mercaptopurine and Pancreatitis

There is an evolving understanding that autoimmune pancreatitis (AIP) is an immunoglobulin (Ig) G4 systemic disease. It can manifest as primarily a pancreatic disorder or in association with other disorders of presumed autoimmune cause. Classic clinical characteristics include obstructive jaundice, abdominal pain, and acute pancreatitis. Thus, AIP can be difficult to distinguish from pancreatic malignancy. However, AIP may respond to therapy with corticosteroids, and has a strong association with other immune mediated diseases. Although primarily a pathologic diagnosis, attempts have been made to reliably diagnose AIP clinically. AIP can be classified as either type 1 or type 2.

Topics: Adrenal Cortex Hormones; Autoimmune Diseases; Azathioprine; Biopsy; Cholangiopancreatography, Endoscopic Retrograde; Cyclophosphamide; Cyclosporine; Disease Management; Endosonography; Humans; Immunoglobulin G; Immunologic Factors; Immunosuppressive Agents; Mercaptopurine; Pancreas; Pancreatitis; Rituximab; Tomography, X-Ray Computed

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.

Topics: Animals; Anti-Inflammatory Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Gastrointestinal Agents; Genetic Predisposition to Disease; Humans; Mercaptopurine; Pancreatitis; Risk Factors

The use of thiopurines is well established in the management of inflammatory bowel disease. A wealth of data and experience, amassed over several decades, supporting their efficacy has recently been challenged by trials that failed to show a benefit in Crohn's disease when used early in the disease course, although other trials continue to support their role both as monotherapy and in combination with anti-TNF. Recent reports of previously unrecognized toxicity have also emerged. Fortunately, the absolute incidence of serious toxicity remains low, and an improved understanding of how best to minimize risk and the recognition of groups of patients at higher risk of toxicity from thiopurines means that they remain a relatively safe therapy in the majority of patients. In this paper, we review the literature evaluating the role of thiopurines in inflammatory bowel disease as well as their toxicity. We conclude that education regarding the spectrum of thiopurine side effects and optimal monitoring during therapy may help with optimizing safety and efficacy of these important medications.

Topics: Azathioprine; Chemical and Drug Induced Liver Injury; Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Nausea; Neoplasms; Neutropenia; Opportunistic Infections; Pancreatitis

Induced pluripotent stem cells (iPSC) can be produced from adult cells by transfecting them with a definite set of pluripotency-associated genes. Under adequate growth conditions and stimulation iPSC can differentiate to almost every somatic lineage in the body. Patients' derived iPSC are an innovative model to study mechanisms of adverse drug reactions in individual patients and in cell types that cannot be easily obtained from human subjects. Proof-of concept studies with known toxicants have been performed for liver, cardiovascular and central nervous system cells: neurons obtained from iPSC have been used to elucidate the mechanism of chemotherapy-induced peripheral neuropathy by evaluating the effects of neurotoxic drugs such as vincristine. However, no study has been performed yet on pancreatic tissue and drug induced pancreatitis. Thiopurines (azathioprine and mercaptopurine) are immunosuppressive antimetabolite drugs, commonly used to treat Crohn's disease. About 5% of Crohn's disease patients treated with thiopurines develop pancreatitis, a severe idiosyncratic adverse event; these patients have to stop thiopurine administration and may require medical treatment, with significant personal and social costs. Molecular mechanism of thiopurine induced pancreatitis (TIP) is currently unknown and no fully validated biomarker is available to assist clinicians in preventing this adverse event. Hence, in this review we have reflected upon the probable research applications of exocrine pancreatic cells generated from patient specific iPS cells. Such pancreatic cells can provide excellent insights into the molecular mechanism of TIP. In particular three hypotheses on the mechanism of TIP could be explored: drug biotransformation, innate immunity and adaptative immunity.

