mercaptopurine and Inflammatory-Bowel-Diseases

Drug rediscovery refers to the principle of using 'old' drugs outside the indications mentioned in the summary of product characteristics. In the past decades, several drugs were rediscovered in a wide variety of medical fields. One of the most recent examples is the unconditional registration of thioguanine (TG), a thiopurine derivative, in patients with inflammatory bowel disease in the Netherlands. In this paper, we aim to visualise potential hurdles that hamper drug rediscovery in general, emphasise the global need for optimal use and development of potentially useful drugs, and provide an overview of the registration process for TG in the Netherlands. With this summary, we aim to guide drug rediscovery trajectories in the near future.

Topics: Azathioprine; Gastroenterology; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Netherlands; Off-Label Use; Thioguanine

Despite the increasing availability of biological treatment in recent years, thiopurines remain an important treatment option in patients with inflammatory bowel diseases (IBD) both as monotherapy and in combination therapy with biologicals. Pre-treatment screening of thiopurine-methyltransferase activity and monitoring of thiopurine metabolites during treatment are essential to optimize the effectiveness and safety of thiopurines. This review provides an evidence-based practical guide to prescribing and monitoring thiopurines in patients with IBD.

Topics: Humans; Immunologic Factors; Inflammatory Bowel Diseases; Mercaptopurine

The inflammatory bowel diseases (IBD) are complex immune-mediated inflammatory diseases that are associated with significant morbidity around the world. As our understanding of IBD, and other immune-mediated inflammatory diseases, advances the number of therapeutic targets has increased which has rapidly driven the development and introduction of new therapies. While these new therapies have shown promise they come with the significant drawback of high costs. For many IBD patients around the world the cost of newer therapies is prohibitive which means treating clinicians often need to turn to optimising simpler, older, and inexpensive medications. The concept of optimising well established cheaper medications is not unique to the management of IBD as health systems all over the world look to reduce costs while simultaneously improving patient outcomes. Despite thiopurines being used in the management IBD for over 60 years, many clinicians are still hesitant to use them due to perceptions around limited efficacy and poor tolerance. One method identified to potentially increase utilisation of thiopurines involves the coadministration of allopurinol. In this review we will explore the history, pharmacology, recent studies and give recommendations for the utilisation of the usual duo of azathioprine combined with allopurinol.

Topics: Allopurinol; Azathioprine; Humans; Immunologic Factors; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine

Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use.. To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response.. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed.. Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance.. The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.

Topics: Allopurinol; Azathioprine; Drug-Related Side Effects and Adverse Reactions; Guanine Nucleotides; Hepatitis, Autoimmune; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Purines; Quality Improvement; Thioguanine; Thionucleotides; Treatment Outcome

The development of anti-drug antibodies (ADA) to tumor necrosis factor (TNF-α) inhibitors is a significant result contributing to the loss of clinical response in inflammatory bowel disease (IBD).. We performed a systematic review and meta-analysis to assess whether the addition of immunomodulators to TNF-α inhibitors lead to reversal of antibody formation in TNF-α inhibitor-treated IBD patients.. We conducted a comprehensive search of electronic databases from inception through October 2018 in order to identify specific studies describing clinical response in IBD patients following the addition of immunomodulators (methotrexate or thiopurines) to TNF-α inhibitors. Clinical response was expressed as an improvement of symptoms, with a noted decrease or complete elimination of ADA against TNF-α inhibitors. The meta-analysis was performed using the DerSimonian and Laird random-effect model.. In our meta-analysis, addition of immunomodulators to TNF-α inhibitors was shown to restore the clinical response in 74% of the patients by either decreasing or completely eliminating anti-drug antibody levels. Further long-term multicenter studies are needed to validate these findings.

Topics: Antibodies; Antibody Formation; Immunologic Factors; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate; Treatment Outcome; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha

The risk of lymphoma in patients with inflammatory bowel disease (IBD) treated with anti-TNF agents remains unclear.. To assess the comparative risk of lymphoma with anti-TNF agents and/or thiopurines in IBD METHODS: We searched PubMed, EMBASE and Cochrane Library to identify studies that evaluated lymphoproliferative disorders associated with anti-TNF agents with or without thiopurines. The risk of lymphoma was assessed through four comparator groups: combination therapy (anti-TNF plus thiopurine), anti-TNF monotherapy, thiopurine monotherapy and control group. Pooled incidence rate ratios (IRR) were estimated through Poisson-normal models.. Four observational studies comprising 261 689 patients were included. As compared with patients unexposed to anti-TNF and thiopurines, those exposed to anti-TNF monotherapy, thiopurine monotherapy or combination therapy had pooled IRR (per 1000 patient-years) of lymphoma of 1.52 (95% CI: 1.06-2.19; P = 0.023), 2.23 (95% CI: 1.79-2.79; P < 0.001) and 3.71 (95% CI: 2.30-6.00; P ≤ 0.01), respectively. The risk of lymphoma associated with combination therapy was higher than with thiopurines or anti-TNF alone with pooled IRR of 1.70 (95% CI: 1.03-2.81; P = 0.039) and 2.49 (95% CI: 1.39-4.47; P = 0.002), respectively. The risk did not differ between anti-TNF monotherapy and thiopurine monotherapy with pooled IRR of 0.72 (95% CI: 0.48-1.07; P = 0.107). All observational studies were of high quality according to the Newcastle-Ottawa scale.. There is an increased risk of lymphoma in IBD patients treated with anti-TNF agents, either alone or when combined with thiopurines.

Topics: Adult; Colitis; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Lymphoma; Male; Mercaptopurine; Middle Aged; Risk Assessment; Risk Factors; Tumor Necrosis Factor-alpha

The need for immune suppressive strategies in the control of chronic inflammatory bowel diseases originated in the 1960s following the perception of a relative inefficacy of salazopyrin and its derivatives. In some 50 years upon an anecdotal claim, the indication for thiopurines in the management of inflammatory bowel diseases has come of age.. The aim of this minireview is to give an overview, after the historical premises, of the current use of thiopurines in the context of inflammatory bowel diseases.. Through MEDLINE searches, we reviewed the literature of the last two decades.. For Crohn's disease, the 1980 trial of 6-mercaptopurine for steroid sparing and fistula closure proved pivotal. The analysis of withdrawal experiments and of numerous open trials has established the efficacy of thiopurines for ulcerative colitis. In this indication, cutting-edge data are now showing that because targeting dysplasia, thiopurines can induce mucosal/histological healing, thus abolishing or delaying the need for pre-emptive (tumor prophylactic) colectomy.. In UC thiopurines may be recognized to effect a treat-to-target strategy, joining the modern algorithms of rheumatologic disorders.

Topics: Adrenal Cortex Hormones; Biological Products; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Evidence-Based Medicine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Prognosis; Randomized Controlled Trials as Topic; Recurrence; Risk Assessment; Severity of Illness Index; Time Factors; Treatment Outcome

The thiopurines are effective in the management of patients with inflammatory bowel disease (IBD), but the association between thiopurines use and the risk of skin cancer (including nonmelanoma skin cancer [NMSC] and melanoma skin cancer) has already been sufficiently reported. However, the results of these studies are inconsistent, and thus, the objective of our analysis was to explore whether thiopurines can lead to an excess risk of skin cancer in IBD patients.. MEDLINE, EMBASE, and the Cochrane Library were searched to identify relevant studies that evaluated the risk of skin cancer in IBD patients treated with thiopurines. A random effects meta-analysis was conducted to calculate the pooled incidence rate ratios as well as risk ratios (RRs). Subgroup analysis was performed to explore the potential source of heterogeneity.. Thirteen studies comprising 149 198 participants were included. The result suggested that thiopurines significantly increased the risk of overall skin cancer in IBD patients (random effects: RR = 1.80, 95% confidence interval [CI] 1.14-2.87, P = 0.013), among which NMSC showed an excess risk associated with thiopurines use (random effects: RR = 1.88, 95% CI 1.48-2.38, P < 0.001) while no increased risk was observed with respect to melanoma skin cancer (random effects: RR = 1.22, 95% CI 0.90-1.65, P = 0.206). Subgroup analysis regarding sample size and geographic distribution in skin cancer and follow-up duration in NMSC reached statistical significance, while other subgroups showed no significance.. Exposition of thiopurines in patients with IBD is associated with a higher risk of skin cancer. Routine skin screening and daily skin protective practice are recommended for these patients.

Topics: Azathioprine; Databases, Bibliographic; Humans; Inflammatory Bowel Diseases; Melanoma; Mercaptopurine; Risk; Skin Neoplasms

Inflammatory bowel disease (IBD) is characterized by activation of both the innate and adaptive immune system in genetically susceptible individuals, resulting in chronic intestinal inflammation. The triggers that initiate and perpetuate this continuous inflammation are the subject of much speculation and research, although the central role of the intestinal microbiota is recognized, and is even a target for treatment in some circumstances. The mainstay of modern IBD treatment is suppression of the immune response towards as yet unspecified antigens, and conventional therapy includes corticosteroids, 5-aminosalicylic acid (5-ASA), thiopurines and methotrexate. Reducing activity of specific mediators has proven efficacious, including adhesion molecules, such as the gut-homing integrin α

Topics: Antibodies, Monoclonal; Electric Stimulation Therapy; Glucocorticoids; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Mesalamine; Tumor Necrosis Factor-alpha; Vagus Nerve

The current goals of treatment in inflammatory bowel disease, both Crohn's disease and ulcerative colitis, are to achieve clinical, endoscopic and ideally histological remission and improve the quality of life of these patients. Current therapies are effective in achieving remission in most cases, but there is a lack of clear guidelines on their optimal duration. This review aims to evaluate the current evidence on the withdrawal of therapy with 5-aminosalicylates, thiopurines and methotrexate. We also aim to identify which specific group of patients, while in remission and in the absence of risk factors, may be able to discontinue therapy without a significant risk of relapse.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Mesalamine; Methotrexate; Remission Induction; Withholding Treatment

The thiopurine drugs 6-mercaptopurine (6-MP) and azathiopurine (AZA) are widely used to treat inflammatory bowel disease. However, the incidence of adverse reactions is high, particularly in Asia, and the mechanisms of toxicity in Asian populations remain unclear. Thiopurine S-methyltransferase (TPMT) is a well-known enzyme that inactivates AZA or 6-MP through methylation and is one of the few pharmacogenetic predictors used in clinical settings in Western countries. Individuals carrying TPMT-deficient genetic variants require reduced drug doses, but this treatment modification is are not applicable to East Asian populations. Several genes code thiopurine-metabolizing enzymes, including TPMT, multidrug-resistance protein 4, and inosine triphosphatase. These genes have been studied as candidate pharmacogenetic markers; however, it remains unclear why Asian populations seem to be more intolerant than other ethnic groups to a full dose of thiopurines. A genome-wide association approach to identify Asian-specific pharmacogenetic markers in Korean patients with Crohn's disease revealed that a non-synonymous single nucelotide polymorphism in nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) which causes p.Arg139Cys was strongly associated with thiopurine-induced early leukopenia. Six common haplotypes of NUDT15 were reported, and five variants showed medium-to-low enzyme activities, compared with the wild haplotype. NUDT15 hydrolyzes the thiopurine active metabolites 6-thio-GTP and 6-thio-dGTP; variants of NUDT15 had lower enzyme activities, causing higher levels of thiopurine active metabolites, resulting in thiopurine-induced leukopenia. In clinical application, NUDT15 genotyping is a good candidate for predicting thiopurine toxicity in East Asian populations. However, the association of NUDT15 diplotypes with thiopurine toxicity remains unclear. Further analyses with large cohorts to confirm the clinical effects of each haplotype are planned.

Topics: Asian People; Gastrointestinal Agents; Genotype; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Pyrophosphatases

Thiopurine drugs, including azathioprine and 6-mercaptopurine, are used commonly in patients with inflammatory bowel disease for maintenance of remission. Although generally well tolerated, adverse effects lead to discontinuation in a significant minority of patients. Pharmacogenomic studies have suggested that metabolic breakdown of azathioprine in an individual is genetically determined. Coupled with the fact that certain thiopurine metabolites, notably 6-thioguanine nucleotide and 6-methylmercaptopurine, are associated with antiinflammatory effects and adverse effects, respectively, some investigators have examined intentionally shunting the metabolism of azathioprine toward increasing 6-thioguanine nucleotide levels by using low doses of the xanthine oxidoreductase inhibitor allopurinol to improve efficacy and decrease toxicity of azathioprine in patients with inflammatory bowel disease. We performed a search of the MEDLINE and Embase databases for basic and clinical research reports of this modality. Pertinent articles were retrieved, reviewed, and assessed by the authors. Case series, cohort studies, and one randomized trial have investigated adding allopurinol to azathioprine therapy in patients with inflammatory bowel disease. Most reports primarily examined metabolite levels in these patients. In general, the literature suggests that this modality was successful at significantly increasing 6-thioguanine nucleotide levels while decreasing 6-methylmercaptopurine levels. Several small reports have suggested that patients with increased 6-thioguanine nucleotide levels had improved symptoms or symptom remission. Adverse effects and discontinuation rates remained similar or were improved in patients who were taking a thiopurine and started allopurinol. In conclusion, the addition of allopurinol may be an option for optimizing thiopurine metabolite production in select patients with low 6-thioguanine nucleotide levels. Appropriate care and monitoring of these patients are mandatory to prevent neutropenia or other adverse effects.

Topics: Allopurinol; Drug Therapy, Combination; Enzyme Inhibitors; Guanine Nucleotides; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Prospective Studies; Retrospective Studies; Thionucleotides

Thiopurines, available as azathioprine, mercaptopurine, and thioguanine, are immunomodulating agents primarily used to maintain corticosteroid-free remission in patients with inflammatory bowel disease. To provide a state-of-the-art overview of thiopurine treatment in inflammatory bowel disease, this clinical review critically summarises the available literature, as assessed by several experts in the field of thiopurine treatment and research in inflammatory bowel disease.

Topics: Azathioprine; Drug Therapy, Combination; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Neoplasms; Risk Factors; Thioguanine

Azathioprine and 6-mercaptopurine (thiopurines) are common adjunct treatments for inflammatory bowel disease (IBD). Although thiopurine therapy in organ transplant recipients is known to increase nonmelanoma skin cancers (NMSCs), dermatologic literature yields less data regarding NMSC risk of thiopurine use in IBD.. The aim of this study was to systematically review current literature on NMSC risk in patients with IBD using thiopurine therapy.. Systematic review of PubMed was performed with keywords "inflammatory bowel disease," "ulcerative colitis," "Crohn's disease," "thiopurine," "azathioprine," "6-mercaptopurine," "skin cancer," "non-melanoma," "squamous cell carcinoma," and "basal cell carcinoma." All available publication years were included. Publications were evaluated using PRISMA guidelines.. The systematic review yielded 67 articles; 18 met final inclusion criteria.. Heterogeneity of study designs limited direct comparisons of thiopurine exposure and NMSC risk.. Patients with IBD using thiopurines seem to have a moderately increased risk of NMSC that is proportional to therapy duration. Risk of NMSC seems to decrease or return to baseline after discontinuing therapy, although additional data are needed to support this trend. Younger patients with IBD using thiopurines seem to be at greater risk of NMSC. Appreciating NMSC risk in patients with IBD undergoing thiopurine therapy should help direct skin cancer screening recommendations and sun protective measures.

Topics: Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Skin Neoplasms

Thiopurines (azathioprine and mercaptopurine) are widely used in patients with inflammatory bowel disease. In this paper, we review the main indications for their use, as well as practical aspects on efficacy, safety and method of administration. They are mainly used to maintain remission in steroid-dependent disease or with ciclosporin to control a severe ulcerative colitis flare-up, as well as to prevent postoperative Crohn's disease recurrence, and also in combination therapy with biologics. About 30-40% of patients will not respond to treatment and 10-20% will not tolerate it due to adverse effects. Before they are prescribed, immunisation status against certain infections should be checked. Determination of thiopurine methyltransferase activity (TPMT) is not mandatory but it increases initial safety. The appropriate dose is 2.5mg/kg/day for azathioprine and 1.5mg/kg/day for mercaptopurine. Some adverse effects are idiosyncratic (digestive intolerance, pancreatitis, fever, arthromyalgia, rash and some forms of hepatotoxicity). Others are dose-dependent (myelotoxicity and other types of hepatotoxicity), and their surveillance should never be interrupted during treatment. If therapy fails or adverse effects develop, management can include switching from one thiopurine to the other, reducing the dose, combining low doses of azathioprine with allopurinol and assessing metabolites, before their use is ruled out. Non-melanoma skin cancer, lymphomas and urinary tract tumours have been linked to thiopurine therapy. Thiopurine use is safe during conception, pregnancy and breastfeeding.

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Humans; Inflammatory Bowel Diseases; Mercaptopurine

The association between thiopurines and colorectal neoplasia risk remains controversial in inflammatory bowel disease [IBD] patients. We performed a systematic review and meta-analysis examining this association.. A comprehensive search of the PubMed, EMBASE and Cochrane Library databases was performed to identify relevant literature. Random-effects models were applied to calculate the pooled odds ratio [OR] and relative risk [RR] with corresponding 95% confidence intervals [CIs] among case-control and cohort studies.. Eleven cohort and 16 case-control studies involving 95397 patients were included in this study. Overall, the use of thiopurines was associated with a reduced risk of colorectal neoplasia both in case-control [OR = 0.49, 95% CI: 0.34-0.70] and cohort studies [RR = 0.96, 95% CI: 0.94-0.98]. Moreover, a protective effect of thiopurines against advanced neoplasia [high-grade dysplasia and cancer] [OR = 0.51, 95% CI: 0.31-0.84 for case-control studies; RR = 0.96, 95% CI: 0.94-0.98 for cohort studies] and colorectal cancer [CRC] [OR = 0.56, 95% CI: 0.34-0.93 for case-control studies; RR = 0.96, 95% CI: 0.94-0.98 for cohort studies] was also observed. Furthermore, when the analysis was conducted on patients at a high risk for colorectal neoplasia, the chemopreventive effect was confirmed in patients with long disease duration [> 8 years] but not in those with extensive colitis or primary sclerosing cholangitis.. This study demonstrated that thiopurine use was associated with a reduced risk of colorectal neoplasia, advanced neoplasia and CRC in IBD patients, especially those with long disease duration [> 8 years].

Topics: Colorectal Neoplasms; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Mercaptopurine; Protective Factors; Risk Factors

The increased use of biologic agents over the past two decades has led to a reappraisal of the role of the immunomodulators (thiopurines and methotrexate) in the treatment of inflammatory bowel disease. The purpose of this review is to summarize recent data on the use of thiopurines and methotrexate either as monotherapy or as part of combination therapy with biologic agents.. Recent studies have addressed the need for concomitant immunomodulatory therapy in treatment-naïve patients starting anti-TNF-α therapy, the appropriate dose of the immunomodulator in this setting, the minimum duration of combination therapy, and the possible mechanisms by which immunomodulators enhance the effectiveness of anti-TNF-α agents. Little is known about the role of immunomodulators in combination with agents belonging to other classes of biologic therapies. Recent studies have shown that methotrexate is not effective in inducing or maintaining remission in ulcerative colitis. Finally, several studies have broadened our understanding of the infection and malignancy risks of the immunomodulators. Immunomodulators continue to have a place in the treatment of inflammatory bowel disease. However, with the ever-increasing list of biologic agents, properly positioning the immunomodulators within the overall therapeutic scheme is a complicated task. In order to optimize outcomes, each patient requires an individualized approach, which takes into account risks, benefits, cost, alternatives, and patient preferences.

Topics: Antibodies, Monoclonal, Humanized; Azathioprine; Biological Factors; Drug Therapy, Combination; Gastrointestinal Agents; Humans; Immunologic Factors; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate; Purines; Sulfur Compounds; Tumor Necrosis Factor-alpha

Thiopurines are central to inflammatory bowel disease (IBD) therapeutics, either as monotherapy or in combination with newer biologic therapies, however it is only recently that focus has increased on improving effectiveness and tolerability through optimisation. Areas covered: We review the role of thiopurines in IBD and the importance of the timing of initiation of therapy. Drug metabolism and pharmacogenetics have increasingly played a role in determining dosing and dose optimisation and we review the rationale for this in both thiopurine monotherapy and in combination with biologic agents. We also discuss allopurinol co-therapy as a strategy for enhancing both efficacy and tolerability of thiopurine therapy. Although immunomodulators carry safety considerations, we discuss methods of optimisation to minimise side-effects and maximise safety to ensure the broadest number of patients can benefit. Expert commentary: We provide a practical guide to drug initiation and dose optimisation in a clinical setting, and address potential treatment duration. The forward view considers the place for thiopurines in the treatment of IBD, and how the application of the plethora of genetic data may help inform thopurine therapy in the future.

Topics: Allopurinol; Drug Dosage Calculations; Drug Therapy, Combination; Humans; Immunologic Factors; Inflammatory Bowel Diseases; Mercaptopurine; Practice Guidelines as Topic

The use of thiopurines in the treatment of inflammatory bowel disease (IBD) can be optimized by the application of therapeutic drug monitoring. In this procedure, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP) metabolites are monitored and related to therapeutic response and adverse events, respectively. Therapeutic drug monitoring of thiopurines, however, is hampered by several analytical limitations resulting in an impaired translation of metabolite levels to clinical outcome in IBD. Thiopurine metabolism is cell specific and requires nucleated cells and particular enzymes for 6-TGN formation. In the current therapeutic drug monitoring, metabolite levels are assessed in erythrocytes, whereas leukocytes are considered the main target cells of these drugs. Furthermore, currently used methods do not distinguish between active nucleotides and their unwanted residual products. Last, there is a lack of a standardized laboratorial procedure for metabolite assessment regarding the substantial instability of erythrocyte 6-TGN. To improve thiopurine therapy in patients with IBD, it is necessary to understand these limitations and recognize the general misconceptions in this procedure.

Topics: Antimetabolites; Azathioprine; Drug Monitoring; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine

Immunosuppressive agents and biological agents are widely used for therapy in patients with inflammatory bowel disease (IBD). However, these therapies may be associated with an increased risk of malignancy. There is evidence that exposure of the therapeutic agents such as thiopurine and anti-tumor necrosis factor for IBD is associated with an increased risk of lymphoproliferative disorders, skin cancers, or uterine cervical cancers. This article reviews the malignancies associated with the use of immunosuppressive agents and biological agents in IBD.

Topics: Adalimumab; Azathioprine; Biological Factors; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Intestinal Neoplasms; Lymphoproliferative Disorders; Mercaptopurine; Risk Factors; Skin Neoplasms

Azathioprine and mercaptopurine have a pivotal role in the treatment of inflammatory bowel disease (IBD). However, because of their complex metabolism and potential toxicities, optimal use of biomarkers to predict adverse effects and therapeutic response is paramount.. To provide a comprehensive review focused on pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in IBD.. A literature search up to July 2015 was performed in PubMed using a combination of relevant MeSH terms.. Pre-treatment thiopurine S-methyltransferase typing plus measurement of 6-tioguanine nucleotides and 6-methylmercaptopurine ribonucleotides levels during treatment have emerged with key roles in facilitating safe and effective thiopurine therapy. Optimal use of these tools has been shown to reduce the risk of adverse effects by 3-7%, and to improve efficacy by 15-30%. For the introduction of aldehyde oxidase (AOX) into clinical practice, the association between AOX activity and AZA dose requirements should be positively confirmed. Inosine triphosphatase assessment associated with adverse effects also shows promise. Nucleoside diphosphate-linked moiety X-type motif 15 variants have been shown to predict myelotoxicity on thiopurines in East Asian patients. However, the impact of assessments of xanthine oxidase, glutathione S-transferase, hypoxanthine guanine phosphoribosyltransferase and inosine monophosphate dehydrogenase appears too low to favour incorporation into clinical practice.. Measurement of thiopurine-related enzymes and metabolites reduces the risk of adverse effects and improves efficacy, and should be considered part of standard management. However, this approach will not predict or avoid all adverse effects, and careful clinical and laboratory monitoring of patients receiving thiopurines remains essential.

Topics: Azathioprine; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Pharmacogenetics; Thioinosine; Thionucleotides

Cancer may be a complication of inflammatory bowel disease (IBD) or its treatments. In older Crohn's disease and ulcerative colitis patients, the risk of malignancy is of particular concern. IBD diagnosis at an advanced age is associated with earlier development of colitis-associated colorectal cancer. Thiopurine use in older IBD patients is tied to an increased risk of non-Hodgkin's lymphoma, nonmelanoma skin cancer, and urinary tract cancers. Additionally, older age is accompanied by multimorbidity, an increased risk of malnutrition, and decreased life expectancy, factors that complicate the management of cancer in the elderly. The optimal approach to the increased risk of malignancy in older age IBD is appropriate cancer screening and medical treatment. This may include age-specific colorectal cancer screening and limiting UV radiation exposure. With a growing number of older IBD patients, further studies are necessary to delineate the risk of cancer in this population.

Topics: Age Factors; Aged; Colorectal Neoplasms; Early Detection of Cancer; Humans; Inflammatory Bowel Diseases; Lymphoma, Non-Hodgkin; Mercaptopurine; Skin Neoplasms; Urologic Neoplasms

The incidence and prevalence of inflammatory bowel disease (IBD) are increasing. Although the etiology of IBD is unknown, it is thought that genetically susceptible individuals display an inappropriate inflammatory response to commensal microbes, resulting in intestinal tissue damage. Key proteins involved in regulating the immune response, and thus in inflammation, are the small triphosphate-binding protein Rac and its regulatory network. Recent data suggest these proteins to be involved in (dys)regulation of the characteristic inflammatory processes in IBD. Moreover, Rac-gene variants have been identified as susceptibility risk factors for IBD, and Rac1 GTPase signaling has been shown to be strongly suppressed in non-inflamed mucosa compared with inflamed colonic mucosa in IBD. In addition, first-line immunosuppressive treatment for IBD includes thiopurine therapy, and its immunosuppressive effect is primarily ascribed to Rac1 suppression. In this review, we focus on Rac modification and its potential role in the development of IBD, Rac as the molecular therapeutic target in current thiopurine therapy, and the modulation of the Rac signal transduction pathway as a promising novel therapeutic strategy.

Topics: Genetic Markers; Genetic Predisposition to Disease; Humans; Immunosuppressive Agents; Inflammation; Inflammatory Bowel Diseases; Mercaptopurine; NADPH Oxidases; Polymorphism, Single Nucleotide; rac1 GTP-Binding Protein; Signal Transduction

Thiopurine therapy for inflammatory bowel disease (IBD) has been associated with increased risk for lymphoma. We estimated the relative risk of lymphoma in patients with IBD exposed to thiopurines and compared relative risk values derived from population-based studies with those from referral center-based studies. We investigated whether active use increased risk compared with past use, and whether sex, age, or duration of use affects risk of lymphoma.. We searched MEDLINE, EMBASE, and Cochrane databases, as well as conference abstracts and international publications, for the terms "6-MP and lymphoma," "6-mercaptopurine and lymphoma," "thiopurines and lymphoma," "azathioprine and cancer and IBD," "azathioprine and malignancy and IBD," "azathioprine and lymphoma," and "lymphoproliferative and thiopurines." Pooled standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were estimated. The deviance statistic from Poisson models was used to calculate heterogeneity.. Eighteen studies (among 4383 citations) met our inclusion criteria. Overall, the SIR for lymphoma was 4.92 (95% CI, 3.10-7.78), ranging from 2.80 (95% CI, 1.82-4.32) in 8 population studies to 9.24 (95% CI, 4.69-18.2) in 10 referral studies. Population studies demonstrated an increased risk among current users (SIR = 5.71; 95% CI, 3.72-10.1) but not former users (SIR = 1.42; 95% CI, 0.86-2.34). Level of risk became significant after 1 year of exposure. Men have a greater risk than women (relative risk = 1.98; P < .05); both sexes were at increased risk for lymphoma (SIR for men = 4.50; 95% CI = 3.71-5.40 and SIR for women = 2.29; 95% CI = 1.69-3.05). Patients younger than 30 years had the highest relative risk (SIR = 6.99; 95% CI, 2.99-16.4); younger men had the highest risk. The absolute risk was highest in patients older than 50 years (1:354 cases per patient-year, with a relative risk of 4.78).. Compared with studies from referral centers, population-based studies of IBD patients show a lower but significantly increased risk of lymphoma among patients taking thiopurines. The increased risk does not appear to persist after discontinuation of therapy. Patients over 50 have the highest absolute risk of lymphoma per year on thiopurines, while men under 35 may also be a high risk group. More study is needed to precisely understand groups highest at risk. The risks of lymphoma and potential benefits of therapy should be considered for all patients with IBD.

