Mériem Belhocine1, Alissar Mourad2, Aurélie Chapdelaine3, Anne-Marie Mansour4, Yves Troyanov5, Maxime Doré6. 1. , MD, FRCPC, is an internal medicine specialist with Hôpital du Sacré-Coeur de Montréal, and a Clinical Professor of Medicine in the Faculty of Medicine, Université de Montréal, Montréal, Quebec. 2. , PharmD, MSc, was, at the time of this study, a PharmD student in the Faculty of Pharmacy, Université de Montréal, Montréal, Quebec. She has now graduated and is a pharmacist with the Centre intégré universitaire de santé et services sociaux du Centre-sud-de-l'Ile-de-Montréal, Montréal, Quebec. 3. , MD, FRCPC, is an internal medicine specialist with the Department of Medicine, Hôpital Notre-Dame, Montréal, Quebec. 4. , MD, MSc, FRCPC, is an internal medicine specialist with the Department of Medicine, Hôpital du Sacré-Coeur de Montréal, and a Clinical Professor of Medicine with the Faculty of Medicine, Université de Montréal, Montréal, Quebec. 5. , MD, FRCPC, is a rheumatologist with the Department of Medicine, Hôpital du Sacré-Coeur de Montréal, and a Clinical Professor of Medicine with the Faculty of Medicine, Université de Montréal, Montréal, Quebec. 6. , BSc, BPharm, MSc, is a Clinical Pharmacist with the Hôpital du Sacré-Coeur de Montréal, Montréal, Quebec.
Abstract
BACKGROUND: Thiopurines are a mainstay of therapy for autoimmune diseases. However, up to 20% to 30% of patients experience overproduction of the methylated metabolites, known as 6-MMP, to the detriment of the active metabolite, 6-thioguanine nucleotide (6-TGN). These patients, commonly referred to as "shunters", are predisposed to thiopurine resistance and hepatotoxicity. In patients with inflammatory bowel diseases, the combination of thiopurine with a xanthine oxidase inhibitor (XOI) is used to reverse this skewed metabolism and to prevent treatment failure or hepatotoxicity. Data on the use of this strategy for patients with other diseases are limited. OBJECTIVES: To investigate and describe the use of thiopurine-XOI combination therapy in shunters with systemic autoimmune diseases. METHODS: Shunters treated in the study hospital between January 1, 2005, and December 31, 2015, were identified using the hospital's laboratory database, and clinical data were collected retrospectively. For each patient with optimization of thiopurine therapy, clinical and laboratory data were assessed over a 6-month period. RESULTS: Thirty-four patients were identified as shunters; for 14 of these patients, thiopurine therapy was optimized with an XOI. In these 14 patients, the median dose of azathioprine was reduced from 1.95 to 0.78 mg/kg with combination therapy. In addition, median 6-TGN level increased from 135 to 385 pmol/8 × 108 erythrocytes (p = 0.001); furthermore, 6-TGN levels rose to above 235 pmol/8 ×108 erythrocytes for 11 of the 14 patients. Conversely, the median 6-MMP level decreased from 6267 to 271 pmol/8 × 108 erythrocytes (p = 0.001). Except for a 12% increase in mean corpuscular volume, no clinically significant changes in blood count were recorded. Notable infections were reported in 3 patients, and 1 patient had to discontinue treatment because of cytopenia. After 6 months, median prednisone daily dose was reduced by 74%, from 16.7 mg to 4.4 mg (p = 0.005), and 4 patients had been weaned off corticosteroids. Of the 14 patients, 11 (79%) were in full remission, and 2 (14%) were in partial remission. CONCLUSION: Optimizing thiopurine therapy with an XOI may be a safe and effective strategy for patients with systemic autoimmune diseases. 2021 Canadian Society of Hospital Pharmacists. All content in the Canadian Journal of Hospital Pharmacy is copyrighted by the Canadian Society of Hospital Pharmacy. In submitting their manuscripts, the authors transfer, assign, and otherwise convey all copyright ownership to CSHP.
BACKGROUND: Thiopurines are a mainstay of therapy for autoimmune diseases. However, up to 20% to 30% of patients experience overproduction of the methylated metabolites, known as 6-MMP, to the detriment of the active metabolite, 6-thioguanine nucleotide (6-TGN). These patients, commonly referred to as "shunters", are predisposed to thiopurine resistance and hepatotoxicity. In patients with inflammatory bowel diseases, the combination of thiopurine with a xanthine oxidase inhibitor (XOI) is used to reverse this skewed metabolism and to prevent treatment failure or hepatotoxicity. Data on the use of this strategy for patients with other diseases are limited. OBJECTIVES: To investigate and describe the use of thiopurine-XOI combination therapy in shunters with systemic autoimmune diseases. METHODS: Shunters treated in the study hospital between January 1, 2005, and December 31, 2015, were identified using the hospital's laboratory database, and clinical data were collected retrospectively. For each patient with optimization of thiopurine therapy, clinical and laboratory data were assessed over a 6-month period. RESULTS: Thirty-four patients were identified as shunters; for 14 of these patients, thiopurine therapy was optimized with an XOI. In these 14 patients, the median dose of azathioprine was reduced from 1.95 to 0.78 mg/kg with combination therapy. In addition, median 6-TGN level increased from 135 to 385 pmol/8 × 108 erythrocytes (p = 0.001); furthermore, 6-TGN levels rose to above 235 pmol/8 ×108 erythrocytes for 11 of the 14 patients. Conversely, the median 6-MMP level decreased from 6267 to 271 pmol/8 × 108 erythrocytes (p = 0.001). Except for a 12% increase in mean corpuscular volume, no clinically significant changes in blood count were recorded. Notable infections were reported in 3 patients, and 1 patient had to discontinue treatment because of cytopenia. After 6 months, median prednisone daily dose was reduced by 74%, from 16.7 mg to 4.4 mg (p = 0.005), and 4 patients had been weaned off corticosteroids. Of the 14 patients, 11 (79%) were in full remission, and 2 (14%) were in partial remission. CONCLUSION: Optimizing thiopurine therapy with an XOI may be a safe and effective strategy for patients with systemic autoimmune diseases. 2021 Canadian Society of Hospital Pharmacists. All content in the Canadian Journal of Hospital Pharmacy is copyrighted by the Canadian Society of Hospital Pharmacy. In submitting their manuscripts, the authors transfer, assign, and otherwise convey all copyright ownership to CSHP.
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