A team of researchers, led by Cecilia Chung, M.D., an associate professor in the Division of Rheumatology at Vanderbilt University Medical Center, published a review in Clinical Rheumatology using azathioprine as a high-stakes example of how pharmacogenetics can help rheumatologists prescribe wisely and the potential of developing risk scores. This notion was developed in another recent manuscript.
The immunosuppressant azathioprine is one of the most prescribed drugs in rheumatology. Because patient responses are highly variable, it is an ideal candidate for gene-based, individualized treatment decisions.
Currently, there are dosing guidelines for patients with variants in two genes: TPMT and NUDT15. Chung and colleagues are working to elucidate how these variants, together with other genes and clinical variables, can improve prediction of azathioprine-associated leukopenia. “In the past, we could only tell our patients what their risks were based on data from the general population,” Chung said. “Thanks to genetic testing, we can now make better predictions of who is at high risk.”
Azathioprine as Test Case
Azathioprine is used to treat systemic vasculitis, systemic lupus erythematosus, inflammatory bowel disease, and other inflammatory diseases, Chung explained. It is also used in certain forms of cancer, and to prevent organ transplant rejection.
Chung’s team chose azathioprine as a test case because of its narrow therapeutic index as well as the severity of many of its side effects. Its effectiveness varies across the full spectrum of indications, and many patients do not respond. Furthermore, many present side effects that are either dose-limiting or can be life-threatening, including lethal infections from bone marrow toxicity. Long exposure of thiopurines is associated with some forms of cancer.
Genes play a substantial role in these variable responses. Studies have shown that variants in TPMT explain approximately 25 percent of the bone marrow toxicity among azathioprine users. Other studies have identified genetic causes of other adverse side effects, like pancreatitis, which affects up to four percent of azathioprine users. Among them is an HLA variant, HLADQA1 –HLA-DRB1, common in patients of European descent.
“In the near term, we see the promise in risk scores for many more drugs with complex metabolism and narrow therapeutic indices, like other immunosuppressants.”
Risk Score Outcomes
As a proof-of-concept, Chung and her team first used deidentified EHR and BioVU genetic profiles to gather data on 750 patients. These data included demographic characteristics, medications that interact pharmacokinetically or pharmacodynamically with azathioprine, leukopenia-associated comorbid conditions, and variants in 17 candidate genes. These genes were chosen because they either encode enzymes involved in azathioprine metabolism or are associated with neutropenia in the general population.
The team then created numerous models, but the one that included all of these clinical variables and genetic information performed best in both the discovery and replication phases of the study. They demonstrated moderate discriminant capacity and performance superior to the current standard of care (TPMT testing).
Toward Risk Scores for All
Said Chung, “In the near term, we see the promise in risk scores for many more drugs with complex metabolism and narrow therapeutic indices, like other immunosuppressants. Recently, our team has begun studying cyclophosphamide and mycophenolate, which are other strong candidates for applied pharmacogenomics in rheumatology.”
At Vanderbilt, polygenic risk scores are being tested to assess patient risk for atrial fibrillation, lung cancer and even suicide ideation. Particularly in rheumatology, though, where the treatment itself is associated with a high rate of side effects, the benefits of this approach could be huge, Chung said.