Topics: Adult; Aged; Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Lymphoma; Male; Mercaptopurine; Middle Aged; Risk; Risk Assessment; Young Adult

Immune modulating drugs such as thiopurines (azathioprine and 6-mercaptopurine) and methotrexate has been a mainstay for treatment of inflammatory bowel disease (IBD) for decades. However, despite widely used in IBD, questions still remain concerning the most rational treatment regimens of these agents. Results from a range of recent studies necessitate increased awareness on how to best use these potent drugs in the clinic. As controversy still remains regarding the most appropriate use of immunomodulators, this review is based on scrutinizing the current literature, with emphasis on randomized controlled trials and Cochrane reviews, focusing on aspects that can lead to optimal and evidence-based thiopurine and methotrexate treatment strategies in IBD.

Topics: Azathioprine; Humans; Immunologic Factors; Immunomodulation; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate; Treatment Outcome

The thiopurine drugs, 6-mercaptopurine (6-MP) and azathioprine (AZA), remain as a mainstay therapy in inflammatory bowel disease (IBD). Differences in metabolism of these drugs lead to individual variation in thiopurine metabolite levels that can determine its therapeutic efficacy and development of adverse reactions. In this update, we will review thiopurine metabolic pathway along with the up-to-date approaches in administering thiopurine medications based on the current literature.. A search of the PubMed database by 2 independent reviewers identifying 98 articles evaluating thiopurine metabolism and IBD management.. Monitoring thiopurine metabolites can assist physicians in optimizing 6-MP and AZA therapy in treating patients with IBD. Of the dosing strategies reviewed, we found evidence for monitoring thiopurine metabolite level, use of allopurinol with thiopurine, use of mesalamine with thiopurine, combination therapy with thiopurine and anti-tumor necrosis factor agents, and split dosing of AZA or 6-MP to optimize thiopurine therapy and minimize adverse effects in IBD.. Based on the currently available literature, various dosing strategies to improve therapeutic response and reduce adverse reactions can be considered, including use of allopurinol with thiopurine, use of mesalamine with thiopurine, combination therapy with thiopurine and anti-tumor necrosis factor agents, and split dosing of thiopurine.

Topics: Azathioprine; Disease Management; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Prognosis; Time Factors

Thiopurines are the cornerstone of treatment for a wide variety of medical disorders, ranging from pediatric leukemia to inflammatory bowel disease. Because of their complex metabolism and potential toxicities, the use of biomarkers to predict risk and response is paramount. Thiopurine S-methyltransferase and thiopurine metabolite levels have emerged as companion diagnostics with crucial roles in facilitating safe and effective treatment. This review serves to update the reader on how these tools are being developed and implemented in clinical practice. A useful paradigm in thiopurine therapeutic strategy is presented, along with fresh insights into the mechanisms underlying these approaches. We elaborate on potential future developments in the optimization of thiopurine therapy.

Topics: Allopurinol; Biomarkers; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukemia; Mercaptopurine; Methyltransferases

Azathioprine and 6-mercaptopurine remain pivotal therapies for the maintenance of disease remission in patients with Crohn's disease and ulcerative colitis. While thiopurine S-methyltransferase deficiency was the first pharmacogenetic phenomenon to be recognized to influence thiopurine toxicity and reliably predict leukopenia, it does not predict other adverse effects, nor does it explain most cases of thiopurine resistance. In recent years, a number of other genetic polymorphisms have received increasing attention in the literature. In particular, SNPs in NUDT15 and in the class II HLA locus have been shown to predict thiopurine-related leukopenia and pancreatitis. The aim of this review is to provide a concise update of genetic variability which may influence patient response to azathioprine and 6-mercaptopurine.

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Genotype; Histocompatibility Antigens Class II; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Pharmacogenetics; Polymorphism, Single Nucleotide; Purine-Pyrimidine Metabolism, Inborn Errors; Pyrophosphatases

Thiopurines are effective in maintaining remission in chronic inflammatory bowel diseases, but incomplete response or side effects are common during standard-dose treatment. In this article thiopurine metabolism and pharmacogenetic aspects are summarized showing their benefits in improving therapy in chronic inflammatory bowel disease. An increasing body of evidence suggests that a large part of the observed non-pancreatic side effects and poor responses can be solved by tailoring thiopurine therapy using measurement of thiopurine methyltransferase and metabolites and by using a combination therapy with low-dose thiopurines and allopurinol.

Topics: Algorithms; Allopurinol; Antimetabolites; Azathioprine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases

The management of patients with moderate to severe inflammatory bowel diseases, that is, Crohn's disease and ulcerative colitis, remains challenging. In recent years, therapeutic goal evolved from clinical remission to mucosal healing and deep remission. In order to achieve remission, it is important to appropriately choose and use available drugs. Therefore, anti-TNFα treatment should be rapidly used for severe and at-risk patients, sometimes in association with thiopurines or methotrexate. The monitoring of through levels and antibodies to anti-TNFα is relevant to optimize the treatment and to reduce drug inefficacy. However, the development of new drugs is required to offer alternative tools to severe and refractory patients.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Azathioprine; Drug Resistance; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate; Tumor Necrosis Factor-alpha

Thiopurines are the mainstay of treatment for patients with inflammatory bowel disease (IBD). Thiopurine therapy increases the risk of nonmelanoma skin cancers (NMSCs) in organ transplant patients. The data on NMSC in patients with IBD on thiopurines is conflicting.. We searched electronic databases for full journal articles reporting on the risk of developing NMSC in patients with IBD on thiopurine and hand searched the reference lists of all retrieved articles. Pooled adjusted hazard ratios and 95% confidence intervals (CIs) were determined using a random-effects model. Publication bias was assessed using Funnel plots and Egger's test. Heterogeneity was assessed using Cochran's Q and the I(2) statistic.. Eight studies involving 60,351 patients provided data on the risk of developing NMSC in patients with IBD on thiopurines. The pooled adjusted hazards ratio of developing NMSC after exposure to thiopurines in patients with IBD was 2.28 (95% CI: 1.50 to 3.45). There was significant heterogeneity (I(2)=76%) between the studies but no evidence of publication bias. Meta regression analysis suggested that the population studied (hospital-based vs. population-based) and duration of follow-up contributed significantly to heterogeneity. Grouping studies based on population studied and duration showed higher hazard rations in hospital-based and shorter duration studies.. The risk of developing NMSC in patients with IBD on thiopurines is only modestly elevated. The difference in pooled risk between population-based and hospital-based studies suggests the possibility that ascertainment bias could have contributed to this increased risk.

Topics: Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cohort Studies; Confidence Intervals; Databases, Factual; Education, Medical, Continuing; Female; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Male; Mercaptopurine; Prognosis; Proportional Hazards Models; Regression Analysis; Risk Assessment; Skin Neoplasms; United Kingdom

The thiopurine medications are standard inflammatory bowel disease treatments. Therapeutic failure is observed, however, often because of variable drug metabolism. Allopurinol can enhance the potency of thiopurine treatment. Our objective is to review the relevant literature, and our own experience, to determine if allopurinol enhancement of thiopurine treatment is a reasonable therapeutic strategy.. Published reports of, and our own experience using, allopurinol-thiopurine combination therapy indicate that the addition of allopurinol will enhance thiopurine treatment in up to 60% of patients. There are risks to this approach, but with appropriate monitoring, these risks should approximate those observed with thiopurine therapy alone.. Combination therapy with allopurinol and a thiopurine is a reasonable alternative for inflammatory bowel disease patients not responding to thiopurine monotherapy. Physicians experienced in thiopurine treatment, who have familiarity with thiopurine metabolism, and are willing to engage in appropriate therapeutic monitoring, should consider this strategy.

Topics: Allopurinol; Azathioprine; Drug Monitoring; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Practice Guidelines as Topic

Crohn's disease and ulcerative colitis affect an increasing number of patients. A variety of medical options exist for the treatment of these diseases including immune suppressants and biologic therapies. Unfortunately, these agents are associated with adverse events ranging from mild nuisance symptoms to potentially life-threatening complications including infections and malignancies. This review discusses adverse events associated with azathioprine, mercaptopurine, and methotrexate as well as anti-TNF-α and anti-integrin antibodies. In addition, adverse events associated with combination therapy are discussed as are clinical scenarios in which it may be reasonable to discontinue or de-escalate drug therapy. It is the responsibility of the treating gastroenterologist to effectively communicate the benefits and risks of therapy with patients; this review offers strategies that may assist providers in communicating risk with patients in addition to offering our perspective on whether modification or cessation of therapy can be considered.

Topics: Antibodies, Anti-Idiotypic; Azathioprine; Biological Products; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Integrins; Mercaptopurine; Methotrexate; Risk Assessment; Tumor Necrosis Factor-alpha; Withholding Treatment

Thiopurines are the mainstay of medical management in inflammatory bowel disease (IBD), especially in the maintenance of disease remission. Given the limited IBD armamentarium it is important to optimize each therapy before switching to an alternative drug. Conventional weight based dosing of thiopurines in IBD leads to intolerance or inefficacy in many patients. More recently increased knowledge of their metabolism has allowed for dose optimization using thiopurine metabolite levels, namely 6-thioguanine nucleotides and 6-methylmercaptopurine, with the potential for improved outcomes in patients with IBD. This review will outline the current understanding of thiopurine metabolism and pharmacogenomics and will describe the clinical application of this knowledge in the optimization of thiopurines in individual patients.

Topics: Allopurinol; Antimetabolites; Azathioprine; Drug Monitoring; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases

Inflammatory bowel disease (IBD) typically affects patients during their adolescent and young adult years. As these are the reproductive years, patients and physicians often have concerns regarding the interaction between IBD, medications and surgery used to treat IBD, and reproduction, pregnancy outcomes, and neonatal outcomes. Studies have shown a lack of knowledge among both patients and physicians regarding reproductive issues in IBD. As the literature is constantly expanding regarding these very issues, with this review, we provide a comprehensive, updated overview of the literature on the management of the IBD patient from conception to delivery, and provide action tips to help guide the clinician in the management of the IBD patient during pregnancy.

Topics: Adrenal Cortex Hormones; Aminosalicylic Acid; Anti-Bacterial Agents; Azathioprine; Biological Products; Breast Feeding; Cyclosporine; Female; Fertility; Humans; Inflammatory Bowel Diseases; Maternal Exposure; Mercaptopurine; Methotrexate; Pregnancy; Pregnancy Complications; Sulfasalazine

Azathioprine is a purine antimetabolite drug commonly used to treat inflammatory bowel disease (IBD). In vivo it is active after reaction with reduced glutathione (GSH) and conversion to mercaptopurine. Although this reaction may occur spontaneously, the presence of isoforms M and A of the enzyme glutathione-S-transferase (GST) may increase its speed. Indeed, in pediatric patients with IBD, deletion of GST-M1, which determines reduced enzymatic activity, was recently associated with reduced sensitivity to azathioprine and reduced production of azathioprine active metabolites. In addition to increase the activation of azathioprine to mercaptopurine, GSTs may contribute to azathioprine effects even by modulating GSH consumption, oxidative stress and apoptosis. Therefore, genetic polymorphisms in genes for GSTs may be useful to predict response to azathioprine even if more in vitro and clinical validation studies are needed.

Topics: Animals; Apoptosis; Azathioprine; Glutathione; Glutathione Transferase; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Oxidative Stress; Pharmacogenetics; Polymorphism, Genetic

The medical management of inflammatory bowel disease (IBD) is evolving toward a personalized medicine-based model. Modern therapeutic algorithms that feature use of tumor necrosis factor (TNF) antagonists in combination with immunosuppressive are highly effective when initiated in high-risk patients early in the course of disease. Defined targets that guide intensification of therapy are critical interventions. In this model, therapy is optimized through appropriate pretreatment testing, therapeutic drug monitoring, and patient-based monitoring strategies. This review discusses the current application of personalized medicine to the management of IBD.

Topics: Algorithms; Azathioprine; Drug Monitoring; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Precision Medicine; Tumor Necrosis Factor-alpha

Patients with inflammatory bowel disease (IBD) are at increased risk for developing colorectal neoplasia. Researchers have debated whether treatment of IBD with thiopurines reduces cancer risk. We performed a meta-analysis of thiopurine exposure and risk of colorectal dysplasia or cancer in patients with IBD.. We used MEDLINE, EMBASE, and Cochrane search engines and abstract books from international conferences to identify relevant literature. We included studies on thiopurine exposure and risk of colorectal neoplasia in patients with ulcerative colitis or Crohn's disease. We calculated pooled odds ratios (ORs) with 95% confidence intervals (CIs) and performed a meta-regression analysis of the effect of year of publication. Various sensitivity analyses were conducted.. Fifteen studies fulfilled the inclusion criteria. Overall, we did not observe a significant effect of thiopurines on risk for colorectal neoplasia (dysplasia and/or cancer) in patients with IBD (OR, 0.87; 95% CI, 0.71-1.06). The estimate did not change markedly in separate assessments of the 2 population-based studies (OR, 0.87; 95% CI, 0.59-1.29), the 13 clinic-based studies (OR, 0.87; 95% CI, 0.59-1.09), the 7 cohort studies (OR, 0.93; 95% CI, 0.67-1.28), or the 8 case-control studies (OR, 0.83; 95% CI, 0.65-1.08). Studies that used neoplasia (dysplasia or cancer) as outcomes tended to show that thiopurines had protective effects (OR for neoplasia, 0.72; 95% CI, 0.50-1.05); these effects were not observed in studies of colorectal cancer (OR, 0.90; 95% CI, 0.72-1.12) or in studies published in recent years (meta-regression; P = .16).. In a meta-analysis, we did not find a significant protective effect of treatment with thiopurines on the risk of colorectal neoplasia in patients with IBD.

Topics: Colorectal Neoplasms; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Risk Assessment; Treatment Outcome

Topics: Adult; Antibodies, Monoclonal; Azathioprine; Comparative Effectiveness Research; Disease Management; Drug Interactions; Drug Therapy, Combination; Female; Humans; Immunologic Factors; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methotrexate; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic; Treatment Outcome; Tumor Necrosis Factor-alpha

It has been proposed that effective disease control through abrogation of inflammation in IBD may also reduce CRC risk in these individual patients. This article summarizes the potential for medical therapy to reduce the risk of CRC via primary and secondary prevention, and offers practical ways in which a goal of mucosal improvement or healing may be incorporated into clinical practice.

Topics: Adenocarcinoma; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Cholagogues and Choleretics; Colonoscopy; Colorectal Neoplasms; Early Detection of Cancer; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Intestinal Mucosa; Mercaptopurine; Mesalamine; Tumor Necrosis Factor-alpha; Ursodeoxycholic Acid

Hepatic involvement is often encountered in gastrointestinal (GI) diseases, in part because of the close anatomic and physiologic relations between the liver and GI tract. Drainage of the mesenteric blood supply to the portal vein permits absorbed and/or translocated nutrients, toxins, bacterial elements, cytokines, and immunocytes to gain hepatic access. Liver problems in digestive disorders may range from nonspecific hepatocellular enzyme elevations to significant pathologic processes that may progress to end-stage liver disease. Hepatobiliary manifestations of primary GI diseases in childhood and adolescence are not uncommon and include several well-described associations, such as sclerosing cholangitis with inflammatory bowel disease. Liver damage may also result from the effects of drugs used to treat GI diseases, for example, the hepatotoxicity of immunomodulatory therapies. This review highlights the important features of the hepatic and biliary abnormalities associated with 3 common pediatric GI conditions: inflammatory bowel disease, celiac disease, and cystic fibrosis.

Topics: Adolescent; Antibodies, Monoclonal; Azathioprine; Celiac Disease; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cholagogues and Choleretics; Cholangitis, Sclerosing; Cystic Fibrosis; Humans; Infant; Inflammatory Bowel Diseases; Infliximab; Liver Diseases; Liver Function Tests; Mercaptopurine; Methotrexate; Tumor Necrosis Factor-alpha; Ursodeoxycholic Acid

Thiopurines are effective in maintaining remission in chronic inflammatory bowel diseases, but incomplete response or side effects are common during standard-dose treatment. In this article thiopurine metabolism and pharmacogenetic aspects are summarized showing their benefits in improving therapy in chronic inflammatory bowel disease. An increasing body of evidence suggests that a large part of the observed non-pancreatic side effects and poor responses can be solved by tailoring thiopurine therapy using measurement of thiopurine methyltransferase and metabolites and by using a combination therapy with low-dose thiopurines and allopurinol.

Topics: Algorithms; Allopurinol; Antimetabolites; Azathioprine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases

Azathioprine is an efficient maintenance treatment of IBD, able to maintain a complete clinical and anatomical remission in about one third of patients. However there are concerns regarding its long term tolerance, particularly myelosuppression and malignancy. Azathioprine is not required in about one third of Crohn's Disease patients and more than half of Ulcerative Colitis patients who will experience a mild disease course. In patients with more severe disease, although anti-TNF agents are more powerful and act more rapidly, there is a subset of patients with moderate-to-severe IBD without important anatomical damage who may achieve a prolonged steroid-free clinical and anatomical remission on azathioprine monotherapy. It is thus advised to initiate azathioprine monotherapy in these intermediate cases, and to continue azathioprine if anatomical remission is achieved.

Topics: Antibodies, Monoclonal; Azathioprine; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Randomized Controlled Trials as Topic; Recurrence; Treatment Outcome; Tumor Necrosis Factor-alpha

Thiopurines maintain remission and modify disease course in inflammatory bowel disease. Use is limited by intolerance and subsequent drug withdrawal in approximately 17% of patients treated with azathioprine. Previous case series have addressed the success rates of re-treatment with mercaptopurine in these individuals.. To determine the rate of tolerance when trialling mercaptopurine in azathioprine-intolerant patients and the factors predictive of success, and to perform a systematic review and meta-analysis of these data with other published data sets.. A retrospective observational study of 149 patients with IBD (82 with Crohn's disease and 67 with ulcerative colitis) previously intolerant of azathioprine subsequently treated with mercaptopurine was performed. A meta-analysis was undertaken of all published studies of mercaptopurine use in azathioprine-intolerant patients (455 patients in 11 included studies).. Mercaptopurine was tolerated by 58% of azathioprine-intolerant patients in the Edinburgh cohort. In the meta-analysis, 68% tolerated mercaptopurine. A higher proportion of those in the meta-analysis with GI toxicity (62%) or hepatotoxicity (81%) were able to tolerate mercaptopurine than those with flu-like illness (36%). Among those patients who ceased mercaptopurine for further adverse effects, 59% experienced the same adverse effect as they had with azathioprine.. This meta-analysis shows that switching to mercaptopurine is a safe therapeutic strategy for over two-thirds of azathioprine-intolerant patients and may help optimise immunomodulatory therapy in inflammatory bowel disease. A trial of mercaptopurine should be attempted in IBD patients (except those with acute pancreatitis or bone marrow aplasia) before considering thiopurine intolerance.

Topics: Adult; Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Retrospective Studies

Inflammatory bowel disease (IBD) is commonly treated with thiopurines such as azathioprine and mercaptopurine for the maintenance of remission. Studies examining chemopreventive of these medications on colorectal neoplasm in IBD patients have yielded conflicting results. We performed a meta-analysis to assess the role of thiopurines for this indication.. We performed a systematic search of PubMed, Web of Science, EMBASE and Cochrane to identify studies reporting colorectal neoplasm from IBD patients treated with thiopurines and conducted a meta-analysis of pooled relative risk (RR) using the random effects model.. Nine case-control and ten cohort studies fulfilled the inclusion criteria. The use of thiopurines was associated with a statistically significant decreased incidence of colorectal neoplasm (summary RR=0.71, 95% CI=0.54-0.94, p=0.017), even after adjustment for duration and extent of the disease, but there was high heterogeneity among studies (I(2)=68.0%, p<0.001). The RR of advanced neoplasm (high-grade dysplasia and cancer) was 0.72 (95%CI=0.50-1.03, p=0.070) and that of cancer was 0.70 (95% CI=0.46-1.09, p=0.111) for thiopurine-treated patients. Heterogeneity of the studies was affected by the sample size (

Topics: Azathioprine; Colorectal Neoplasms; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Risk

Inflammatory bowel disease (IBD) affects people during their prime reproductive years. The thiopurines (6-mercaptopurine and azathioprine), commonly used for induction and maintenance of remission, are U.S. Food and Drug Administration (FDA) pregnancy category D, raising concern for fetal risk. We performed a systematic review and meta-analysis to evaluate the effects of thiopurine exposure during pregnancy or at the time of conception on three measures of fetal risk in women and men with IBD.. A systematic search of PubMed and Web of Science using a combination of Mesh and text terms was performed to identify studies reporting birth outcomes from IBD women and men exposed to thiopurines within 3 months of conception and/or during pregnancy. A meta-analysis was performed using the random effects model to pool estimates and report odds ratio (OR) for three outcomes in women: low birth weight (LBW), preterm birth, and congenital abnormalities and one in men: congenital abnormalities.. In women with IBD exposed to thiopurines, the pooled ORs for LBW, preterm birth, and congenital abnormalities were 1.01 (95% confidence interval [CI] 0.96, 1.06), 1.67 (95% CI 1.26, 2.20), and 1.45 (95% CI 0.99, 2.13), respectively. In men, the pooled OR for congenital abnormality was 1.87 (95% CI 0.67, 5.25).. Thiopurine exposure in women with IBD was not associated with LBW or congenital abnormalities, but was associated with preterm birth. Exposure in men at the time of conception was not associated with congenital abnormalities.

Topics: Azathioprine; Congenital Abnormalities; Female; Humans; Immunosuppressive Agents; Infant, Low Birth Weight; Infant, Newborn; Inflammatory Bowel Diseases; Male; Mercaptopurine; Meta-Analysis as Topic; Odds Ratio; Pregnancy; Pregnancy Complications; Premature Birth; Prognosis

The lymphoproliferative disorders (LDs) are a heterogeneous group of at least 70 conditions that result from the clonal proliferation of B, T, and NK cells. Inflammatory bowel disease (IBD)-associated lymphomas are typically B-cell LD, while T-cell or Hodgkin's lymphomas are rare. In IBD patients not on immunosuppression, the risk of LD seems to be similar or slightly higher than the background population risk. Thiopurine therapy is associated with an increased risk: the relative risk is increased four- to sixfold and the absolute risk varies between 1 in 4000-5000 for those aged 20-29 to 1 in 300-400 in those over 70. It is difficult to quantify the risk of anti- tumor necrosis factor (TNF) therapy alone; however, it appears to be less than for thiopurines alone. There is particular concern regarding the development of post-transplant-like LD in those with latent epstein-barr virus (EBV) infection exposed to immunosuppressives, the occurrence of hepatosplenic T cell lymphoma in patients treated with combination anti-TNF and thiopurine therapy, and the development of hemophagocytic lymphohistiocytosis in those who acquire a primary EBV or other infections while on immunosuppressive medication. There are currently no guidelines for monitoring EBV (or other virus) status in patients on immunosuppression, although it could be used to monitor those who have a prior history of lymphoma and are about to start a thiopurine or anti-TNF agent. In discussing the risks of lymphoproliferative disorders associated with agents used for the treatment of IBD, patients can often be reassured that the benefits of such therapy still outweigh the small, but real, risks.

Topics: Age Factors; Azathioprine; Epstein-Barr Virus Infections; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Lymphohistiocytosis, Hemophagocytic; Lymphoma; Lymphoproliferative Disorders; Mercaptopurine; Risk Factors; Tumor Necrosis Factor-alpha

Maintaining remission of inflammatory bowel disease (IBD) during pregnancy is critical for positive pregnancy outcomes. Conflicting data exist regarding the association between thiopurine use for IBD treatment in pregnancy and adverse pregnancy outcomes and this meta-analysis aims to clarify this association. A meta-analysis was performed of all original human studies reporting outcomes in pregnancy in patients receiving thiopurines. Nine studies satisfied the inclusion criteria and a total of 494 patients with IBD and 2,782 IBD controls were reported. When compared with healthy women, those receiving thiopurines had an increased risk for congenital malformations (RR 1.45; 95% CI 1.07-1.96; p = 0.02); however, when compared with IBD controls, there was no increased risk (RR 1.37; 95% CI 0.92-2.05; p = 0.1). These data provide support for thiopurines having a minimal risk, if any, to the fetus.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Animals; Azathioprine; Birth Weight; Case-Control Studies; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Premature Birth

Despite recent advances, the therapeutic armamentarium for inflammatory bowel disease (IBD) is still limited. In addition, a step-up approach is recommended for most IBD patients. Thus, optimizing each medical therapy before switching to another drug class is the rule in clinical practice. Conventional therapies for IBD have not received the same amount of attention as biologic therapies over the last decade. However, due to their efficacy, safety, and low cost the thiopurine drugs azathioprine and 6-mercaptopurine remain the backbone of therapy for IBD. Pharmacogenomic advances and increased knowledge of their metabolism are allowing dosage optimization. Herein, after describing the pharmacogenetics and pharmacokinetics of thiopurines, we will discuss how to optimize thiopurine therapy. We will then underscore the need to take into account safety issues when optimizing thiopurine treatment.

Topics: Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases

The aim of this article is to review current evidence-based approaches to treatment of ulcerative colitis and Crohn's disease.. The primary goal of treatment is to induce and to maintain remission in a safe and efficacious fashion. The 5-aminosalicylic acid (5-ASA) agents and oral steroids remain the first-line approach for the treatment of ulcerative colitis and Crohn's disease. The 'step-up' approach includes the use of immunomodulators [azathioprine (AZA), or 6-mercaptopurine (6-MP)] and newer biologic agents (infliximab, adalimumab, and natalizumab). The 'step-down' approach can also be considered individually on the basis of the severity of Crohn's disease.. Current treatment regimens still involve medications with well known efficacy and safety profiles and progress to more potent treatments such as immunomodulators and biologic agents. Adverse events of potent treatment with biologics and immunomodulators have been recognized. In some cases, aggressive approaches with the use of more potent agents as first-line therapy has been proposed, but they are still not considered a routine approach.

Topics: Adrenal Cortex Hormones; Aminosalicylic Acids; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Budesonide; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Natalizumab

The thiopurine drugs, 6-mercaptopurine (6-MP) and azathioprine, are efficacious in the arsenal of inflammatory bowel disease (IBD) therapy. Previous reports indicate that 6-thioguanine nucleotide (6-TGN) levels correlate with therapeutic efficacy, whereas high 6-methylmercaptopurine (6-MMP) levels are associated with hepatotoxicity and myelotoxicity. Due to their complex metabolism, there is wide individual variation in patient response therein, both in achieving therapeutic drug levels as well as in developing adverse reactions. Several strategies to optimize 6-TGN while minimizing 6-MMP levels have been adopted to administer the thiopurine class of drugs to patients who otherwise would not tolerate these drugs due to side-effects. In this report, we will review different approaches to administer the thiopurine medications, including the administration of 6-mercaptopurine in those unsuccessfully treated with azathioprine; co-administration of thiopurine with allopurinol; co-administration of thiopurine with anti-tumor necrosis factor α; 6-TGN administration; desensitization trials; and split dosing of 6-MP.

Topics: Azathioprine; Disease Management; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Purines

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

Thiopurine drugs are widely used as immunomodulatory and corticosteroid-sparing agents in inflammatory bowel disease. Despite being old drugs, a renewed research and clinical interest in their application has emerged during the last decade. The application of pharmacogenetic insights and metabolic monitoring, together with treatment strategies in combination with anti-TNFalpha-antibodies and possibilities to modulate their metabolism, has paved the way to a "modern" use of the thiopurines. These aspects are briefly overviewed herein.

Topics: Animals; Antibodies, Monoclonal; Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Thionucleosides

To evaluate the relationship between thiopurine S-methyltransferase (TPMT) polymorphisms and thiopurine-induced adverse drug reactions (ADRs) in inflammatory bowel disease (IBD).. Eligible articles that compared the frequency of TPMT polymorphisms among thiopurine-tolerant and -intolerant adult IBD patients were included. Statistical analysis was performed with Review Manager 5.0. Sub-analysis/sensitivity analysis was also performed.. Nine studies that investigated a total of 1309 participants met our inclusion criteria. The incidence of TPMT gene mutation was increased 2.93-fold (95% CI: 1.68-5.09, P = 0.0001) and 5.93-fold (95% CI: 2.96-11.88, P < 0.00001), respectively, in IBD patients with thiopurine-induced overall ADRs and bone marrow toxicity (BMT), compared with controls. The OR for TPMT gene mutation in IBD patients with thiopurine-induced hepatotoxicity and pancreatitis was 1.51 (95% CI: 0.54-4.19, P = 0.43) and 1.02 (95% CI: 0.26-3.99, P = 0.98) vs controls, respectively.. This meta-analysis suggests that the TPMT polymorphisms are associated with thiopurine-induced overall ADRs and BMT, but not with hepatotoxicity and pancreatitis.

