Why anti-TNF drugs don’t work for some kids with Crohn's disease

A study from Michigan Medicine researchers has investigated possible genetic factors for drug efficacy for children with Crohn’s disease.

The resulting paper, “HLA DQA1*05 and risk of anti-TNF treatment failure and anti-drug antibody development in children with Crohn's Disease” appeared in the American Journal of Gastroenterology.

Previous studies of adults with Crohn’s disease had found that the allele HLA-DQA1*05 was associated with developing anti-drug antibodies to a group of medicines known as tumor necrosis factor antagonists (anti-TNF).

These anti-inflammatory drugs, including infliximab and adalimumab, are a mainstay of treatment for Crohn’s Disease.

For many pediatric patients prescribed anti-TNF medicines, the drugs stop working, resulting in about 1 in 3 children discontinuing them. 

This is a serious problem since while there are other few medications approved for treating adults, no other medicines are approved for children with Crohn’s disease.

In this latest study, HLA DQA1*05 positive children just taking the anti-TNF mediation had the highest rate of drug failure.

Children without the genetic marker—and who were also taking methotrexate—had the lowest rate of drug failure and anti-drug antibody development.

“The big issue in pediatric Crohn’s Disease is that it’s a lifelong disease,” said Jeremy Adler, M.D., M.Sc., U-M clinical professor of Pediatrics and lead author on the paper.

“We don't have a cure. So that's why drug persistence is one of the main things we looked at. We want the drug to work and to keep working.”

When anti-TNF medicines stop working in children with Crohn’s disease, physicians weigh various options: increasing the dose, adding methotrexate, or using other medicines such as more expensive off-label medicines approved only for adults with Crohn’s disease.

Introducing methotrexate carries some risks, as the child’s immune system becomes further suppressed. Researchers hope a further investigation of why drugs stop working will help physicians as they navigate these decisions.

This research utilized existing blood samples from a previous multi-center, double blind trial conducted by the same group, which compared the efficacy of patients taking anti-TNF medications on their own to taking them in combination with methotrexate. The initial results of the trial, published in 2023, showed that the combined therapy led to a two-fold reduction in treatment failure.

In this trial, 43% of patients were HLA DQ-A1*05 positive, and 30% experienced treatment failure. HLA DQ-A1*05 positive children were twice as likely to develop antidrug antibodies, though the results were not statistically significant. 

Still, Adler hopes one day a blood screen for this genetic marker will be a standard part of treating children with Crohn’s Disease. 

“I’m not testing everybody yet,” said Adler. “But if somebody has developed anti-drug antibodies, or I need to escalate the dose, or they've already had reactions—those are the people I'm checking.” 

HLA DQ-A1*05 can help planning next steps for treatment escalation, combination therapy, or switching to a second anti-TNF medication.

Funding/disclosures: PCS-1406-18643/Gary and Rachel Glick Charitable Fund, Patient-Centered Outcomes Research Institute, Leona M. and Harry B. Helmsley Charitable Trust.

Paper cited: “HLA DQA1*05 and risk of anti-TNF treatment failure and anti-drug antibody development in children with Crohn's Disease: HLA DQA1*05 and Pediatric Crohn's Disease,” The American Journal of Gastroenterology. DOI: 10.14309/ajg.0000000000003135

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