Topics: Adaptive Immunity; Animals; Azathioprine; Humans; Immunosuppressive Agents; Induced Pluripotent Stem Cells; Mercaptopurine; Pancreatitis; Predictive Value of Tests; Risk Factors

Crohn's disease and ulcerative colitis, together popularly known as inflammatory bowel disease (IBD), are characterized by a number of extraintestinal manifestations. Although infrequent, acute pancreatitis, and less often chronic pancreatitis, may occur as a result of the disease itself or secondary to the medications used in the treatment. The increased incidence of acute pancreatitis in Crohn's disease can be explained based on the high predisposition to cholesterol as well as pigment stones as a result of ileal disease, anatomic abnormalities of the duodenum, immunologic disturbances associated with IBD, and, above all, to the side effects of many medications used in the treatment. Sulfasalazine, 5-aminosalicylic acid, azathioprine, and 6-mercaptopurine are well known to cause acute pancreatitis as a result of a possible idiosyncratic mechanism. Crohn's disease and ulcerative colitis share many clinical manifestations and treatment modalities. Nonspecific elevations of serum pancreatic enzymes in IBD make it difficult to avoid over diagnosis of acute pancreatitis, particularly in patients with Crohn's disease who suffer from abdominal pain often. The IBD-pancreas association is further reflected in many reports of exocrine as well as endocrine pancreatic insufficiency.

Topics: Acute Disease; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Mercaptopurine; Mesalamine; Pancreatitis; Sulfasalazine

We critically reviewed the English language literature pertaining to drug-induced pancreatitis and attempted to determine whether the reported association between each drug and pancreatitis was valid. The following drugs seem to cause pancreatitis: azathioprine, thiazides, sulfonamides, furosemide, estrogens, and tetracycline. Less convincing, but suggestive evidence exists for: 1-asparaginase, iatrogenic hypercalcemia, chlorthalidine, corticosteroids, ethacrynic acid, phenformin, and procainamide. Evidence implicating other drugs is either inadequate or contradictory. Little is known about the pathogenesis of drug-induced pancreatitis. Ethanol was not considered in this review.

Topics: Acetaminophen; Adrenal Cortex Hormones; Amphetamines; Asparaginase; Azathioprine; Chlorthalidone; Cholestyramine Resin; Cimetidine; Cyproheptadine; Dextropropoxyphene; Diazoxide; Diuretics; Estrogens; Ethacrynic Acid; Furosemide; Histamine; Humans; Hypercalcemia; Indomethacin; Isoniazid; Mercaptopurine; Narcotics; Pancreatitis; Phenformin; Procainamide; Rifampin; Salicylates; Sodium Chloride Symporter Inhibitors; Sulfonamides; Tetracycline

Topics: Adrenal Cortex Hormones; Adult; Allopurinol; Autoimmune Diseases; Azathioprine; Bone Diseases; Diabetes Mellitus; Drug Synergism; Duodenal Ulcer; Embolism, Fat; Glomerulonephritis; Histocompatibility; Humans; Hypertension, Renal; Immunosuppressive Agents; Infections; Kidney Glomerulus; Kidney Transplantation; Malabsorption Syndromes; Male; Mercaptopurine; Neoplasm Transplantation; Neoplasms; Obesity; Osteoporosis; Pancreatitis; Peptic Ulcer Hemorrhage; Phenylbutazone; Postoperative Complications; Proteinuria; Transplantation, Homologous

