Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nanyang Technological University on 04/28/15 For personal use only.
Special Report
Thiopurine-induced pancreatitis in inflammatory bowel diseases Expert Rev. Gastroenterol. Hepatol. 9(4), 399–403 (2015)
Oren Ledder1, Daniel A Lemberg2,3 and Andrew S Day*2–4 1 Department of Paediatric Gastroenterology, Shaare Zedek Medical Centre, Jerusalem, Israel 2 Department of Gastroenterology, Sydney Children’s Hospital, Randwick, Sydney 3 School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW, Australia 4 Department of Paediatrics, University of Otago (Christchurch), Christchurch, New Zealand *Author for correspondence Tel.: +64 336 40747 Fax: +64 336 40919 [email protected]
informahealthcare.com
Crohn’s disease and ulcerative colitis are chronic inflammatory conditions affecting the gut and can present at any age with increased numbers of diagnoses seen in many countries in recent years. The thiopurine drugs, azathioprine and 6-mercaptopurine, are commonly used to maintain remission in Crohn’s disease and ulcerative colitis; however, the use of these drugs may be limited by the development of pancreatitis in some individuals. Recent data indicate a genetic risk factor and provides a potential immune-mediated mechanism for thiopurine-induced pancreatitis. Management of thiopurine-induced pancreatitis requires exclusion of the triggering drug, which leads to prompt resolution of symptoms. This thiopurine side-effect may limit therapeutic options for future management of patients. KEYWORDS: 6-mercaptopurine . azathioprine . Crohn’s disease . pancreatitis . thiopurines . ulcerative colitis
Crohn’s disease (CD) and ulcerative colitis (UC) are both chronic incurable diseases featuring acute and chronic inflammatory changes in the GI tract [1]. Collectively termed the inflammatory bowel diseases (IBDs), both CD and UC can present at any age with a variety of symptoms, including pain, diarrhea and disrupted nutrition. CD and UC can lead to significant morbidity with disrupted daily activities, interruptions to schooling and work attendance in addition to frequent hospital admissions. Rates of IBD have been rising in the last decades, with some of the highest rates recently described in Australia [2]. Recent data also illustrate that this diagnosis is now made more frequently in countries previously thought to have very low rates of IBD [3]. The overall principles of management for both CD and UC relies upon nutritional, medical or surgical interventions to first induce remission and second to maintain remission. The thiopurines, azathioprine (AZA) and 6-mercaptopurine (6MP) are widely used to maintain remission [4]. However, the use of these drugs can be limited by side effects, including thiopurine-induced acute pancreatitis (TIP). This report aims to present the current role of the thiopurines in the management of IBD and highlight the patterns and impact of
10.1586/17474124.2015.992879
TIP. In addition, this report reviews recent data that advance our understanding of the mechanisms of TIP and risk for the development of this side effect. General principles of the management of CD & UC
Active CD or UC is generally characterized by symptoms, such as diarrhea, pain or rectal bleeding. These symptoms may limit daily activities, interfere with school or work and lead to hospitalization. Furthermore, CD and UC commonly compromise nutrition, leading to weight loss and impaired linear growth. In children and adolescents, CD and UC may also compromise pubertal development, leading to delayed puberty and an impaired pubertal growth spurt [5]. Along with symptoms, most individuals will also have altered systemic or fecal inflammatory markers. Systemic markers such as erythrocyte sedimentation rate, C-reactive protein and platelets are commonly used but tend to have low specificity for gut inflammation. Fecal markers, such as calprotectin and S100A12, have greater specificity for gut inflammation [6]. Acute and chronic inflammatory changes in the gut mucosa are characteristic features of CD and UC. In CD, these may be present in any location from the mouth to the anus. On
2014 Informa UK Ltd
ISSN 1747-4124
399
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nanyang Technological University on 04/28/15 For personal use only.
Special Report
Ledder, Lemberg & Day
the other hand, UC typically features more superficial inflammation extending proximally from the rectum for a variable distance around the colon [1]. Traditionally, the primary goals of management in CD and UC have been to reduce and eliminate symptoms and normalize altered inflammatory markers. In children and adolescents, this is not sufficient: optimization of growth and development are additional important management goals [5]. More recently, a further key goal encompasses the acquisition of mucosal healing – resolution of the endoscopic abnormalities and even deep healing, manifest as histological healing [7]. Various drugs and interventions can be used to induce remission in patients with active IBD. Treatments include exclusive enteral nutrition, corticosteroids, antibiotics and biologic therapies. Each intervention may lead to resolution of symptoms. However, high rates of mucosal healing in CD are seen only with exclusive enteral nutrition and biologic therapies [8,9]. A number of drugs have roles in the maintenance of remission and prevention of disease relapse. The thiopurines are commonly used in the maintenance of remission in both CD and UC [10]. Other maintenance drugs include the 5-aminosalicylates, methotrexate and the biologics. The thiopurines
The thiopurines are a group of purine anti-metabolite drugs used in a variety of settings, including IBD. The group comprises AZA, 6MP and 6-thioguanine (6TG). AZA and 6MP have predominantly been utilized in the context of IBD. The initial metabolism of AZA leads to 6MP: AZA can be considered a pro-drug for 6MP [11]. Subsequently, the metabolism of both drugs is characterized by a number of well-defined steps within the liver, with production of various metabolites [12]. The active metabolite, 6-thioguanine nucleotide, is associated closely with efficacy, and with bone marrow toxicity at higher levels. High levels of a second metabolite, 6methylmercaptopurine, are linked with hepatotoxicity. Both AZA and 6MP have delayed onset of action with full efficacy typically seen after 3–6 months of therapy. Consequently, these drugs do not have a role in the management of current symptoms or in the induction of remission of active disease, but are commonly used in the maintenance of remission. Substantial benefits have been shown with early introduction of a thiopurine shortly after diagnosis in children with CD [13,14]. Similar findings were reported in a large study involving 1075 Australian adult patients with CD: the early use of an immunosuppressive drug (a thiopurine or methotrexate) resulted in reduced rates of abdominal or perianal surgery [15]. However, two European studies in adult populations have not confirmed a benefit of early use [16,17]. The benefits of AZA or 6MP can be limited by direct (predictable) or indirect (unpredictable) side effects. Predictable adverse effects include bone marrow suppression (e.g., with excess levels of 6-thioguanine nucleotide) and hepatotoxicity (commonly associated with high levels of 6-MMP). These 400
adverse outcomes can be avoided with measurement of thiopurine methyl transferase activity prior to use, to guide dosing regimens and close monitoring of blood count and liver chemistry after commencement. Measurement of thiopurine metabolites also helps to identify higher risk of these adverse effects. Allergic and idiosyncratic reactions are, however, unpredictable. One of these is the entity of TIP. In contrast to AZA and 6MP, 6TG has a faster onset of action, with less direct side effects [18]. However, the more widespread use of this drug has been limited by hepatic toxicity, including veno-occlusive disease [19]. Patterns of TIP