Topics: Adult; Azathioprine; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Polymorphism, Genetic

Topics: Chromosome Disorders; Humans; Inflammatory Bowel Diseases; Lymphoma, T-Cell; Mercaptopurine; Splenic Neoplasms

The thiopurines azathioprine and 6-mercaptopurine have been used in the treatment of Crohn's disease and ulcerative colitis for over 40 years. Randomized controlled trials have supported their use in the treatment of active disease, as well as for the maintenance of disease remission. Presently, the most debated issues surrounding the thiopurines include: the role of thiopurine methyltransferase and metabolite-adjusted dosing in enhancing efficacy and minimizing toxicity; the timing of thiopurine use, that is, earlier versus later use during the course of the disease; the selection of thiopurine monotherapy versus combination therapy with an anti-TNF-α; agent; and the safety profile of thiopurines. Accumulated evidence has supported the safety of 6-mercaptopurine/azathioprine use in pregnancy and lactation. Thiopurine therapy in inflammatory bowel diseases is associated with an increased risk of lymphoproliferative disorders. Factoring their proven efficacy over a broad range of clinical scenarios within Crohn's disease and ulcerative colitis together with their overall safety profile and convenient and inexpensive once-daily oral administration, azathioprine and 6-mercaptopurine remain among the mainstays of Crohn's disease and ulcerative colitis therapy.

Topics: Animals; Anti-Inflammatory Agents; Azathioprine; Drug Therapy, Combination; Evidence-Based Medicine; Gastrointestinal Agents; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Risk Assessment; Treatment Outcome

This article reviews the current literature and knowledge about hepatosplenic T-cell lymphoma (HSTCL), providing an overview of the clinical features, a description of its pathology and immunophenotypic traits in relation to other lymphomas. In addition, we explore the history of reported cases of hepatosplenic T-cell lymphoma in relation to the possible existence of a causal relationship between infliximab use and HSTCL. The treatments for HSTCL will be briefly addressed.. A comprehensive literature search using multiple databases was performed. Keyword search phrases including "lymphoma," "hepatosplenic T-cell lymphoma," "Inflammatory bowel disease," "6-mercaptopurine," and "infliximab" were used in various combinations. In addition references from published papers were reviewed as well.. There are over 200 reported cases of HSTCL. Only 22 cases of hepatosplenic T-cell lymphoma are associated with IBD treatment. Clinicians usually reserve immunomodulators and biologics for moderate to severe IBD cases. The ultimate goal of therapy is to control inflammation and therefore allow mucosal healing. IBD patients demonstrating mucosal healing are less likely to undergo surgery and experience complications related to their disease. We manipulate the immune system with corticosteroids, immunomodulators, and biologics, therefore causing bone marrow suppression. With bone marrow suppression, malignant degeneration may begin through selective uncontrolled cell proliferation, initiating HSTCL development in the genetically susceptible.. Hepatosplenic T-cell lymphoma is a rare disease, often with a poor outcome. With the increasing number of reported cases of HSTCL linked to the use of infliximab, adalimumab, and AZA/6-MP, there appears to be an undeniable association of HSTCL development with the use of these agents. This risk is unquantifiable. When considering the rarity of cases and the multiple complications with uncontrolled disease, however, the benefit of treatment far outweighs the risk.

Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal; Azathioprine; Humans; Immunophenotyping; Immunosuppression Therapy; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Liver Neoplasms; Lymphoma, T-Cell, Peripheral; Mercaptopurine; Splenic Neoplasms; Tumor Necrosis Factor-alpha

Topics: Adaptation, Psychological; Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Female; Humans; Immunosuppressive Agents; Infertility, Female; Infertility, Male; Inflammatory Bowel Diseases; Male; Mercaptopurine; Mesalamine; Pregnancy; Pregnancy Complications; Reproductive Behavior; Stress, Psychological; Sulfasalazine

Young women with inflammatory bowel disease (IBD) pose a unique set of challenges. These women and their treating physicians must make difficult choices in matters regarding conception, pregnancy, and breastfeeding. This review highlights recent evidence and management issues that arise when taking care of women with IBD in terms of fertility, outcomes, and medication safety in pregnancy and breastfeeding. Ultimately, treatment must be individualized for each patient based on the available evidence and the woman's preferences.

Topics: Animals; Azathioprine; Breast Feeding; Drug Therapy, Combination; Evidence-Based Medicine; Female; Fertility; Gastrointestinal Agents; Glucocorticoids; Humans; Immunosuppressive Agents; Infertility, Female; Inflammatory Bowel Diseases; Mercaptopurine; Meta-Analysis as Topic; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Risk Factors

This article summarizes the David Sun Lecture at the American College of Gastroenterology in Orlando, Florida, that was delivered on October 4, 2008. The lecture, entitled "The Future Direction of IBD Care," reviewed the future use of current drugs (such as 5-aminosalicylate, steroids, immunosuppressive medications, and biologic agents) and upcoming drugs in the treatment of IBD.

Topics: Adalimumab; Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Certolizumab Pegol; Clinical Trials as Topic; Gastrointestinal Agents; Humans; Immunoglobulin Fab Fragments; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Mesalamine; Natalizumab; Polyethylene Glycols; Tumor Necrosis Factor-alpha

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the intestine, which frequently require surgery for complications or failure of medical therapy.. To seek evidence and provide direction for clinicians on optimal strategies to enable steroid free remission in inflammatory bowel disease.. Scientific literature was reviewed using MEDLINIE with a specific focus on medical therapies for inducing and maintaining remission of CD and UC. The results were discussed at a roundtable meeting to reach a consensus on key issues.. Several therapies have demonstrated efficacy for the treatment of active, moderate-to-severe CD and UC. These include agents, which induce remission [corticosteroids, infliximab and adalimumab (CD only)] or maintain remission and spare corticosteroids [azathioprine, mercaptopurine, methotrexate (CD only), infliximab and adalimumab (CD only)]. Wide variability exists in the use of these agents.. Treatment strategy algorithms are developed for use of these therapies that maximize remission and minimize corticosteroid dependence in patients with moderate-to-severe CD and UC.

Topics: Adalimumab; Adolescent; Adrenal Cortex Hormones; Adult; Algorithms; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Child; Clinical Protocols; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Intestinal Mucosa; Mercaptopurine; Methotrexate; Randomized Controlled Trials as Topic; Remission Induction; Severity of Illness Index

Probably, the most important and potentially lethal adverse event of azathioprine (AZA) and mercaptopurine (MP) is myelosuppression. Our aim was to conduct a review of AZA/MP-induced myelotoxicity in inflammatory bowel disease (IBD) patients.. Bibliographical searches were performed in MEDLINE/EMBASE. The studies evaluating thiopurine-induced myelotoxicity in patients with IBD were reviewed. The cumulative incidence and the incidence rate of AZA/MP-induced myelotoxicity were calculated by a meta-analysis.. In total, 66 studies (8,302 patients) were included. The cumulative incidence of AZA/MP-induced myelotoxicity was 7% (95% confidence interval [CI] 6-8%). The incidence rate (per patient and year of treatment) of the drug-induced myelotoxicity was 3% (95% CI 3-4%). The risk was roughly similar with AZA and with MP (7%vs 9%). The duration of AZA/MP treatment in patients with myelotoxicity ranged from 12 days to 27 yr. The cumulative incidence of infections among AZA/MP-induced myelotoxicity patients was 6.5%. The cumulative incidence of severe myelotoxicity was 1.1% (incidence rate 0.9%). Three deaths were reported due to myelotoxicity (cumulative incidence 0.06%, 95% CI 0.02-0.17%). The risk of death among patients who developed myelotoxicity was 0.94% (95% CI 0.32-2.70%).. The incidence rate of myelotoxicity in IBD patients receiving AZA/MP is approximately 3% per patient and year of treatment. Although bone marrow toxicity may develop at any time after starting the therapy, this happens more frequently during the first months. The incidence rate of severe myelotoxicity is less than 1% per patient and year of treatment, and the mortality risk is less than 0.1% (which means that the risk of death among IBD patients who develop myelotoxicity is approximately 1%).

Topics: Azathioprine; Bone Marrow Diseases; Humans; Inflammatory Bowel Diseases; Leukopenia; Mercaptopurine

Immunomodulator therapy with the thiopurine analogues azathioprine or 6-mercaptopurine is commonly prescribed for the treatment of inflammatory bowel disease (IBD). Drug adverse effects and the lack of efficacy, however, commonly require withdrawal of therapy. Allopurinol, a xanthine oxidase inhibitor, was recently evaluated in its role in modifying thiopurine metabolism and improving drug efficacy in IBD.. This article reviews the role and safety of allopurinol co-therapy in the setting of thiopurine hepatotoxicity and/or non-responsiveness in IBD.. Published articles on thiopurines in the treatment of IBD were examined.. The addition of low dose allopurinol to dose-reduced thiopurine analogue seems safe but careful monitoring for adverse effects and profiling of thiopurine metabolites is essential. There is evidence of improved immunomodulator efficacy and reduced hepatotoxicity clinically but further confirmatory studies are required before more definitive treatment recommendations can be given.

Topics: Allopurinol; Azathioprine; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Enzyme Inhibitors; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Liver Diseases; Mercaptopurine

Recognizing inflammatory bowel disease (IBD) is straightforward when alarm symptoms are present, such as bloody diarrhea and weight loss. When the presentation is subtle or atypical, physicians must determine which patients warrant evaluation for IBD. Appropriate use of noninvasive tests can help identify which patients should undergo further investigation.. Currently IBD serologies lack high enough sensitivity and specificity to make them useful as a screening test for distinguishing IBD from other disorders, but they may have a role in classifying subtypes of IBD. Fecal markers seem promising for helping to differentiate IBD from irritable bowl syndrome and for monitoring disease activity. Pharmacogenetically guided dosing is recommended for safe use of thiopurines but ongoing routine laboratory monitoring remains important. Thiopurine metabolite measurement can be useful but may not be needed in all cases.. Primary care physicians should continue to rely on routine laboratory tests and clinical suspicion to decide which patients with abdominal pain to refer to a gastroenterologist. Serology panels are not useful for IBD screening as the results may lead to unnecessary procedures. Although fecal markers do show promise as a screening test for IBD, patient resistance to providing stool samples may limit its usefulness in disease monitoring. Thiopurine metabolite levels are best used in conjunction with clinical status and routine laboratory tests to monitor clinical response and adverse events.

Topics: Adolescent; Azathioprine; Biomarkers; Child; Child, Preschool; Clinical Laboratory Techniques; Colitis, Ulcerative; Crohn Disease; Diagnosis, Differential; Feces; Female; Humans; Incidence; Inflammatory Bowel Diseases; Male; Mercaptopurine; Pediatrics; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index

Topics: Adrenal Cortex Hormones; Azathioprine; Cyclosporine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate; Quality of Life; Remission Induction; Risk Assessment; Risk Factors

At least one-third of patients with inflammatory bowel disease do not respond or are intolerant to therapy with 6-mercaptopurine (6-MP). A subgroup fails to attain optimal levels of 6-thioguanine nucleotide (6-TGN) and instead shunts to 6-methylmercaptopurine nucleotide (6-MMPN).. A retrospective chart review was conducted, and four patients are described who had been previously unable to achieve optimal 6-TGN metabolite levels until allopurinol was added to their treatment.. All four patients achieved optimal 6-TGN levels and undetectable 6-MMPN with a mean 6-MP dose of 0.49 mg/kg. Three achieved steroid-free clinical remission. Two of those three patients had normalization of liver enzymes; one patient had baseline normal liver enzymes despite an initial 6-MMPN level of 27,369 pmol/8 x 10(8) red blood cells. Two patients experienced reversible leukopenia.. Combination allopurinol and low-dose 6-MP is an effective means to achieve optimal metabolite levels and steroid-free clinical remission in previously refractory patients. Caution is advised.

Topics: Adult; Allopurinol; Antimetabolites; Biotransformation; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged

It is anticipated that unraveling the human genome will have a direct impact on the management of specific diseases. Variations or mutations in genes involved in drug metabolism or disease pathophysiology in gastroenterology and hepatology are expected to have effect on response to therapy. The spectrum of diseases is vast. Thus, we focus this review on clinical pharmacogenetics of inflammatory bowel disease, Helicobacter pylori infections, gastroesophageal reflux disease, irritable bowel syndrome, liver transplantation, and colon cancer. Although only a few genotyping tests are used regularly in clinical practice, we anticipate that in the future there will be more routine use of many of the tests described in this review.

Topics: Antineoplastic Agents; Azathioprine; Biotransformation; Colorectal Neoplasms; Gastrointestinal Agents; Gastrointestinal Diseases; Genetic Predisposition to Disease; Genotype; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Irritable Bowel Syndrome; Liver Diseases; Liver Transplantation; Mercaptopurine; Patient Selection; Pharmacogenetics; Phenotype; Polymorphism, Genetic; Treatment Outcome

Topics: Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine

This review summarises clinical pharmacological aspects of thiopurines in the treatment of chronic inflammatory bowel disease (IBD). Current knowledge of pharmacogenetically guided dosing is discussed for individualisation of thiopurine therapy, particularly to avoid severe adverse effects. Both azathioprine and mercaptopurine are pro-drugs that undergo extensive metabolism. The catabolic enzyme thiopurine S-methyltransferase (TPMT) is polymorphically expressed, and currently 23 genetic variants have been described. On the basis of an excellent phenotype-genotype correlation for TPMT, genotyping has become a safe and reliable tool for determination of a patient's individual phenotype. Thiopurine-related adverse drug reactions are frequent, ranging from 5% up to 40%, in both a dose-dependent and -independent manner. IBD patients with low TPMT activity are at high risk of developing severe haematotoxicity if pharmacogenetically guided dosing is not performed. Based on several cost-benefit analyses, assessment of TPMT activity is recommended prior to thiopurine therapy in patients with IBD. The underlying mechanisms of azathioprine/mercaptopurine-related hepatotoxicity, pancreatitis and azathioprine intolerance are still unknown. Although the therapeutic response appears to be related to 6-thioguanine nucleotide (6-TGN) concentrations above a threshold of 230-260 pmol per 8 x 10(8) red blood cells, at present therapeutic drug monitoring of 6-TGN can be recommended only to estimate patients' compliance.Drug-drug interactions between azathioprine/mercaptopurine and aminosalicylates, diuretics, NSAIDs, warfarin and infliximab are discussed. The concomitant use of allopurinol without dosage adjustment of azathioprine/mercaptopurine leads to clinically relevant severe haematotoxicity due to elevated thiopurine levels. Several studies indicate that thiopurine therapy in IBD during pregnancy is safe. Thus, azathioprine/mercaptopurine should not be withdrawn in strictly indicated cases of pregnant IBD patients. However, breastfeeding is contraindicated during azathioprine/mercaptopurine therapy. Use of azathioprine/mercaptopurine for induction and maintenance of remission in corticosteroid-dependent or corticosteroid-refractory IBD, particularly Crohn's disease, is evidence based. To improve response rates in thiopurine therapy of IBD, comprehensive analyses including metabolic patterns and genome-wide profiling in patients with azathioprine/mercaptopurine treatment

Topics: Adult; Animals; Drug Interactions; Female; Fertility; Humans; Inflammatory Bowel Diseases; Lactation; Mercaptopurine; Pharmacogenetics; Pregnancy

The mean prevalence of azathioprine (AZA) or 6-mercaptopurine (MP)-induced liver injury in patients with inflammatory bowel disease was approximately 3%, and the mean annual drug-induced liver disorder rate was only 1.4%. However, this low figure calculated from retrospective studies contrasts with a much higher incidence (>10%) reported by a prospective study. Thiopurine-induced hepatotoxicity can be grouped into three syndromes: hypersensitivity, idiosyncratic cholestatic reaction, and endothelial cell injury (with resultant raised portal pressures, veno-occlusive disease, or peliosis hepatis). A small percentage of patients present with a slight elevation of liver tests (LTs) that do not have clinical implications and LTs return to normal values during the follow-up, indicating that it is not always necessary to adjust the dose of the immunomodulator. However, when abnormalities in LTs are more marked, the dose of AZA/MP may be reduced 50%, with posterior clinical and analytical controls. With this strategy, LTs frequently normalize spontaneously, and the initial AZA/MP dose may be cautiously prescribed again. Thiopurines may induce an unusual severe cholestatic jaundice that may not regress but even progress despite thiopurine withdrawal. Therefore, these drugs should be completely withdrawn, and not only tapered, in those patients presenting clinically significant jaundice. Despite a lack of evidence that monitoring of LTs is necessary in patients receiving AZA/MP, routinely performed laboratory controls including LTs seem recommendable. However, the optimal monitoring schedule remains to be established. As long-term hepatotoxicity seems to be an unpredictable and potentially severe adverse drug reaction of 6-thioguanine, this drug should not be administered outside a clinical trial setting. (Am J Gastroenterol 2007;102:1518-527).

Topics: Antimetabolites, Antineoplastic; Azathioprine; Chemical and Drug Induced Liver Injury; Global Health; Humans; Inflammatory Bowel Diseases; Liver Diseases; Mercaptopurine; Practice Guidelines as Topic; Prevalence; Thioguanine

Ulcerative colitis and Crohn's disease both confer an increased risk of developing colorectal cancer. The use of 5-aminosalicylate as a remission-inducing agent has been long accepted. Its use as a potential chemoprophylactic agent has been proposed and is used by some practitioners. This review examines the most recent data on 5-aminosalicylate as a chemoprophylactic drug as well as ursodeoxycholic acid, folic acid, azathioprine, and 6-mercaptopurine.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Cholagogues and Choleretics; Colorectal Neoplasms; Folic Acid; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Mesalamine; Treatment Outcome; Ursodeoxycholic Acid; Vitamin B Complex

Topics: Ambulatory Care; Aminosalicylic Acids; Anemia; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Colonoscopy; Constriction, Pathologic; Digestive System Surgical Procedures; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Pregnancy; Pregnancy Complications

Inflammatory bowel disease encompasses a group of diseases with poorly defined etiology that affect the digestive tract. These diseases are characterized by their chronic course and by periods of disease activity, of variable severity, that alternate with periods of clinical remission. In the last few years, inflammatory bowel disease has been the object of intense research, which has increased knowledge of the physiopathogenic mechanisms involved. This has enabled the development of a new generation of biotechnological drugs effective in patients previously considered to be refractory to medical treatment and has allowed the accumulated corticosteroid dose to be reduced and the indications for surgery and hospital admissions to be decreased, thus improving quality of life. In addition, some classical drugs have been demonstrated to be effective in recurrence prevention after surgery for Crohn's disease and in the prevention of dysplasia and colorectal cancer in inflammatory bowel disease.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Certolizumab Pegol; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colectomy; Colitis, Ulcerative; Colorectal Neoplasms; Controlled Clinical Trials as Topic; Crohn Disease; Cyclosporine; Gastrointestinal Agents; Humans; Immunoglobulin Fab Fragments; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Infusions, Intravenous; Mercaptopurine; Meta-Analysis as Topic; Polyethylene Glycols; Quality of Life; Rectal Fistula; Recurrence; Time Factors

This article reviews current data to optimize the use of both older and newer drugs in inflammatory bowel disease. For patients with severe ulcerative colitis (UC), steroid dosing has been clarified, and a mega-analysis of steroid outcomes and toxicities has been reported. In regard to mesalamine, recent information has suggested benefit of a higher dose of pH-dependent release mesalamine for patients with moderate UC. Also, a once-daily formulation with Multi-Matrix System (MMX) technology (Shire Pharmaceuticals, Wayne, PA), has been approved. In regard to cyclosporine, two centers have reported an increased rate of colectomy over a long-duration follow-up of a cyclosporin A course given for UC. Additional information regarding thiopurines has been published, including the use of metabolite testing and duration of therapy for these drugs. Lastly, additional information regarding the optimal method for using anti-tumor necrosis factor therapy continues to accumulate.

Topics: Absorptiometry, Photon; Adalimumab; Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Colectomy; Colitis, Ulcerative; Combined Modality Therapy; Crohn Disease; Cyclosporine; Humans; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Mesalamine; Patient Compliance; Prednisone; Treatment Failure

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Azathioprine; Calcineurin Inhibitors; Cyclosporine; Drug Interactions; Humans; Immunologic Factors; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Methotrexate; Mycophenolic Acid; Recurrence

This systematic review examined the use of immunomodulators and the risk of postoperative complications after abdominal surgery in patients with inflammatory bowel disease.. Electronic databases (PubMed, Embase, Ingenta, Zetoc and Ovid) were searched and the reference lists in all articles identified were hand-searched for further relevant papers. Studies were included if they evaluated postoperative complications and defined exposure to individual immunomodulators.. All 11 studies that met the inclusion criteria were observational studies; two were reported only in abstract form. Five studies reported risks associated with azathioprine, five reported risks associated with cyclosporin and three reported risks associated with infliximab. None showed an increased risk of either total or infectious complications associated with immunomodulator use. However, subgroup analysis in one study, published as an abstract, suggested increased rates of anastomotic complications and reoperation associated with azathioprine.. Available evidence does not suggest an increased rate of postoperative complications associated with immunomodulator use.

Topics: Aged; Antibodies, Monoclonal; Azathioprine; Cyclosporine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Middle Aged; Postoperative Complications; Risk Factors

Crohn's disease (CD) and ulcerative colitis (UC) are common and heterogeneous chronic inflammatory bowel disorders of childhood that account for up to 25% of all patients with inflammatory bowel disease (IBD). In CD, the familial pattern of disease concordance would suggest that genetics contribute to disease etiology. Children are more likely to have proximal small bowel disease complicated by stricture formation, fistulization and the need for surgical intervention. The predisposition for small bowel disease has been associated with mutations of the nucleotide oligomerization domain 2 (NOD2)/Caspase activation and recruitment domain 15 (CARD15) gene on chromosome 16 in 1/3 of patients with CD. Homozygous patients also show an early age at disease onset and a relatively high relative risk for isolated stricturing distal ileal disease. The potential clinical role for NOD2 testing in either the diagnosis or the therapeutic management of patients with CD has yet to be determined. The precise age of onset of CD and UC can be difficult in children. Subclinical phases of disease can be identified through a decrease in weight and height velocity, and a delay in pubertal development. However, a confident distinction between CD and UC also remains a taxonomic dilemma in 25% of pediatric patients with IBD, despite recent technological advances in diagnostic techniques, including gadolinium enhanced magnetic resonance imaging (MRI) and capsule endoscopy, and serological testing. The early introduction of immunomodulators, including azathioprine and 6-mercaptopurine have proven efficacy in maintaining long-term remission without concurrent corticosteroids. The pharmacogenomic of 6-MP metabolism has been shown to be useful in predicting susceptibility to antimetabolite induced toxicity, and possibly allowing physician's to individualize drug therapy to improve clinical response. Novel treatment strategies, including infliximab are being developed in Pediatrics with the aim at improving overall treatment efficacy and potentially avoid surgery.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites; Child; Colitis, Ulcerative; Environment; Genetic Predisposition to Disease; Humans; Ileus; Immunoglobulin A; Immunoglobulin G; Inflammatory Bowel Diseases; Intracellular Signaling Peptides and Proteins; Mass Screening; Mercaptopurine; Mesalamine; Nod2 Signaling Adaptor Protein; Risk Factors

In the past 10-20 years, knowledge of both thiopurine pharmacology and -pharmacogenetics has been extended dramatically and used to develop new strategies to improve efficacy and reduce toxicity.. To review thiopurine efficacy, toxicity, pharmacology, pharmacogenetics, interactions in patients with inflammatory bowel disease. Special attention was paid to new strategies for optimization of pharmacotherapy.. To collect relevant scientific articles, a Pubmed search was performed from 1966 through January 2006 with the following key words (MeSH terms preferentially) in multiple combinations: 'azathioprine', '6-mercaptopurine', '6-MP', '6-thioguanine', '6-TG', 'thiopurine(s)', 'metabolites', 'level(s)', 'TDM', 'TMPT', 'ITPA', 'genotype(s)', 'phenotype(s)', 'inflammatory bowel disease', 'Crohn('s) disease', 'ulcerative colitis'.. Strategies for optimization of pharmacotherapy include therapeutic drug monitoring of thiopurine metabolites, geno- or phenotyping crucial enzymes in thiopurine metabolism like thiopurine S-methyltransferase and inosine triphosphate pyrophosphatase, and the use of thioguanine as such.. Thiopurine S-methyltransferase genotyping and therapeutic drug monitoring are useful instruments for individualizing thiopurine pharmacotherapy of inflammatory bowel disease. Inosine triphosphate pyrophosphatase genotyping may be helpful in case of unexplainable myelotoxicity. In case of azathioprine- or mercaptopurine-intolerance, thioguanine seems a promising alternative. However, more knowledge needs to be gathered about its potential hepatotoxicity.

Topics: Azathioprine; Drug Interactions; Gastrointestinal Agents; Genotype; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Phenotype; Purines; Thioguanine; Treatment Outcome; Xanthine Oxidase

The armamentarium of medications for the treatment of inflammatory bowel disease is growing and becoming more complicated to use. Immunomodulators are a class of medications that have found a niche for the treatment of Crohn's disease and ulcerative colitis. Because of the mounting supporting evidence for efficacy, the most commonly-used immunomodulators are azathioprine, mercaptopurine, methotrexate and ciclosporin. These medications are being used more often due to their steroid-sparing and potentially surgery-sparing effects. Immunomodulators are also known for a significant side-effect profile and require careful monitoring. This review provides the latest information for clinicians on efficacy, side-effects, dosing and monitoring of these medications for treatment of inflammatory bowel disease.

Topics: Azathioprine; Cyclosporine; Drug Monitoring; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate

The first intention in the management of patients with inflammatory bowel disease (IBD) is the improvement of quality of life. It is important to avoid unnecessary investigations and to protect the patients from therapeutic approaches, which efficacy is not proven. The following remarks are based on the guidelines of The German Society of Gastroenterology for diagnosis and therapy of ulcerative colitis and Crohn's disease, which include an accurate diagnosis, the treatment of the acute phase, the maintaining of remission and the management of complications. The therapy depends on the severity of the acute phase and on the localisation of the disease. Immunosuppressive therapy with azathioprine or mercaptopurine is indicated in patients with steroid-dependent or steroid-resistant disease.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Azathioprine; Colitis, Ulcerative; Controlled Clinical Trials as Topic; Crohn Disease; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Placebos; Practice Guidelines as Topic; Quality of Life; Remission Induction; Time Factors

There is a growing interest in the use of thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) for the management of inflammatory bowel disease. The genetically controlled thiopurine (S)-methyltransferase enzyme is involved in the metabolism of these agents and is hypothesised to determine the clinical response to thiopurines. Diminished activity of this enzyme decreases the methylation of thiopurines, theoretically resulting in potential overdosing, while high thiopurine (S)-methyltransferase status leads to overproduction of toxic metabolites and ineffectiveness of azathioprine and 6-mercaptopurine. In practice, controversies exist regarding the utility of standard thiopurine (S)-methyltransferase pheno- and genotyping. Current pharmacogenetic insights suggest that another enzyme system may participate in the efficacy and toxicity of thiopurines; inosine triphosphate pyrophosphatase. Other topics discussed in this review are the utilisation of therapeutic drug monitoring and the experimental use of 6-thioguanine in the treatment of inflammatory bowel disease. 6-Thioguanine has a less genetically controlled metabolism and skips genetically determined metabolic steps. On theoretical basis, 6-thioguanine might therefore have a more predictable profile than azathioprine and 6-mercaptopurine. However, the use of 6-thioguanine has been associated with an increased risk of nodular regenerative hyperplasia of the liver and veno-occlusive disease. Further research is warranted before 6-thioguanine can be considered as a treatment option for inflammatory bowel disease.

Topics: Antimetabolites; Azathioprine; Gene Frequency; Genotype; Guanine Nucleotides; Humans; Inflammatory Bowel Diseases; Inosine Triphosphatase; Mercaptopurine; Methyltransferases; Phenotype; Practice Guidelines as Topic; Pyrophosphatases; Racial Groups; Thionucleotides

There are interindividual variations with regard to efficacy and toxicity of many commonly employed drugs. Major causes of interindividual differences of drug effects include genetic variations of drug-metabolizing enzymes, transporters and targets. Pharmacogenetics studies the genetic background of the interindividual variations of drug response. By means of preliminary genetic screening personalized treatment can be achieved, drugs with low efficacy and many side-effects can be avoided. The pharmacogenetically best studied medications of inflammatory bowel disease are azathioprine/6-mercaptopurine. It is obvious that there is a genetic background of the efficacy and toxicity of corticosteroids, 5-ASA drugs, infliximab and other immunosuppressors as well, but further studies now require to confirm the functional significance of it. Therefore, at present, the application and clinical usefulness of pharmacogenetics in the management of inflammatory bowel disease is limited. The aims of future investigations are understanding of the mechanism of drug action, identification of new drug targets and acquainting with genetic factors that determine drug response.