No randomised study has shown whether stratification of treatment by minimal residual disease (MRD) response improves outcome in children and young people with acute lymphoblastic leukaemia (ALL). We assessed whether children and young people with clinical standard and intermediate-risk ALL who have persistent MRD at the end of induction therapy benefit from augmented post-remission therapy.. Between Oct 1, 2003, and June 30, 2011, we enrolled eligible patients aged 1-24 years and initially categorised them into clinical standard-risk, intermediate-risk, and high-risk groups on the basis of a combination of National Cancer Institute criteria, cytogenetics, and early morphological response to induction therapy. Clinical standard-risk and intermediate-risk patients with MRD of 0·01% or higher at day 29 of induction (MRD high risk) were randomly assigned (1:1) to standard therapy (treatment regimens A and B) or augmented post-remission therapy (regimen C). Compared with standard therapy, the augmented treatment regimen (regimen C) included an additional eight doses of pegylated asparaginase, 18 doses of vincristine, and escalated-dose intravenous methotrexate without folinic acid rescue during interim maintenance courses. Computer randomisation was used for treatment allocation and was balanced for sex, age (<10 years vs ≥10 years), and white blood cell count at diagnosis (<50 × 10(9)/L vs ≥50 × 10(9)/L) by minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcomes were event-free survival and overall survival. Analyses were by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN07355119.. 533 MRD high-risk patients were randomly assigned to receive standard (n=266) or augmented (n=267) post-remission therapy. After a median follow-up of 70 months (IQR 52-91), 5-year event-free survival was better in the augmented treatment group (89·6% [95% CI 85·9-93·3]) than in the standard group (82·8% [78·1-87·5]; odds ratio [OR] 0·61 [95% CI 0·39-0·98], p=0·04). Overall survival at 5 years was numerically, but not significantly, higher in the augmented treatment group (92·9% [95% CI 89·8-96·0]) than in the standard therapy group (88·9% [85·0-92·8]; OR 0·67 [95% CI 0·38-1·17], p=0·16). More adverse events occurred in the augmented treatment group than in the standard group (asparaginase-related hypersensitivity in 18 [6·7%] in the augmented group vs two [0·8%] in the standard group and asparaginase-related pancreatitis in eight [3·0%] vs one [0·4%]; intravenous methotrexate-related mucositis in 11 [4·1%] vs three [1·1%] and methotrexate-related stomatitis in 48 [18·0%] vs 12 [4·5%]).. Our findings suggest that children and young people with acute lymphoblastic leukaemia and 0·01% or more MRD at the end of remission induction therapy could benefit from augmented post-remission therapy. However, the asparaginase and intravenous methotrexate used in the augmented treatment regimen is associated with more adverse events than is the standard post-remission treatment regimen.. Medical Research Council and Leukaemia and Lymphoma Research.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Consolidation Chemotherapy; Cyclophosphamide; Cytarabine; Dexamethasone; Disease-Free Survival; Doxorubicin; Drug Hypersensitivity; Female; Follow-Up Studies; Humans; Infant; Male; Mercaptopurine; Methotrexate; Mucositis; Neoplasm, Residual; Pancreatitis; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Risk Assessment; Stomatitis; Survival Rate; Vincristine

This study explored the feasibility and toxicity of individualized toxicity-titrated 6-mercaptopurine (6MP) dose increments during post-remission treatment with High-dose methotrexate (HDM) (5000 mg/m(2), ×3) in 38 patients with Childhood (ALL). Patients were increased in steps of 25 mg 6MP/m(2) per day if they did not develop myelotoxicity within 2 weeks after HDM. 6MP could be increased in 31 patients (81%). Toxicity was acceptable and did not differ significantly between groups. Patients receiving 75 mg/m(2) per day had significantly shorter duration of treatment interruptions of 6MP than the remaining patients (P = 0·03). This study shows individualized toxicity-titrated 6MP dosing during consolidation is feasible without increased risk of toxicity.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Feasibility Studies; Female; Fever; Humans; Infant; Male; Mercaptopurine; Methotrexate; Mucositis; Pancreatitis; Pilot Projects; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Adrenal Cortex Hormones; Adult; Azathioprine; Clinical Trials as Topic; Crohn Disease; Double-Blind Method; Drug Therapy, Combination; Humans; Mercaptopurine; Pancreatitis; Placebos; Prednisone; Random Allocation; Remission, Spontaneous; Sulfasalazine; Time Factors

Thioguanine (TG) has been shown as a safe alternative in adults with inflammatory bowel disease (IBD) who did not tolerate conventional thiopurines [azathioprine (AZA)/mercaptopurine]. However, data in pediatric IBD are scarce. Therefore, we aimed to assess the safety of TG as maintenance therapy.. A retrospective, multicenter cohort study of children with IBD on TG was performed in the Netherlands. TG-related adverse events (AE) were assessed and listed according to the common terminology criteria for AE.. Thirty-six children with IBD (median age 14.5 years) on TG (median dose 15 mg/day) were included in 6 centers. Five AE occurred during follow-up [pancreatitis (grade 3), hepatotoxicity (grade 3) (n = 2), Clostridium difficile infection (grade 2), and abdominal pain (grade 2)]. All patients (n = 8) with a previously AZA-induced pancreatitis did not redevelop pancreatitis on TG.. In pediatric IBD, TG seems a safe alternative in case of AZA-induced pancreatitis. Further research assessing long-term TG-related safety and efficacy is needed.