TIP is generally considered to be a minor complication of therapy with AZA or 6MP, usually causing a mild acute pancreatitis in the first month after commencement of therapy in approximately 3% of patients with IBD [12]. Female gender is a recognized risk factor for development of TIP [odds ratio: 3.4; 95% CI: 1.3–9.3] [20]. Pediatric patients are also mentioned to be at risk of TIP. However, this may be conferred, since other risk factors and causes of pancreatitis (such as hyperlipidemia, gallstones or alcohol) are less common in children. As a consequence, it is easier to exclude other possible causes in pediatric patients. Overall, acute pancreatitis in children is often viral in etiology, which may not be adequately excluded in the standard diagnostic workup of AP [21,22]. Other potential causes of AP in IBD include drug-related pancreatitis (e.g., 5-aminosalicylates or metronidazole [23]), common bile duct obstruction secondary to duodenal CD [24] and related autoimmune conditions (primary sclerosing cholangitis or autoimmune pancreatitis [25,26]). TIP was seen in 3.25% of a group of 400 patients with IBD treated with 6MP [27]. In these subjects, symptoms began after a mean of 23 days (range 8–32 days, with two outliers). Typical symptoms of pancreatitis, such as epigastric pain and tenderness, occurred in almost all cases. Approximately half of the subjects also experienced nausea and vomiting, back pain or fever. Serum amylase levels were universally elevated at diagnosis, and 57% of the group required hospital admission. Drug withdrawal resulted in immediate improvement in symptoms, with subsequent complete resolution of symptoms within 3 days. The elevated amylase levels also normalized promptly. More recent reports support these findings. TIP was seen in 3.1% of a cohort seen in nine hospitals in Madrid, Spain [20]. These individuals suffered mild pancreatitis, with onset of symptoms seen within 35 days of drug exposure. Symptoms again resolved rapidly after drug withdrawal. The mild nature of TIP was also observed in a further large case series [28]. The absence of published case reports of severe TIP suggests that severe cases of TIP are likely to be exceedingly rare. Mechanisms of TIP
Several pathophysiologic mechanisms of drug-induced AP have been described. These include direct toxic effects (as seen with metronidazole), accumulation of toxic metabolites Expert Rev. Gastroenterol. Hepatol. 9(4), (2015)
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nanyang Technological University on 04/28/15 For personal use only.
Thiopurine-induced pancreatitis in inflammatory bowel diseases
(as seen with tetracycline) or an immunologic reaction [29]. Recent data suggest the latter mechanism may be most important. Polymorphisms in the gene encoding thiopurine methyltransferase enzyme are associated with dose-dependent side effects, including myelosuppression and hepatotoxicity, but are not associated with the risk of TIP [30]. One study suggested that a missense mutation in the gene encoding inosine triphosphate pyrophosphohydrolase, an enzyme involved in thiopurine metabolism, may increase the risk of TIP [31], but this finding was not confirmed in subsequent studies [32–34]. Of interest is the disproportionately high incidence of TIP in IBD compared to other diseases in which thiopurines are used. In a large retrospective review of all patients treated with AZA in a single large centre between 1995 and 2002, AP was identified as a complication of AZA in 4.9% of CD, 1.1% of UC and 1.5% of autoimmune hepatitis patients, compared to less than 0.5% of patients with renal or liver transplant, or patients with autoimmune conditions such as systemic lupus erythematosus [35]. The reason for this association remains unclear. A recently published comprehensive study identified 441 IBD patients from 168 sites who developed pancreatitis within 3 months of starting thiopurines [36]. A genome-wide association study was performed on 172 cases, and 2035 IBD controls, identifying a strong association within the class II HLA region, with the most significant association at rs2647087 (odds ratio: 2.59; 95% CI: 2.07–3.26, p = 2 10 16). Imputation fine mapping of the HLA region identified an association with the HLADQA1*02:01-HLA-DRB1*07:01 haplotype. These findings were replicated in an independent set of 78 cases and 472 IBD controls matched for drug exposure. These data suggest the likelihood of a genetic predisposition to the development of TIP with those patients homozygous for the at-risk allele having a 17% risk of developing pancreatitis after administration of a thiopurine. The significance of these findings has not yet reached clinical relevance, and at present there is no available predictive test to identify patients at higher risk of TIP. Interestingly, however, this work also suggested an immunemediated mechanism for TIP [36]. The authors developed a computational docking model and demonstrate that 6MP was able to bind to the HLA molecule at this location. The functional implications of this model have not yet been delineated. Subsequent use of thiopurines after TIP
Thiopurine-induced AP is generally considered an indication to cease thiopurine therapy, with rapid improvement following cessation. Furthermore, TIP is also considered a contraindication to recommencement of the same drug, due to the assumed risk of recurrence of AP on reintroduction [37]. This suggestion is based on multiple early case series demonstrating a high rate of repeat pancreatitis on re-exposure to the same drug [20,38–40]. According to this approach, alternative medications must be utilized to aid maintenance of IBD remission, such as methotrexate or a biologic medication. informahealthcare.com
Special Report
While the arsenal of medication available for the treatment of IBD is growing, it is still somewhat limited. Consequently, the effect of excluding an effective, generally well-tolerated and relatively cheap medication may be significant. At present, methotrexate as an alternative immunosuppressant is thought to be less effective in the management of UC than in CD, further limiting alternative therapies. More recent data and anecdotal evidence suggest that reintroducing a different thiopurine following an episode of presumptive TIP can be well tolerated. Alexander et al. [41] describe three patients managed with AZA and two with convincing pancreatitis, who tolerated the subsequent commencement of 6MP. Interestingly, in one case, a second bout of pancreatitis occurred after an accidental dose of AZA, despite 6MP being well tolerated. Lees et al. [42] presented mixed data with one patient with possible pancreatitis due to AZA tolerating 6MP later, and another patient who developed a second attack following 6MP. A case series by Ledder et al. [43] outlined four pediatric patients with IBD who developed typical TIP after AZA. All of these patients were successfully restarted on 6MP without subsequently developing pancreatitis and were able to maintain effective disease control using this medication. Beswick et al. [44] showed that three of seven patients who had presented with TIP due to AZA were subsequently able to tolerate 6MP. More recently, Kennedy and co-authors [45] undertook a retrospective observational study of 149 patients with IBD who were previously intolerant of AZA and then switched to 6MP. The authors showed that approximately two-thirds of these patients were able to tolerate 6MP. However, the only patient in this cohort who had suffered pancreatitis with AZA had recurrence with 6MP. Although the authors concluded that a switch because of intolerance was reasonable, TIP was not included in that recommendation. Further prospective studies are now required to clarify the appropriate indications to consider a switch and also to identify risk factors for an unsuccessful switch procedure. Interestingly, pancreatitis appears to be much less common in patients treated with 6TG. Indeed, a change from AZA or 6MP to 6TG has been suggested as an alternative approach to this dilemma. Conclusions
The thiopurine class of drugs is commonly utilized in the management of CD and UC, for which they provide a key component of the therapeutic armamentarium. The use of these drugs is, however, limited by various side effects, which include the development of acute pancreatitis. TIP typically occurs early after commencement of a thiopurine and is unpredictable. Although TIP is usually short-lived and mild, it may provide significant morbidity to the individual patient due to symptoms (especially pain and vomiting), requirement for investigations (e.g., ultrasound scan and blood tests) and disruption of usual activities (i.e., time off school or work and possibly admission to hospital). Furthermore, the development of TIP requires 401
Special Report
Ledder, Lemberg & Day
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nanyang Technological University on 04/28/15 For personal use only.
