SHORT COMMUNICATION
Allopurinol: A Useful Adjunct to Thiopurine Therapy for Pediatric Ulcerative Colitis in the Biologic Era Faith D. Ihekweazu and Richard Kellermayer
ABSTRACT Thiopurines are used as a maintenance therapy in patients with ulcerative colitis (UC). For some patients the metabolism of thiopurines is unfavorable, leading to increased adverse effects, including hepatotoxicity. There are many reports in the adult literature concerning the manipulation of thiopurine metabolism with allopurinol; however, there is only 1 publication in this respect for pediatric UC. We present 3 pediatric cases of UC wherein the combination of allopurinol and low-dose 6-mercaptopurine allowed for shunting of thiopurine metabolites to a more favorable pattern. This intervention supported clinical remission in all, including one case poorly responsive to infliximab. Key Words: 6-MMP, 6-thioguanine nucleotide, allopurinol, hepatotoxicity, thioguanine, thiopurines, ulcerative colitis
(JPGN 2014;59: 22–24)
T
he use of thiopurines, including 6-mercaptopurine (6-MP) and azathioprine (AZA), is an accepted maintenance therapy in patients with inflammatory bowel disease, including ulcerative colitis (UC) and Crohn disease. Thiopurines are metabolized by 3 enzymatic pathways. Xanthine oxidase and thiopurine methyltransferase (TPMT) produce the inactive metabolites 6-thiouracil and 6-methylmercaptopurine (6-MMP), whereas hypoxanthine phosphoribosyltransferase (HPRT) produces the pharmacologically active metabolite, 6-thioguanine nucleotide (6-TGN) (1). For some patients, the metabolism of thiopurines may lead to a disproportionately high level of 6-MMP relative to 6-TGN. A 6-MMP/6-TG ratio of >20 significantly increases this risk of hepatotoxicity and decreased therapeutic effect (2), resulting in discontinuation of the medication (2,3). There are many reports in the adult literature on the manipulation of thiopurine metabolism with allopurinol, a xanthine oxidase inhibitor. It is not clearly understood how allopurinol facilitates the shift from 6-MMP to 6-TG, but secondary enhancement of HPRT activity has been raised as a possible mechanism (4) (Fig. 1). There is only 1 study on the pediatric use of allopurinol in inflammatory bowel disease (1), and it is rarely applied by pediatric gastroenterologists (personal communications). We present 3 cases
Received September 18, 2013; accepted February 12, 2014. From the Section of Pediatric Gastroenterology, Baylor College of Medicine, USDA/ARS Children’s Nutrition Research Center, Texas Children’s Hospital, Houston, TX. Address correspondence and reprint requests to Richard Kellermayer, MD, PhD, Section of Pediatric Gastroenterology, Hepatology & Nutrition, Baylor College of Medicine, 6621 Fannin St, CC1010.00, Houston, TX 77030-2399 (e-mail: [email protected]). The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000344
of pediatric UC with normal TPMT genotype or enzyme tests, but 6-MMP/6-TGN ratio >20 after thiopurine administration. The first patient presented at 12 years of age with chronic pancolitis. He was started on a steroid taper and mesalamine. 6-MP (50 mg, 1.3 mg/kg) was added after demonstration of normal TPMT enzyme activity (29 EU/mL red blood cell [RBC], normal >21). In 1 month he had a clinical flare requiring hospitalization and was with a normal 6-TGN level of 348 pmol/8x10E8 RBC (reference range 230–400) and a severely elevated 6-MMP level of 15,709 pmol/8x10E8 RBC (reference range 21). His symptoms resolved and he was able to be weaned off steroids. Interestingly, metabolite levels were notably low 4 months into therapy: 6-TGN 129 pmol/8x10E8 RBC and 6-MMP undetectable (20, and demonstrated a significant decrease in this ratio with the allopurinol and 6-MP combination therapy (Fig. 2). All of the patients experienced remission with optimal liver and blood tests on 6-MP 0.7 to 1 mg/kg and a 6-MP to allopurinol ratio of 1:2. Importantly, 1 child with poorly controlled symptoms on infliximab was able to discontinue the biologic