Topics: Adolescent; Adult; Azathioprine; Child; Chronic Disease; Cohort Studies; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Pancreatitis; Retrospective Studies; Thioguanine

We report a rare case of hypercalcemia and acute pancreatitis in a subject with acute promyelocytic leukemia (APL) and pulmonary tuberculosis, during all-trans-retinoic acid (ATRA) treatment. Both associated complications were potentially due to several causes. A careful monitoring and exclusion of all causative factors must be addressed. Further research is necessary to improve our understanding of risk factors for these complications in patients with (APL). Studying these patterns may help us to improve outcomes for all children and young adults with hematologic malignancies.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Causality; Febrile Neutropenia; Humans; Hypercalcemia; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Models, Biological; Pancreatitis; Pleural Effusion; Prednisone; Pulmonary Aspergillosis; Risk Factors; Tretinoin; Tuberculosis, Pulmonary; Vincristine

Topics: Adult; Antibodies, Monoclonal, Humanized; Crohn Disease; Digestive System Surgical Procedures; Female; Glucocorticoids; Humans; Infusions, Intravenous; Jejunum; Male; Mercaptopurine; Pancreatitis; Recurrence; Risk Assessment; Young Adult

Mercaptopurine (6-mercaptopurine, 6MP) is a mainstay of curative therapy in childhood acute lymphoblastic leukemia (ALL), and contributes to its 90% overall survival rate. We present two patients with ALL who suffered with severe pancreatitis secondary to 6MP. Through the use of allopurinol in conjunction with reduced dose 6MP, we were able to continue 6MP without further pancreatitis. This report contributes to the small body of literature on 6MP associated pancreatitis in childhood ALL and describes a novel approach to continued use of 6MP during therapy.

Topics: Allopurinol; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Humans; Male; Mercaptopurine; Pancreatitis; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Azathioprine [AZA] and mercaptopurine [MP] are recommended for maintenance of steroid-free remission in children with Crohn`s disease [CD]. Azathioprine-induced pancreatitis, an idiosyncratic and major side effect, has been considered as an absolute contraindication for the use of a second thiopurine in IBD patients.. We describe two children with CD in whom MP were successfully trialled after a confirmed azathioprine-induced pancreatitis, being well tolerated in both cases.. Two boys [13 and 10 years old] started exclusive enteral nutrition after diagnosis of moderate (Pediatric Crohn's Disease Activity Index [wPCDAI] = 45) and mild [wPCDAI = 35] CD. Both developed an acute mild to moderate pancreatitis after 2 and 3 weeks, respectively, of AZA treatment but recovered fully in hospital after AZA withdrawal. They started on MP treatment without any adverse effect. They were tested for the presence of polymorphisms 238G>C, 460G>A, and 719A>G in the TPMT gene and 94C>A and 21>C in the ITPase. Both patients were wild-type for all tested polymorphisms.. Azathioprine-induced acute pancreatitis should not be considered as an absolute contraindication for the use of MP. Further investigation is required to create a better understanding of the mechanism underlying the adverse events and to allow more possibilities for personalised therapy.

Topics: Adolescent; Azathioprine; Child; Crohn Disease; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Pancreatitis

Topics: Antimetabolites, Antineoplastic; Humans; Male; Mercaptopurine; Pancreatitis; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Mesalamine and thiopurines (6-mercaptopurine and azathioprine) have been shown to increase the risk of developing acute pancreatitis in inflammatory bowel disease (IBD) patients. Tumor necrosis factor-α (TNF-α) inhibitors have been shown to protect against pancreatitis in animal models.. To determine the risk of pancreatitis when comparing thiopurine monotherapy, mesalamine monotherapy, and thiopurine and mesalamine dual therapy to identical treatments but with the addition of a TNF-α inhibitor.. Using a case-control design, the Food and Drug Administration Adverse Event Reporting System was queried for cases of pancreatitis and control reactions in IBD patients on a thiopurine or mesalamine. The proportional reporting ratio method was used to compare the different therapy regimens with the same regimen combined with a TNF-α inhibitor.. In all, 549 cases and controls were identified. When comparing thiopurine monotherapy with thiopurines combined with a TNF-α inhibitor, the odds of pancreatitis were lower in those on combination therapy (odds ratio [OR] = 0.04; 95% CI = 0.01-0.12). A similar trend was seen when comparing mesalamine monotherapy to mesalamine combined with a TNF-α inhibitor (OR = 0.08; 95% CI = 0.04-0.14) and when comparing those on both a thiopurine and mesalamine with those on all 3 therapies (OR = 0.04; 95% CI = 0.01-0.16).. Combination therapy with TNF-α inhibitors appears to be associated with a lower risk of pancreatitis in IBD patients on mesalamine, thiopurines, or a combination of both. Physicians should consider using TNF-α inhibitors in those with the greatest risk of pancreatitis, although prospective studies are needed.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Case-Control Studies; Drug Therapy, Combination; Female; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Mesalamine; Middle Aged; Odds Ratio; Pancreatitis; Tumor Necrosis Factor-alpha; United States; United States Food and Drug Administration; Young Adult

Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 × 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.