cessation of the current thiopurine and subsequent reconsideration of further medical therapies for that patient. New developments, especially recent genetic studies, and new approaches, such as the consideration of prescribing an alternate thiopurine, may lead to new approaches to the management of patients with TIP. Expert commentary
The thiopurines, AZA and 6-MP continue to play a significant role in the management of CD and UC in children and adults. TIP is known to occur more commonly in CD and UC than in some other inflammatory conditions. Recent data suggest that this increased frequency of acute pancreatitis could reflect genetic factors. Traditionally, the development of TIP has meant that thiopurines can no longer be prescribed to that patient. Recent case-based experience indicates that some patients will be able to tolerate the alternate thiopurine without redeveloping TIP. By enabling the continued use of a thiopurine, this option provides a significant advantage to the management of the individual patient. Consequently, our practice has been to consider the use of the alternate thiopurine. The difficulty, however, is that not all patients are able to tolerate a second thiopurine and there are no current guidelines to identify if a patient is at risk or not. Prospective studies should help to develop more clear guidelines to support this practice, by identifying factors that may increase or decrease the risk. Such factors could
include disease location, previous drug history, concurrent drug usage or age. Five-year view
At present, the development of TIP in a patient with CD or UC is considered to be a contraindication to the further use of any thiopurine drug in that individual. Recent case reports and case series indicate that a number of patients can subsequently tolerate an alternate thiopurine without again developing TIP. It is not clear, however, whether a minority or majority of patients are able to tolerate the alternate drug in this setting. Prospective studies underway currently should help to ascertain the rate at which the alternate drug is tolerated: the answers from these studies should be available to better inform practitioners in 5 years’ time. Furthermore, the recent genome-wide association study indicates that genetic profiling may provide the potential to stratify an individual’s risk for developing TIP after commencing a thiopurine. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues .
The thiopurine group of drugs includes azathioprine and 6-mercaptopurine.
.
The thiopurines are commonly utilized in the maintenance of remission in Crohn’s disease and ulcerative colitis.
.
Approximately 5% of individuals with Crohn’s disease or ulcerative colitis who are treated with a thiopurine develop acute pancreatitis
.
TIP is typically self-limited and mild.
.
TIP typically recurs upon recommencement of the same thiopurine, but in some patients, it does not recur upon commencement of the
(thiopurine-induced pancreatitis: TIP).
alternate thiopurine drug. .
The onset of TIP in individuals with Crohn’s disease or ulcerative colitis has been considered an unpredictable and idiosyncratic reaction.
.
Developing data suggest that genetic factors may provide increased risk of developing TIP.
review of international trends. Inflamm Bowel Dis 2011;17:423-39
References 1.
2.
3.
Griffiths AM, Hugot J-P. Crohn’s Disease. Chapter 41, In: Walker A, Goulet O, Kleinman RE, et al. editors. Pediatric Gastrointestinal Disease. 4th edition. BC Decker; Hamilton Ontario: 2004 Wilson J, Hair C, Knight R, et al. High incidence of Inflammatory Bowel Disease in Australia: a prospective population-based Australian incidence study. Inflamm Bowel Dis 2010;16:1550-6 Benchimol EI, Fortinsky KJ, Gozdyra P, et al. Epidemiology of pediatric inflammatory bowel disease: a systematic
402
4.
Bar F, Sina C, Fellermann K. Thiopurines in inflammatory bowel disease revisited. World J Gastroenterol 2013;19:1699-706
5.
Lemberg DA, Day AS. Crohn’s and colitis in children: an update for 2014. J Paediatr Child Health 2014. [Epub ahead of print]
6.
Sidler MA, Leach ST, Day AS. Fecal S100A12 and fecal calprotectin as noninvasive markers for inflammatory bowel disease in children. Inflamm Bowel Dis 2008;14:359-66
7.
Froslie K, Jahnsen J, Moum B, et al. Mucosal Healing in Inflammatory Bowel Disease: results From a Norwegian Population-Based Cohort. Gastroenterology 2007;133(2):412-22
8.
Borrelli O, Cordischi L, Cirulli M, et al. Polymeric Diet Alone Versus Corticosteroids in the Treatment of Active Pediatric Crohn’s Disease: a randomised Controlled Open-Label Trial. Clin Gastroenterol Hepatol 2006;4:744-53
9.
Colombel JF, Rutgeerts P, Reinisch W, et al. Early mucosal healing with infliximab is associated with improved long-term
Expert Rev. Gastroenterol. Hepatol. 9(4), (2015)
Thiopurine-induced pancreatitis in inflammatory bowel diseases
clinical outcomes in ulcerative colitis. Gastroenterology 2011;141:1194-201
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nanyang Technological University on 04/28/15 For personal use only.
10.
11.
12.
13.
14.
15.
16.
