TPMT and HLA-DQA1-HLA-DRB genetic profiling to guide the use of azathioprine in the treatment of interstitial lung disease: First experience

Nada Taha; Karishma Hosein; Amanda Grant-Orser; Ammy Lin-Shaw; Marco Mura

doi:10.1016/j.pupt.2020.101988

TPMT and HLA-DQA1-HLA-DRB genetic profiling to guide the use of azathioprine in the treatment of interstitial lung disease: First experience

Pulm Pharmacol Ther. 2021 Feb:66:101988. doi: 10.1016/j.pupt.2020.101988. Epub 2021 Jan 3.

Authors

Nada Taha¹, Karishma Hosein¹, Amanda Grant-Orser¹, Ammy Lin-Shaw², Marco Mura³

Affiliations

¹ Division of Respirology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
² Department of Pharmacy Services, London Health Sciences Centre, London, Canada.
³ Division of Respirology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. Electronic address: marco.mura@lhsc.on.ca.

PMID: 33406412
DOI: 10.1016/j.pupt.2020.101988

Abstract

Background: The choice of immunosuppressive therapy in interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF) is based on safety profile and expected efficacy. Azathioprine is one of the most commonly used agents to treat ILD. The immunosuppressive effect and pancreatitis risk of azathioprine are influenced by the activity of the enzyme thiopurine methyltransferase (TPMT) and by the genetic mutations in HLA-DQA1-HLA-DRB locus, respectively. We hypothesized that systematic genotyping prior to starting azathioprine improves the rate of discontinuation of immunosuppressive therapy and the total incidence of adverse drug reactions (ADRs).

Methods: Eighty-two patients with ILD other than IPF were included in the study. The rate of immunosuppressive therapy discontinuation due to major ADRs and the total incidence of ADRs were compared between a cohort of genotyped patients (n = 49) and an untested cohort of patients (n = 33).

Results: Thirty-seven out of 49 patients in the genotyped cohort and 27 out of 33 patients in the untested cohort were started on azathioprine. The rate of immunosuppressive therapy discontinuation due to major ADRs was significantly lower (6/49) in the genotyped cohort compared to the untested cohort (11/33; p = 0.0276). All but one discontinuation due to severe ADRs occurred within a month of therapy. However, the total incidence rate of ADRs was very similar in the 2 cohorts (0.025 in the genotyped cohort vs. 0.023 in the untested cohort).

Conclusion: In patients with ILD other than IPF, genotyping for azathioprine metabolism prior to starting therapy is associated with a significantly reduced rate of immunosuppressive therapy discontinuation due to major ADRs, with prevention of bone marrow suppression and pancreatitis, but without a reduction of the total incidence of ADRs. While these data support the use of genetic profiling prior to starting azathioprine to treat ILD, its cost effectiveness remains to be established.

Keywords: Genotyping. azathioprine; Interstitial lung disease; TPMT.

MeSH terms

Azathioprine* / adverse effects
HLA-DQ alpha-Chains
Humans
Lung Diseases, Interstitial* / chemically induced
Lung Diseases, Interstitial* / drug therapy
Lung Diseases, Interstitial* / genetics
Methyltransferases

Substances

HLA-DQ alpha-Chains
HLA-DQA1 antigen
Methyltransferases
thiopurine methyltransferase
Azathioprine