Using Personalized Medical Therapy to Help Guide Decisions in Treatment of IBD

Personalized medicine can help customize health care and guide decisions about therapeutics and patient management, Kim Isaacs, MD, explained in her talk at the April 2 Advances in Inflammatory Bowel Disease Regional Meeting in Raleigh, North Carolina.

Dr Isaacs is the codirector of the Multidisciplinary Center for IBD Research and Treatment and a professor of medicine in the division of gastroenterology and hepatology at University of North Carolina at Chapel Hill.

Personalized medical therapy “is a concept,” Dr Isaacs explained. “It’s a medical model where we customize our health care. This includes medical decisions, therapeutics, and management. And it’s directed toward a subgroup of patients, instead of one-drug-fits-all.” Genetic and other biomarker information is used to guide treatment decisions about what kind of therapy should be used, which patients need to be monitored more closely, and what doses of a therapy should be administered. To make these decisions, Dr Isaacs said, the provider is required to have the drug, biologic, or therapeutic intervention, and the diagnostic test. There are certain methods that currently apply to IBD, which fit the model of personalized medical therapy.

The first concept that Dr Isaacs outlined is the use of thiopurine methyltrasferase (TPMT) and nudix hydrolase (NUDT) 15, enzymes that affect thiopurine metabolism. If a patient has low TPMT activity or if the presence of NUDT 15 is detected, the patient will have increased 6-TGN and increased myelotoxicity. “If we have these polymorphisms…in these patients,” Dr Isaacs said, “we want to consider an alternative therapy…or drug adjustment.”

Taking genotype into consideration when treating patients with thiopurine can reduce the incidence of myelosuppression. In a recent study, researchers compared 2 cohorts of patients — one cohort received genotype-based therapy while the other received nongenotype-based therapy. The patients in the genotyping cohort had a significantly lower risk for developing myelosuppression and leukopenia than the group who received nongenotype-based therapy.

Another existing concept is the allele HLA-DQA1*05 and its association with the development of antibodies against anti-tumor necrosis factor (TNF) agents. In the PANTS study, patients who carried this allele and were treated with infliximab monotherapy were found to have the highest rate of immunogenicity (92% at 1 year). Those patients who were not carriers and were treated with adalimumab combination therapy achieved the lowest rates of immunogenicity (10% at 1 year). “It’s not unreasonable to check [for this allele], and those patients [who carry the allele] should probably be on combination therapy, or you need to be fairly aggressive about their proactive monitoring, or you can use a different mechanism of action,” Dr Isaacs advised.

There are now many different therapies to choose from when treating IBD, and Dr Isaacs explained that personalized medical therapy can help providers decided on a mechanism of action.

Dr Isaacs pointed out that several studies have been looking into predictors of the efficacy of IL-23 inhibitors. A phase 2 trial investigating serum IL-22 levels in patients and found that those patients with higher levels of serum IL-22 were more likely to respond to IL-23 inhibition therapy. “We don’t have this now,” Dr Isaacs addended, “we can’t commercially send this out. But it’s something to look forward to, and it may lead us to use this mechanism of action.”

Early studies have also shown that expansion of IL-23 receptor T cells is associated with resistance to anti-TNF therapy; elevated colonic levels of Oncostatin M were a predictor of poor prognosis and an early need for biologic therapy; high levels of histidine and cysteine correlated with response to anti-TNFs; reduction of alpha diversity, increase in members of proteobacteria phylum, and decrease in members of Firmicutes phylum in microbiome profile at the time of surgery were associated with higher recurrence rates; and patients exposed to cephalosporins or penicillin with β lactamase inhibitors before or during anti-TNF therapy were at a higher risk of developing antidrug antibodies.

While precision medicine requires a genetic test or biomarker and a therapy, Dr Isaacs stated that other things to consider are comorbidities and risks, features that might predict a fast or sustained response, and whether the patient has responded to prior therapies and the mechanisms of action of those therapies. Considering these other aspects doesn’t exactly fit the concept of personalized medicine, Dr Isaacs said, “but I think, in IBD, it is personalized medicine.”

Dr Isaacs gave a case example of a 33-year-old male patient with moderate to severe Crohn disease, diagnosed when he was 12 years old. The patient first responded to methotrexate, flared, and had infliximab added. The patient lost response to infliximab and was then treated with combination therapy and had an excellent response.

“Precision medicine may have helped us pick his first therapy,” Dr Isaacs stated. “Should he have been on combination therapy right from the outset? Probably. If we had checked his HLA type, would we have found that he was of high likelihood of developing antibodies? Possibly.”

Currently, the patient has increased disease activity with significant abdominal pain. In choosing the next treatment, Dr Isaac explained that personalized medical therapy can help: “Is there a predictor of lack of response to anti-TNF? Or do we know that he is going to respond better to something like ustekinumab, or do we need to be thinking vedolizumab?”

Dr Isaacs stated, “Some of this information we can use right now: we may be able to answer who needs combination therapy to prevent antibody formation, who’s more likely to respond to a different class of medication, and who’s more likely to relapse after surgery.” Many tests, though, are still yet in the future. “Hopefully, at some point, we can do a stool sample, draw a blood sample, check all these things, and know what drug to use.”

—Allison Casey

Isaacs KL. Personalized medical therapy. Presented at: Advances in Inflammatory Bowel Disease Regional Meeting; April 2, 2022; Raleigh, North Carolina.