Topics: Aminosalicylic Acids; Animals; Antibodies, Monoclonal; Azathioprine; Glucocorticoids; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Sulfasalazine

Inflammatory bowel disease (IBD) is commonly treated with immunomodulators such as azathioprine and 6-mercaptopurine (6-MP). Studies examining lymphoma risk in IBD patients treated with these medications have been underpowered and have yielded conflicting conclusions.. The purpose of this meta-analysis was to provide a more precise estimate of the relative risk of lymphoma among IBD patients treated with azathioprine or 6-MP.. Studies were included if they were English language, full article, cohort studies specifically designed to evaluate cancer as an adverse outcome of treatment with azathioprine or 6-MP. Pooled standardised incidence ratios were calculated to estimate the relative risk of lymphoma associated with therapy. Heterogeneity was assessed using Poisson regression. Sensitivity analyses examined the influence of individual studies on risk estimate and heterogeneity statistics.. Six studies were identified that met our inclusion criteria. When the data were combined across all studies, the pooled relative risk was 4.18 (95% confidence interval 2.07-7.51; 11 observed cases, 2.63 expected). Sensitivity analysis showed that exclusion of any one study had a relatively small effect on the pooled relative risk estimate (range 3.49-5.21) but excluding either the study with the highest or lowest estimated relative risk eliminated the statistically significant heterogeneity.. Our data suggest an approximate fourfold increased risk of lymphoma in IBD patients treated with azathioprine/6-MP. The increased risk of lymphoma could be a result of the medications, the severity of the underlying disease, or a combination of the two.

Topics: Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Lymphoma; Male; Mercaptopurine; Risk Factors

The thiopurine drugs azathioprine and 6-mercaptopurine (6-MP) are well-established in the treatment of inflammatory bowel disease (IBD). However, there is a wide inter- and intra-patient variation in the concentrations of active and toxic metabolites due to their complex metabolism and genetic polymorphisms in metabolizing enzymes. Serious drug toxicity leads to cessation of therapy in 9-25% of patients, and there is failure to achieve efficacy in approximately 15% of cases. Advances in the understanding of thiopurine drug metabolism have led to new genetic and metabolite tests to help clinicians optimize thiopurine use. Thiopurine methyltransferase (TPMT) enzyme activity can predict life-threatening myelotoxicity in the one in 300 patients who are TPMT-deficient. However, myelotoxicity can also occur in the presence of normal TPMT activity so blood count monitoring should remain standard practice. TPMT testing may also aid in dose individualization. 6-Thioguanine nucleotides (6-TGN) are thought to be the predominant active metabolites of the thiopurines. 6-thioguanine nucleotide concentration is correlated with bone marrow toxicity and may also correlate with efficacy in IBD. Measurement of 6-TGN and 6-methylmercaptopurine (6-MMP) concentration is most useful in determining why a patient is not responding to a standard dose of a thiopurine drug and may help in avoiding myelosuppression. The ratio of these metabolites can help distinguish non-compliance, under-dosing, thiopurine-resistant and thiopurine-refractory disease. Some of these investigations are entering routine clinical practice but more research is required to determine their optimal use in patients with IBD.

Topics: Antimetabolites, Antineoplastic; Azathioprine; Bone Marrow; Erythrocytes; Guanine Nucleotides; Humans; Inflammatory Bowel Diseases; Inosine Triphosphatase; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Pyrophosphatases; Thionucleotides

Inflammatory bowel disease often affects women during their reproductive years, causing management concerns for obstetricians caring for these patients during pregnancy.. Apart from methotrexate, most drugs used regularly to treat ulcerative colitis and Crohn's disease can safely be used by pregnant women. No causal relationship has been established between exposure to sulfasalazine or other 5-aminosalicylic acid drugs and the development of congenital malformations and these drugs may be used with relative safety during pregnancy and lactation. Current evidence indicates that maternal use of azathioprine and mercaptopurine is not associated with an increased risk of congenital malformations, though impaired foetal immunity, intrauterine growth retardation and prematurity are occasionally observed. Cyclosporin is not teratogenic, but may be associated with growth retardation and prematurity.. Pregnancy should be avoided in women treated with methotrexate because of its known abortifacient effects and risk of causing typical malformations. There is no actual evidence of adverse effect in pregnant women receiving Infliximab but the amount of clinical information is small. The treatment with metronidazole or ciprofloxacin for short durations appear to be safe, but there is no data about the effects of increased length of treatment as required in Crohn's disease remains unknown. Control of disease activity before conception and during pregnancy is critical to optimise both maternal and foetal health. A multidisciplined approach involving both obstetrician and gastroenterologist and education about pregnancy are essential components of the treatment of any young women with IBD.

Topics: Abnormalities, Drug-Induced; Adrenal Cortex Hormones; Aminosalicylic Acids; Anti-Bacterial Agents; Azathioprine; Breast Feeding; Contraindications; Cyclosporine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Maternal Nutritional Physiological Phenomena; MEDLINE; Mercaptopurine; Methotrexate; Pregnancy; Pregnancy Complications; Pregnancy Outcome

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Azathioprine; Drug Therapy, Combination; Female; Forecasting; Genetic Predisposition to Disease; Genotype; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Male; Mercaptopurine; Methotrexate; Pharmacogenetics; Prognosis; Risk Assessment; Treatment Outcome

Topics: Azathioprine; Drug Monitoring; Gene Expression Regulation, Enzymologic; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Inosine Triphosphatase; Mercaptopurine; Methyltransferases; Pyrophosphatases

Ulcerative colitis and Crohn's disease are chronic gastrointestinal diseases that affect patients in the prime of their lives. Because inflammatory bowel disease (IBD) patients generally live a normal lifespan, chronic medical therapy for IBD must be tolerable, simple to adhere to, and have as few side effects as possible. This article discusses the impact of IBD on quality of life and stresses the importance of appropriate and individualized medical therapy. To help clinicians determine the efficacy of particular IBD medications, this article offers a brief, practical interpretation of clinical, endoscopic, and quality-of-life end points used in clinical trials. Finally, it provides a summary of the current accepted medical therapies for ulcerative colitis adn Crohn's disease and recommendations for using these medications in clinical practice.

Topics: Adrenal Cortex Hormones; Aminosalicylic Acids; Antibodies, Monoclonal; Azathioprine; Cyclosporine; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Methotrexate; Quality of Life

6-Mercaptopurine and azathioprine have become important therapeutic options for patients with inflammatory bowel disease (IBD). Although accumulating data in the literature have supported the use of these immunomodulators in the management of IBD, marked variation exists in the pattern of clinical practice regarding azathioprine or 6-mercaptopurine therapy in patients with IBD. This article provides a critical review of the data on the clinical efficacy and toxicities of 6-mercaptopurine and azathioprine in the management of IBD. Emerging literature on the potential application of pharmacogenetic testing and metabolite monitoring are also discussed.

Topics: Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Randomized Controlled Trials as Topic

Gastroenterologists are not infrequently faced with questions regarding pregnancy when advising or treating their patients with inflammatory bowel disease (IBD). To advise patients effectively, the following factors must be considered: (1) the inheritance patterns of IBD for accurate counseling and family planning; (2) the effects of active IBD versus medications or surgery on fertility; (3) the effects of pregnancy on the course of IBD; (4) the effects and potential risks of active IBD versus those of diagnostic tests, medical treatments, and surgical treatments on the developing fetus; (5) approach to delivery; and (6) the risks of breast-feeding while receiving treatment for IBD.

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Pregnancy; Pregnancy Complications

Topics: Adrenal Cortex Hormones; Adult; Aminosalicylic Acids; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Azathioprine; Budesonide; Colitis, Ulcerative; Colonoscopy; Controlled Clinical Trials as Topic; Crohn Disease; Diagnosis, Differential; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Magnetic Resonance Imaging; Mercaptopurine; Methotrexate; Metronidazole; Pouchitis; Remission Induction; Tacrolimus; Time Factors; Tomography, X-Ray Computed; Ultrasonography

The introduction and rapid diffusion of biological agents in the treatment of inflammatory bowel disease had led us to believe that the old immunosuppressive drugs were destined to disappear. However, despite a decade of clinical experience in the use of biological agents, the old immunosuppressive drugs continue to play a pivotal role in the management of inflammatory bowel disease. Various factors may account for this change of view. Aim of the present review was to summarise key information currently available regarding the use of immunosuppressive drugs in the treatment of inflammatory bowel disease.

Topics: Azathioprine; Cyclosporine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate; Mycophenolic Acid; Tacrolimus; Thalidomide

Topics: Azathioprine; Bone Marrow; Drug Interactions; Drug Monitoring; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Lymphoma, Non-Hodgkin; Mercaptopurine; Methyltransferases; Structure-Activity Relationship; Thioguanine

The thiopurines azathioprine and 6-mercaptopurine are effective both for active disease and for maintaining remission in both Crohn's disease and ulcerative colitis. This review describes criteria for starting thiopurines (two or more courses of steroids in a calendar year, relapse as prednisolone is reduced below 15 mg/day, within 6 weeks of stopping steroids) and the benefits of continuing treatment for up to 5 years. Challenging issues, such as thiopurine intolerance, relative merits of azathioprine, 6-mercaptopurine, monitoring therapy and thiopurines in pregnancy are addressed.

Topics: Azathioprine; Drug Administration Schedule; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Pregnancy; Pregnancy Complications

Thioguanine derivatives, azathioprine and 6-mercaptopurine, represent major drugs in the treatment of chronic active inflammatory bowel disease. They are effective in two-thirds of the patients and safe over the long term in patients who can tolerate them (80-90%). Recent progress in understanding the metabolism of these drugs and its implication in clinical practice have brought up new tools and strategies that are proposed to optimize treatment. In particular, the measurement and characterization of key enzymes and metabolites may have clinical impact. Thus, thiopurine methyl transferase genotyping and activity measurement, as well as erythrocytes, 6-thioguanine nucleotides and 6-methyl mercaptopurine levels, may help in some situations of intolerance or inefficacy with these drugs. Indications for starting and stopping treatment with thioguanine derivatives are also discussed.

Topics: Azathioprine; Chronic Disease; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine

Thiopurines have proven efficacy in inflammatory bowel disease. However, concerns regarding toxicity have limited the use of these agents as first line of medical therapy.. Review of the literature regarding metabolism, efficacy and side effects.. In clinical trials, up to 15% of patients discontinued 6-mercaptopurine or its pro-drug azathioprine prematurely due to adverse events. These events may be divided into dose-independent idiosyncratic reactions and dose-related, pharmacologically explainable toxicity. Dose-independent reactions include skin rash, fever, diarrhoea and pancreatitis. Most frequently observed dose-dependent adverse events are nausea, malaise and myelotoxicity. Furthermore, dose-dependent and dose-independent hepatotoxicity may occur. Recent insights obtained by therapeutic drug monitoring in patients on azathioprine or 6-mercaptopurine have led to strategies to reduce toxicity. One strategy is to detect poor metabolisers of thiopurines by establishing the activity of the key enzyme thiopurine methyltransferase. However, the clinical relevance of this strategy is still a point of debate. Another strategy is to administer 6-thioguanine, which is an agent close to the effective 6-thioguanine nucleotides.. Therapeutic drug monitoring of thiopurines resulted in strategies to reduce toxicity. The value of these strategies has yet to be proven in prospective randomized trials.

Topics: Azathioprine; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Treatment Outcome

In the past years there have been many exciting developments in IBD management. New therapies and concepts of remission induction and of maintenance have been developed. This paper is intending to bring together the basic topics in patient-management in the various medical fields that represent the most accepted ways of therapies. The introduction deals with the most common aspects of Crohn's disease and that of the ulcerative colitis. It describes the treatment of ulcerative colitis according to the different groups of patients and the degree of activity. First it analyses the possible ways leading to the remission, then the prevention of relapse, lastly the other therapeutic options which have not been given any evidence of so far. The main standards of Crohn's disease therapy are presented on the bases of the small bowel Crohn's disease. After discussing the essential principles in treating the complications it carries on the treating of the large bowel Crohn's disease and then it is completed with the consideration of prevention of the relapse and the supportive therapeutic possibilities.

Topics: Acute Disease; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Chronic Disease; Colitis, Ulcerative; Crohn Disease; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Mesalamine; Prednisolone; Recurrence; Risk Factors; Severity of Illness Index; Sulfasalazine

The side-effects suitable for monitoring in patients with inflammatory bowel disease being treated with the four main groups of drugs (5-aminosalicylic acid preparations, azathioprine and 6-mercaptopurine, methotrexate, and corticosteroids) are reviewed. On the basis of the reported frequency, severity and timing of side-effects, a practical scheme of monitoring is recommended. This includes a baseline measurement of full blood count, creatinine and liver function tests in all patients. In the absence of worrying symptoms, we recommend the following: (i) no monitoring for sulfasalazine; (ii) for other 5-aminosalicylic acid preparations, the measurement of creatinine at 6 and 12 months and then annually; (iii) for azathioprine/6-mercaptopurine, thiopurine methyltransferase genotype/phenotype determination has no role in treatment monitoring, but a full blood count at 2 weeks, 1 month, 3 months and then every 3 months should be performed; (iv) for methotrexate, a full blood count and liver function tests should be performed every 3 months; (v) for steroids, dual energy X-ray absorptiometry bone scanning should be performed at the start of therapy, every year in which steroids are used if the T score is < 0, and every 3-5 years if the T score is > 0.

Topics: Adrenal Cortex Hormones; Aminosalicylic Acids; Azathioprine; Blood Cell Count; Creatinine; Drug Monitoring; Inflammatory Bowel Diseases; Liver Function Tests; Mercaptopurine; Methotrexate

To identify the frequency of use and appropriate monitoring guidelines for the adverse effects of azathioprine and 6-mercaptopurine (6-MP) in the therapy of patients with inflammatory bowel disease (IBD).. Surveys were sent to all physician members of the Canadian Association of Gastroenterology. Physicians were asked to describe their monitoring practices for IBD patients receiving azathioprine or 6-MP. A systematic literature search was also performed using MEDLINE for articles published in English between 1966 and 1999 using the MeSH terms 'azathioprine', '6-mercaptopurine', 'inflammatory bowel disease' and 'drug monitoring'.. Azathioprine and 6-MP were used to treat an average of 7% of patients - a surprisingly low number given the proven efficacy of these agents. All respondents reported monitoring complete blood counts (CBC), while liver enzyme and pancreatic enzyme levels were monitored by 62% and 29% of respondents, respectively. The most commonly reported initial CBC testing frequencies were weekly (42%), monthly (26%) and biweekly (23%). From the literature, it was determined that severe leukopenia (less than 2.10 g/L) occurs in less than 2% of cases and is sometimes associated with serious outcomes, including death. Most cases of severe leukopenia occurred abruptly, early in treatment. Other reported adverse effects and incidences were pancreatitis (3% to 5%), hepatotoxicity (less than 1%) and hypersensitivity (2% to 3%). Data concerning an increased risk of non-Hodgkin's lymphoma were equivocal.. Use of azathioprine or 6-MP is low in patients with IBD. A CBC should be performed at weeks 1, 2, 4, 6, 8 and 12, with subsequent testing every eight weeks for the duration of azathioprine or 6-MP treatment. The evidence in support of pancreatic and hepatic monitoring is weak. The risk of non-Hodgkin's lymphoma is likely low.

Topics: Azathioprine; Canada; Drug Utilization; Gastroenterology; Health Care Surveys; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Mercaptopurine; Practice Patterns, Physicians'

Lymphoma complicating inflammatory bowel disease is well described. Whether the risk of lymphoma is increased by immunosuppressive treatment with azathioprine, 6-mercaptopurine or infliximab is a common concern among patients and physicians considering using these agents. This review aims to quantify the lymphoma risk in inflammatory bowel disease and the added risk attributable to these treatments. The evidence from published cases is that lymphomas occur at sites of active inflammatory bowel disease more often than expected for this to be a chance association. Studies on inflammatory bowel disease populations are conflicting, with some follow-up studies from large inflammatory bowel disease clinics showing an increase in lymphoma incidence, while other population-based studies show little or no increase in risk of lymphoma. A small increase in lymphoma risk in inflammatory bowel disease, perhaps 2-3-fold, may be compatible with both sets of data. Studies of the risks associated with immuno- suppression are less satisfactory, with smaller numbers of patients and relatively short follow-up. The available evidence would support a further increase in lymphoma risk associated with immunosuppressive treatment in inflammatory bowel disease of around fivefold compared to no immunosuppressive use, and tenfold compared to the general population. The risks appear to be less than that associated with renal and hepatic transplant-related immunosuppression. Infliximab treatment is still too new to make a full assessment of its long-term safety, but post-marketing surveillance currently suggests that lymphoma risk may not be any greater than that associated with azathioprine and 6-mercaptopurine. Population-wide surveillance for lymphoma in inflammatory bowel disease would be required to narrow the confidence intervals on these estimates of lymphoma risk in inflammatory bowel disease and immunosuppressive treatment.

Topics: Antibodies, Monoclonal; Azathioprine; Epidemiologic Studies; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Lymphoma; Mercaptopurine; Risk Factors; Tumor Necrosis Factor-alpha

The thioguanine derivative, azathioprine, is a prodrug of 6-mercaptopurine that is further metabolized by various enzymes present in the liver and gut. Azathioprine and 6-mercaptopurine have been used in the treatment of inflammatory bowel disease, i.e. ulcerative colitis and Crohn's disease, for more than 30 years. However, widespread use of azathioprine or 6-mercaptopurine in inflammatory bowel disease is of more recent origin, the primary reason being a long-standing debate on the efficacy of these agents in inflammatory bowel disease. Both drugs are slow acting, which is why clinical efficacy cannot be expected until several weeks or even months of treatment have elapsed. Consequently, azathioprine and 6-mercaptopurine have no place as monotherapy in the treatment of acute relapsing inflammatory bowel disease. Today, azathioprine and 6-mercaptopurine are the most commonly used immunomodulatory drugs in the treatment of inflammatory bowel disease. Their clinical effects are probably identical, although their exact mode of action is still unknown. The mode of action of azathioprine is thought to be multifactorial, including conversion to 6-mercaptopurine (which acts as a purine antimetabolite), possible blockade of thiol groups by alkylation, inhibition of several pathways in nucleic acid biosynthesis (preventing proliferation of cells involved in the determination and amplification of the immune response) and damage to DNA through the incorporation of thiopurine analogues. However, 6-thioguanine nucleotides may accumulate in toxic doses in myeloid precursor cells, resulting in life-threatening myelosuppression. Azathioprine and 6-mercaptopurine are further known to alter lymphocyte function, reduce the number of lamina propria plasma cells and affect natural killer cell function. The purpose of this comprehensive review is to suggest guidelines for the application of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease.

Topics: Azathioprine; Clinical Trials as Topic; DNA Damage; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Killer Cells, Natural; Lactation; Lymphocytes; Male; Mercaptopurine; Neoplasms; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications; Risk Factors

The diagnosis and management of inflammatory bowel disease (IBD) in children and adolescents is a challenge to patients, their families, and to the healthcare team. This review highlights recent advances in the epidemiology, diagnosis, and management of pediatric IBD. Among the most prominent advances are the new diagnostic serologic assays that can help screen for IBD in the absence of physical signs of disease and help discriminate between ulcerative and Crohn's colitis. Other tests have been identified as potential noninvasive markers of disease activity, including color Doppler abdominal ultrasound and sugar permeability tests. Recent advances in pharmacogenetics afford clinicians the ability to optimize and individualize therapy using azathioprine or 6-mercaptopurine. Finally, bone health has come forth as a major issue in the complete management of pediatric IBD.

Topics: Adolescent; Azathioprine; Biomarkers; Child; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Osteoporosis; Pharmacogenetics

The idiopathic inflammatory bowel diseases (IBD), comprised of Crohn's disease (CD) and ulcerative colitis (UC), are related, complex genetic disorders. With the completion of the human genomic sequence, identification of genetic variants contributing to IBD susceptibility can now more systematically be identified. Significant genetic linkages have been observed on chromosomes 16, 12, 14, 19, 6, and 1, of which the linkage to CD on chromosome 16 is the most well-established. For many of the other regions, evidence for linkage has been observed for both CD and UC. Candidate gene association studies have largely focused on genes involved in inflammatory pathways, such as cytokines and cytokine receptors. With greater understanding of genetic differences underlying both disease susceptibility and response to medical therapy, the individualization of medical approaches based on this knowledge may soon be possible in patients with IBD.

Topics: Base Sequence; Colitis, Ulcerative; Crohn Disease; Cytokines; Gene Expression Profiling; Genetic Linkage; HLA Antigens; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Polymorphism, Genetic; Receptors, Cytokine

Topics: Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate; Recurrence; Severity of Illness Index; Time Factors

The use of 6-mercaptopurine (6MP) and its prodrug azathioprine (AZA) for inflammatory bowel disease (IBD) has increased in recent years. The pharmacology, patient response in controlled trials, new formulations and routes of administration and safety for these agents are reviewed.. AZA is rapidly converted to 6MP, which is then further metabolized to the active metabolites, the 6-thioguanine nucleotides (6TGN). The half-life of 6TGN in erythrocytes is prolonged and weeks to months may be required to reach steady state. This prolonged time to 6TGN steady state may help explain the clinical observation that prolonged treatment (3-4 months) with 6MP/AZA for IBD is required before a therapeutic response occurs. CLINICAL RESPONSE: Controlled trials of 6MP (1.5 mg/kg/d) or AZA (1.0-3.0 mg/kg/d) support the following treatment indications for 6MP/AZA: inflammatory Crohn's disease; fistulizing Crohn's disease; steroid-sparing; and remission maintenance. Controlled trials of AZA (1.5-2.5 mg/kg/d) in UC have suggested efficacy for the indications of steroid sparing and remission maintenance, as well as a possible effect in chronically active disease. A therapeutic response appears to require > or = 17 weeks for most patients, and it has been suggested that a greater cumulative dose of AZA may result in increased likelihood of response to AZA. A recent pilot study suggested that administration of an i.v. loading dose of AZA (20-44 mg/kg over 36 h) may decrease the time to response in Crohn's disease patients treated with AZA, perhaps by administering a portion of the necessary cumulative dose more rapidly. Two recent pharmacokinetic studies demonstrated that use of a delayed release oral AZA formulation which delivers AZA directly to the ileocolon markedly reduces systemic absorption of AZA. This 'topical' or 'local' approach to AZA treatment of IBD holds the promise of equal or improved efficacy with a significant reduction in toxicity, and dose-ranging clinical trials with delayed release oral AZA are planned in the near future.. Side effects of AZA/6MP include pancreatitis, fever, nausea, leukopenia, infection, and hepatitis. It appears that the risk of malignancy during or following monotherapy with AZA/6MP for IBD is not increased relative to the general population.. AZA/6MP therapy is efficacious and reasonably safe for selected patients with IBD. Indications for treatment with AZA/6MP include refractory Crohn's disease, fistulizing Crohn's disease, steroid-dependent Crohn's disease, Crohn's disease remission maintenance, and possibly refractory UC, steroid dependent UC, and UC remission maintenance. The use of these immune modifier drugs in patients with IBD represents a significant therapeutic advance.

Topics: Azathioprine; Half-Life; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Odds Ratio; Randomized Controlled Trials as Topic

Immunosuppressive (IS) drugs are an important option in the management of both forms of inflammatory bowel disease (IBD): Crohn's disease and ulcerative colitis. As the experience of using these agents in the treatment of IBD has increased and more data have become available on their efficacy, these drugs are being used more extensively. The principle drugs used in clinical practice at this time include: azathioprine (AZA) and its metabolite 6-mercaptopurine (6-MP), methotrexate, and cyclosporin A. AZA and 6-MP are generally considered the first line immunosuppressive agents. These drugs are effective and generally well tolerated by the majority of patients started on them, enabling many patients to avoid the predictable side effects of steroid therapy. Because of their extensive use, it is important that clinicians involved in the care of IBD patients are familiar with the IS drugs used to treat IBD, especially AZA and 6-MP.

Topics: Adult; Azathioprine; Cyclosporine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate

Different hematologic abnormalities are often encountered in patients with inflammatory bowel disease. Among them anemia, leukocytosis, and thrombocytosis are commonly seen. Leukopenia and thrombocytopenia are observed mostly as a side effect of therapy, particularly with use of immunosuppressive drugs. Immune thrombocytopenic purpura is rarely reported in association with inflammatory bowel disease. We present two cases with combination of these entities along with a literature review and treatment options. Immune thrombocytopenic purpura in these patients presented as an extraintestinal manifestation of inflammatory bowel disease mediated by a disturbance of the immune system.

Topics: Adolescent; Adult; Anemia; Anti-Inflammatory Agents; Colitis, Ulcerative; Crohn Disease; Female; Humans; Hydrocortisone; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukocytosis; Leukopenia; Male; Mercaptopurine; Prednisone; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Thrombocytosis

Topics: Algorithms; Azathioprine; Controlled Clinical Trials as Topic; Cyclosporine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate

Despite intense investigative efforts, the causes of ulcerative colitis and Crohn's disease remain elusive. The mainstay of medical therapy focuses on inhibition of the effects of the inflammatory mediators operant in inflammatory bowel disease because the causes of these two chronic disorders are unknown. During recent years, the physician's armamentarium for medical treatment of inflammatory bowel disease has increased substantially. In this article, the current standard medical therapies available for treatment of patients with inflammatory bowel disease are reviewed along with their efficacy; the side effects and status of other investigative drugs also are reviewed.

Topics: Adrenal Cortex Hormones; Aminosalicylic Acids; Anti-Bacterial Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate; Nutritional Physiological Phenomena

Refractory inflammatory bowel disease can be treated by surgery or using nutritional supplementation or replacement. Immunosuppressive agents may also play a role for refractory disease; they have gained widespread acceptance, due not only to trials that demonstrate efficacy but also to the realization that these side-effects are minor compared to those associated with long-term, high-dose corticosteroids. To date, 6-mercaptopurine and azathioprine remain the drugs of choice based upon extensive clinical experience, but both methotrexate and cyclosporin are promising immunosuppressants for otherwise refractory disease.

Topics: Azathioprine; Cyclosporine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate

Chronotherapy is the timing of medication according to biological rhythms of the host to optimize drug efficacy and minimize toxicity. Efficacy and myelosuppression of azathioprine/6-mercaptopurine (AZA/6-MP) are correlated with the metabolite 6-thioguanine, while the metabolite 6-methylmercaptopurine correlates with hepatotoxicity.. This was a single-center, 10-week prospective crossover trial involving 26 participants with inactive inflammatory bowel disease (IBD) on a stable dose and time of AZA or 6-MP therapy. Participants were switched to the opposite delivery time (morning or evening) for 10 weeks, and metabolite measurements were at both time points.. In the morning vs evening dosing, 6-thioguanine levels were 225.7 ± 155.1 vs 175.0 ± 106.9 ( P < 0.01), and 6-methylmercaptopurine levels were 825.1 ± 1,023.3 vs 2,395.3 ± 2,880.3 ( P < 0.01), with 69% (18 out of 26) of participants had better metabolite profiles in the morning. Participants with optimal dosing in the morning had an earlier chronotype by corrected midpoint of sleep.. In the first study on a potential role of chronotherapy in IBD, we found (i) morning dosing of AZA or 6-MP resulted in more optimal metabolite profiles and (ii) host chronotype could help identify one-third of patients who would benefit from evening dosing. Circadian regulation of metabolic enzymes of AZA/6-MP activity in the liver is the likely cause of these differences. This pilot study confirms the need to incorporate chronotherapy in future multicenter clinical trials on IBD disease.

Topics: Azathioprine; Chronotherapy; Cross-Over Studies; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Pilot Projects; Prospective Studies; Thioguanine

Thiopurine-related myelosuppression (most frequently leukopenia) interferes with thiopurine therapy for patients with inflammatory bowel diseases (IBD). We investigated whether pretreatment analyses genetic variants associated with thiopurine-induced leukopenia could be used to effectively identify patients who required dose adjustments.. We performed a multicenter, prospective study of patients with IBD at 5 tertiary medical centers in Korea, from January 2016 through September 2018. Seventy-two patients were randomly assigned to a group that underwent genotype analysis for the NUDT15 variant (rs116855232) and FTO variant (rs79206939) and 3 common TPMT variants (rs1800460, rs1800462, rs1142345) associated with myelosuppression and 92 patients were assigned to a group that did not undergo genotype analysis (non-genotyping group). Patients heterozygous for any variant received 50 mg azathioprine equivalents, whereas those who were homozygous for any variant received alternative drugs. Patients who did not carry any of the genetic variants and patients in the non-genotyping group received 50 mg azathioprine equivalents followed by dose escalation up to 2-2.5 mg/kg. Myelosuppression was defined as white blood cell counts below 3000/μL, levels of hemoglobin 10 g/dL, or platelet counts below 100 K/μL.. Twelve patients (16.7%) in the genotype analysis group and 33 patients (35.9%) in the non-genotyping group developed myelosuppression (P=.005). A multivariate analysis revealed that body mass indices above 21 kg/m. In a randomized controlled study of patients undergoing thiopurine therapy for IBD, we found that selection of therapy based on genetic variants associated with thiopurine-induced leukopenia significantly reduced the proportion of patients with myelosuppression during treatment. ClinicalTrials.gov no: NCT03719118.

Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Azathioprine; Genotype; Humans; Incidence; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Prospective Studies

The aim of the study was to validate the impact of the single-nucleotide polymorphism rs2413739 (T > C) in the PACSIN2 gene on thiopurines pharmacological parameters and clinical response in an Italian cohort of pediatric patients with acute lymphoblastic leukemia (ALL) and inflammatory bowel disease (IBD). In ALL, PACSIN2 rs2413739 T allele was associated with a significant reduction of TPMT activity in erythrocytes (p = 0.0094, linear mixed-effect model, multivariate analysis considering TPMT genotype) and increased severe gastrointestinal toxicity during consolidation therapy (p = 0.049). A similar trend was present also for severe hematological toxicity during maintenance. In IBD, no significant effect of rs2413739 could be found on TPMT activity, however azathioprine effectiveness was reduced in patients carrying the T allele (linear mixed effect, p = 0.0058). In PBMC from healthy donors, a positive correlation between PACSIN2 and TPMT protein concentration could be detected (linear mixed effect, p = 0.045). These results support the role of PACSIN2 polymorphism on TPMT activity and mercaptopurine adverse effects in patients with ALL. Further evidence on PBMC and pediatric patients with IBD supports an association between PACSIN2 variants, TPMT activity, and thiopurines effects, even if more studies are needed since some of these effects may be tissue specific.

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adult; Azathioprine; Child; Child, Preschool; Cohort Studies; Female; Humans; Inflammatory Bowel Diseases; Italy; Male; Mercaptopurine; Middle Aged; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Decreased thiopurine S-methyltransferase [TPMT] enzyme activity increases the risk of haematological adverse drug reactions [ADRs] in patients treated with thiopurines. Clinical studies have shown that in patients with inflammatory bowel disease [IBD], pharmacogenetic TPMT-guided thiopurine treatment reduces this risk of ADRs. The aim of this study was to investigate whether this intervention impacts on healthcare costs and/or quality of life.. An a priori defined cost-effectiveness analysis was conducted in the Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory bowel disease Clinics [TOPIC] trial, a randomized controlled trial performed in 30 Dutch hospitals. Patients diagnosed with IBD [age ≥18 years] were randomly assigned to the intervention [i.e. pre-treatment genotyping] or control group. Total costs in terms of volumes of care, and effects in quality-adjusted life years [QALYs], based on EuroQol-5D3L utility scores, were measured for 20 weeks. Mean incremental cost savings and QALYs with confidence intervals were calculated using non-parametric bootstrapping with 1000 replications.. The intervention group consisted of 381 patients and the control group 347 patients. The mean incremental cost savings were €52 per patient [95% percentiles -682, 569]. Mean incremental QALYs were 0.001 [95% percentiles -0.009, 0.010]. Sensitivity analysis showed that the results were robust for potential change in costs of screening, costs of biologicals and costs associated with productivity loss.. Genotype-guided thiopurine treatment in IBD patients reduced the risk of ADRs among patients carrying a TPMT variant, without increasing overall healthcare costs and resulting in comparable quality of life, as compared to standard treatment.

Topics: Adult; Age of Onset; Azathioprine; Cost-Benefit Analysis; Female; Genotype; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Netherlands; Quality of Life

Patients' beliefs about medicine may either reflect the necessity for treatment or concerns regarding the treatment. We explored the extent to which these beliefs have an effect on thiopurine metabolite levels and premature discontinuation in patients with inflammatory bowel disease (IBD).. Patients enrolled in the 'Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory Bowel Disease Clinics' (TOPIC) trial were asked to complete the Beliefs about Medicine Questionnaire (BMQ) 4 weeks after thiopurine initiation. The BMQ measures perceptions about treatment necessity and concerns. On the basis of the necessity and concern scores, patients can be categorized as accepting, ambivalent, indifferent, or skeptical. The thiopurine discontinuation rates for these belief subgroups were compared by Kaplan-Meier curves. Furthermore, clinical response and metabolite levels were compared between the belief subgroups.. A total of 767 patients with IBD started thiopurine treatment, of whom 576 (75%) completed the BMQ. Patients could be classified as accepting (34%), indifferent (17%), ambivalent (34%), or skeptical (15%). Compared with patients in the accepting group (discontinuation rate 22%), patients with an indifferent (35%; P=0.02), ambivalent (37%; P<0.01), or skeptical belief (54%; P<0.01) had higher thiopurine discontinuation rates. No differences were observed in the steady-state thiopurine metabolite levels between the different belief subgroups.. Patients with a low perceived treatment necessity or high concerns toward IBD treatment were more likely to discontinue thiopurine treatment prematurely. Extra attention toward these patients might prevent premature discontinuation.

Topics: Adult; Female; Guanine Nucleotides; Health Knowledge, Attitudes, Practice; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Medication Adherence; Mercaptopurine; Middle Aged; Surveys and Questionnaires; Thioinosine; Thionucleotides; Treatment Outcome; Young Adult

Thiopurine hypermethylation towards 6-methylmercaptopurine (6MMP) instead of 6-thioguanine nucleotides (6TGN) is associated with inefficacy in patients with IBD. Allopurinol reverses such hypermethylation.. To prospectively determine efficacy of allopurinol-thiopurine combination and to compare 2 doses of allopurinol.. In a multicentre, double-blind trial, patients with clinically active or steroid-dependent IBD and thiopurine shunting were randomised to 50 or 100 mg/d allopurinol and 25% of their screening thiopurine dose, which was subsequently optimised, aiming for 6TGN of 260-500 pmol/8x10. Of 73 patients, 39 (53% [95% CI 42-65]) achieved steroid-free remission, (54% with 50 mg/d and 53% with 100 mg/d). 81% were able to discontinue steroids. Therapeutic 6TGN levels were achieved in both groups. Final thiopurine doses were lower with 100 mg/d allopurinol (P < 0.005). 6MMP: 6TGN ratio decreased from mean 64 to 4 (P < 0.001), being higher with 50 mg/d (6 ± 1.83) than for 100 mg/d ([1 ± 0.16], P = 0.003). Three patients on 50 mg/d failed to sustain low ratios at 24 weeks. Toxicity was minimal; three patients on 50 mg/d allopurinol developed transient leukopenia. Alanine aminotransferase concentrations decreased (P < 0.001) similarly in both arms. Faecal calprotectin levels at study end were lower in patients who achieved the primary endpoint (median 171 [85-541] vs 821[110-5892] ug/g, P = 0.03).. Low-dose allopurinol-thiopurine combination safely reverses shunting and optimises 6TGN with associated improvement in disease activity. 100 mg/d allopurinol is preferable due to greater metabolite profile stability and lower thiopurine dose without additional toxicity.

Topics: Adolescent; Adult; Allopurinol; Azathioprine; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Treatment Outcome; Young Adult

There are substantial global differences in the preference for mercaptopurine (MP) or its prodrug azathioprine (AZA) as first-choice thiopurine to treat inflammatory bowel diseases. Studies comparing both agents are scarce. Our aim was to compare AZA and MP in thiopurine-naive patients with inflammatory bowel disease for the frequency of side effects and efficacy.. Post hoc analysis of the "Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory bowel disease Clinics" (TOPIC) trial, in which thiopurine-naive patients with inflammatory bowel disease with an indication for a thiopurine were randomized for a genotype-based dose versus standard of care. For this study, Cox proportional hazard ratios (HRs) were calculated to compare AZA and MP for discontinuation rates within 5 months, incidence of hepatotoxicity, leukopenia, and gastrointestinal side effects. Treatment efficacy was compared by logistic regression.. Patient characteristics were similar for patients treated with AZA (n = 494, 64.4%) and MP (n = 273, 35.6%), yet patients with MP were relatively higher dosed compared with those on AZA. Discontinuation rates within 5 months were not different, 39.3% (AZA) and 38.1% (MP), HR 0.92 (95% confidence interval, 0.72-1.17; P = 0.50); however, patients on MP were more often subjected to dose reductions (30% versus 14%, P < 0.01). Higher rates of hepatotoxicity, HR 1.93 (95% confidence interval, 1.35-2.76; P < 0.01) and leukopenia, HR 2.55 (95% confidence interval, 1.51-4.30; P < 0.01) were observed with MP, which annulled in a secondary analysis with adjustment for the higher dose and metabolite levels.. Patients treated with MP were relatively higher dosed, which resulted in more dose-dependent side effects and a higher rate of dose reductions.

Topics: Adult; Azathioprine; Chemical and Drug Induced Liver Injury; Female; Humans; Inflammatory Bowel Diseases; Leukopenia; Logistic Models; Male; Mercaptopurine; Middle Aged; Netherlands; Proportional Hazards Models; Retrospective Studies; Treatment Outcome

Leucopenia is a common side effect in patients treated with thiopurines. Variants in the thiopurine S-methyltransferase (TPMT) gene are the best-known risk factor, but only explain up to 25% of leucopenia cases.. To identify the clinical risk factors for thiopurine-induced leucopenia in patients without a common TPMT variant, and explore if these patients are at increased risk for infections.. Sixty hundred and ninety-five patients (90.6%) included in the TOPIC-trial had no variant in TPMT, of which 45 (6.5%) developed leucopenia. Median time to leucopenia was 56 (29-112) days. Multivariate analysis showed that use of mercaptopurine compared to azathioprine was associated with leucopenia (hazard ratio [HR] 2.61 [95% CIs, 1.39-4.88; P < .01]) and a higher baseline WBC count was protective (HR 0.80 [95% CIs, 0.71-0.89; P < .01]). Risk factors for infections were older age (per 10 year; HR 2.07 [95% CIs, 1.18-3.63; P = .01]) and concomitant use of biologic drugs (HR 2.15 [95% CIs, 1.14-4.07; P = .02]).. Low baseline WBC count and mercaptopurine, due to a relatively higher dose, were risk factors for thiopurine-induced leucopenia in patients without a TPMT variant.

Topics: Adult; Azathioprine; Case-Control Studies; Female; Genotype; Humans; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Polymorphism, Genetic; Risk Factors

Hepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady-state 6-methylmercaptopurine ribonucleotide (6-MMPR) metabolite concentrations.. To determine the predictive value of 6-MMPR concentrations 1 week after treatment initiation (T1) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment.. The cohort study consisted of the first 270 IBD patients starting thiopurine treatment as part of the Dutch randomised-controlled trial evaluating pre-treatment thiopurine S-methyltransferase genotype testing (ClinicalTrials.gov NCT00521950). Blood samples for metabolite assessment were collected at T1. Hepatotoxicity was defined by alanine aminotransaminase elevations >2 times the upper normal limit or a ratio of alanine aminotransaminase/alkaline phosphatase ≥5.. Forty-seven patients (17%) presented hepatotoxicity during the first 20 weeks of thiopurine treatment. A T1 6-MMPR threshold of 3615 pmol/8 × 10. In more than 80% of patients, thiopurine-induced hepatotoxicity could be explained by elevated T1 6-MMPR concentrations and the independent risk factors age, gender and BMI, allowing personalised thiopurine treatment in IBD to prevent early failure.

Topics: Adult; Aged; Aged, 80 and over; Azathioprine; Chemical and Drug Induced Liver Injury; Cohort Studies; Early Diagnosis; Female; Genotype; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Middle Aged; Prognosis; Risk Factors; Thioinosine; Thionucleotides; Treatment Outcome; Young Adult

Azathioprine and mercaptopurine (MP) are effective in treating patients with inflammatory bowel disease (IBD). Immunosuppressive effects of thiopurines involve T-cell apoptosis after inhibition of GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1). This study aimed to assess whether expression and activity of Rac1 or phosphorylated ezrin-radixin-moesin (pERM) in patients with IBD could provide a useful biomarker for the pharmacodynamic thiopurine effect and might be related to clinical effectiveness.. This was a 2-stage study: stage 1 concerned a cross-sectional cohort of patients with IBD clinically in remission and treated with (n = 10) or without stable weight-based thiopurine therapy (n = 11) and healthy controls (n = 6); stage 2 concerned a prospective study regarding IBD patients with clinically active disease who initiated MP therapy (n = 11) compared with healthy controls (n = 11). Expression and activity of Rac1 and ERM and pERM were determined.. The median Rac1 expression was statistically significantly reduced by thiopurine maintenance therapy {0.54 [interquartile range (IQR) 0.47-0.88] versus 0.80 arbitrary units [IQR 0.64-1.46]} compared with patients without immunosuppressive therapy (P = 0.042), but not Rac1 activity and pERM. In responders to MP therapy (n = 6), both median active Rac1 [93 (IQR 81-151) to 76 ng Rac1/mg protein (IQR 62-98)] and Rac1 expression [16.2 (8.8-29.4) to 1.5 arbitrary units (0.9-5.3)] decreased (P = 0.028). In nonresponders (n = 3), Rac1 expression and activity increased.. IBD patients treated with thiopurines had a lower expression of Rac1 compared with those not treated with thiopurine. Effective MP therapy led to decreasing concentrations of Rac1-GTP and Rac1 expression. Therefore, Rac1-GTP and expression of Rac1, but not phosphorylation of ERM, form potentially pharmacodynamic markers of therapeutic thiopurine effectiveness in patients with IBD.

Topics: Adult; Azathioprine; Biomarkers, Pharmacological; Cross-Sectional Studies; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Phosphoproteins; Phosphorylation; Prospective Studies; rac1 GTP-Binding Protein; Sodium-Hydrogen Exchangers; Young Adult

Several studies have demonstrated a favourable safety profile for thiopurine use for inflammatory bowel disease (IBD) during pregnancy. We performed a study in pregnant patients with IBD who were using thiopurines, in order to determine the influence of pregnancy on thiopurine metabolism and to assess intrauterine exposure of the fetus to thiopurines.. Female patients with IBD receiving steady-state thiopurines and planning a pregnancy were prospectively enrolled. 6-Thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) concentrations were determined, combined with routine laboratory tests, before, during and after pregnancy. Thiopurine metabolites were measured in umbilical cord blood immediately after delivery.. Thirty patients who were using azathioprine (28 patients, median dose 1.93 mg/kg) or mercaptopurine (two patients, doses 1.32 and 0.94 mg/kg) were included. During pregnancy, median 6-TGN decreased over time (p=0.001). while 6-MMP increased, without causing myelotoxicity or hepatotoxicity. After delivery, both 6-TGN and 6-MMP levels returned to preconception baseline levels. Fetal 6-TGN concentrations correlated positively with maternal 6-TGN levels (p<0.0001). No 6-MMP was detected in the newborns, except one born with pancytopenia and high alkaline phosphatase activity; the mother of this infant had severe pre-eclampsia. All infants had normal Apgar scores, but 60% had anaemia at birth. No major congenital abnormalities were observed.. Pregnancy has a major effect on maternal thiopurine metabolism. In utero the unborn child is exposed to 6-TGN, but not to 6-MMP. Sixty per cent of the infants were born with anaemia, which raises the question whether infants should be tested for possible anaemia immediately after birth.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Anemia, Neonatal; Azathioprine; Biomarkers; Female; Fetal Blood; Follow-Up Studies; Guanine Nucleotides; Humans; Immunosuppressive Agents; Infant, Newborn; Inflammatory Bowel Diseases; Mercaptopurine; Middle Aged; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prospective Studies; Thionucleotides; Treatment Outcome; Young Adult

Recent studies in patients with inflammatory bowel diseases (IBD) on thiopurine therapy suggest that too low 6-thioguanine nucleotide concentrations (6-TGN) and too high methylmercaptopurine nucleotide concentrations (MMPN) can be reversed by a combination therapy of allopurinol and low-dose thiopurines. To date, however, optimal dosing has not been established. The aim of this study was to evaluate the minimal allopurinol doses necessary to achieve adequate 6-TGN concentrations in combination with low-dose azathioprine.. A stepwise dose-escalation of allopurinol was performed in 11 azathioprine-pretreated IBD patients with inadequately low 6-TGN concentrations (<235 pmol/8 × 10(8) erythrocytes) and/or elevated MMPN concentrations (>5,000 pmol/8 × 10(8) erythrocytes) and/or elevated liver enzymes (alanine aminotransferase and/or aspartate aminotransferase levels one- to threefold the upper limit of normal). Six patients were recruited into an open study, and five were treated in the context of an individualized therapeutic approach. Adverse effects, azathioprine metabolites, liver enzymes and whole blood counts were monitored two to three times per month.. Adequate 6-TGN concentrations were achieved with a combination of 25 mg allopurinol and 50 mg azathioprine in one patient and with 50 mg allopurinol and 50 mg azathioprine in nine patients. Median 6-TGN concentrations (range) were 336 (290-488) pmol/8 × 10(8) erythrocytes after an 8-week-long intake of the final dose combination. One patient dropped out due to nausea after the first intake. MMPN concentrations and liver enzymes normalized immediately in all affected patients. All patients finishing the dose-escalation regimen tolerated the treatment without toxicity.. Combination therapy with only 50 mg allopurinol and 50 mg azathioprine daily is sufficient, efficacious and safe in most IBD patients with inadequate thiopurine metabolite concentrations to optimize azathioprine-based IBD therapy.

Topics: Adult; Aged; Allopurinol; Azathioprine; Female; Guanine Nucleotides; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Thionucleotides

To evaluate an individually tailored multicomponent nonadherence treatment protocol using a telehealth delivery approach in adolescents with inflammatory bowel disease.. Nine participants, age 13.71±1.35 years, completed a brief treatment online through Skype. Medication nonadherence, severity of disease, and feasibility/acceptability data were obtained.. Adherence increased markedly from 62% at baseline to 91% for mesalamine (δ=0.63), but decreased slightly from 61% at baseline to 53% for 6-mercaptopurine /azathioprine. The telehealth delivery approach resulted in cost savings of $100 in mileage and 4 h of travel time/patient. Treatment session attendance was 100%, and the intervention was rated as acceptable, particularly in terms of treatment convenience.. Individually tailored treatment of nonadherence through telehealth delivery is feasible and acceptable. This treatment shows promise for clinical efficacy to improve medication adherence and reduce costs. Large-scale testing is necessary to determine the impact of this intervention on adherence and health outcomes.

Topics: Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Behavior Therapy; Child; Cost of Illness; Delivery of Health Care; Drug Therapy, Combination; Feasibility Studies; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Medication Adherence; Mercaptopurine; Mesalamine; Ohio; Pilot Projects; Severity of Illness Index; Telemedicine; Treatment Outcome

Thiopurines are considered immunosuppressive agents and may be associated with an increased risk for infections. However, few inflammatory bowel disease (IBD) patients are appropriately vaccinated, and data on their ability to mount an immune response are vague. We evaluated the effects of the thiopurines, azathioprine (AZA) and 6-mercaptopurine (6-MP), on cellular and humoral immune responses in IBD patients.. A prospective clinical investigation was conducted on IBD patients referred for thiopurine treatment. Immune competence was evaluated by assessing lymphocyte counts and phenotype, response to mitogen and antigen stimulation, immunoglobulin levels, and response to pneumococcal and tetanus vaccines (before treatment, week 0), and to Haemophilus influenza type b vaccine (at week 24).. Thirty-one Crohn's disease and 12 ulcerative colitis patients who completed at least 24 weeks of therapy were included. The posttherapy average 6-MP dose was 1.05 ± 0.30 mg/kg, and white blood cell counts had decreased significantly from baseline values (P < 0.002). The posttreatment response to mitogens and antigens and the immunoglobulin levels were unchanged. Responses to vaccines were normal both in thiopurine-naïve and thiopurine-treated patients, suggesting that these patients were immunologically intact while on thiopurine therapy and capable of generating normal immune responses in vivo.. There is no evidence for any intrinsic systemic immunodeficiency in IBD patients. Thiopurines at the doses used for treating IBD showed no significant suppressive effect on the systemic cellular and humoral immune responses evaluated. Thiopurine-treated IBD patients can be safely and efficiently vaccinated.

Topics: Adult; Azathioprine; Female; Gastrointestinal Agents; Humans; Immune Tolerance; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukocyte Count; Male; Mercaptopurine; Middle Aged; Vaccines; Young Adult

To pilot test the feasibility and acceptability of a family-based group behavioral intervention and to improve medication adherence in adolescents diagnosed with inflammatory bowel disease.. Participants were 40 adolescents aged 11-18 years diagnosed with inflammatory bowel disease and their primary caregivers, who were randomized to either a four-session Family-Based Group Behavioral Treatment or Usual Care over a 6-week period. Adherence was measured using a multi-method, multi-informant assessment involving caregiver-report and patient-report, pill count data, and electronic monitoring.. Adherence rates ranged from 66 to 89% for 6-mercaptopurine/azathioprine and 51 to 93% for mesalamine across assessment methods. The intervention was feasible, as evidenced by the 99% treatment session attendance rate, and acceptable based on patient and caregiver report. Repeated measures analysis of variance tests revealed nonsignificant differences between the conditions from baseline to post-treatment assessments for pill count, electronic monitor, and primary caregiver-reported adherence (P's>0.05). There was a statistically significant improvement in patient-reported mesalamine adherence represented by a significant main effect for Condition (F=22.24, P<0.01; δ=0.79) and Condition×Time interaction (F=13.32, P<0.05; δ=0.69).. Findings suggest potential for use of behavioral intervention to improve medication adherence in this population. This intervention may be more effective with more complex regimens (e.g. multiple doses per day) such as those prescribed with mesalamine. Further research is needed to examine this type of intervention in more diverse samples with more active disease. Use of alternative adherence measurement approaches, including electronic pill boxes and/or real-time self-report (e.g. by text messaging, electronic diaries, etc.) is also recommended.

Topics: Adolescent; Adolescent Behavior; Adult; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Behavior Therapy; Caregivers; Child; Drug Administration Schedule; Drug Combinations; Epidemiologic Methods; Family Therapy; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Medication Adherence; Mercaptopurine; Mesalamine; Middle Aged; Self Administration; United States

Therapeutic drug monitoring of active metabolites of thiopurines, azathioprine and 6-mercaptopurine, is relatively new. The proposed therapeutic threshold level of the active 6-thioguanine nucleotides (6-TGN) is ≥235 pmol/8×10(8) erythrocytes. The aim of this prospective cross-sectional study was to compare 6-TGN levels in adult thiopurine tolerant IBD patients with an exacerbation with those in remission, and to determine the therapeutic 6-TGN cut-off level.. Hundred IBD patients were included. Outcome measures were thiopurine metabolite levels, calculated therapeutic 6-TGN cut-off level, CDAI/CAI scores, thiopurine dose and TPMT enzyme activity.. Forty-one patients had an exacerbation, 59 patients were in remission. In 17% of all patients 6-TGN levels were compatible with non-compliance. The median 6-TGN levels were not significantly different between the exacerbation and remission group (227 versus 263 pmol/8×10(8) erythrocytes, p=0.29). The previous reported therapeutic 6-TGN cut-off level of 235 pmol/8×10(8) erythrocytes was confirmed in this study. Twenty-six of the 41 patients (63%) with active disease had 6-TGN levels below this threshold and 24 of 59 IBD patients (41%) in clinical remission (p=0.04).. Thiopurine non-compliance occurs frequently both in active and quiescent disease. 6-TGN levels below or above the therapeutic threshold are associated with a significant higher chance of IBD exacerbation and remission, respectively. These data support the role of therapeutic drug monitoring in thiopurine maintenance therapy in IBD to reveal non-compliance or underdosing, and can be used as a practical tool to optimize thiopurine therapy, especially in case of thiopurine non-response.

Topics: Adolescent; Adult; Aged; Azathioprine; Biomarkers, Pharmacological; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Disease Progression; Dose-Response Relationship, Drug; Drug Monitoring; Female; Genetic Markers; Guanine Nucleotides; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Maintenance Chemotherapy; Male; Medication Adherence; Mercaptopurine; Methyltransferases; Middle Aged; Prospective Studies; Severity of Illness Index; Thioinosine; Thionucleotides; Young Adult

Nonadherence is a significant health care issue in pediatric inflammatory bowel disease (IBD) that requires intervention to improve outcomes. This pilot randomized controlled trial was designed to evaluate the feasibility, acceptability, and preliminary efficacy of an individually tailored behavioral treatment for nonadherence in adolescents with IBD.. Fourteen adolescents ages 14.89 ± 2.01 years were randomly assigned to immediate care or wait list control conditions and received a manualized individually tailored behavioral intervention for nonadherence. Medication adherence, measured by pill count, served as the primary endpoint. Parents provided demographic data and ratings of intervention acceptability and patients provided disease-severity data.. Feasibility of the treatment was demonstrated by 100% treatment session attendance for all of the patients enrolled in the trial. Both parent and patient acceptability ratings were favorable. Comparison of baseline with posttreatment percent adherence across both conditions demonstrated that treatment resulted in a 4% gain in 6-mercaptopurine/azathioprine adherence (52% at baseline; 56% at posttreatment; δ = 0.07) and a 25% gain in mesalamine adherence (43% at baseline; 68% at posttreatment; δ = 0.57).. Individually tailored treatment of nonadherence in adolescents with IBD is feasible and may result in substantial improvement in medication adherence. Differential effect of the intervention on medications requires further investigation, but it may reflect differences in regimen complexity, concerns about medication adverse effects, and/or patient/parent preference to target more complex regimens. Large-scale testing of this intervention is needed to demonstrate effect on clinical outcomes.

Topics: Adolescent; Azathioprine; Child; Feasibility Studies; Female; Humans; Inflammatory Bowel Diseases; Interviews as Topic; Male; Medication Adherence; Mercaptopurine; Mesalamine; Patient Education as Topic; Pilot Projects; Precision Medicine; Surveys and Questionnaires; Treatment Outcome

Thiopurines are crucial in the treatment of inflammatory bowel disease. The phenotype of pivotal metabolic enzymes determines whether thioguanine nucleotides (6-TGN) are generated in clinically sufficiently high levels. The first step in activation of thiopurine prodrugs to 6-TGN is catalysis by hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Often, patients exhibit a clinically unfavorable metabolism, leading to discontinuation of conventional thiopurine therapy. The combination of allopurinol and low-dose thiopurine therapy may optimize this variant metabolism, presumably by affecting enzyme activities. We performed a prospective pharmacodynamic study to determine the effect of combination therapy on the activity of HGPRT. The activity of HGPRT and 6-TGN concentrations was measured in red blood cells during thiopurine monotherapy and after 4 weeks of combination therapy. The activity of HGPRT was also measured after 12 weeks of combination therapy. From the results, we conclude that combination therapy increases the activity of HGPRT and subsequently 6-TGN concentrations.

