To optimize treatment, clinicians have the option to increase dose, shorten intervals between infusions, or add an immunomodulator to a patient’s treatment regimen. However, the best approach to individualizing infliximab therapy, whether using it as monotherapy or in combination with immunomodulators, has remained unknown.

Valentina Shakhnovich, MD, from the divisions of gastroenterology, hepatology and nutrition and clinical pharmacology at Children’s Mercy Hospital in Kansas City, Missouri, is the lead author of a study¹ that compared pharmacokinetics and dosing of infliximab monotherapy with a combination regimen of infliximab and an immunomodulator, as maintenance treatment for IBD. 

In the study, participants with steroid-dependent IBD received either infliximab monotherapy (n=51) or combination therapy with infliximab and methotrexate (n=23) as part of their standard care. The researchers found that infliximab troughs did not differ between participants who received monotherapy compared with those who received combination therapy, or between those with active vs inactive disease. Gastroenterology Consultant caught up with Dr Shakhnovich about her research. 

Gastroenterology Consultant: Why do you think there are significant knowledge gaps in how specialists understand how to personalize infliximab therapy for children with IBD?

Valentina Shakhnovich: Treatment options for pediatric IBD are extremely limited, as many of the new and exciting biologics available for the treatment of adult disease are lacking FDA approval or labeling for pediatric patients. Because of this, infliximab is often the only, easily titratable, biologic available for the treatment of IBD in children, making it paramount that we optimize its dosing to achieve lasting therapeutic effect without losing efficacy from formation of antibodies to the drug. 
This is where methotrexate is thought to come into play. Some studies have suggested that it increases infliximab levels in the bloodstream while minimizing the potential for antibody formation to infliximab. Yet, other studies fail to show this, leaving a critical information gap regarding infliximab dose optimization and individualization in pediatrics.

GASTRO CON: Why are the findings from your study significant?

VS: There are different ways to achieve optimal infliximab levels and treatment efficacy in IBD and physicians need to start thinking beyond the traditional approach of 5mg/kg every 8 weeks for every child. We show that dose escalation—both in terms of infliximab mg/kg and interval between infusions—can get you the infliximab levels you are looking for. 
Most importantly, we demonstrate that methotrexate doesn't appear to influence infliximab levels or propensity toward infliximab antibody formation, but rather exerts its effect by improving the efficacy of infliximab therapy. Not only that, but higher levels of methotrexate, which were assessed by intracellular concentrations of methotrexate polyglutamates, is what actually appears to be associated with disease response. This phenomenon has been demonstrated in the rheumatology literature, but never in IBD.
To me, these findings raise the questions of should we be monitoring methotrexate polyglutamates levels and targeting certain levels of methotrexate polyglutamates by increasing methotrexate doses in children who show promise for methotrexate-responsiveness.

GASTRO CON: What are the next steps in your research?

VS: We need longitudinal studies that monitor both infliximab levels and methotrexate polyglutamates levels in children receiving combination therapy with these drugs to see whether higher methotrexate polyglutamates levels are associated with better disease control over time. We also need studies with larger sample size, which may be easiest to achieve if we, as a gastrointestinal community, collaborate on multicenter investigations. 
I personally think the time is ripe for methotrexate dose optimization and individualization, especially now that we recognize that IBD therapy with thiopurines is falling out of favor due to lack of efficacy and rising concern for carcinogenicity in humans, as discussed at the NASPGHAN Annual Meeting. I believe our data show promise for methotrexate polyglutamates utility for therapeutic drug monitoring of methotrexate levels in IBD and/or as biomarkers of drug responsiveness to methotrexate.

For more on pediatric IBD, visit Gastroenterology Consultant. 

Reference:

1)    Shakhnovich V, Casini R, Morrow R, et al. Infliximab monotherapy vs. combination therapy with immunomodulators for maintenance treatment of pediatric inflammatory bowel disease: an evolving role for methotrexate polyglutamates monitoring. Paper presented at: 2018 NASPGHAN/APGNN/CPNP Annual Meeting; October 24-27, 2018; Hollywood, FL. Accessed Nov. 5. https://members.naspghan.org/Annualmeeting/Program/Annual_Meeting_Saturday/Annualmeeting/Speaker_Tabs/Saturday__October_27_2018.aspx?hkey=644b66dc-193c-4763-b35b-72b813f7e6b9.