Dassopoulos T, Sultan S, Falck-Ytter YT, et al. American Gastroenterological Association Institute technical report on the use of thiopurines, methotrexate, and anti-TNF-a biologic drugs for the induction and maintenance of remission in inflammatory Crohn’s disease. Gastroenterology 2013;145:1464-78 Dubinksy MC. Azathioprine, 6-mercaptopurine in inflammatory bowel disease: pharmacology, efficacy and safety. Clin Gastroenterol Hepatol 2004;2:731-43 Ooi CY, Bohane TD, Lee D, et al. Thiopurine metabolite levels in pediatric inflammatory bowel disease. Aliment Pharmacol Ther 2007;25:941-7 Markowitz J, Grancher K, Kohn N, et al. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterology 2000;119:895-902 Punati J, Markowitz J, Lerer T, et al. Effect of early immunomodulator use in moderate to severe pediatric Crohn disease. Inflamm Bowel Dis 2008;14(7):949-54 Kuriyawasam VC, Selinger CP, Katelaris PH, et al. Early use of thiopurines or methotrexate reduces major abdominal and perianal surgery in Crohn’s disease. Inflamma Bowel Dis 2014;20:1382-90 Panes J, Lopez-Sanroman A, Bermejo F, et al. Early azathioprine therapy is no more effective than placebo for newly diagnosed Crohn’s disease. Gastroenterology 2013;145: 766-74
17.
Cosnes J, Bourrier A, Laharie D, et al. Early administration of azathioprine vs conventional management of Crohn’s disease: a randomised controlled trial. Gastroenterology 2013;145:758-65
18.
Dubinsky MC, Hassard PV, Seidman EG, et al. An open-label pilot study using thioguanine as a therapeutic alternative in Crohn’s disease patients resistant to 6-mercaptopurine therapy. Inflamm Bowel Dis 2001;7:181-9
19.
20.
Pavlidis P, Ansari A, Duley J, et al. Splitting a therapeutic dose of thioguanine may avoid liver toxicity and be an efficacious treatment for severe inflammatory bowel disease: a 2-center observational cohort study. Inflamm Bowel Dis 2014;20(12):2239-46 Bermejo F, Lopez-Sanroman A, Taxonera C, et al. Acute pancreatitis in inflammatory bowel disease, with special reference to
informahealthcare.com
azathioprine induced pancreatitis. Aliment Pharmacol Ther 2008;28:623-8 21.
Parenti DM, Steinberg W, Kang P. Infectious causes of acute pancreatitis. Pancreas 1996;13(4):356-71
22.
Sibert JR. Pancreatitis in children. A study in the North of England. Arch Dis Child 1975;50(6):443-8
23.
Pitchumoni CS, Rubin A, Das K. Pancreatitis in Inflammatory Bowel Disease. J Clin Gastroenterol 2010;44(4):246-53
24.
25.
26.
27.
28.
Special Report
adverse effects from azathioprine. Pharmacogenetics 2004;14:779-81 34.
Wroblova K, Kolorz M, Batovsky M, et al. Gene polymorphisms involved in manifestation of leucopenia, digestive intolerance and pancreatitis in azathioprine-treated patients. Dig Dis Sci 2012;57(9):2394-401
35.
Foutch PG, Ferguson DR. Duodenal Crohn’s disease complicated by common bile duct obstruction: report of a case and review of the literature. Am J Gastroenterol 1984;79:520-4
Weersma RK, Peters FT, Oostenbrug LE, et al. Increased incidence of azathioprine-induced pancreatitis in Crohn’s disease compared with other diseases. Aliment Pharmacol Ther 2004;20(8):843-50
36.
Ravi K, Chari ST, Vege SS, et al. Inflammatory bowel disease in the setting of autoimmune pancreatitis. Inflamm Bowel Dis 2009;15(9):1326-30
Heap G, Singh A, Bewshea CM, et al. HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants. Nat Genet 2014;46:1131-4
37.
Balani AR, Grendell JH. Drug-induced pancreatitis: incidence, management and prevention. Drug Saf 2008;31(10):823-37
38.
Kawanishi H, Rudolph E, Bull FE. Azathioprine-induced acute pancreatitis. letter N Engl J Med 1973;289:357
39.
Paloyan D, Levin B, Simonowitz D. Azathioprine associated acute pancreatitis. Dig Dis 1977;22:839-46
40.
Cappell MS, Das KM. Rapid development of pancreatitis following reuse of 6-mercaptopurine. J Clin Gastroenterol 1989;11:679-81
41.
Alexander S, Dowling D. Azathioprine pancreatitis in inflammatory bowel disease and successful subsequent treatment with mercaptopurine. Intern Med J 2005;35(9): 570-1
Saeki K, Hozawa S, Miyata N, et al. IgG4-negative autoimmune pancreatitis with sclerosing cholangitis and colitis: possible association with primary sclerosing cholangitis? Intern Med 2008;47:943-8 Haber CJ, Meltzer SJ, Present DH, Korelitz BI. Nature and course of pancreatitis caused by 6-Mercaptopurine in the treatment of inflammatory bowel disease. Gastroenterol 1986;91:982-6 Moolsintong P, Loftus EV, Chari ST, et al. Acute pancreatitis in patients with Crohn’s disease: clinical features and outcomes. Inflamm Bowel Dis 2005;11:1080-4
29.
Balani AR, Grendell JH. Drug-induced pancreatitis: incidence, management and prevention. Drug Saf 2008;31(10):823-37
42.
30.
Krynetski EY, Tai HL, Yates CR, et al. Genetic polymorphism of thiopurine S methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics 1996;6:279-90
Lees CW, Maan AK, Hansoti B, et al. Tolerability and safety of mercaptopurine in azathioprine-intolerant patients with inflammatory bowel disease. Aliment Pharmacol Ther 2008;27(3):220-7
43.
31.
Marinaki AM, Ansari A, Duley JA, et al. Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics 2004;14:181-7
Ledder O, Lemberg DA, Ooi CY, Day AS. Are thiopurines always contraindicated after thiopurine-induced pancreatitis in inflammatory bowel disease? J Pediatr Gastroenterol Nutr 2013;57(5):583-6
44.
Beswick L, Hair CS, Dowling D. Successful mercaptopurine therapy after azathioprine-related pancreatitis in patients with IBD. Aliment Pharmacol Ther 2013;37:162
45.
Kennedy NA, Rhatigan E, Arnott ID, et al. A trial of mercaptopurine is a safe strategy in patients with inflammatory bowel disease intolerant to azathioprine: an observational study, systematic review and meta-analysis. Aliment Pharmacol Ther 2014;38:1255-66
32.
33.