Topics: Azathioprine; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Haplotypes; HLA-DQ alpha-Chains; HLA-DRB1 Chains; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Models, Molecular; Molecular Structure; Pancreatitis; Polymorphism, Single Nucleotide; Protein Binding; Protein Structure, Tertiary; Risk Factors

Thiopurine use in inflammatory bowel disease (IBD) is well established for maintenance of disease remission. Approximately 3% of patients with IBD develop thiopurine-induced pancreatitis (TIP) as an idiosyncratic reaction. Patients diagnosed as having TIP are largely considered not to be candidates for future use of this drug. We hypothesize that previous TIP is not an absolute contraindication to retrialing a different thiopurine.. This case series is a retrospective chart review of those patients with IBD in whom thiopurines were successfully reintroduced following suspected TIP. The patients were all cared for in 2 Australasian pediatric IBD services. Four cases are presented of TIP appropriately related temporally to azathioprine commencement, with no other apparent cause of pancreatitis identified. All of these patients were trialled on 6-mercaptopurine according to clinical need and this was well tolerated in all cases.. This report is the largest case series to date focusing on the reintroduction of a thiopurine following suspected thiopurine induced pancreatitis. All of the patients had a typical presentation of TIP. This case series should call into question the assumption that suspected TIP is an absolute contraindication for the future use of this class of drug. Cautious reintroduction of a thiopurine, in a controlled setting, should be considered in certain circumstances. The clinical relevance of this option is most marked in patients with complicated disease requiring long-term immunosuppression, in whom other therapies are poorly tolerated or contraindicated.

Topics: Adolescent; Azathioprine; Child; Child, Preschool; Contraindications; Crohn Disease; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Medical Records; Mercaptopurine; Pancreatitis; Retrospective Studies; Secondary Prevention

Thiopurines are effective in attaining and maintaining remission in patients with inflammatory bowel diseases (IBD). The major drawback of these drugs are their serious adverse effects (SAE), highlighting the importance of preemptive identification of patients at risk. We aimed to examine whether gene polymorphisms in GSTM1, GSTT1 and TPMT, combined with various clinical parameters, can predict thiopurine induced SAE.. A retrospective cohort of 176 Crohn's Disease (CD) patients treated with thiopurines (131 with 6MP and 45 with azathioprine) was genotyped for common polymorphisms in GSTM1, GSTT1 and TPMT. Clinical data including SAE, age, ethnicity, gender and smoking status were extracted from patient charts. SAEs evaluated were myelosuppression, hepatotoxicity and pancreatitis. Associations between demographic, clinical, and genetic variables and thiopurine induced SAE were assessed.. Twenty-four patients (14%) developed SAE, revealing a significant association between thiopurine induced SAE and GSTM1-null genotype (P=0.05), older age (P=0.016) and active smoking status (P=0.043) and SAE. On multi-variant analysis, past or current smokers were at increased risk for developing thiopurine related SAE (OR 2.915, CI 95%: 1.199- 7.084), specifically pancreatitis (p<0.001). No association was found between TPMT or GSTT1 polymorphisms and the development of SAE.. Active smoking and GSTM1-null genotype appear to be risk factors for thiopurine induced SAEs (i.e. myelosuppression, hepatotoxicity and pancreatitis) in patients with CD. Corroboration of these associations in larger cohorts is warranted.

