Genotype linked to azathioprine discontinuation in patients with lupus and IBD

Researchers have found in a new study that Genotype is linked to azathioprine discontinuation in patients with lupus and IBD.

The retrospective cohort study has found that new thiopurine users with the rs2814778-CC genotype variant, a gene more common in persons of African ancestry, experienced azathioprine discontinuation due to hematopoietic toxicity at an almost 3-fold higher rate than patients with other genotypes. Based on their results, the authors recommend that testing for the Duffy-null phenotype be considered in all patients before azathioprine initiation or if leukopenia is detected while a patient is using azathioprine. The findings are published in Annals of Internal Medicine.

Thiopurine azathioprine, an immunosuppressant used to treat conditions including lupus and inflammatory bowel disease (IBD), has been associated with adverse effects, primarily hematopoietic toxicity. Researchers observed that Black patients discontinued use of azathioprine for hematopoietic toxicity at a higher rate than White patients.

They hypothesized that this difference was associated with the presence of the rs2814778-CC genotype variant independent of race. The variant is found in approximately half of Americans with recent African ancestry and causes lower white blood cell counts without increased risk of infection, also known as benign neutropenia.

Researchers from Vanderbilt University Medical Center studied data for 1,466 new azathioprine users with indications of lupus, IBD, or other rheumatic conditions. They found that the presence of rs2814778-CC was associated with a difference in thiopurine discontinuation and tolerated dose across multiple disease settings. The authors also report that patients with rs2814778-CC had lower dosing while patients in the validation cohort had no difference in thiopurine metabolites by genotype.

They note that the "normal" cell counts which clinicians typically use in decisions about dose and need to discontinue azathioprine are primarily derived from patients with European ancestry. Basing decisions for many Black patients based on low leukocyte counts rather than genotype could trigger unnecessary discontinuation or inappropriate dosing of azathioprine. Based on the results, the authors recommend that testing for the Duffy-null phenotype be considered in all patients before azathioprine initiation or if leukopenia is detected while a patient is using azathioprine.