Van Dieren JM, Hansen BE, Kuipers EJ, et al. Meta-analysis: inosine triphosphate pyrophosphatase polymorphisms and thiopurine toxicity in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther 2007;26:643-52 Gearry RB, Roberts RL, Barclay ML, Kennedy MA. Lack of association between the ITPA 94C>A polymorphism and
403
Special Report
Thiopurine-induced pancreatitis in inflammatory bowel diseases Expert Rev. Gastroenterol. Hepatol. 9(4), 399–403 (2015)
Oren Ledder1, Daniel A Lemberg2,3 and Andrew S Day*2–4 1 Department of Paediatric Gastroenterology, Shaare Zedek Medical Centre, Jerusalem, Israel 2 Department of Gastroenterology, Sydney Children’s Hospital, Randwick, Sydney 3 School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW, Australia 4 Department of Paediatrics, University of Otago (Christchurch), Christchurch, New Zealand *Author for correspondence Tel.: +64 336 40747 Fax: +64 336 40919 [email protected]
informahealthcare.com
Crohn’s disease and ulcerative colitis are chronic inflammatory conditions affecting the gut and can present at any age with increased numbers of diagnoses seen in many countries in recent years. The thiopurine drugs, azathioprine and 6-mercaptopurine, are commonly used to maintain remission in Crohn’s disease and ulcerative colitis; however, the use of these drugs may be limited by the development of pancreatitis in some individuals. Recent data indicate a genetic risk factor and provides a potential immune-mediated mechanism for thiopurine-induced pancreatitis. Management of thiopurine-induced pancreatitis requires exclusion of the triggering drug, which leads to prompt resolution of symptoms. This thiopurine side-effect may limit therapeutic options for future management of patients. KEYWORDS: 6-mercaptopurine . azathioprine . Crohn’s disease . pancreatitis . thiopurines . ulcerative colitis
Crohn’s disease (CD) and ulcerative colitis (UC) are both chronic incurable diseases featuring acute and chronic inflammatory changes in the GI tract [1]. Collectively termed the inflammatory bowel diseases (IBDs), both CD and UC can present at any age with a variety of symptoms, including pain, diarrhea and disrupted nutrition. CD and UC can lead to significant morbidity with disrupted daily activities, interruptions to schooling and work attendance in addition to frequent hospital admissions. Rates of IBD have been rising in the last decades, with some of the highest rates recently described in Australia [2]. Recent data also illustrate that this diagnosis is now made more frequently in countries previously thought to have very low rates of IBD [3]. The overall principles of management for both CD and UC relies upon nutritional, medical or surgical interventions to first induce remission and second to maintain remission. The thiopurines, azathioprine (AZA) and 6-mercaptopurine (6MP) are widely used to maintain remission [4]. However, the use of these drugs can be limited by side effects, including thiopurine-induced acute pancreatitis (TIP). This report aims to present the current role of the thiopurines in the management of IBD and highlight the patterns and impact of
10.1586/17474124.2015.992879
TIP. In addition, this report reviews recent data that advance our understanding of the mechanisms of TIP and risk for the development of this side effect. General principles of the management of CD & UC
Active CD or UC is generally characterized by symptoms, such as diarrhea, pain or rectal bleeding. These symptoms may limit daily activities, interfere with school or work and lead to hospitalization. Furthermore, CD and UC commonly compromise nutrition, leading to weight loss and impaired linear growth. In children and adolescents, CD and UC may also compromise pubertal development, leading to delayed puberty and an impaired pubertal growth spurt [5]. Along with symptoms, most individuals will also have altered systemic or fecal inflammatory markers. Systemic markers such as erythrocyte sedimentation rate, C-reactive protein and platelets are commonly used but tend to have low specificity for gut inflammation. Fecal markers, such as calprotectin and S100A12, have greater specificity for gut inflammation [6]. Acute and chronic inflammatory changes in the gut mucosa are characteristic features of CD and UC. In CD, these may be present in any location from the mouth to the anus. On
2014 Informa UK Ltd
ISSN 1747-4124
399
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nanyang Technological University on 04/28/15 For personal use only.
Special Report
Ledder, Lemberg & Day
the other hand, UC typically features more superficial inflammation extending proximally from the rectum for a variable distance around the colon [1]. Traditionally, the primary goals of management in CD and UC have been to reduce and eliminate symptoms and normalize altered inflammatory markers. In children and adolescents, this is not sufficient: optimization of growth and development are additional important management goals [5]. More recently, a further key goal encompasses the acquisition of mucosal healing – resolution of the endoscopic abnormalities and even deep healing, manifest as histological healing [7]. Various drugs and interventions can be used to induce remission in patients with active IBD. Treatments include exclusive enteral nutrition, corticosteroids, antibiotics and biologic therapies. Each intervention may lead to resolution of symptoms. However, high rates of mucosal healing in CD are seen only with exclusive enteral nutrition and biologic therapies [8,9]. A number of drugs have roles in the maintenance of remission and prevention of disease relapse. The thiopurines are commonly used in the maintenance of remission in both CD and UC [10]. Other maintenance drugs include the 5-aminosalicylates, methotrexate and the biologics. The thiopurines
The thiopurines are a group of purine anti-metabolite drugs used in a variety of settings, including IBD. The group comprises AZA, 6MP and 6-thioguanine (6TG). AZA and 6MP have predominantly been utilized in the context of IBD. The initial metabolism of AZA leads to 6MP: AZA can be considered a pro-drug for 6MP [11]. Subsequently, the metabolism of both drugs is characterized by a number of well-defined steps within the liver, with production of various metabolites [12]. The active metabolite, 6-thioguanine nucleotide, is associated closely with efficacy, and with bone marrow toxicity at higher levels. High levels of a second metabolite, 6methylmercaptopurine, are linked with hepatotoxicity. Both AZA and 6MP have delayed onset of action with full efficacy typically seen after 3–6 months of therapy. Consequently, these drugs do not have a role in the management of current symptoms or in the induction of remission of active disease, but are commonly used in the maintenance of remission. Substantial benefits have been shown with early introduction of a thiopurine shortly after diagnosis in children with CD [13,14]. Similar findings were reported in a large study involving 1075 Australian adult patients with CD: the early use of an immunosuppressive drug (a thiopurine or methotrexate) resulted in reduced rates of abdominal or perianal surgery [15]. However, two European studies in adult populations have not confirmed a benefit of early use [16,17]. The benefits of AZA or 6MP can be limited by direct (predictable) or indirect (unpredictable) side effects. Predictable adverse effects include bone marrow suppression (e.g., with excess levels of 6-thioguanine nucleotide) and hepatotoxicity (commonly associated with high levels of 6-MMP). These 400
adverse outcomes can be avoided with measurement of thiopurine methyl transferase activity prior to use, to guide dosing regimens and close monitoring of blood count and liver chemistry after commencement. Measurement of thiopurine metabolites also helps to identify higher risk of these adverse effects. Allergic and idiosyncratic reactions are, however, unpredictable. One of these is the entity of TIP. In contrast to AZA and 6MP, 6TG has a faster onset of action, with less direct side effects [18]. However, the more widespread use of this drug has been limited by hepatic toxicity, including veno-occlusive disease [19]. Patterns of TIP