Topics: Adolescent; Adult; Age Factors; Chemical and Drug Induced Liver Injury; Cohort Studies; Crohn Disease; Female; Genotype; Glutathione Transferase; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methyltransferases; Multivariate Analysis; Pancreatitis; Polymorphism, Genetic; Retrospective Studies; Risk Factors; Severity of Illness Index; Smoking; Young Adult

Two children with acute lymphoblastic leukemia/lymphoma developed recurrent acute pancreatitis during treatment; the etiology was presumed to be secondary to 6-mercaptopurine (6MP). Both had no further attacks after discontinuation of 6MP. Acute pancreatitis secondary to 6MP is extremely rare in acute leukemia/lymphoma although it has been reported in patients with other conditions like inflammatory bowel disease; the reason for this difference is not clearly understood.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Humans; Male; Mercaptopurine; Pancreatitis; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Thiopurine drugs have been widely used in the treatment of inflammatory bowel disease. However, their use is limited by adverse effect that can lead to cessation of therapy. We report 2 cases of thiopurine-induced acute pancreatitis in patients with inflammatory bowel disease. Both patients complained of abdominal pain, showed elevated pancreatic enzymes, and swollen pancreases on computed tomography. The patients' signs and symptoms resolved uneventfully after withdrawal of the thiopurine drugs. Although the mechanism of thiopurine-induced pancreatitis remains unclear, close monitoring and early recognition of acute pancreatitis is important in the management of new thiopurine users.

Topics: Acute Disease; Adolescent; Adult; Azathioprine; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Pancreatitis

Several reports suggest an increased rate of adverse reactions to azathioprine in patients with Crohn's disease.. To compare the incidence of thiopurine-induced acute pancreatitis in patients with inflammatory bowel disease (IBD) with that in patients with vasculitis.. This retrospective analysis was performed using data collected in three databases by two university hospitals (241 patients with IBD and 108 patients with vasculitis) and one general district hospital (72 patients with IBD).. The cumulative incidence of thiopurine-induced acute pancreatitis in Crohn's disease equalled that of ulcerative colitis (UC) (2.6% vs. 3.7%) and this did not differ from vasculitis patients (2.6% vs.1.9%). In addition, the cumulative incidence of thiopurine-induced acute pancreatitis in UC patients was not different from that in vasculitis patients. In the IBD group, 100% of thiopurine-induced acute pancreatitis patients were women, whereas in the vasculitis group the two observed thiopurine-induced acute pancreatitis cases (n = 2 of 2) concerned were men (P = 0.012).. In this study, the alleged higher cumulative incidence of thiopurine-induced acute pancreatitis in Crohn's disease compared with vasculitis or UC patients was not confirmed. Female gender appears to be a risk factor for developing thiopurine-induced acute pancreatitis in IBD patients.

Topics: Acute Disease; Adolescent; Adult; Aged; Antimetabolites; Azathioprine; Crohn Disease; Female; Humans; Male; Mercaptopurine; Middle Aged; Pancreatitis; Retrospective Studies; Statistics as Topic; Young Adult

Autoimmune pancreatitis is increasingly being diagnosed as a multiorgan disorder and a small group of patient present a diagnostic and management dilemma.. We report a complicated case of autoimmune pancreatitis with multiorgan involvement. This is the first reported case of pericardial involvement and agrees with other authors that autoimmune pancreatitis is a multisystem disorder predominantly affecting the pancreas.. In such cases more intensive immunosuppressive therapy may be necessary to get better control of the disease as is apparent from this case.

Topics: Autoimmune Diseases; Disease Progression; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Pancreatitis; Pericarditis; Pericardium

Measurement of thiopurine metabolite levels may be useful as a clinical tool to optimize thiopurine treatment of paediatric inflammatory bowel disease (IBD).. The authors evaluated correlations between 6-thioguanine nucleotide (6-TGN) and therapeutic response, metabolite levels and drug toxicity.. Fifty-six paediatric IBD patients treated with thiopurines had 326 metabolite level measurements and were retrospectively reviewed. Clinical status and laboratory parameters were compared with metabolite levels.. There was significant correlation between 6-TGN levels and therapeutic response, with higher median 6-TGN levels among patients with therapeutic response than those with non-therapeutic response (194 vs. 146 pmol/8 x 10(8) RBC; P = 0.0004). Patients with 6-TGN levels >235 pmol/8 x 10(8) RBC were more likely to achieve therapeutic response than those below the cut-off (odds ratio, 2.5; 95% CI, 1.5-4.1). Patients who developed leukopenia tended to have higher median 6-TGN levels than those without leukopenia (261 vs. 160 pmol/8 x 10(8) RBC) but the difference was not statistically significant. There was no correlation between 6-methylmercaptopurine levels and hepatotoxicity. Two patients developed acute pancreatitis. Metabolite level measurements were helpful in identifying non-compliance in nine patients.. Monitoring of thiopurine metabolite levels is useful to guide and optimize dosing, as an adjunct to clinical judgement, blood count and liver biochemistry measurements to minimize the risk of drug toxicity and to confirm non-compliance.