Topics: Adolescent; Adult; Allopurinol; Azathioprine; Child; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Gout Suppressants; Humans; Hypoxanthine Phosphoribosyltransferase; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Young Adult

5-aminosalicylate (5-ASA) raises levels of 6-thioguanine nucleotides (6-TGN), the active metabolites of thiopurines such as azathioprine (AZA). Changes in levels of each individual TGN - 6-thioguanosine mono-, di- and triphosphate (6-TGMP, 6-TGDP, 6-TGTP) - and of 6-methylmercaptopurine ribonucleotides (6-MMPR) after 5-ASA are not known.. Effects of increasing 5-ASA doses on AZA metabolites were investigated prospectively in 22 patients with inflammatory bowel disease in 4-week study periods. Patients started with 2 g 5-ASA daily, and then were increased to 4 g daily and followed by a washout period. Thiopurine doses remained unchanged throughout the entire study. Levels of 6-TGMP, 6-TGDP, 6-TGTP and 6-MMPR as well as of 5-ASA and N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA) were determined each study period.. Median baseline levels in 17 patients of 6-TGDP, 6-TGTP and 6-MMPR were 52, 319 and 1676 pmol per 8 x 10(8) red blood cells respectively. After co-administration of 2 g 5-ASA daily, median 6-TGDP and 6-TGTP levels increased but median 6-MMPR levels were unchanged. Increasing 5-ASA to 4 g daily did not affect median 6-TGDP and 6-TGTP levels, but median 6-MMPR levels decreased. After discontinuation of 5-ASA, both 6-TGDP and 6-TGTP levels decreased and median 6-MMPR levels increased. The 6-TGTP/(6-TGDP+6-TGTP)-ratio did not change during the study, but 6-MMPR/6-TGN ratios decreased.. Individual 6-TGN metabolites increased after addition of 5-ASA, but 6-MMPR-levels and the 6-MMPR/6-TGN ratios decreased. Further studies are needed to decide whether this pharmacokinetic interaction would result in improvement of efficacy and/or increased risk of toxicity of AZA.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Mesalamine; Middle Aged; Prospective Studies

6-Mercaptopurine and its prodrug azathioprine are effective for the treatment of inflammatory bowel disease. Thiopurine methyltransferase is important for the metabolism of thiopurines. However, there is controversy as to the clinical utility of measuring thiopurine methyltransferase enzyme activity and 6-thioguanine nucleotide levels. Our aim was to determine if thiopurine methyltransferase enzyme activity and 6-thioguanine nucleotide level monitoring would predict response to therapy with thiopurines in patients with inflammatory bowel disease.. Baseline thiopurine methyltransferase enzyme activity prior to initiation of therapy with either 6-mercaptopurine or azathioprine was determined in 39 patients with inflammatory bowel disease. The association between clinical response and thiopurine methyltransferase activity and 6-thioguanine nucleotide levels singly or in combination were analysed.. Seventeen of 39 patients (44%) responded to 6-mercaptopurine or azathioprine therapy. Thiopurine methyltransferase enzyme activity below the mean of 30.5 U was significantly associated with clinical response. The thiopurine methyltransferase low phenotype was associated with response in 65% vs. 29% in individuals with thiopurine methyltransferase enzyme activity above 30.5 U (p = 0.05). There was no correlation between thiopurine methyltransferase activity and 6-thioguanine nucleotide levels. The maximal 6-thioguanine nucleotide levels did not predict clinical response. When combining thiopurine methyltransferase enzyme activity and 6-thioguanine nucleotide levels, the combination of thiopurine methyltransferase low/6-thioguanine nucleotide high was associated with response in 7/7 (100%) vs. only 2/8 (25%) with the combination of thiopurine methyltransferase high/6-thioguanine nucleotide low (p=0.01).. Thiopurine methyltransferase activity inversely correlated with clinical response to thiopurine treatment in inflammatory bowel disease. Thiopurine methyltransferase enzyme activity below 30.5 U combined with a post-treatment 6-thioguanine nucleotide level > 230 pmol/8 x 10(8) erythrocytes was the best predictor of response.

Topics: Adult; Antimetabolites, Antineoplastic; Azathioprine; Female; Forecasting; Guanine Nucleotides; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Thionucleotides; Treatment Outcome

Patients with inflammatory bowel disease (IBD) may have different thiopurine dose requirements in relation to thiopurine methyltransferase (TPMT) genotype and/or phenotype. The purpose of this study was to determine thiopurine dose requirements in intermediate versus normal TPMT metabolism status.. Consecutive patients starting azathioprine or 6-mercaptopurine for IBD were followed up for 9 months. The thiopurine dose was individualized using 6-thioguanine nucleotide (6-TGN) concentrations (range, 235-450 pmol/8 x 10(8) red blood cells [RBCs]) and clinical status. Additional assessments undertaken every three months included measures of disease activity.. Eight (10%) of 77 participants were withdrawn because of protocol violation. Fifty-two (75%) of the remaining 69 subjects ( approximately 90% and 10% with the TPMT*1/*1 and *1/*3 genotypes, respectively) completed follow-up on azathioprine (n = 46) or 6-mercaptopurine (n = 6). The mean initial dose (as azathioprine equivalents) was similar ( approximately 1 mg/kg/d) for the 2 TPMT genotypes, but after 9 months the dose was 50% lower in the TPMT*1/*3 group (0.9 vs 1.8 mg/kg/d, P < .0001). Despite dose adjustment, median 6-TGN concentrations still were 2-fold higher in the TPMT*1/*3 group at the end of the follow-up period (505 vs 273 pmol/8 x 10(8) RBCs, P = .02). This difference was 3-fold when the concentration was adjusted for dose (578 vs 183 pmol/8 x 10(8) per mg/kg/d, P = .0007). Results were similar if TPMT phenotype was used instead of genotype. Clinical outcomes did not differ between groups.. Initial target doses to attain therapeutic 6-TGN concentrations (>235 pmol/8 x 10(8) RBCs) in patients with IBD might be 1 and 3 mg/kg/d in intermediate and normal metabolizers, respectively.

Topics: Adult; Azathioprine; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Prospective Studies; Treatment Outcome

In vitro studies suggest interactions between mesalazine (mesalamine) and thiopurines by thiopurine S-methyltransferase (TPMT) inhibition, influencing the balance of hepatotoxic 6-methylmercaptopurine ribonucleotide and immunosuppressive tioguanine (thioguanine) metabolites.. To examine the in vivo pharmacokinetic interaction between mesalazine and mercaptopurine.. A prospective study was performed in quiescent inflammatory bowel disease patients using the combination of mercaptopurine and mesalazine. Laboratory parameters, 6-methylmercaptopurine ribonucleotide and tioguanine levels and thiopurine S-methyltransferase activity in erythrocytes were measured at stable medication, after mesalazine discontinuation and mesalazine reintroduction, further mercaptopurine was continued.. Seventeen patients were participated. Mean mercaptopurine dose was 0.78 mg/kg/day and median of mesalazine dose was 3000 mg/day. After mesalazine discontinuation, mean tioguanine levels changed significantly from 262 to 209 pmol/8 x 10(8) red blood cell, increasing to 270 after reintroduction. Mean 6-methylmercaptopurine ribonucleotide levels were 1422, 2149 and 1503 pmol/8 x 10(8) red blood cell respectively. Mean 6-methylmercaptopurine ribonucleotide/tioguanine ratio increased significantly from 6.3 at baseline to 11.2. Mean baseline thiopurine S-methyltransferase activity was 0.58 pmol/10(6) red blood cell/h and stable. All patients had wild-type thiopurine S-methyltransferase genotypes however, leucocyte counts were stable.. A significantly higher tioguanine levels and improving 6-methylmercaptopurine ribonucleotide/tioguanine ratio were found during mesalazine/mercaptopurine combination. Theoretically, mesalazine inhibits thiopurine S-methyltransferase activity. In vivo thiopurine S-methyltransferase activity did not change, however.. Mesalazine has synergistic effects on mercaptopurine therapy, but the mechanism is unclear. Combining these drugs may be further indication for mesalazine in inflammatory bowel disease treatment.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites; Antimetabolites, Antineoplastic; Drug Combinations; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Mesalamine; Prospective Studies; Thioguanine

Proper prospective pharmacokinetic studies of 6-mercaptopurine (6-MP) in inflammatory bowel disease (IBD) patients are lacking. As a result, conflicting recommendations have been made for metabolite monitoring in routine practice. The authors have evaluated 6-MP pharmacokinetics in IBD patients, including the genetic background for thiopurine methyltransferase (TPMT). Red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine ribonucleotide (6-MMPR) concentrations were measured in 30 IBD patients at 1, 2, 4, and 8 weeks after starting 6-MP, 50 mg once daily. Outcome measures included mean 6-TGN and 6-MMPR concentrations (+/- 95% confidence interval, CI95%) and their associations with TPMT genotype, 6-MP dose, and hematologic, hepatic, pancreatic, and efficacy parameters during the 8-week period. Steady-state concentrations were reached after 4 weeks, indicating a half-life of approximately 5 days for both 6-TGN and 6-MMPR; the concentrations were 368 (CI95% 284-452) and 2837 (CI95% 2101-3573) pmol/8 x 10 RBCs, respectively. Large interpatient variability occurred at all time points. TPMT genotype correlated with 6-TGN concentrations (0.576, P < 0.01), and patients with mutant alleles had a relative risk (RR) of 12.0 (CI95% 1.7-92.3) of developing leukopenia. A 6-MMPR/6-TGN ratio less than 11 was associated with therapeutic efficacy. Based on this pharmacokinetic analysis, therapeutic drug monitoring is essential for rational 6-MP dosing.

Topics: Adult; Aged; Drug Monitoring; Female; Genotype; Guanine Nucleotides; Half-Life; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Middle Aged; Prospective Studies; Purine Nucleotides; Thionucleotides

There is some uncertainty regarding how to best dose and therapeutically monitor 6-mercaptopurine or azathioprine in patients with inflammatory bowel disease. The purpose of this study was to assess the relation between clinical response, 6-mercaptopurine metabolite levels, relative leukopenia, and drug dose.. 60 patients with inflammatory bowel disease who were on stable doses of 6-mercaptopurine or azathioprine for > or = 3 months and who had measurements of 6-mercaptopurine metabolite levels were evaluated. Patients were classified as complete responders (N = 24), partial responders (N = 7), or non-responders (N = 29).. Drug dose was associated with clinical response when we analyzed adjusted doses based on molecular drug weight (P = 0.002). 6-Thioguanine levels also were associated with clinical response (P = 0.003) and the maximal difference between responders and non-responders was seen at 6-thioguanine levels greater than 260 pmol/8 x 10(8) RBC. Relative leukopenia, defined as white blood cell count less than either 5.0 or 4.0 K/uL, was not associated with clinical response (P = 0.13 and 0.77 respectively).. 1. Drug dose and 6-thioguanine levels are related to clinical response in patients with inflammatory bowel disease on 6-mercaptopurine or azathioprine. 2. For 6-thioguanine levels, there is a fair amount of overlap, but maximal differentiation between responders and non-responders is seen at levels > 260 pmol/8 x 10(8) RBC. 3. Relative leukopenia does not correlate well with clinical response.

Topics: Adult; Antirheumatic Agents; Azathioprine; Dose-Response Relationship, Drug; Endpoint Determination; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Middle Aged; Treatment Outcome

6-Mercaptopurine (6-MP) and azathioprine (AZA) have proven efficacy in the treatment of inflammatory bowel disease (IBD). However, adverse events leading to discontinuation may occur in 10-20% of patients. The efficacy of AZA and 6-MP is based on formation of their active metabolites, the 6-thioguaninenucleotides (6-TGNs). Therefore, 6-thioguanine (6-TG), an agent leading more directly to the formation of 6-TGNs and until recently used only in patients suffering from leukaemia, may be an alternative in AZA or 6-MP intolerance. The purpose of our study was to assess the short-term safety of 6-TG.. Thirty-two IBD patients with previously established AZA or 6-MP intolerance were treated with 6-TG in doses of 20 mg (n = 19) or 40 mg (n = 13) once daily. Safety parameters were obtained at 0, 1, 2, 4 and 8 weeks after start of medication. Primary outcome measures were the ability to tolerate 6-TG and the occurrence of adverse events. Secondary outcome definitions included laboratory parameters.. Twenty-six (81%) patients were able to tolerate 6-TG during the first 8 weeks. In three of six patients, side effects leading to discontinuation were probably (n = 2) or obviously (n = 1) related to 6-TG. No clinically relevant haematological events or hepatotoxicity occurred in the observed period. Steady-state 6-TG levels were significantly higher with 40 mg once daily (1621 +/- 828 picomol/8 x 10(8) red blood cells (RBC)) than with 20 mg once daily (937 +/- 325 picomol/8 x 10(8) RBC; n = 0.001).. 6-TG treatment seems promising in AZA- or 6-MP-intolerant IBD patients. However, long-term safety and efficacy have yet to be determined.

Topics: Adult; Azathioprine; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Monitoring; Erythrocytes; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Prospective Studies; Thioguanine

Mean corpuscular volume may correlate with erythrocyte 6-thioguanine nucleotide concentrations in patients treated with azathioprine and 6-mercaptourine. We conducted a study of 166 patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine to determine the relationship between mean corpuscular volume and erythrocyte 6-thioguanine nucleotide concentrations, disease activity as measured by the Inflammatory Bowel Disease Questionnaire (active disease <170, remission >170), and leukopenia. Blood was submitted for mean corpuscular volume, whole blood 6-thioguanine nucleotide concentration, and leukocyte count. The mean +/- SD mean corpuscular volume during treatment was 94.7 +/- 6.6 fL and the mean +/- SD change in mean corpuscular volume was 7.5 +/- 6.3 fL. There were significant correlations between mean corpuscular volume and erythrocyte 6-thioguanine nucleotide concentration (r(s) = 0.33, p < 0.001) and between change from baseline in mean corpuscular volume and erythrocyte 6-thioguanine nucleotide concentration (r(s) = 0.26, p = 0.001). There was no correlation between Inflammatory Bowel Disease Questionnaire scores and mean corpuscular volume values (r(s) = 0.01, p = 0.94). The mean corpuscular volume values in 55 patients with active disease and 111 patients in remission were similar (95.1 vs. 94.5 fL, p = 0.57). There was a weak negative correlation between the mean corpuscular volume and the leukocyte count, (r(s) = -0.18, p = 0.022). In patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine, mean corpuscular volume and change from baseline in mean corpuscular volume correlated with erythrocyte 6-thioguanine nucleotide concentrations and negatively with leukocyte counts, but did not correlate with disease activity as measured by the Inflammatory Bowel Disease Questionnaire. Measurement of mean corpuscular volume is a simple and inexpensive alternative to measurement of 6-thioguanine nucleotide concentrations in patients treated with azathioprine or 6-mercaptopurine.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azathioprine; Biomarkers; Endpoint Determination; Erythrocyte Indices; Erythrocytes; Female; Guanine Nucleotides; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukocyte Count; Male; Mercaptopurine; Middle Aged; Severity of Illness Index; Surveys and Questionnaires; Thionucleotides; Treatment Outcome

Azathioprine and mercaptopurine (MP) are well established treatments for inflammatory bowel disease but they have severe adverse effects that prevent their use in some patients. The likelihood and type of adverse effect may relate to thiopurine methyltransferase (TPMT) enzyme activity and genotype.. To compare the TPMT genotype frequencies in patients with inflammatory bowel disease who have had severe adverse effects to those who tolerate azathioprine or MP (controls).. Patients with inflammatory bowel disease who had been treated with azathioprine or MP in Christchurch between 1996 and 2002 were identified. Patients with adverse effects, and controls, were invited to provide a peripheral blood sample for analysis of TPMT genotype. The genotype frequencies were then compared between the two groups.. Fifty-six patients were identified with adverse effects requiring cessation of therapy, of which 50 were genotyped. Reactions included allergic-type (25%), hepatitis (33%), nausea/vomiting (14%), bone marrow suppression (10%), pancreatitis (6%) and other (12%). Five of 50 patients with reactions had TPMT genotype *1/*3, one had *3/*3, and the rest had the wildtype genotype *1/*1. The patient with genotype *3/*3 had severe pancytopenia requiring hospitalization. Three of 50 controls had the *1/*3 genotype and the rest were *1/*1.. The TPMT allele frequency in our population with inflammatory bowel disease is similar to that reported elsewhere. There was a slight trend for more frequent TPMT mutations in the patients with adverse reactions, but this was not statistically significant. Most patients with reactions did not have gene mutations.

Topics: Adolescent; Adult; Aged; Azathioprine; Female; Genotype; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Middle Aged

Approximately 40% of inflammatory bowel disease (IBD) patients fail to benefit from 6-mercaptopurine (6-MP)/azathioprine (AZA). Recent reports suggest 6-thioguanine nucleotide (6-TGN) levels (>235) independently correlate with remission. An inverse correlation between 6-TGN and thiopurine methyltransferase (TPMT) has been described. The objectives of this study were to determine whether dose escalation optimizes both 6-TGN levels and efficacy in patients failing therapy because of subtherapeutic 6-TGN levels and its effect on TPMT.. Therapeutic efficacy and adverse events were recorded at baseline and upon reevaluation after dose escalation in 51 IBD patients. 6-MP metabolite levels and TPMT activity were recorded blinded to clinical information.. Fourteen of 51 failing 6-MP/AZA at baseline achieved remission upon dose escalation, which coincided with significant rises in 6-TGN levels. Despite increased 6-MP/AZA doses, 37 continued to fail therapy at follow-up. Dose escalation resulted in minor changes in 6-TGN, yet a significant increase in 6-methylmercaptopurine ribonucleotides (6-MMPR) (P < or = 0.01) and 6-MMPR:6-TGN ratio (P < 0.001). 6-MMPR rises were associated with dose-dependent hepatotoxicity in 12 patients (24%). TPMT was not influenced by dose escalation.. Serial metabolite monitoring identifies a novel phenotype of IBD patients resistant to 6-MP/AZA therapy biochemically characterized by suboptimal 6-TGN and preferential 6-MMPR production upon dose escalation.

Topics: Adolescent; Adult; Aged; Azathioprine; Chemical and Drug Induced Liver Injury; Drug Resistance; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Middle Aged; Patient Selection; Treatment Failure

This study examined the role of thiopurine methyltransferase (TPMT) polymorphism in the metabolism and clinical effects of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease and childhood leukemia. The current hypothesis is that the cytotoxic effects of thiopurines are caused by the incorporation of thioguanine nucleotides into DNA. In this context, S-methylation catalyzed by TPMT can be regarded as a competing metabolic pathway. The authors assayed the TPMT activity in red blood cells from 122 patients treated with azathioprine or 6-mercaptopurine (83 adults with inflammatory bowel disease and 39 children with acute lymphoblastic leukemia) and in 290 untreated controls (219 adult blood donors and 71 children). The concentrations of thioguanine nucleotides and methylthioinosine monophosphate were also assayed in red blood cells from the patients. The TPMT activity and the concentrations of methylthioinosine monophosphate and thioguanine nucleotides were higher in children than in adults. All children but no adult patient received concomitant methotrexate. Interaction between methotrexate and 6-mercaptopurine has been described, and may explain the results. Low TPMT activity in adult patients with inflammatory bowel disease correlated to an increased incidence of adverse drug reactions. However, there was no correlation between TPMT activity and the red blood cell concentrations of methylthioinosine monophosphate or thioguanine nucleotides, or between the concentrations of these metabolites and the occurrence of adverse effects. The results show that the role of thiopurine metabolism for drug effects is complex.

Topics: Adult; Age Factors; Antimetabolites, Antineoplastic; Azathioprine; Child; Drug Therapy, Combination; Erythrocytes; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methotrexate; Methyltransferases; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioinosine; Thionucleotides

The effects of 6-mercaptopurine (6-MP) are mediated via its intracellular conversion to 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) nucleotide metabolites, the latter genetically controlled by thiopurine methyltransferase (TPMT). We sought to determine optimal therapeutic 6-MP metabolite levels and their correlation with medication-induced toxicity and TPMT genotype.. Therapeutic response was determined in 92 pediatric patients with inflammatory bowel disease coincidentally with hematologic, pancreatic, and hepatic laboratory parameters, and compared with erythrocyte metabolite levels and TPMT genotype.. Clinical response was highly correlated with 6-TG levels (P < 0.0001) but not with any other variable, including 6-MMP levels, drug dose, gender, and concurrent medications. The frequency of therapeutic response increased at 6-TG levels > 235 pmol/8 x 10(8) erythrocytes (P < 0.001). Hepatotoxicity correlated with elevated 6-MMP levels (>5700 pmol/8 x 10(8) erythrocytes; P < 0.05). Although leukopenia was associated with higher 6-TG levels (P < 0.03), it was observed in only 8% of responders. Patients heterozygous for TPMT (8/92) had higher 6-TG levels (P < 0.0001), and all responded to therapy.. 6-MP metabolite levels and TPMT genotyping may assist clinicians in optimizing therapeutic response to 6-MP and identifying individuals at increased risk for drug-induced toxicity.

Topics: Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Genotype; Humans; Immunosuppressive Agents; Infant; Inflammatory Bowel Diseases; Leukopenia; Liver; Male; Mercaptopurine; Mesalamine; Methyltransferases; Prospective Studies; Thioguanine; Treatment Outcome

As treatment of steroid-dependent patients with inflammatory bowel disease (IBD) is controversial, we analysed the efficacy and tolerance of 6-mercaptopurine (6-MP) and methotrexate (MTX) added to prednisone in increasing and maintaining the disease remission rate.. Seventy-two steroid-dependent IBD patients, 34 with ulcerative colitis (UC) and 38 with Crohn's disease (CD), receiving treatment with prednisone were randomly assigned in a 2:2:1 ratio to additionally receive, orally, over a period of 30 weeks 1.5 mg/kg/day of 6-MP (group A) or 15 mg/week of MTX (group B), or 3 g/day of 5-aminosalicylic acid (5-ASA) (group C). All patients who achieved remission were included in a maintaining remission study for 76 weeks. Remission was defined after stopping prednisone as a CD activity index of <150 and normal serum orosomucoid concentration for CD patients and a Mayo Clinic score <7 for UC patients.. With regard to achieved remission, a significantly higher (P< 0.05) rate existed for UC patients in group A (78.6%) than in group C (25%), with no statistical differences in group B (58.3%) versus C. For CD patients, the rates were significantly higher (P< 0.001 and 0.01, respectively) in groups A (93.7%) and B (80%) versus C (14%). With regard to maintaining remission, UC patients in group A (63.6%) presented significantly higher rates (P < 0.0015 and P < 0.001, respectively) versus 14.3% in group B and none in group C. For CD patients, statistical differences (P < 0.001) existed when comparing rates in groups A (53.3%) and B (66.6%) versus none in group C. Noticeable side effects appeared in 13.3% of patients from group A and 11.5% from group B.. These results suggest that 6-MP or MTX added to prednisone could be effective in steroid sparing, as well as in achieving and maintaining remission in steroid-dependent IBD patients. MTX was less effective in maintaining remission in UC patients.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents; Antimetabolites; Chi-Square Distribution; Drug Therapy, Combination; Female; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methotrexate; Middle Aged; Prednisone; Remission Induction; Survival Analysis; Treatment Outcome

The aim of this study was to assess whether in steroid-resistant patients with pediatric inflammatory bowel disease (IBD) a combination of cyclosporine and azathioprine (or 6-mercaptopurine) could induce remission and subsequently permit maintenance on azathioprine/6-mercaptopurine as the sole immunosuppressive agent. Two boys and six girls (six with ulcerative colitis and two with Crohn's disease; ages 3-17 years) received 100-200 micrograms/kg/day cyclosporine intravenously and then 4-10 mg/kg/day orally. Doses were adjusted to achieve trough serum cyclosporine levels of 100-200 mu/L (Abbott's TDX assay). Seven of the eight patients received azathioprine/6-mercaptopurine, and all were given a 5-aminosalicylate preparation and corticosteroids. The latter drugs were continued and then tapered off as clinical status allowed. Cyclosporine was continued for 3-10 months in those who responded. In seven of eight patients, there was a rapid clinical response; one patient showed a transient response, but recurrent bleeding led to total colectomy 9 days after starting cyclosporine. Of the seven responders, three were able to discontinue prednisone and cyclosporine and are doing well on azathioprine at long-term follow-up (2-5 years). One who did not receive azathioprine/6-mercaptopurine maintained remission for 2 years after cyclosporine was stopped, one experienced a disease flare-up 5 months after start of cyclosporine treatment and required colectomy, one who did not tolerate 6-mercaptopurine had a flare-up during cyclosporine tapering and underwent surgery at 6 months, and one started to flare up with cyclosporine tapering at 6 months and was scheduled for surgery. No significant complications of treatment were observed. Seven patients had an initial response and four of them have so far not required surgery. These preliminary findings suggest that azathioprine/6-mercaptopurine can be used safely to maintain cyclosporine-induced remission in children with IBD.

Topics: Adolescent; Azathioprine; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Drug Therapy, Combination; Female; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Remission Induction; Treatment Outcome

Topics: Adolescent; Adult; Azathioprine; Child; Colitis, Ulcerative; Crohn Disease; Double-Blind Method; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Metronidazole

Thiopurines are effective therapies for inflammatory bowel disease (IBD); however, treatment comes with safety concerns and adverse effects. Knowledge of the impact of pharmacists performing thiopurine monitoring is limited.. To determine the impact of a pharmacist-led monitoring service in patients with IBD commencing thiopurine therapy managed in the ambulatory care setting.. Patients commencing thiopurine therapy for IBD pre- and post-introduction of a pharmacist-led monitoring intervention were assessed. Pre-intervention patients received standard of care, while the post-intervention cohort was managed by the pharmacist. Data were acquired via retrospective audit of hospital medical records. The primary end-point was the proportion of patients with documented review for thiopurine adverse effects within the initial 3 weeks. Secondary end-points included achievement of therapeutic drug levels, persistence with thiopurine therapy, IBD-related episodes of care and number of outpatient medical reviews.. Pre- and post-intervention cohorts comprised of 37 and 33 patients respectively. Pharmacist intervention increased the proportion of patients with documented monitoring within 3 weeks from 8.1% to 84.8% (P < 0.01). No difference in thiopurine dose optimisation was seen (27% vs 27.3%). Persistence with thiopurine therapy increased from 65.7% to 87.9% (P < 0.03) at 6 months. IBD-related emergency department presentations were not significantly decreased (8.1% vs 3%; P = 0.62). No significant change was observed in hospital admissions (16.2% vs 12.1%; P = 0.74) or outpatient medical reviews.. Pharmacist monitoring of thiopurine therapy initiation in IBD outpatients improves adverse effect monitoring and increases medication persistence.

Topics: Azathioprine; Drug-Related Side Effects and Adverse Reactions; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Outpatients; Pharmacists; Retrospective Studies

The thiopurine medications are well established in the treatment of inflammatory bowel disease (IBD). There is significant variation in levels of toxic and therapeutic metabolites. Current data from small or short-term studies support therapeutic drug monitoring (TDM) in assessing azathioprine (AZA) and 6-mercaptopurine (6MP). TDM of thiopurines involves measurement and interpretation of metabolites 6-TGN and 6-MMPR.. This study aimed to assess long-cterm outcomes of patients on thiopurines following therapeutic drug monitoring.. A multicenter retrospective observational study of outcomes post thiopurine TDM was conducted. Demographics, disease characteristics, physician global assessment, IBD therapy at baseline TDM and again at 12 months were collected. Clinical outcomes were analyzed according to TDM result, and indication for TDM including proactive and other indications.. The study included 541 patients. Only 39% of patients had appropriate dosing of thiopurines. AZA/6MP TDM informed a management change in 61.9%, and enabled 88.8% of the cohort to continue AZA/6MP following TDM. At 12 months following TDM the majority (74.1%) of the cohort remained on AZA/6MP. Clinical remission was higher at 12-months following thiopurines TDM (68%) compared to baseline (37%), including proactive TDM. Post TDM, 13.0% of patients were identified as shunters and commenced on thiopurine-allopurinol co-therapy.. Thiopurine TDM resulted in a change in management for the majority of patients. Post TDM significantly more patients were in remission. TDM allowed the identification of non-adherence and shunters who, without intervention, would not reach therapeutic drug levels. Proactive TDM allowed identification and management of inappropriate dosing, and was associated with increased levels of clinical remission.

Topics: Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methylthioinosine; Retrospective Studies

PACSIN2 variants are associated with gastrointestinal effects of thiopurines and thiopurine methyltransferase activity through an uncharacterized mechanism that is postulated to involve autophagy. This study aims to clarify the role of PACSIN2 in autophagy and in thiopurine cytotoxicity in leukemic and intestinal models. Higher autophagy and lower PACSIN2 levels were observed in inflamed compared with non-inflamed colon biopsies of inflammatory bowel disease pediatric patients at diagnosis. PACSIN2 was identified as an inhibitor of autophagy, putatively through inhibition of autophagosome formation by a protein-protein interaction with LC3-II, mediated by a LIR motif. Moreover, PACSIN2 resulted a modulator of mercaptopurine-induced cytotoxicity in intestinal cells, suggesting that PACSIN2-regulated autophagy levels might influence thiopurine sensitivity. However, PACSIN2 modulates cellular thiopurine methyltransferase activity via mechanisms distinct from its modulation of autophagy.

Topics: Adaptor Proteins, Signal Transducing; Autophagy; Child; Humans; Inflammatory Bowel Diseases; Intestines; Mercaptopurine

Thioguanine is a well-tolerated and effective therapy for inflammatory bowel disease [IBD] patients. Prospective effectiveness data are needed to substantiate the role of thioguanine as a maintenance therapy for IBD.. IBD patients who previously failed azathioprine or mercaptopurine and initiated thioguanine were prospectively followed for 12 months starting when corticosteroid-free clinical remission was achieved (Harvey-Bradshaw Index [HBI] ≤ 4 or Simple Clinical Colitis Activity Index [SCCAI] ≤ 2). The primary endpoint was corticosteroid-free clinical remission throughout 12 months. Loss of clinical remission was defined as SCCAI > 2 or HBI > 4, need of surgery, escalation of therapy, initiation of corticosteroids or study discontinuation. Additional endpoints were adverse events, drug survival, physician global assessment [PGA] and quality of life [QoL].. Sustained corticosteroid-free clinical remission at 3, 6 or 12 months was observed in 75 [69%], 66 [61%] and 49 [45%] of 108 patients, respectively. Thioguanine was continued in 86 patients [80%] for at least 12 months. Loss of response [55%] included escalation to biologicals in 15%, corticosteroids in 10% and surgery in 3%. According to PGA scores, 82% of patients were still in remission after 12 months and QoL scores remained stable. Adverse events leading to discontinuation were reported in 11%, infections in 10%, myelo- and hepatotoxicity each in 6%, and portal hypertension in 1% of patients.. Sustained corticosteroid-free clinical remission over 12 months was achieved in 45% of IBD patients on monotherapy with thioguanine. A drug continuation rate of 80%, together with favourable PGA and QoL scores, underlines the tolerability and effectiveness of thioguanine for IBD.