TIP is generally considered to be a minor complication of therapy with AZA or 6MP, usually causing a mild acute pancreatitis in the first month after commencement of therapy in approximately 3% of patients with IBD [12]. Female gender is a recognized risk factor for development of TIP [odds ratio: 3.4; 95% CI: 1.3–9.3] [20]. Pediatric patients are also mentioned to be at risk of TIP. However, this may be conferred, since other risk factors and causes of pancreatitis (such as hyperlipidemia, gallstones or alcohol) are less common in children. As a consequence, it is easier to exclude other possible causes in pediatric patients. Overall, acute pancreatitis in children is often viral in etiology, which may not be adequately excluded in the standard diagnostic workup of AP [21,22]. Other potential causes of AP in IBD include drug-related pancreatitis (e.g., 5-aminosalicylates or metronidazole [23]), common bile duct obstruction secondary to duodenal CD [24] and related autoimmune conditions (primary sclerosing cholangitis or autoimmune pancreatitis [25,26]). TIP was seen in 3.25% of a group of 400 patients with IBD treated with 6MP [27]. In these subjects, symptoms began after a mean of 23 days (range 8–32 days, with two outliers). Typical symptoms of pancreatitis, such as epigastric pain and tenderness, occurred in almost all cases. Approximately half of the subjects also experienced nausea and vomiting, back pain or fever. Serum amylase levels were universally elevated at diagnosis, and 57% of the group required hospital admission. Drug withdrawal resulted in immediate improvement in symptoms, with subsequent complete resolution of symptoms within 3 days. The elevated amylase levels also normalized promptly. More recent reports support these findings. TIP was seen in 3.1% of a cohort seen in nine hospitals in Madrid, Spain [20]. These individuals suffered mild pancreatitis, with onset of symptoms seen within 35 days of drug exposure. Symptoms again resolved rapidly after drug withdrawal. The mild nature of TIP was also observed in a further large case series [28]. The absence of published case reports of severe TIP suggests that severe cases of TIP are likely to be exceedingly rare. Mechanisms of TIP
Several pathophysiologic mechanisms of drug-induced AP have been described. These include direct toxic effects (as seen with metronidazole), accumulation of toxic metabolites Expert Rev. Gastroenterol. Hepatol. 9(4), (2015)
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nanyang Technological University on 04/28/15 For personal use only.
Thiopurine-induced pancreatitis in inflammatory bowel diseases
(as seen with tetracycline) or an immunologic reaction [29]. Recent data suggest the latter mechanism may be most important. Polymorphisms in the gene encoding thiopurine methyltransferase enzyme are associated with dose-dependent side effects, including myelosuppression and hepatotoxicity, but are not associated with the risk of TIP [30]. One study suggested that a missense mutation in the gene encoding inosine triphosphate pyrophosphohydrolase, an enzyme involved in thiopurine metabolism, may increase the risk of TIP [31], but this finding was not confirmed in subsequent studies [32–34]. Of interest is the disproportionately high incidence of TIP in IBD compared to other diseases in which thiopurines are used. In a large retrospective review of all patients treated with AZA in a single large centre between 1995 and 2002, AP was identified as a complication of AZA in 4.9% of CD, 1.1% of UC and 1.5% of autoimmune hepatitis patients, compared to less than 0.5% of patients with renal or liver transplant, or patients with autoimmune conditions such as systemic lupus erythematosus [35]. The reason for this association remains unclear. A recently published comprehensive study identified 441 IBD patients from 168 sites who developed pancreatitis within 3 months of starting thiopurines [36]. A genome-wide association study was performed on 172 cases, and 2035 IBD controls, identifying a strong association within the class II HLA region, with the most significant association at rs2647087 (odds ratio: 2.59; 95% CI: 2.07–3.26, p = 2 10 16). Imputation fine mapping of the HLA region identified an association with the HLADQA1*02:01-HLA-DRB1*07:01 haplotype. These findings were replicated in an independent set of 78 cases and 472 IBD controls matched for drug exposure. These data suggest the likelihood of a genetic predisposition to the development of TIP with those patients homozygous for the at-risk allele having a 17% risk of developing pancreatitis after administration of a thiopurine. The significance of these findings has not yet reached clinical relevance, and at present there is no available predictive test to identify patients at higher risk of TIP. Interestingly, however, this work also suggested an immunemediated mechanism for TIP [36]. The authors developed a computational docking model and demonstrate that 6MP was able to bind to the HLA molecule at this location. The functional implications of this model have not yet been delineated. Subsequent use of thiopurines after TIP
Thiopurine-induced AP is generally considered an indication to cease thiopurine therapy, with rapid improvement following cessation. Furthermore, TIP is also considered a contraindication to recommencement of the same drug, due to the assumed risk of recurrence of AP on reintroduction [37]. This suggestion is based on multiple early case series demonstrating a high rate of repeat pancreatitis on re-exposure to the same drug [20,38–40]. According to this approach, alternative medications must be utilized to aid maintenance of IBD remission, such as methotrexate or a biologic medication. informahealthcare.com
Special Report
While the arsenal of medication available for the treatment of IBD is growing, it is still somewhat limited. Consequently, the effect of excluding an effective, generally well-tolerated and relatively cheap medication may be significant. At present, methotrexate as an alternative immunosuppressant is thought to be less effective in the management of UC than in CD, further limiting alternative therapies. More recent data and anecdotal evidence suggest that reintroducing a different thiopurine following an episode of presumptive TIP can be well tolerated. Alexander et al. [41] describe three patients managed with AZA and two with convincing pancreatitis, who tolerated the subsequent commencement of 6MP. Interestingly, in one case, a second bout of pancreatitis occurred after an accidental dose of AZA, despite 6MP being well tolerated. Lees et al. [42] presented mixed data with one patient with possible pancreatitis due to AZA tolerating 6MP later, and another patient who developed a second attack following 6MP. A case series by Ledder et al. [43] outlined four pediatric patients with IBD who developed typical TIP after AZA. All of these patients were successfully restarted on 6MP without subsequently developing pancreatitis and were able to maintain effective disease control using this medication. Beswick et al. [44] showed that three of seven patients who had presented with TIP due to AZA were subsequently able to tolerate 6MP. More recently, Kennedy and co-authors [45] undertook a retrospective observational study of 149 patients with IBD who were previously intolerant of AZA and then switched to 6MP. The authors showed that approximately two-thirds of these patients were able to tolerate 6MP. However, the only patient in this cohort who had suffered pancreatitis with AZA had recurrence with 6MP. Although the authors concluded that a switch because of intolerance was reasonable, TIP was not included in that recommendation. Further prospective studies are now required to clarify the appropriate indications to consider a switch and also to identify risk factors for an unsuccessful switch procedure. Interestingly, pancreatitis appears to be much less common in patients treated with 6TG. Indeed, a change from AZA or 6MP to 6TG has been suggested as an alternative approach to this dilemma. Conclusions
The thiopurine class of drugs is commonly utilized in the management of CD and UC, for which they provide a key component of the therapeutic armamentarium. The use of these drugs is, however, limited by various side effects, which include the development of acute pancreatitis. TIP typically occurs early after commencement of a thiopurine and is unpredictable. Although TIP is usually short-lived and mild, it may provide significant morbidity to the individual patient due to symptoms (especially pain and vomiting), requirement for investigations (e.g., ultrasound scan and blood tests) and disruption of usual activities (i.e., time off school or work and possibly admission to hospital). Furthermore, the development of TIP requires 401
Special Report
Ledder, Lemberg & Day
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nanyang Technological University on 04/28/15 For personal use only.