Topics: Adolescent; Azathioprine; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Infant; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Pancreatitis; Retrospective Studies; Thioguanine; Thrombocytopenia; Treatment Refusal

Topics: Adult; Azathioprine; Crohn Disease; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Pancreatitis

Thiopurines are used in the treatment of inflammatory bowel disease. They are metabolised via methylation by thiopurine-S-methyltransferase (TPMT), which displays a genetically determined polymorphic activity. Subjects with reduced TPMT activity have a higher concentration of active thiopurine metabolites and may be at increased risk of bone-marrow suppression.. To evaluate the relevance of TPMT genotyping in the management of thiopurines therapy in inflammatory bowel disease patients.. Adverse effects and clinical response were determined retrospectively and correlated with TPMT genotype in 70 paediatric inflammatory bowel disease patients.. Nineteen patients (27.1%) developed adverse effects; of the 51 who did not, 34 (66.7%) responded to treatment. Five patients (7.1%) were heterozygous for a variant TPMT allele; two of these (40%) were intolerant to thiopurines, compared to 17 of the 65 patients (26.2%) with a wild type gene (O.R. 1.88, 95% CI 0.29-12.2, p=0.61); among the 34 responders, the median dosage of the drug required to obtain remission was lower for mutated than for wild type patients (1.6mgkg(-1)day(-1) versus 2.0mgkg(-1)day(-1), p=0.043).. There was no significant association between adverse effects of thiopurines and TPMT heterozygous genotype, but TPMT genotyping could be useful in establishing the most appropriate dose of thiopurines to start treatment.

Topics: Adolescent; Adult; Azathioprine; Bone Marrow Diseases; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Genotype; Humans; Immunosuppressive Agents; Infant; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Pancreatitis; Polymorphism, Genetic

Topics: Acute Disease; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Pancreatitis

Topics: Acute Disease; Adolescent; Antimetabolites, Antineoplastic; Child; Female; Humans; Male; Mercaptopurine; Pancreatitis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence

Topics: Adult; Azathioprine; Child; Colitis, Ulcerative; Crohn Disease; Drug Interactions; Drug Therapy, Combination; Humans; Mercaptopurine; Pancreatitis

Topics: Adolescent; Adult; Azathioprine; Bone Marrow; Child; Colorectal Neoplasms; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Pancreatitis; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Randomized Controlled Trials as Topic

Topics: Acute Disease; Adult; Humans; Male; Mercaptopurine; Pancreatitis

A patient with Crohn's disease developed acute pancreatitis 4 h after retaking one 50 mg dose of orally administered 6-mercaptopurine (6-MP). All seven previously reported patients who were rechallenged with 50 mg or more of 6-MP developed pancreatitis within 48 h. These findings suggest that 6-MP can produce pancreatitis due to an idiosyncratic immune-mediated response. Patients with this complication should not reuse 6-MP.

Topics: Adult; Crohn Disease; Drug Hypersensitivity; Humans; Male; Mercaptopurine; Pancreatitis; Time Factors

We assess toxicity related to 6-mercaptopurine in the treatment of inflammatory bowel disease by reporting our experience with 396 patients (120 patients with ulcerative colitis, 276 with Crohn disease) observed over 18 years. Follow-up data for a mean period of 60.3 months were obtained for 90% of the patients. Toxicity directly induced by 6-mercaptopurine included pancreatitis in 13 patients (3.3%), bone marrow depression in 8 (2%), allergic reactions in 8 (2%), and drug hepatitis in 1 (0.3%). These complications were reversible in all cases with no mortality. Most cases of marrow depression occurred earlier in our experience, when the initial drug doses used were higher. Infectious complications were seen in 29 patients (7.4%), of which 7 (1.8%) were severe, including one instance of herpes zoster encephalitis. All infections were reversible with no deaths. Twelve neoplasms (3.1%) were observed, but only 1 (0.3%), a diffuse histiocytic lymphoma of the brain, had a probable association with the use of 6-mercaptopurine. Our data, showing a low incidence of toxicity in 396 patients, coupled with the previously demonstrated efficacy of 6-mercaptopurine in the treatment of inflammatory bowel disease, indicate that the drug is a reasonable alternative in the management of patients with intractable inflammatory bowel disease.