and achieve full remission on combination therapy with allopurinol and 6-MP. Indeed, adult cases support the utility of the combination therapy in cases poorly controlled by anti-tumor necrosis factor-a treatment (2). One of our 3 patients developed a mild transaminase elevation before initiation of allopurinol, which resolved on combination therapy. Another patient developed mild leukopenia, which resolved with medication dose adjustment. Thiopurine medications can have both dose-dependent (myelosuppression, infections, hepatotoxicity) and idiosyncratic (pancreatitis, malaise) adverse effects (8). In the Rahhal and Bishop study (1), combination therapy was discontinued in patients with myelosuppression, and leukocyte indices normalized within 2 weeks of therapy discontinuation. In adult studies, however, myelosuppression resolved with thiopurine dose reduction in all of the patients (2,6). Importantly, our single case indicates that myelosuppresion responds favorably to thiopurine-to-allopurinol dose adjustments in children as well. Nevertheless, it is important to carefully monitor patients taking thiopurine and thiopurine–allopurinol combination therapy for these adverse reactions with routine complete blood count and liver panels. In adults, combination therapy has been shown to increase steroid-free remission rates with an excellent long-term safety profile when properly monitored (2). Our report furthers the
23
Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Ihekweazu and Kellermayer
JPGN
potential utility of this therapeutic approach in pediatric UC. There is still a need for prospective studies in children to further clarify the long-term risks of such pharmacologic interventions.
REFERENCES 1. Rahhal RM, Bishop WP. Initial clinical experience with allopurinolthiopurine combination therapy in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2008;14:1678–82. 2. Hoentjen F, Seinen ML, Hanauer SB, et al. Safety and effectiveness of long-term allopurinol-thiopurine maintenance treatment in inflammatory bowel disease. Inflamm Bowel Dis 2013;19:363–9. 3. Hoentjen F, Hanauer SB, de Boer NK, et al. Two brothers with skewed thiopurine metabolism in ulcerative colitis treated successfully with allopurinol and mercaptopurine dose reduction. Dig Dis Sci 2012;57: 250–3.
Volume 59, Number 1, July 2014
4. Seinen ML, de Boer NK, Smid K, et al. Allopurinol enhances the activity of hypoxanthine-guanine phosphoribosyltransferase in inflammatory bowel disease patients during low-dose thiopurine therapy: preliminary data of an ongoing series. Nucleosides Nucleotides Nucleic Acids 2011;30:1085–90. 5. Turner D, Otley AR, Mack D, et al. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology 2007;133:423–32. 6. Ansari A, Elliott T, Baburajan B, et al. Long-term outcome of using allopurinol co-therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease. Aliment Pharmacol Ther 2008;28:734–41. 7. Benkov K, Lu Y, Patel A, et al. Role of thiopurine metabolite testing and thiopurine methyltransferase determination in pediatric IBD. J Pediatr Gastroenterol Nutr 2013;56:333–40. 8. Frei P, Biedermann L, Nielsen OH, et al. Use of thiopurines in inflammatory bowel disease. World J Gastroenterol 2013;19:1040–8.
Maternal Milk Paraphernalia—I In 1577, in Verona, Italy, Ognibene Ferrari, better known by his Latinized name, Omnibonus Ferrarius, published De Arte Medica Infantium. A popular text, it had many printings, the last one in Leipzig, Germany, in 1605. It was written in 3 parts on the topics of breast-feeding, newborn care, and childhood disease. Aphoristic as well as descriptive, Ferrarius liberally illustrated his book. His section on breast-feeding included a drawing of a nursing suction glass or breast pump (left) that could be used to relieve engorged breasts and supply breast milk as a mixing medium for pap. The figure on the right shows a breast pump from the Muse´e d’Assistance Publique-Hoˆpitaux de Paris (Photographs courtesy of the National Library of Medicine and the author.)