cessation of the current thiopurine and subsequent reconsideration of further medical therapies for that patient. New developments, especially recent genetic studies, and new approaches, such as the consideration of prescribing an alternate thiopurine, may lead to new approaches to the management of patients with TIP. Expert commentary
The thiopurines, AZA and 6-MP continue to play a significant role in the management of CD and UC in children and adults. TIP is known to occur more commonly in CD and UC than in some other inflammatory conditions. Recent data suggest that this increased frequency of acute pancreatitis could reflect genetic factors. Traditionally, the development of TIP has meant that thiopurines can no longer be prescribed to that patient. Recent case-based experience indicates that some patients will be able to tolerate the alternate thiopurine without redeveloping TIP. By enabling the continued use of a thiopurine, this option provides a significant advantage to the management of the individual patient. Consequently, our practice has been to consider the use of the alternate thiopurine. The difficulty, however, is that not all patients are able to tolerate a second thiopurine and there are no current guidelines to identify if a patient is at risk or not. Prospective studies should help to develop more clear guidelines to support this practice, by identifying factors that may increase or decrease the risk. Such factors could
include disease location, previous drug history, concurrent drug usage or age. Five-year view
At present, the development of TIP in a patient with CD or UC is considered to be a contraindication to the further use of any thiopurine drug in that individual. Recent case reports and case series indicate that a number of patients can subsequently tolerate an alternate thiopurine without again developing TIP. It is not clear, however, whether a minority or majority of patients are able to tolerate the alternate drug in this setting. Prospective studies underway currently should help to ascertain the rate at which the alternate drug is tolerated: the answers from these studies should be available to better inform practitioners in 5 years’ time. Furthermore, the recent genome-wide association study indicates that genetic profiling may provide the potential to stratify an individual’s risk for developing TIP after commencing a thiopurine. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues .
The thiopurine group of drugs includes azathioprine and 6-mercaptopurine.
.
The thiopurines are commonly utilized in the maintenance of remission in Crohn’s disease and ulcerative colitis.
.
Approximately 5% of individuals with Crohn’s disease or ulcerative colitis who are treated with a thiopurine develop acute pancreatitis
.
TIP is typically self-limited and mild.
.
TIP typically recurs upon recommencement of the same thiopurine, but in some patients, it does not recur upon commencement of the
(thiopurine-induced pancreatitis: TIP).
alternate thiopurine drug. .
The onset of TIP in individuals with Crohn’s disease or ulcerative colitis has been considered an unpredictable and idiosyncratic reaction.
.
Developing data suggest that genetic factors may provide increased risk of developing TIP.
review of international trends. Inflamm Bowel Dis 2011;17:423-39
References 1.
2.
3.
Griffiths AM, Hugot J-P. Crohn’s Disease. Chapter 41, In: Walker A, Goulet O, Kleinman RE, et al. editors. Pediatric Gastrointestinal Disease. 4th edition. BC Decker; Hamilton Ontario: 2004 Wilson J, Hair C, Knight R, et al. High incidence of Inflammatory Bowel Disease in Australia: a prospective population-based Australian incidence study. Inflamm Bowel Dis 2010;16:1550-6 Benchimol EI, Fortinsky KJ, Gozdyra P, et al. Epidemiology of pediatric inflammatory bowel disease: a systematic
402
4.
Bar F, Sina C, Fellermann K. Thiopurines in inflammatory bowel disease revisited. World J Gastroenterol 2013;19:1699-706
5.
Lemberg DA, Day AS. Crohn’s and colitis in children: an update for 2014. J Paediatr Child Health 2014. [Epub ahead of print]
6.
Sidler MA, Leach ST, Day AS. Fecal S100A12 and fecal calprotectin as noninvasive markers for inflammatory bowel disease in children. Inflamm Bowel Dis 2008;14:359-66
7.
Froslie K, Jahnsen J, Moum B, et al. Mucosal Healing in Inflammatory Bowel Disease: results From a Norwegian Population-Based Cohort. Gastroenterology 2007;133(2):412-22
8.
Borrelli O, Cordischi L, Cirulli M, et al. Polymeric Diet Alone Versus Corticosteroids in the Treatment of Active Pediatric Crohn’s Disease: a randomised Controlled Open-Label Trial. Clin Gastroenterol Hepatol 2006;4:744-53
9.
Colombel JF, Rutgeerts P, Reinisch W, et al. Early mucosal healing with infliximab is associated with improved long-term
Expert Rev. Gastroenterol. Hepatol. 9(4), (2015)
Thiopurine-induced pancreatitis in inflammatory bowel diseases
clinical outcomes in ulcerative colitis. Gastroenterology 2011;141:1194-201
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nanyang Technological University on 04/28/15 For personal use only.
10.
11.
12.
13.
14.
15.
16.
