GENETIC PREDICTORS OF AZATHIOPRINE TOXICITY AND CLINICAL RESPONSE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Main Article Content

B Al-Judaibi
UI Schwarz
N Huda
GK Dresser
JC Gregor
T Ponich
N Chande
M Mosli
RB Kim

Keywords

Inflammatory bowel disease, azathioprine, TPMT, GSTM1, ITPA

Abstract

Background


Thiopurines ( Azathioprine (AZA) and 6 -Mercaptopurine (6-MP ) are considered a well -established therapy for patients with Inflammatory Bowel Disease (IBD) including ulcerative colitis (UC) and Crohn’s Disease (CD ). However, nearly 20% of patients discontinue thiopurines due to adverse events. Functional polymorphisms of several enzymes involved in the metab olism of thiopurine s have been linked with toxicity. The clinical value of variant carriers such as TPMT, ITPA and GSTs in predict ing toxicity and adverse events for IBD patients treated with thiopurines remains to be clarified .


Objectives


To determine if variation in TPMT, ITPA and GST genotypes can predict adverse effects such as neutropenia, pancreatitis, liver enzyme elevation , as well as clinical response for patients with IBD treated with thiopurines .


Methods


Patients known to have IBD and treated with AZ A or 6MP were enrolled. Adverse effects were calculated and their correlation with TPMT, ITPA and GST genotypes was evaluated. Further, the correlation between clinical response and TPMT , ITPA and GST genotypes w ere assessed .


Results


A total of 53 patients were enrolle d. 16/53 patients (28.6%) responded to AZA therapy. 17 patients experienced adverse events with 10 having to discontinue treatment . Three patients (5.4%) developed severe myelosuppression (WBC< 2.0 or neutrophils < 1.0). Loss of function TPMT genotype was associated with adverse events (OR 3.64, 95% CI 0.55 - 24.23, p=0.0313) . ITPA and GST polymorphisms were not associated with toxicity. GSTM1 deletion was associated with poor clinical response to therapy (OR 3.75, 95% CI 0.940 - 14.97, p= 0.1028 ), however, neither TPMT*3A nor ITPA polymorphisms were associated with clinical response.


Conclusion


In addition to TPMT for adverse events, genotyping for GSTM1 appears to predict clinical response in IBD patients treated with thiopurines .

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