—Contributed by Angel R. Colo´n, MD
24
www.jpgn.org
Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Allopurinol: A Useful Adjunct to Thiopurine Therapy for Pediatric Ulcerative Colitis in the Biologic Era Faith D. Ihekweazu and Richard Kellermayer
ABSTRACT Thiopurines are used as a maintenance therapy in patients with ulcerative colitis (UC). For some patients the metabolism of thiopurines is unfavorable, leading to increased adverse effects, including hepatotoxicity. There are many reports in the adult literature concerning the manipulation of thiopurine metabolism with allopurinol; however, there is only 1 publication in this respect for pediatric UC. We present 3 pediatric cases of UC wherein the combination of allopurinol and low-dose 6-mercaptopurine allowed for shunting of thiopurine metabolites to a more favorable pattern. This intervention supported clinical remission in all, including one case poorly responsive to infliximab. Key Words: 6-MMP, 6-thioguanine nucleotide, allopurinol, hepatotoxicity, thioguanine, thiopurines, ulcerative colitis
(JPGN 2014;59: 22–24)
T
he use of thiopurines, including 6-mercaptopurine (6-MP) and azathioprine (AZA), is an accepted maintenance therapy in patients with inflammatory bowel disease, including ulcerative colitis (UC) and Crohn disease. Thiopurines are metabolized by 3 enzymatic pathways. Xanthine oxidase and thiopurine methyltransferase (TPMT) produce the inactive metabolites 6-thiouracil and 6-methylmercaptopurine (6-MMP), whereas hypoxanthine phosphoribosyltransferase (HPRT) produces the pharmacologically active metabolite, 6-thioguanine nucleotide (6-TGN) (1). For some patients, the metabolism of thiopurines may lead to a disproportionately high level of 6-MMP relative to 6-TGN. A 6-MMP/6-TG ratio of >20 significantly increases this risk of hepatotoxicity and decreased therapeutic effect (2), resulting in discontinuation of the medication (2,3). There are many reports in the adult literature on the manipulation of thiopurine metabolism with allopurinol, a xanthine oxidase inhibitor. It is not clearly understood how allopurinol facilitates the shift from 6-MMP to 6-TG, but secondary enhancement of HPRT activity has been raised as a possible mechanism (4) (Fig. 1). There is only 1 study on the pediatric use of allopurinol in inflammatory bowel disease (1), and it is rarely applied by pediatric gastroenterologists (personal communications). We present 3 cases
Received September 18, 2013; accepted February 12, 2014. From the Section of Pediatric Gastroenterology, Baylor College of Medicine, USDA/ARS Children’s Nutrition Research Center, Texas Children’s Hospital, Houston, TX. Address correspondence and reprint requests to Richard Kellermayer, MD, PhD, Section of Pediatric Gastroenterology, Hepatology & Nutrition, Baylor College of Medicine, 6621 Fannin St, CC1010.00, Houston, TX 77030-2399 (e-mail: [email protected]). The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000344
of pediatric UC with normal TPMT genotype or enzyme tests, but 6-MMP/6-TGN ratio >20 after thiopurine administration. The first patient presented at 12 years of age with chronic pancolitis. He was started on a steroid taper and mesalamine. 6-MP (50 mg, 1.3 mg/kg) was added after demonstration of normal TPMT enzyme activity (29 EU/mL red blood cell [RBC], normal >21). In 1 month he had a clinical flare requiring hospitalization and was with a normal 6-TGN level of 348 pmol/8x10E8 RBC (reference range 230–400) and a severely elevated 6-MMP level of 15,709 pmol/8x10E8 RBC (reference range 21). His symptoms resolved and he was able to be weaned off steroids. Interestingly, metabolite levels were notably low 4 months into therapy: 6-TGN 129 pmol/8x10E8 RBC and 6-MMP undetectable (20, and demonstrated a significant decrease in this ratio with the allopurinol and 6-MP combination therapy (Fig. 2). All of the patients experienced remission with optimal liver and blood tests on 6-MP 0.7 to 1 mg/kg and a 6-MP to allopurinol ratio of 1:2. Importantly, 1 child with poorly controlled symptoms on infliximab was able to discontinue the biologic and achieve