Topics: Adolescent; Adult; Aged; Bone Marrow Diseases; Chemical and Drug Induced Liver Injury; Child; Colitis, Ulcerative; Crohn Disease; Double-Blind Method; Drug Hypersensitivity; Female; Follow-Up Studies; Humans; Infections; Male; Mercaptopurine; Middle Aged; Neoplasms; Pancreatitis; Pregnancy; Time Factors

Topics: Aclarubicin; Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Humans; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Naphthacenes; Pancreatitis; Vincristine

6-Mercaptopurine (6-MP) has an important role in the treatment of inflammatory bowel disease. Its most frequent short-term complication has proven to be pancreatitis, which we have now seen in 13 of 400 (3.25%) patients (12 Crohn's disease, 1 ulcerative colitis) and which we here describe. The timing of the pancreatitis was such that it could not be attributed to sulfasalazine, which was also being taken by 9 patients, or corticosteroids, which were being taken by 7 patients. The dosage of 6-MP ranged from 50 to 100 mg daily, and the pancreatitis, which was uncomplicated in all cases, occurred within 8-32 days with one exception (6.5 mo). Symptoms included epigastric pain, back pain, fever, and nausea. The serum amylase was elevated in 12 patients. The average elevation was 5.9 times normal. In all cases, the 6-MP was discontinued and symptoms and signs returned to normal over a period of 1-11 days. No other complications of 6-MP occurred; there was no leukopenia. Of 7 patients rechallenged with 6-MP, all developed recurrent pancreatitis, including 4 in less than 24 h. In 3 patients, desensitization attempted by a gradual increase in dose from 1/8 tablet (approximately 6 mg) daily also led to recurrence. The timing of the initial pancreatitis and the recurrence at rechallenge are best explained by an allergic reaction. 6-Mercaptopurine should not be reinstituted once it has caused pancreatitis.

Topics: Amylases; Colitis, Ulcerative; Crohn Disease; Humans; Mercaptopurine; Pancreatitis; Time Factors

Two patients with inflammatory bowel disease who developed acute pancreatitis within 21 days of commencing treatment with 6-mercaptopurine are presented. Both were inadvertently reexposed to the drug and developed recurrent pancreatitis within 3 hr of a single dose.

Topics: Acute Disease; Adult; Colitis, Ulcerative; Crohn Disease; Female; Follow-Up Studies; Humans; Male; Mercaptopurine; Pancreatitis; Recurrence

Topics: Aclarubicin; Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Humans; Leukemia; Male; Mercaptopurine; Middle Aged; Naphthacenes; Pancreatitis; Prednisolone

Topics: Adolescent; Anaphylaxis; Asparaginase; Child; Child, Preschool; Confusion; Daunorubicin; Female; Hallucinations; Hemorrhage; Humans; Injections, Spinal; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Mercaptopurine; Methotrexate; Pancreatitis; Prednisolone; Retroperitoneal Space; Vinblastine; Vincristine

Topics: Acute Disease; Asparaginase; Child, Preschool; Humans; Leukemia, Lymphoid; Male; Mercaptopurine; Pancreas; Pancreatitis; Prednisolone; Vincristine

Topics: Adolescent; Appendicitis; Child; Child, Preschool; Gastrointestinal Diseases; Humans; Hypersplenism; Infant; Intestinal Obstruction; Intussusception; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Mercaptopurine; Pancreatitis; Postoperative Complications; Prednisone; Thrombocytopenia; Time Factors

Topics: Adolescent; Adult; Aged; Asparaginase; Azaserine; Burkitt Lymphoma; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Child; Drug Hypersensitivity; Escherichia coli; Female; Humans; Leukemia, Lymphoid; Leukopenia; Lymphoma, Non-Hodgkin; Lymphopenia; Male; Mercaptopurine; Methotrexate; Middle Aged; Neoplasms; Pancreatitis; Thrombocytopenia