Topics: Azathioprine; Colitis; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Prospective Studies; Quality of Life; Thioguanine

Split-dose thiopurine and allopurinol-thiopurine cotherapy strategies have been suggested as rescue therapeutic options for children with inflammatory bowel disease (IBD) and impaired thiopurine metabolism. We compared the efficacy and safety of these regimens in patients who previously failed conventional thiopurine treatment.. Children with IBD treated with split-dose thiopurine or low-dose thiopurine-allopurinol cotherapy were retrospectively identified. Medical records were reviewed for demographics, treatment regimen, reason for thiopurine failure, side effects, and discontinuation of treatment. Laboratory findings were evaluated at different time points.. After prior therapeutic failure, 42 patients were on split-dose regimen (group A) and 20 patients were on thiopurine-allopurinol cotherapy (group B). Twelve patients crossed from group A to group B because of treatment failure, 1 patient was lost at follow-up, and 1 patient discontinued the treatment. The final cotherapy group comprised 29 children (group C), while the split-dose group (group D) included 31 children. Intention-to-treat analysis showed significant differences between split-dose regimen and thiopurine-allopurinol cotherapy for 6-thioguanine nucleotide (6-TGN)/6-methyl mercaptopurine (6-MeMP) ratio ( P < 0.001), 6-TGN ( P < 0.05), and 6-MeMP ( P < 0.001) at 1-3 months. As per protocol analysis, there was a significant difference between group C and group D at 6 months for 6-MeMP ( P < 0.05) and 6-TGN/6-MeMP ratio ( P < 0.05) and at 12 months for 6-MeMP ( P < 0.05) and 6-TGN/6-MeMP ratio ( P < 0.001). Side effects were more frequent in allopurinol-thiopurine cotherapy ( P < 0.05).. In children with IBD and impaired thiopurine metabolism, split-dose thiopurine and low-dose thiopurine-allopurinol cotherapy are both effective therapeutic strategies. The latter shows higher efficacy but a higher side effect rate, suggesting the use of split-dose regimen as the first-line approach.

Topics: Allopurinol; Azathioprine; Child; Drug Therapy, Combination; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Retrospective Studies; Treatment Outcome

The use of thiopurines is an independent risk factor for active tuberculosis in patients with inflammatory bowel disease.

Topics: Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Purine Nucleosides; Risk Factors; Tuberculosis

Outpatient visits and laboratory assessments are routinely scheduled every 3 to 4 months in thiopurine-treated patients with inflammatory bowel disease (IBD) to timely detect thiopurine-related adverse events (AEs). AEs that require therapy adjustment beyond 12 months of treatment are rare.. This single-center prospective cohort study evaluated the safety of a reduced 6-monthly monitoring strategy in steroid-free patients with quiescent IBD on stable dose of azathioprine, mercaptopurine, or thioguanine monotherapy. The primary outcome was thiopurine-related AEs requiring therapy adjustments during a follow-up period of 24 months. Secondary outcomes included all AEs including laboratory toxicity, disease flares until 12 months, and the net monetary benefit from this strategy concerning IBD-related health care use.. We enrolled 85 patients with IBD (median age 42 years, 61% Crohn's disease, 62% female), with a median disease duration of 12.5 years and median thiopurine treatment duration of 6.7 years. During follow-up, 3 patients (4%) ceased thiopurines due to AEs: recurrent infections, non-melanoma skin cancer, and gastrointestinal complaints (nausea, vomiting). At 12 months, 25 laboratory toxicities were observed (including 13% myelotoxicity, 17% hepatotoxicity); none required therapy adjustments and all were transient. A reduced monitoring strategy had a net benefit of €136 per patient.. Three patients (4%) ceased thiopurine therapy due to thiopurine-related AEs, while no laboratory toxicity required therapy adjustments. Monitoring frequency of every 6 months seems feasible in patients with stable IBD on long-term (median duration > 6 years) maintenance thiopurine therapy and may contribute to reduced patient-burden and health care costs.

Topics: Adult; Azathioprine; Feasibility Studies; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Prospective Studies

Topics: Azathioprine; Child; Drug Monitoring; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine

Topics: Azathioprine; Child; Drug Monitoring; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine

Thiopurines continue to play an important role in the treatment of inflammatory bowel disease (IBD). It is well known that thiopurines can cause several adverse reactions. Especially, hematopoietic toxicity may lead to severe agranulocytosis. In a previous prospective study, we investigated the relationship between inosine triphosphate pyrophosphatase (ITPA) c.94c > a polymorphism, 6-thioguanine nucleotide (6-TGN) concentration and toxicity.. To clarify the cause of thiopurine toxicity, we analysed nucleoside disphosphate-linked moiety X-type motif 15 (NUDT15) gene polymorphisms, i.e., R139C, V18I, and V19_V19insGV, and measured 6-mercaptopurines and 6-methylmercaptopurines (6-MMP) using the archived blood samples collected from 49 IBD patients for our previous study.. The ITPA c.94c > a polymorphism was detected in 19 patients (38.7%, all heterozygous). The R139C polymorphism was found in 10 patients (20.4%, 1 homozygous, 9 heterozygous), V18_V19insGV in 7 patients (14.3%, all heterozygous), and V18I in 2 patients (4.08%, all heterozygous). Although R139C was more strongly associated with leukopenia than c.94c > a, there were no significant correlations with 6-TGN and 6-MMP levels, as for c.94c > a. The leukopenia incidence rates for each gene polymorphism were 0% in those with all wild-type genes, 21.4% for c.94c > a only, 42.9% for NUDT15 polymorphism (s) only, and 80.0% for both polymorphisms.. All cases of leukopenia were associated with ITPA c.94c > a and/or polymorphism of NUDT15 and the risk of developing leukopenia was synergistically increased by ITPA and NUDT15 gene polymorphism. However, there was no association between the level of azathioprine metabolites and these polymorphisms.

Topics: Azathioprine; East Asian People; Humans; Inflammatory Bowel Diseases; Leukopenia; Mercaptopurine; Pyrophosphatases

Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role of gut microbiota in AZA therapy failure remains poorly understood. We found a high prevalence of Blautia wexlerae in patients with IBD with AZA therapy failure, associated with shorter disease flare survival time. Colonization of B. wexlerae increased inflammatory macrophages and compromised AZA's therapeutic efficacy in mice with intestinal colitis. B. wexlerae colonization reduced 6-mercaptopurine (6-MP) bioavailability by enhancing selenium-dependent xanthine dehydrogenase (sd-XDH) activity. The enzyme sd-XDH converts 6-MP into its inactive metabolite, 6-thioxanthine (6-TX), thereby impairing its ability to inhibit inflammation in mice. Supplementation with Bacillus (B.) subtilis enriched in hypoxanthine phosphoribosyltransferase (HPRT) effectively mitigated B. wexlerae-induced AZA treatment failure in mice with intestinal colitis. These findings emphasize the need for tailored management strategies based on B. wexlerae levels in patients with IBD.

Topics: Animals; Azathioprine; Bacteria; Biological Availability; Colitis; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Mice

Though not exempt from adverse events, azathioprine (AZA) is an inexpensive and effective drug in the induction and maintenance treatment of patients with inflammatory bowel disease. We present the case of a 20-year-old female patient with left-side ulcerative colitis in whom AZA was started at a dose of 1.5 mg/kg/day due to dependence on corticoids (thiopurine methyltransferase activity: 14.9 U/mL). Two weeks after starting treatment she began to report excessive hair loss, resulting in an almost complete loss of scalp hair.

Topics: Adult; Alopecia; Azathioprine; Biomarkers; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Young Adult

Thiopurine derivatives, such as azathioprine and mercaptopurine, are standard conventional treatment options in inflammatory bowel disease (IBD). Unfortunately, approximately half of patients discontinue thiopurine therapy within 2 years. To improve the prediction of clinical effectiveness, thiopurine therapy is currently optimized using therapeutic drug monitoring. Ras-related C3 botulinum toxin substrate 1 (Rac1) has been suggested as a potential pharmacodynamic marker of the thiopurine effect in lymphocytes. The active thiopurine metabolite 6-thioguanine triphosphate (6-Thio-GTP) causes T cell apoptosis via Rac1 and the downstream transcription factor signal transducer and activator of transcription 3 (STAT3). The aim of this study was to develop and validate a functional pharmacodynamic multiparameter flow cytometric assay to determine Rac1/pSTAT3 expression in the various leukocyte subpopulations in peripheral blood in order to predict therapeutic response in IBD patients in the future. Peripheral blood samples of healthy subjects (no fever or clinical complaints of active disease, C-reactive protein < 10 mg/L) were used for immunocytochemical labeling, applying an optimized fixation and permeabilization strategy. A gating procedure was performed to separate all leukocyte subpopulations. Quantitative data were obtained by measuring presence and median fluorescent intensity. In vitro, Rac1 presence and expression were detectable in all leukocyte subpopulations. After IL-6 stimulation, used as proxy for inflammation, a distinct pSTAT3 signal could be detected in T lymphocytes of healthy subjects. In vivo, an upregulated pSTAT3 signal was detected in nearly all IBD patients with active disease and differed substantially from the signal found in IBD patients in remission on thiopurines and healthy subjects. We developed and validated a functional flow cytometric assay to assess Rac1 and pSTAT3 presence and expression. This opens a venue for a pharmacodynamic assay to predict thiopurine effectiveness in IBD patients.

Topics: Azathioprine; Biomarkers; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; rac1 GTP-Binding Protein; T-Lymphocytes

Beneficial response to first-line immunosuppressive azathioprine in patients with inflammatory bowel disease (IBD) is low due to high rates of adverse events. Co-administrating allopurinol has been shown to improve tolerability. However, data on this co-therapy as first-line treatment are scarce.. Retrospective comparison of long-term effectiveness and safety of first-line low-dose azathioprine-allopurinol co-therapy (LDAA) with first-line azathioprine monotherapy (AZAm) in patients with IBD without metabolite monitoring.. Clinical benefit was defined as ongoing therapy without initiation of steroids, biologics or surgery. Secondary outcomes included CRP, HBI/SCCAI, steroid withdrawal and adverse events.. In total, 166 LDAA and 118 AZAm patients (median follow-up 25 and 27 months) were evaluated. Clinical benefit was more frequently observed in LDAA patients at 6 months (74% vs. 53%, p = 0.0003), 12 months (54% vs. 37%, p = 0.01) and in the long-term (median 36 months; 37% vs. 24%, p = 0.04). Throughout follow-up, AZAm patients were 60% more likely to fail therapy, due to a higher intolerance rate (45% vs. 26%, p = 0.001). Only 73% of the effective AZA dose was tolerated in AZAm patients, while LDAA could be initiated and maintained at its target dose. Incidence of myelotoxicity and elevated liver enzymes was similar in both cohorts, and both conditions led to LDAA withdrawal in only 2%. Increasing allopurinol from 100 to 200-300 mg/day significantly lowered liver enzymes in 5/6 LDAA patients with hepatotoxicity.. Our poor AZAm outcomes emphasize that optimization of azathioprine is needed. We demonstrated a long-term safe and more effective profile of first-line LDAA. This co-therapy may therefore be considered standard first-line immunosuppressive.

Topics: Allopurinol; Azathioprine; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Retrospective Studies; Treatment Outcome

Topics: Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Pyrophosphatases; White People

Immunomodulator therapy (e.g., thiopurines) has been linked to an increased malignancy risk, in patients with inflammatory bowel diseases (IBDs), which increases with treatment duration, based on studies mainly in Caucasian patients. However, our previous real-world study, of Japanese patients with IBDs, indicated no overall increased risk of non-Hodgkin lymphoma (NHL) with thiopurine treatment.. This subanalysis investigated the influence of thiopurine IBD treatment dose and duration, on incidence of NHL in Japanese patients.. The Medical Data Vision (MDV) claims database (17.8 million patients; April 2008-January 2018) was used to analyze incidence rate ratios (IRRs) of NHL, in eligible patients (≥1 diagnosis of ulcerative colitis or Crohn's disease) and no malignancy at diagnosis or first prescription of a thiopurine. Age- and sex-adjusted IRRs and 95% confidence interval for NHL were calculated as the incident cases compared in the subgroups versus the overall IBD population.. Among 75,673 patients with IBDs, 103 cases of NHL were recorded. There was no overall increase in the risk of developing NHL among Japanese patients treated with thiopurines. The IRRs relative to the overall IBD population were 1.88, 1.42, and 0.38 for <1 year, 1-3 years, and ≥3 years of thiopurine treatment. There were no differences in NHL incidence when grouping patients by mean daily thiopurine dose prescribed, age, or disease subgroups.. Dose or duration of thiopurine treatment did not explain a lack of increased risk of NHL with thiopurine use in Japanese patients with IBDs.

Topics: Azathioprine; Duration of Therapy; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Japan; Lymphoma; Mercaptopurine; Risk Factors

Exactly 70 years ago [1951] mercaptopurine was discovered by Gertrude Elion as a novel treatment option for acute leukaemia. A total of three thiopurines (also thioguanine [1950] and azathioprine [1957]) were developed over time. These immunosuppressive drugs were also successfully introduced a few decades later to prevent rejection of transplanted organs and to treat several autoimmune diseases. For her discovery of thiopurines and other antimetabolite drugs, in 1988 Elion was rewarded, together with George Hitchings and James Black, with the Nobel Prize in Physiology or Medicine. Important steps have been made in recent years to unravel its metabolism, mode of action and pharmacogenetics. Today thiopurine [based] therapy remains an essential immunosuppressive approach in treating patients with inflammatory bowel disease.

Topics: Antimetabolites; Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine

Topics: Allopurinol; Azathioprine; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine

Thiopurines are widely used to maintain remission in both ulcerative colitis (UC) and Crohn's disease (CD). Reported effectiveness and tolerability rates have been variable across studies. There are only sparse data in Asian population regarding the long-term efficacy and safety of thiopurines.. Records of 5351 patients followed up at inflammatory bowel disease (IBD) clinic, All India Institute of Medical Sciences, New Delhi from 2004 to 2020 were evaluated retrospectively. Safety was evaluated in terms of long-term adverse events and development of malignancy.. Of 5351 patients with IBD, 1093 who received thiopurine for > 3 months (UC = 788 [proctitis-1.9%, left-sided colitis-44.9%, & pancolitis-53.1%] & CD = 305 [inflammatory-42.6%, stricturing-46.9%, & fistulizing-10.5%]) were included (60.8%-male patients). Follow up and treatment duration on thiopurine were 7 (4-12) years and 39.4 ± 40.3 months, respectively, with 254 (23.2%) patients receiving thiopurines for more than 5 and 68 (6.2%) receiving for more than 10 years. Three hundred and fifty-nine (UC: 249 [31.6%]; CD: 110 [36.1%]; P = 0.1) patients developed adverse events; commonest was myelosuppression (23.4%) followed by gastrointestinal intolerance (3%), flu-like illness (1.7%), and arthralgia/myalgia (1.4%). Myelosuppression was the commonest cause of thiopurine withdrawal. No patient (including 254 patients on thiopurine for ≥ 5 years) developed lymphoma or non-melanoma skin cancer. The cumulative probability of staying free from adverse events in overall IBD cohort at 1, 2, and 5 years was 78.6%, 71.9%, and 68.4%, respectively, and this was comparable between UC and CD (P = 0.09).. Long-term follow up of patients with IBD from northern India on thiopurine monotherapy demonstrated minimal risk of development of lymphoma as well as non-melanoma skin cancer.

Topics: Azathioprine; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Humans; India; Inflammatory Bowel Diseases; Lymphoma; Male; Mercaptopurine; Retrospective Studies; Risk Factors; Skin Neoplasms

Approximately 25% of patients with inflammatory bowel disease (IBD) discontinue azathioprine (AZA) or mercaptopurine (MP) therapy within 3 months of treatment initiation because of adverse drug reactions. Of these side-effects, about half are because of hepatotoxicity. The aim of this study was to validate and (subsequently) optimize a previously reported predictive algorithm for thiopurine-associated hepatotoxicity by increasing the number of patients with IBD benefitting from conventional thiopurine therapy.. This multicenter observational study included consecutive thiopurine-naive patients with IBD who received AZA or MP treatment. The primary outcome was hepatotoxicity within 12 weeks. The patients with and without hepatotoxicity were compared. Four determinants, namely, age, sex, body mass index (BMI), and 6-methylmercaptopurine ribonucleotide concentrations 1 week after treatment initiation (T = 1) were used to validate and optimize 2 (1 dichotomous and 1 continuous) algorithms using multivariable logistic regression analysis.. Of 229 patients, 21 (9%) developed hepatotoxicity and 93% of the patients received MP with a median dose of 0.7 mg/kg (95% confidence interval 0.3-1.4 mg/kg). A difference in BMI was found between with and without hepatotoxicity groups (median 27.6 versus 24.2, P = 0.022). Specificities of 68% (Algorithm 1) and 77% (Algorithm 2) and sensitivities of 56% (Algorithm 1) and 50% (Algorithm 2) were obtained.. Both algorithms demonstrated limited predictive accuracy for thiopurine-induced hepatotoxicity in the validation cohort. Relevant factors contributing to this outcome were changes in thiopurine prescription behavior over time, with more MP prescriptions at relatively lower dosages of MP.

Topics: Algorithms; Azathioprine; Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine

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

The thiopurine derivatives azathioprine (AZA), mercaptopurine (MP) and tioguanine (TG) remain standard treatment of inflammatory bowel disease (IBD). The immune suppressive effect of thiopurines is primarily based on blocking the Ras-related C3 botulinum toxin substrate 1 (Rac1) causing apoptosis of T lymphocytes by inhibition of the phosphorylated downstream transcription factor Signal Transducer and Activator of Transcription 3 (pSTAT3). A functional pharmacodynamic marker in T lymphocytes may be useful to predict therapeutic outcome of thiopurine therapy. The aim of this study was to explore whether protein levels of Rac1 and pSTAT3 in T lymphocytes may be applied as a specific pharmacodynamic marker for thiopurine therapy in IBD patients. Rac1 and pSTAT3 protein levels in T lymphocytes were explored in 57 IBD patients (median age 51 years, 56% female), subdivided into six groups based on IBD activity and its treatment: patients with active disease without IBD maintenance medication (1) or patients in remission on AZA/MP (2), TG (3), infliximab (IFX) (4), thiopurine and IFX combination-treatment (5) or without IBD medication (6). Reference values were obtained from healthy subjects. Rac1 and pSTAT3 protein levels in T lymphocytes from patients on thiopurine monotherapy (group 2 and 3) were compared to the other groups, and to healthy subjects. Absolute Rac1 and pSTAT3 protein levels showed no differences between the thiopurine monotherapy groups when compared to patients with active disease. However, the ratio of Rac1 and pSTAT3 protein levels was lower in thiopurine patients groups compared to patients with active disease. Rac1-corrected pSTAT3 protein levels may serve as a pharmacodynamic marker of thiopurine monotherapy and may be a potential tool to predict therapeutic effectiveness in IBD patients.

Topics: Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Male; Mercaptopurine; Middle Aged; rac1 GTP-Binding Protein; STAT3 Transcription Factor; T-Lymphocytes; Thioguanine

Thiopurine drugs azathioprine (AZA) and 6-mercaptopurine (6-MP) are used extensively in pediatric and adult patients with inflammatory and neoplastic diseases. They are metabolized to 6-thioguanine nucleotides (6-TGN) or to 6-methyl-mercaptopurine nucleotides (6-MMPN). The balance between 6-TGN and 6-MMPN is highly variable and monitoring is recommended, but its benefit in outcome gives rise to conflicting results, potentially increased by differences in quantifying 6-MP metabolism. Our aim was to report (1) the HPLC-UV procedure used in our laboratory to quantify red blood cells (RBCs) with 6-TGN and 6-MMPN (as its derivate: 6-MMP(d)) in patients treated with thiopurines and (2) additional tests, sometimes confirmatory, to improve method standardization. The comparison of two methods to count RBCs shows that metabolite concentrations were slightly lower in the washed and resuspended RBCs than in whole blood. Perchloric acid (0.7 M), dithiothreitol (DTT, final 0.013 M sample concentration) and 60 min hydrolysis were selected for acid hydrolysis. (3) Monitoring data from 83 patients receiving AZA or 6-MP showed that at steady state, only 53/183 (29%) had 6-TGN and 6-MMPN in the recommended therapeutic range. Our method is discussed in light of the technical conditions and sample stability data from 17 publications identified since the first analytical report in 1987. Monitoring data demonstrate, if required, that inter-patient variability in 6-TGN and 6-MMPN concentrations is high in samples from treated patients.

Topics: Adult; Azathioprine; Child; Chromatography, High Pressure Liquid; Dithiothreitol; Erythrocytes; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Nucleotides; Thioguanine

In inflammatory bowel disease (IBD), conventional thiopurine users cease treatment in 60% of cases within 5 years, mostly because of adverse events or nonresponse. In this study, the authors aimed to investigate the role of 6-thioguanine nucleotide (TGN) measurements, geno/phenotyping of thiopurine S-methyltransferase (TPMT), and their mutual relationship with TG therapy in IBD.. An international retrospective, multicenter cohort study was performed at 4 centers in the Netherlands (Máxima Medical Centre) and the United Kingdom (Guy's and St. Thomas' Hospital, Queen Elizabeth Hospital, and East Surrey Hospital).. Overall, 526 6-TGN measurements were performed in 316 patients with IBD. The median daily dosage of TG was 20 mg/d (range 10-40 mg/d), and the median duration of TG use was 21.1 months (SD, 28.0). In total, 129 patients (40.8%) had a known TPMT status. In the variant-type and wild-type TPMT genotype metabolism groups, median 6-TGN values were 1126 [interquartile range (IQR) 948-1562] and 467.5 pmol/8 × 10E8 red blood cells (RBCs) (IQR 334-593). A significant difference was observed between the 2 groups (P = 0.0001, t test). For TPMT phenotypes, in the slow, fast, and normal metabolism groups, the median 6-TGN values were 772.0 (IQR 459-1724), 296.0 (IQR 200-705), and 774.5 pmol/8 × 10E8 RBCs (IQR 500.5-981.5), with a significant difference observed between groups (P < 0.001, analysis of variance).. Our findings indicated that TPMT measurements at TG initiation can be useful but are not necessary for daily practice. TPMT genotypes and phenotypes are both associated with significant differences in 6-TGN levels between metabolic groups. However, the advantage of TG remains that RBC 6-TGN measurements are not crucial to monitor treatments in patients with IBD because these measurements did not correlate with laboratory result abnormalities. This presents as a major advantage in countries where patients cannot access these diagnostic tests.

Topics: Adult; Azathioprine; Female; Genotype; Guanine Nucleotides; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Middle Aged; Phenotype; Retrospective Studies; Thioguanine; Thionucleotides

Despite new treatment options for inflammatory bowel disease (IBD), conventional thiopurines remain a common treatment option for maintaining remission, particularly in non-Westernized countries. Therapeutic drug monitoring (TDM) is advised in standard care for optimizing therapy strategies to improve effectiveness, reveal nonadherence, and reduce toxicity. Still, the rationale of TDM is debated.. Key insights on TDM of thiopurine metabolites are discussed. The pharmacology of thiopurines is described, emphasizing the interindividual differences in pharmacogenetics, pharmacokinetics, and pharmacodynamics. Pharmacological differences between conventional thiopurines and tioguanine are outlined. Finally, several optimization strategies for thiopurine therapy in IBD are discussed.. TDM has been a useful, but limited, tool to individualize thiopurine therapy. Pharmacokinetic data on the active thiopurine metabolites, derived from measurements in erythrocytes, associated with clinical response only partially predict effectiveness and toxicity. An additional pharmacodynamic marker, such as Rac1/pSTAT3 expression in leukocytes, may improve applicability of TDM in the future.

Topics: Azathioprine; Drug Monitoring; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine

Topics: Humans; Inflammatory Bowel Diseases; Loneliness; Mercaptopurine

The aim of this study was to describe the long-term health outcomes of children born to mothers with inflammatory bowel disease (IBD) and to assess the impact of maternal IBD medication use on these outcomes.. We performed a multicentre retrospective study in The Netherlands. Women with IBD who gave birth between 1999 and 2018 were enrolled from 20 participating hospitals. Information regarding disease characteristics, medication use, lifestyle, pregnancy outcomes and long-term health outcomes of children was retrieved from mothers and medical charts. After consent of both parents, outcomes until 5 years were also collected from general practitioners. Our primary aim was to assess infection rate and our secondary aims were to assess adverse reactions to vaccinations, growth, autoimmune diseases and malignancies.. We included 1000 children born to 626 mothers (381 (61%) Crohn's disease, 225 (36%) ulcerative colitis and 20 (3%) IBD unclassified). In total, 196 (20%) had intrauterine exposure to anti-tumour necrosis factor-α (anti-TNF-α) (60 with concomitant thiopurine) and 240 (24%) were exposed to thiopurine monotherapy. The 564 children (56%) not exposed to anti-TNF-α and/or thiopurine served as control group. There was no association between adverse long-term health outcomes and in utero exposure to IBD treatment. We did find an increased rate of intrahepatic cholestasis of pregnancy (ICP) in case thiopurine was used during the pregnancy without affecting birth outcomes and long-term health outcomes of children. All outcomes correspond with the general age-adjusted population.. In our study, we found no association between in utero exposure to anti-TNF-α and/or thiopurine and the long-term outcomes antibiotic-treated infections, severe infections needing hospital admission, adverse reactions to vaccinations, growth failure, autoimmune diseases and malignancies.

Topics: Adalimumab; Adult; Anti-Bacterial Agents; Autoimmune Diseases; Cesarean Section; Child Development; Child, Preschool; Congenital Abnormalities; Drug Prescriptions; Drug Therapy, Combination; Female; Gastrointestinal Agents; Humans; Infant; Infant, Newborn; Infant, Small for Gestational Age; Infections; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Neoplasms; Netherlands; Patient Admission; Pregnancy; Pregnancy Complications; Premature Birth; Prenatal Exposure Delayed Effects; Retrospective Studies; Tumor Necrosis Factor Inhibitors; Vaccines

We sought to evaluate COVID-19 clinical course in patients with IBD treated with different medication classes and combinations.. Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) is a large, international registry created to monitor outcomes of IBD patients with confirmed COVID-19. We used multivariable regression with a generalised estimating equation accounting for country as a random effect to analyse the association of different medication classes with severe COVID-19, defined as intensive care unit admission, ventilator use and/or death.. 1439 cases from 47 countries were included (mean age 44.1 years, 51.4% men) of whom 112 patients (7.8%) had severe COVID-19. Compared with tumour necrosis factor (TNF) antagonist monotherapy, thiopurine monotherapy (adjusted OR (aOR) 4.08, 95% CI 1.73 to 9.61) and combination therapy with TNF antagonist and thiopurine (aOR 4.01, 95% CI 1.65 to 9.78) were associated with an increased risk of severe COVID-19. Any mesalamine/sulfasalazine compared with no mesalamine/sulfasalazine use was associated with an increased risk (aOR 1.70, 95% CI 1.26 to 2.29). This risk estimate increased when using TNF antagonist monotherapy as a reference group (aOR 3.52, 95% CI 1.93 to 6.45). Interleukin-12/23 and integrin antagonists were not associated with significantly different risk than TNF antagonist monotherapy (aOR 0.98, 95% CI 0.12 to 8.06 and aOR 2.42, 95% CI 0.59 to 9.96, respectively).. Combination therapy and thiopurines may be associated with an increased risk of severe COVID-19. No significant differences were observed when comparing classes of biologicals. These findings warrant confirmation in large population-based cohorts.MKH should be changed to MDK for co-last author line.