full remission on combination therapy with allopurinol and 6-MP. Indeed, adult cases support the utility of the combination therapy in cases poorly controlled by anti-tumor necrosis factor-a treatment (2). One of our 3 patients developed a mild transaminase elevation before initiation of allopurinol, which resolved on combination therapy. Another patient developed mild leukopenia, which resolved with medication dose adjustment. Thiopurine medications can have both dose-dependent (myelosuppression, infections, hepatotoxicity) and idiosyncratic (pancreatitis, malaise) adverse effects (8). In the Rahhal and Bishop study (1), combination therapy was discontinued in patients with myelosuppression, and leukocyte indices normalized within 2 weeks of therapy discontinuation. In adult studies, however, myelosuppression resolved with thiopurine dose reduction in all of the patients (2,6). Importantly, our single case indicates that myelosuppresion responds favorably to thiopurine-to-allopurinol dose adjustments in children as well. Nevertheless, it is important to carefully monitor patients taking thiopurine and thiopurine–allopurinol combination therapy for these adverse reactions with routine complete blood count and liver panels. In adults, combination therapy has been shown to increase steroid-free remission rates with an excellent long-term safety profile when properly monitored (2). Our report furthers the
23
Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Ihekweazu and Kellermayer
JPGN
potential utility of this therapeutic approach in pediatric UC. There is still a need for prospective studies in children to further clarify the long-term risks of such pharmacologic interventions.
REFERENCES 1. Rahhal RM, Bishop WP. Initial clinical experience with allopurinolthiopurine combination therapy in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2008;14:1678–82. 2. Hoentjen F, Seinen ML, Hanauer SB, et al. Safety and effectiveness of long-term allopurinol-thiopurine maintenance treatment in inflammatory bowel disease. Inflamm Bowel Dis 2013;19:363–9. 3. Hoentjen F, Hanauer SB, de Boer NK, et al. Two brothers with skewed thiopurine metabolism in ulcerative colitis treated successfully with allopurinol and mercaptopurine dose reduction. Dig Dis Sci 2012;57: 250–3.
Volume 59, Number 1, July 2014
4. Seinen ML, de Boer NK, Smid K, et al. Allopurinol enhances the activity of hypoxanthine-guanine phosphoribosyltransferase in inflammatory bowel disease patients during low-dose thiopurine therapy: preliminary data of an ongoing series. Nucleosides Nucleotides Nucleic Acids 2011;30:1085–90. 5. Turner D, Otley AR, Mack D, et al. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology 2007;133:423–32. 6. Ansari A, Elliott T, Baburajan B, et al. Long-term outcome of using allopurinol co-therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease. Aliment Pharmacol Ther 2008;28:734–41. 7. Benkov K, Lu Y, Patel A, et al. Role of thiopurine metabolite testing and thiopurine methyltransferase determination in pediatric IBD. J Pediatr Gastroenterol Nutr 2013;56:333–40. 8. Frei P, Biedermann L, Nielsen OH, et al. Use of thiopurines in inflammatory bowel disease. World J Gastroenterol 2013;19:1040–8.
Maternal Milk Paraphernalia—I In 1577, in Verona, Italy, Ognibene Ferrari, better known by his Latinized name, Omnibonus Ferrarius, published De Arte Medica Infantium. A popular text, it had many printings, the last one in Leipzig, Germany, in 1605. It was written in 3 parts on the topics of breast-feeding, newborn care, and childhood disease. Aphoristic as well as descriptive, Ferrarius liberally illustrated his book. His section on breast-feeding included a drawing of a nursing suction glass or breast pump (left) that could be used to relieve engorged breasts and supply breast milk as a mixing medium for pap. The figure on the right shows a breast pump from the Muse´e d’Assistance Publique-Hoˆpitaux de Paris (Photographs courtesy of the National Library of Medicine and the author.)
—Contributed by Angel R. Colo´n, MD
24
www.jpgn.org
Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