Dassopoulos T, Sultan S, Falck-Ytter YT, et al. American Gastroenterological Association Institute technical report on the use of thiopurines, methotrexate, and anti-TNF-a biologic drugs for the induction and maintenance of remission in inflammatory Crohn’s disease. Gastroenterology 2013;145:1464-78 Dubinksy MC. Azathioprine, 6-mercaptopurine in inflammatory bowel disease: pharmacology, efficacy and safety. Clin Gastroenterol Hepatol 2004;2:731-43 Ooi CY, Bohane TD, Lee D, et al. Thiopurine metabolite levels in pediatric inflammatory bowel disease. Aliment Pharmacol Ther 2007;25:941-7 Markowitz J, Grancher K, Kohn N, et al. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterology 2000;119:895-902 Punati J, Markowitz J, Lerer T, et al. Effect of early immunomodulator use in moderate to severe pediatric Crohn disease. Inflamm Bowel Dis 2008;14(7):949-54 Kuriyawasam VC, Selinger CP, Katelaris PH, et al. Early use of thiopurines or methotrexate reduces major abdominal and perianal surgery in Crohn’s disease. Inflamma Bowel Dis 2014;20:1382-90 Panes J, Lopez-Sanroman A, Bermejo F, et al. Early azathioprine therapy is no more effective than placebo for newly diagnosed Crohn’s disease. Gastroenterology 2013;145: 766-74
17.
Cosnes J, Bourrier A, Laharie D, et al. Early administration of azathioprine vs conventional management of Crohn’s disease: a randomised controlled trial. Gastroenterology 2013;145:758-65
18.
Dubinsky MC, Hassard PV, Seidman EG, et al. An open-label pilot study using thioguanine as a therapeutic alternative in Crohn’s disease patients resistant to 6-mercaptopurine therapy. Inflamm Bowel Dis 2001;7:181-9
19.
20.
Pavlidis P, Ansari A, Duley J, et al. Splitting a therapeutic dose of thioguanine may avoid liver toxicity and be an efficacious treatment for severe inflammatory bowel disease: a 2-center observational cohort study. Inflamm Bowel Dis 2014;20(12):2239-46 Bermejo F, Lopez-Sanroman A, Taxonera C, et al. Acute pancreatitis in inflammatory bowel disease, with special reference to
informahealthcare.com
azathioprine induced pancreatitis. Aliment Pharmacol Ther 2008;28:623-8 21.
Parenti DM, Steinberg W, Kang P. Infectious causes of acute pancreatitis. Pancreas 1996;13(4):356-71
22.
Sibert JR. Pancreatitis in children. A study in the North of England. Arch Dis Child 1975;50(6):443-8
23.
Pitchumoni CS, Rubin A, Das K. Pancreatitis in Inflammatory Bowel Disease. J Clin Gastroenterol 2010;44(4):246-53
24.
25.
26.
27.
28.
Special Report
adverse effects from azathioprine. Pharmacogenetics 2004;14:779-81 34.
Wroblova K, Kolorz M, Batovsky M, et al. Gene polymorphisms involved in manifestation of leucopenia, digestive intolerance and pancreatitis in azathioprine-treated patients. Dig Dis Sci 2012;57(9):2394-401
35.
Foutch PG, Ferguson DR. Duodenal Crohn’s disease complicated by common bile duct obstruction: report of a case and review of the literature. Am J Gastroenterol 1984;79:520-4
Weersma RK, Peters FT, Oostenbrug LE, et al. Increased incidence of azathioprine-induced pancreatitis in Crohn’s disease compared with other diseases. Aliment Pharmacol Ther 2004;20(8):843-50
36.
Ravi K, Chari ST, Vege SS, et al. Inflammatory bowel disease in the setting of autoimmune pancreatitis. Inflamm Bowel Dis 2009;15(9):1326-30
Heap G, Singh A, Bewshea CM, et al. HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants. Nat Genet 2014;46:1131-4
37.
Balani AR, Grendell JH. Drug-induced pancreatitis: incidence, management and prevention. Drug Saf 2008;31(10):823-37
38.
Kawanishi H, Rudolph E, Bull FE. Azathioprine-induced acute pancreatitis. letter N Engl J Med 1973;289:357
39.
Paloyan D, Levin B, Simonowitz D. Azathioprine associated acute pancreatitis. Dig Dis 1977;22:839-46
40.
Cappell MS, Das KM. Rapid development of pancreatitis following reuse of 6-mercaptopurine. J Clin Gastroenterol 1989;11:679-81
41.
Alexander S, Dowling D. Azathioprine pancreatitis in inflammatory bowel disease and successful subsequent treatment with mercaptopurine. Intern Med J 2005;35(9): 570-1
Saeki K, Hozawa S, Miyata N, et al. IgG4-negative autoimmune pancreatitis with sclerosing cholangitis and colitis: possible association with primary sclerosing cholangitis? Intern Med 2008;47:943-8 Haber CJ, Meltzer SJ, Present DH, Korelitz BI. Nature and course of pancreatitis caused by 6-Mercaptopurine in the treatment of inflammatory bowel disease. Gastroenterol 1986;91:982-6 Moolsintong P, Loftus EV, Chari ST, et al. Acute pancreatitis in patients with Crohn’s disease: clinical features and outcomes. Inflamm Bowel Dis 2005;11:1080-4
29.
Balani AR, Grendell JH. Drug-induced pancreatitis: incidence, management and prevention. Drug Saf 2008;31(10):823-37
42.
30.
Krynetski EY, Tai HL, Yates CR, et al. Genetic polymorphism of thiopurine S methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics 1996;6:279-90
Lees CW, Maan AK, Hansoti B, et al. Tolerability and safety of mercaptopurine in azathioprine-intolerant patients with inflammatory bowel disease. Aliment Pharmacol Ther 2008;27(3):220-7
43.
31.
Marinaki AM, Ansari A, Duley JA, et al. Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics 2004;14:181-7
Ledder O, Lemberg DA, Ooi CY, Day AS. Are thiopurines always contraindicated after thiopurine-induced pancreatitis in inflammatory bowel disease? J Pediatr Gastroenterol Nutr 2013;57(5):583-6
44.
Beswick L, Hair CS, Dowling D. Successful mercaptopurine therapy after azathioprine-related pancreatitis in patients with IBD. Aliment Pharmacol Ther 2013;37:162
45.
Kennedy NA, Rhatigan E, Arnott ID, et al. A trial of mercaptopurine is a safe strategy in patients with inflammatory bowel disease intolerant to azathioprine: an observational study, systematic review and meta-analysis. Aliment Pharmacol Ther 2014;38:1255-66
32.
33.
Van Dieren JM, Hansen BE, Kuipers EJ, et al. Meta-analysis: inosine triphosphate pyrophosphatase polymorphisms and thiopurine toxicity in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther 2007;26:643-52 Gearry RB, Roberts RL, Barclay ML, Kennedy MA. Lack of association between the ITPA 94C>A polymorphism and
403
![[Pain management in chronic pancreatitis and chronic inflammatory bowel diseases].](/assets/img/hold.png)