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; COVID-19; Drug Therapy, Combination; Female; Humans; Inflammatory Bowel Diseases; International Cooperation; Male; Mercaptopurine; Registries; Risk Adjustment; SARS-CoV-2; Severity of Illness Index; Tumor Necrosis Factor Inhibitors

Thiopurines are important for treating inflammatory bowel disease, but are often discontinued due to adverse effects. Concomitant use of allopurinol might lower the risk of these unwanted effects, but large studies in the general population are lacking. The aims of this study were to evaluate rates of hepatotoxicity, myelotoxicity, pancreas toxicity and therapy persistence in adult thiopurine users with or without allopurinol.. A retrospective population-based cohort study was conducted within current thiopurine users (Clinical Practice Research Datalink). Among these patients, co-use of allopurinol was compared to non-use. Hazard ratios (HRs) for hepatotoxicity, myelotoxicity and pancreatitis were derived using time-dependent Cox proportional hazards models, and were adjusted for potential confounders. Persistence of thiopurine use was evaluated using Log-rank statistics.. Patients using thiopurines (n = 37 360) were identified of which 1077 were concomitantly taking allopurinol. A 58% decreased risk of hepatotoxicity was observed in those concomitantly taking allopurinol (HR 0.42; 95% CI 0.30-0.60; NNT 46). Rate of myelotoxicity (HR 0.96; 95% CI 0.89-1.03) was not influenced. Risk of pancreatitis was increased (HR 3.00; 95% CI 1.01-8.93; NNH 337), but was only seen in those with active gout (suggesting confounding by indication). Finally, allopurinol co-users were able to maintain thiopurine therapy over twice as long as those not on allopurinol (3.9 years vs. 1.8 years, P < 0.0001).. In thiopurine users, allopurinol is associated with a 58% reduced risk of hepatotoxicity. In addition, thiopurine persistence was prolonged by 2.1 years in allopurinol users. These data support the use of allopurinol in individuals requiring thiopurine therapy.

Topics: Adult; Allopurinol; Azathioprine; Cohort Studies; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Retrospective Studies; Treatment Outcome

Nodular regenerative hyperplasia (NRH) has been associated with thiopurine therapy in patients with inflammatory bowel disease (IBD), but prevalence and prognosis of NRH remain unclear. This study is a cross-sectional search for NRH in IBD patients with long-term azathioprine or 6-mercaptopurine treatment.. Thirty-three IBD patients with continuous azathioprine/6-mercaptopurine treatment for at least 5 years were included. Laboratory tests, thiopurine metabolite levels, liver histology, MRI were examined for NRH and signs of portal hypertension.. NRH was not observed in this cohort of 33 patients. Nevertheless, some possibly related signs of vascular changes were found by MRI in three patients. Also, splenomegaly, which may be associated with portal hypertension, was found in one patient. No high thiopurine dose neither high metabolite levels were found in these patients.. No NRH was found in this group of IBD patients with long-term azathioprine/6-mercaptopurine treatment. Larger multicenter studies are needed to determine the prevalence of NRH in thiopurine-treated IBD patients.

Topics: Azathioprine; Chronic Disease; Cross-Sectional Studies; Humans; Hyperplasia; Hypertension, Portal; Inflammatory Bowel Diseases; Mercaptopurine; Prevalence

Infective issues about anti-tumor necrosis factor (TNF)-α agents in inflammatory bowel disease (IBD) remain controversial, especially when compared with nonbiological treatments. This study aimed to evaluate the incidence and prevalence of several infections in anti-TNF-α-exposed patients compared with nonbiological treatments.. All naïve IBD subjects treated with anti-TNF-α and matched nonbiologic-exposed patients were included.. Among 3453 patients in the database, 288 anti-TNF-α-exposed subjects and 288 nonbiologic-exposed IBD controls met inclusion criteria. Fifty-eight infections (20.1%) occurred during anti-TNF-α treatment versus 23 (8%) in the matched group (odds ratio [OR] 2.9, P < 0.001) (incidence 5.72 vs 0.96/100 patient-years, incidence ratio [IR] 6, P < 0.001). IR was higher for anti-TNF-α versus mesalamine/sulfasalazine (IR 40.8, P < 0.001), similar to azathioprine/6-mercaptopurine/methotrexate (IR 0.78, P = 0.32) and lower than corticosteroids (IR 0.05, P < 0.001). The incidence rate of serious infections was 1.3 in the anti-TNF-α-exposed versus 0.38/100 patient-years in nonexposed subjects (IR 3.44, P = 0.002), without significant difference between anti-TNF-α and azathioprine/6-mercaptopurine/methotrexate (1.3 vs 3.03/100 patient-years, IR 0.43, P = 0.1). Predictors of infections in anti-TNF-α-exposed patients were concomitant use of systemic steroids (OR 1.9, P = 0.02) or azathioprine (OR 2.6, P = 0.01) and a body mass index < 18.5 at time of infection (OR 2.2, P = 0.01).. The risk of developing infections during anti-TNF-α therapy remains high, although not dissimilar to that found for other immunosuppressants, while concomitant immunosuppression and malnutrition appear the most important causes of infection.

Topics: Azathioprine; Colitis; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate; Risk Assessment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha

Inflammatory bowel disease (IBD) frequently requires chronic immunosuppressive treatment and active involvement from patients during treatment decision making. Information about the risk of developing adverse drug reactions (ADRs) to IBD therapies is required in this process.. The aim of this study was to describe the ADRs reported in IBD patients from real-world data, using the Dutch nationwide IBDREAM registry, and compare the occurrence and cumulative incidences with the Summary of Product Characteristics (SmPC) of the associated drugs.. In this retrospective multicentre study, ADRs related to IBD medication were assessed. Only reports associated with the use of drugs used for the maintenance treatment of IBD were included. All ADRs were verified by healthcare professionals and coded by trained pharmacovigilance assessors.. In total, 3080 ADRs were reported in 1179 patients. Twenty-three new drug-ADR associations related to the use of azathioprine, mercaptopurine, infliximab, oral mesalamine and thioguanine were reported in the IBDREAM registry that were not mentioned in the corresponding SmPCs. The most frequently reported new association was pyrexia for azathioprine (3.1%) and mercaptopurine (4.9%). In addition, there were seven ADRs with a higher cumulative incidence in IBDREAM compared with the SmPC, and included, among others, arthralgia during mercaptopurine use (2.5%), and diarrhoea (1.4%), alopecia (1.2%) and infections (1.6%) during azathioprine use.. Based on real-world data, ADR reporting demonstrated new ADRs and higher incidences of ADRs to IBD therapies. This information will contribute to drug safety by updating the SmPCs, allowing better risk assessment and communication towards patients.

Topics: Adverse Drug Reaction Reporting Systems; Azathioprine; Drug-Related Side Effects and Adverse Reactions; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Pharmacovigilance; Registries; Retrospective Studies

Inflammatory bowel disease (IBD) is a complex disease with variable presentation, progression, and response to therapies. Current disease classification is based on subjective clinical phenotypes. The peripheral blood immunophenome can reflect local inflammation, and thus we measured 39 circulating immune cell types in a large cohort of IBD and control subjects and performed immunotype:phenotype associations.. We performed fluorescence-activated cell sorting or CyTOF analysis on blood from 728 Crohn's disease, 464 ulcerative colitis, and 334 non-IBD patients, with available demographics, endoscopic and clinical examinations and medication use.. We observed few immune cell types commonly affected in IBD (lowered natural killer cells, B cells, and CD45RA. We present a peripheral map of immune cell changes in IBD related to disease entity and therapies as a resource for hypothesis generation. We propose the changes in B cell subsets could affect antibody formation and potentially explain the mechanism behind the superiority of combination therapy through the impact of thiopurines on pharmacokinetics of anti-TNFs.

Topics: Adult; B-Lymphocytes; Case-Control Studies; Cohort Studies; Colitis, Ulcerative; Combined Modality Therapy; Crohn Disease; Female; Humans; Immune System; Immunophenotyping; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Severity of Illness Index; Surveys and Questionnaires; T-Lymphocytes; Tumor Necrosis Factor-alpha

Xanthine oxidase (XO) competes with thiopurine S-methyltransferase (TPMT) and hypoxanthine guanine phosphoribosyltransferase (HPRT) to metabolize azathioprine (AZA)/6-mercaptopurine (6-MP) in vivo. A retrospective investigation was performed to detect the activity of XO in thiopurine curative Chinese inflammatory bowel disease (IBD) patients. We also evaluated whether a relationship between XO activity and incidence of thiopurine-induced adverse effects (AEs) existed. Clinical data and blood samples were collected from 140 IBD patients before receiving AZA/6-MP therapy, and the erythrocyte XO activity was measured. The XO activities of all patients were 20.29 ± 4.43 U/g Hb. No sex difference in XO activity was observed (p = .728), and the XO activity showed no difference between the UC and CD patients (p = .082). AEs were observed in 41 (29.3%) patients including leukopenia (26, 18.57%), gastrointestinal intolerance (11, 7.86%), flu-like symptom (5, 3.57%), alopecia (5, 3.57%), and hepatotoxicity (1, 0.71%). XO activity was significantly lower in the patients with AEs than in those without AEs (18.40 ± 3.73 vs. 21.07 ± 4.48 U/g Hb, p = .001), especially in the patients with leukopenia (18.29 ± 3.68 vs. 21.07 ± 4.48 U/g Hb, p = .004). However, no significant difference in XO activity was found between patients with and without other AEs. Decreased XO activity was observed in the patients who developed flu-like symptoms (17.58 ± 3.50 U/g Hb) and alopecia (18.67 ± 2.91 U/g Hb) compared to those who did not, although the differences did not reach statistical significance. These findings suggested that patients with low XO expression might have a high risk of thiopurine-induced toxicity.

Topics: Adolescent; Adult; Aged; Asian People; Azathioprine; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Xanthine Oxidase; Young Adult

The genetic variants of NUDT15 have been verified to induce adverse events (AEs) of thiopurines. Codon 139 variants are frequently observed in Asians, while multiple variants are seen in codon 18 which also cause AEs including the European ancestry. The purpose of this study is to establish a technique capable of the simple genotyping of NUDT15 codon 18 and to evaluate its efficacy.. A high-resolution melt (HRM) technique is performed to simply determine genotypes. The accuracy of HRM analysis was evaluated with DNAs from 1245 Japanese patients with inflammatory bowel diseases. Subsequently, another group of 572 patients was analyzed to verify the method. The diplotypes and the frequency of their AEs were estimated on the basis of codon 18 and 139 genotypes.. The HRM analysis enabled the correct identification of the three main genotypes, ref/ref, ref/ins, and ref/V18I, in 1236 of 1241 cases. All rare genotypes including ref/del were identified as the impossible-to-determine group, the proper diagnosis rate was 99.6%. In the verification test using other samples, the diagnosis rate was 99.7%. By estimating diplotypes using both codon 18 and 139 genotypes, 2.74% and 2.13% of Japanese patients with Arg/Arg and Arg/Cys of codon 139 have a lower enzymatic activity of NUDT15 and a higher risk for adverse responses than those estimated by codon 139 genotypes alone.. Our study showed that HRM method enables simple genotyping of complicated codon 18 variants essential to haplotype estimation of the NUDT15.

Topics: Female; Genetic Markers; Genotyping Techniques; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Pharmacogenomic Variants; Pyrophosphatases

Thiopurines are used in the treatment of inflammatory bowel disease (IBD) but remain clinically challenging to manage due to wide interpatient variability in clinical outcomes and adverse events. Apart from genetic variants in thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) genes, polymorphisms in FTO alpha-ketoglutarate dependent dioxygenase (FTO) were found predictive of thiopurine-induced leukopenia, albeit with conflicting results. To clarify the role of FTO variants in a multiethnic Asian IBD cohort, we recruited 149 patients on thiopurine-based therapy and genotyped two FTO variants p.Ala134Thr (rs79206939) and rs16952570 T > C using Sanger sequencing. FTO p.Ala134Thr (rs79206939) was non-polymorphic and absent whereas intronic rs16952570 T > C was equally prevalent in Chinese (22%) and Indians (18%) and higher in Malays (28%). Higher nadir white blood cell (WBC) and absolute neutrophil count (ANC) levels were observed in patients harboring FTO rs16952570 CC genotypes compared with TT carriers at 4, 8, and 12 weeks after start of thiopurine therapy (P < 0.05). A similar trend was observed in patients carrying the previously well-characterized NUDT15 rs116855232 wild-type CC genotypes. Further in silico analysis suggests that FTO variants linked to rs16952570, particularly rs74018601, may play a regulatory role in altering the FTO expression. The findings from this study indicate a novel protective association with the FTO variant rs16952570 CC genotype and hematological parameters.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Asian People; Azathioprine; Female; Genetic Variation; Humans; Inflammatory Bowel Diseases; Introns; Leukopenia; Male; Mercaptopurine; Middle Aged; Neutropenia; Retrospective Studies; Young Adult

There is paucity of data on safety and efficacy of anti-tumour necrosis factor [TNF] in elderly inflammatory bowel disease [IBD] patients. We aimed to compare the long-term treatment failure rates and safety of a first anti-TNF agent in IBD patients between different age groups [<40 years/40-59 years/≥60 years].. IBD patients who started a first anti-TNF agent were identified through IBDREAM, a multicentre prospective IBD registry. Competing risk regression was used to study treatment failure, defined as time to drug discontinuation due to adverse events [AEs] or lack of effectiveness, with discontinuation due to remission as a competing risk.. A total of 895 IBD patients were included; 546 started anti-TNF at age <40 [61.0%], 268 at age 40-59 [29.9%], and 81 at age ≥60 [9.1%]. Treatment failure rate was higher in the two older groups (subhazard rate [SHR] age ≥60 1.46, SHR age 40-59 1.21; p = 0.03). The SHR in the elderly [>60] was 1.52 for discontinuation due to AEs and 1.11 for lack of effectiveness. Concomitant thiopurine use was associated with a lower treatment failure rate (SHR 0.78, 95% confidence interval [CI] 0.62-0.98, p = 0.031). Serious adverse event [SAE] rate, as well as serious infection rate, were significantly higher in elderly IBD patients [61.2 versus 16.0 and 12.4 per 1000 patient-years, respectively] whereas the malignancy rate was low in all age groups.. Elderly IBD patients starting a first anti-TNF agent showed higher treatment failure rates, but concomitant thiopurine use at baseline was associated with lower failure rates. Elderly IBD patients demonstrated higher rates of SAEs and serious infections.

Topics: Adalimumab; Adolescent; Adult; Age Factors; Aged; Deprescriptions; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Male; Mercaptopurine; Middle Aged; Proportional Hazards Models; Prospective Studies; Registries; Remission Induction; Treatment Failure; Tumor Necrosis Factor Inhibitors; Young Adult

Topics: Child; Erythrocyte Indices; Humans; Inflammatory Bowel Diseases; Leukocytes; Mercaptopurine

Topics: Child; Erythrocyte Indices; Humans; Inflammatory Bowel Diseases; Leukocytes; Mercaptopurine

Ras-related C3 botulinum substrate 1 (Rac1) is a member of the small molecule family Rho guanosine triphosphate (GTP)ases. Recent findings reveal epigenetic downregulation of Rac1 is a mechanism of depression.. The purpose of this study was to evaluate Rac1 as a therapeutic target for depression we examine the association between thiopurines, which inhibit Rac1, and the risk of depression among US veterans.. This study uses data spanning January 2000-May 2019, comparing thiopurine exposure (no exposure, less than one year, 1-2.9 years, 3-5 years, and greater than five years) in two separate cohorts, a rheumatoid arthritis cohort and inflammatory bowel disease cohort. We estimate the hazard of depression using a time dependent cox proportional hazards model.. A total of 76,763 rheumatoid arthritis and 46,787 inflammatory bowel disease patients met all inclusion criteria. Patients exposed to thiopurines less than one year have a 27% (hazard ratio=1.272; 95% confidence interval=(1.038-1.559)) and 67% (hazard ratio=1.667 95% confidence interval=(1.501-1.850)) higher risk of depression in the rheumatoid arthritis and inflammatory bowel disease cohorts, respectively. In the inflammatory bowel disease cohort, we find the risk of depression is increased for up to five years of thiopurine exposure.. These results provide evidence that Rac1 regulation is a viable therapeutic target for depression. Further research into therapeutics targeting Rac1 for the treatment of depression is warranted.

Topics: Adult; Aged; Aged, 80 and over; Antirheumatic Agents; Arthritis, Rheumatoid; Azathioprine; Cohort Studies; Depression; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; rac1 GTP-Binding Protein; Retrospective Studies; Veterans

Measurement of the degree of adherence is a key element for the evaluation of treatment efficacy and safety; thus, adherence plays an important role in clinical research and practice. The aim of this study was to investigate medication adherence in children with inflammatory bowel disease (IBD) utilizing a multimethod assessment approach. A further aim was to examine factors that can influence adherence within this population.. Medication adherence in 47 children (age range 3 to 17 years) with IBD in three centers in Northern Ireland and Jordan was assessed via subjective (parent and child versions of the Medication Adherence Report Scale (MARS) specific questionnaire) and objective methods, that is, high-performance liquid chromatography (HPLC) determination of the 6-mercaptopurine (6-MP) and azathioprine (AZA) metabolites in packed red blood cell samples taken during a clinic visit. Beliefs about prescribed medicines were also assessed in parents/guardians using the Beliefs about Medicines Questionnaire (BMQ).. Results provide evidence for ongoing adherence challenges in the paediatric population with IBD. It is recommended that parents/guardians (particularly of older children) and older children themselves, should receive enhanced counselling and education about their prescribed medicines.

Topics: Adolescent; Antimetabolites; Azathioprine; Child; Child, Preschool; Female; Humans; Inflammatory Bowel Diseases; Male; Medication Adherence; Mercaptopurine; Surveys and Questionnaires

Although commonly used in inflammatory bowel disease [IBD], thiopurines frequently cause intolerance, and switching to a second thiopurine has only been reported in some small series. Ours aims in this study were to evaluate the safety of switching to a second thiopurine in a large cohort, and to assess the impact of age on tolerance.. Adult IBD patients from the ENEIDA registry, who were switched to a second thiopurine due to adverse events [excluding malignancies and infections], were identified. At the beginning of thiopurine treatment, patients were divided by age into two groups: 18-50 and over 60 years of age. The rate and concordance of adverse events between the first and second thiopurines, treatment intolerance, and persistence with the second thiopurine were evaluated.. A total of 1278 patients [13% over 60 years of age] were switched to a second thiopurine. At 12 months, the cumulative probability of switch intolerance was 43%, and persistence with treatment was 49%. Independent risk factors of switch intolerance were age over 60 years (odds ratio [OR] 1.49; 95% confidence interval [CI] 1.07-2.07; p = 0.017) , previous gastrointestinal toxicity [OR 1.4; 95% CI 1.11-1.78; p = 0.005], previous acute pancreatitis [OR 6.78; 95% CI 2.55-18.05; p <0.001], and exposure to the first thiopurine <6 months [OR 1.59; 95% CI 1.14-2.23; p = 0.007].. In a large series in clinical practice, switching to a second thiopurine proved to be a valid strategy. Tight monitoring of elderly IBD patients switching to a second thiopurine because of adverse events is recommended.

Topics: Adult; Age Factors; Aged; Azathioprine; Drug Monitoring; Drug Substitution; Drug Tolerance; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Practice Patterns, Physicians'; Risk Adjustment; Spain

To timely detect myelotoxicity and hepatotoxicity, laboratory monitoring at 3-month intervals is advised throughout thiopurine maintenance treatment for IBD. However, reported incidence rates of myelotoxicity and hepatotoxicity in maintenance treatment are low.. To assess incidence rates and clinical consequences of myelotoxicity and hepatotoxicity in thiopurine maintenance therapy after at least 1 year of thiopurine treatment.. Retrospective analysis of therapy adjustment for laboratory toxicity in adult IBD patients after 12 consecutive months of azathioprine (AZA) or mercaptopurine monotherapy (ie baseline) between 2000 and 2016. Incidence rates of laboratory toxicity (ie myelotoxicity [leucocyte count <4.0 × 10e9/L, and/or platelet count <150 × 10e9/L] and/or hepatotoxicity (gamma-glutamyltransferase [GGT], alkaline phosphatase [AP], ALT and/or AST above ULN, excluding isolated increased AST/AP]) and associated diagnostic procedures and complications were assessed.. In total, 12,391 laboratory assessments were performed on 1132 patients (56% female, AZA 74%) during 3.3 years of median follow-up. Median monitoring frequency was 3.1 assessments/treatment year. Only 83/12,391 (0.7%) assessments resulted in therapy adjustment, dose reduction in 46 patients, cessation in 28 and allopurinol initiation in nine; risk of therapy adjustment was 1.9% per treatment year. Incidence rates of myelotoxicity were 7.1% (5.1% mild/1.8% moderate/0.1% severe) and hepatotoxicity 5.1% (3.8% mild/1.1% moderate/0.2% severe) per treatment year. Treatment-related complications with concurrent laboratory toxicity occurred in 12 patients (1.1%) and would not have been prevented by monitoring.. Severe laboratory toxicity is uncommon after 1 year of thiopurine monotherapy at 4-month monitoring intervals. Therapy adjustments are rare after detection of laboratory toxicity. After 1 year of thiopurine monotherapy, laboratory monitoring may be lowered to less than a 4-month interval.

Topics: Adult; Allopurinol; Azathioprine; Clinical Laboratory Techniques; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Maintenance Chemotherapy; Male; Mercaptopurine; Middle Aged; Netherlands; Predictive Value of Tests; Prognosis; Purines; Retrospective Studies; Young Adult

Topics: Asymptomatic Diseases; Colonoscopy; Drug Therapy, Combination; Humans; Inflammatory Bowel Diseases; Infliximab; Lymphoma, B-Cell; Male; Mercaptopurine; Middle Aged; Mutation; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-bcl-6; Proto-Oncogene Proteins c-myc; Rare Diseases; Sigmoid Neoplasms

Use of thiopurines for inflammatory bowel diseases (IBDs) is declining in some parts of the world. We aimed to explore outcomes of thiopurines and predictors of response in a real-world prospective cohort of children with dose optimization.. Children with IBD treated with thiopurines without biologics were enrolled. Dosing was guided by thiopurine S-methyltransferase-activity at baseline and by clinical response and toxicity at 4 months; 1 year into the study, therapeutic drug monitoring at 4 months was also considered in the decision making. The primary outcome was steroid-free remission without treatment escalation by 12 months (SFR), using the intention-to-treat approach.. A total of 129 children were included (74% Crohn disease [CD] and 26% ulcerative colitis [UC]). SFR was achieved in 37 (39%) CD and 13 (39%) UC patients, and SFR with normal erythrocyte sedimentation rate/C-reactive protein in 20 (21%) and 9 (27%), respectively. At 4 months, mean corpuscular volume/white blood cell ratio and Δ absolute neutrophil count weakly correlated with 6-thioguanine (r = 0.33, P = 0.02 and r = 0.32, P = 0.02, respectively). In CD, SFR was associated with 4-month median weighted Pediatric Crohn Disease Activity Index (2.5 [IQR 0-7.5] in responders vs 5 in nonresponders [0-12.5], P = 0.048) and Δabsolute neutrophil count (1.7 [IQR 0.7-4.1] vs 0.05 [-2.3-0.9]; P = 0.03). Mild drug-related adverse events were recorded in 30 children (22%), 3 required stopping the drug.. In this real-life prospective cohort using dose optimization, thiopurines were safe and effective in 21% of CD and 27% of UC patients, including normalization of C-reactive protein and erythrocyte sedimentation rate. Thiopurines remain a viable option in the treatment algorithm of mild-moderate pediatric IBD, especially in girls whose risk for lymphoma is lower.

Topics: Azathioprine; Child; Cohort Studies; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Prospective Studies

Topics: Adult; Aged; Azathioprine; Betacoronavirus; Coronavirus Infections; COVID-19; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Middle Aged; Pandemics; Pneumonia, Viral; Retrospective Studies; SARS-CoV-2; Tumor Necrosis Factor-alpha; United States; United States Department of Veterans Affairs

Thiopurines, alone or in combination with other agents, have a pivotal role in the treatment of specific gastrointestinal and hepatological disorders. In inflammatory bowel disease and autoimmune hepatitis thiopurines have proven their value as steroid sparing agents for the maintenance of remission and may be considered for preventing postoperative Crohn disease recurrence where there is moderate risk of this occurring. Their use with infliximab therapy reduces antibody formation and increases biologic drug levels. The routine clinical use of thiopurines has, however, been questioned due to a number of potential adverse effects. The aim of this article is to provide information regarding the use, and in particular, safety of these agents in clinical practice in the light of such potentially severe, albeit rare, effects.

Topics: Azathioprine; Child; Crohn Disease; Gastrointestinal Agents; Humans; Immunologic Factors; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Recurrence

Topics: Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Treatment Outcome

Topics: Humans; Inflammatory Bowel Diseases; Mercaptopurine

Thioguanine (TG) is a thiopurine which has been used for patients with inflammatory bowel disease (IBD), who have failed azathioprine (AZA) or mercaptopurine (MP) due to adverse events or suboptimal response. Its widespread use has been hampered due to concerns about nodular regenerative hyperplasia (NRH) of the liver. The aim of this study was to investigate the long-term efficacy and safety of low-dose TG therapy in IBD patients failing AZA and MP.. A retrospective multicentre study was performed in IBD patients who failed prior treatment with conventional thiopurines with or without following immunomodulation (thiopurine-allopurinol, biologicals, methotrexate, tacrolimus) and were subsequently treated with TG as rescue monotherapy between 2003 and 2019 at three hospitals in the United Kingdom. Clinical response, adverse events, laboratory results, imaging and liver biopsies were retrospectively collected.. Long-term follow-up suggests that TG can be an effective and well-tolerated therapy in more than half of difficult-to-treat and multi-therapy failing IBD patients. Findings of this study indicate that TG can be used safely and the occurrence of hepatotoxicity was low. The incidence rate of NRH was within the background incidence.

Topics: Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Pharmaceutical Preparations; Retrospective Studies; Thioguanine; Treatment Outcome; United Kingdom

The 6-thioguanine nucleotide (6-TGN) level, may be used to estimate dose-adequacy of azathioprine (AZA) therapy. 6-TGN test is not commercially available. The aim of the study was to determine whether a blood cell changes correlate also with the dose of AZA and may serve as a predictor of the dose adequacy (for MCV > 6 fl).. Retrospective, multicentre study in subjects with IBD treated with azathioprine. Demographic data, leukocyte, platelet counts, erythrocyte (MCV) and thrombocyte (MPV) volume, azathioprine dose, inflammatory activity in the 3rd, 6th and 12th months of treatment and presence of sideropenia were recorded.. 103 subjects analysed. To increase the MCV by 6 fl, the AZA dose above 2 mg/kg is needed (p = 0.04). The MCV increases within 165 days (95% CI, 154-181 days, p = 0.002). Sideropenia has no impact on the MCV change. Number of leukocytes and thrombocytes decreases during treatment (p < 0.001). Change in their number as well as MPV, does not correlate with MCV change and is not affected by activity of the inflammation.. The MCV dynamics (> 6 fl within 6 months) is the only relevant indicator during AZA treatment. Changes in the number of leukocytes, platelets and their volume can not be used to assess the sufficiency of the AZA dose. Sideropenia has no impact on the dynamics of MCV.

Topics: Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Retrospective Studies

Topics: Adolescent; Child; Denmark; Female; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Outcome Assessment, Health Care; Pregnancy; Tumor Necrosis Factor-alpha

Topics: Humans; Immunologic Factors; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine

Topics: Colorectal Neoplasms; DNA; DNA Methylation; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Proto-Oncogene Proteins c-vav

Thiopurines are the most widely used immunosuppressants in IBD although drug-related adverse events (AE) occur in 20%-30% of cases.. To evaluate the safety of thiopurines in elderly IBD patients METHODS: Cohort study including all adult patients in the ENEIDA registry who received thiopurines. Patients were grouped in terms of age at the beginning of thiopurine treatment, specifically in those who started thiopurines over 60 years or between 18 and 50 years of age. Thiopurine-related AEs registered in the ENEIDA database were compared.. Out of 48 752 patients, 1888 started thiopurines when over 60 years of age and 15 477 under 50 years of age. Median treatment duration was significantly shorter for those who started thiopurines >60 years (13 [IQR 2-55] vs 32 [IQR 5-82] months; P < .001). Patients starting >60 years had higher rates of all types of myelotoxicity, digestive intolerance and hepatotoxicity. Thiopurines were discontinued due to AEs (excluding malignancies and infections) in more patients starting >60 years (67.2% vs 63.1%; P < .001). Elderly age and female sex were independent risk factors for most AEs.. In elderly IBD patients, thiopurines are associated with an increased risk of non-infectious, non-neoplastic, AEs.

Topics: Adult; Aged; Azathioprine; Cohort Studies; Databases, Factual; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Registries; Retrospective Studies; Risk Factors

Therapeutic drug monitoring of thiopurine erythrocyte levels is not available in all centers and it usually requires quite a long time to obtain the results. The aims of this study were to build a model predicting low levels of 6-thioguanine and 6-methylmercaptopurine in pediatric inflammatory bowel disease (IBD) patients and to build a model to predict nonadherence in patients treated with azathioprine (AZA).. The study consisted of 332 observations in 88 pediatric IBD patients. Low AZA dosing was defined as 6-thioguanine levels <125 pmol/8 × 10 erythrocytes and 6-methylmercaptopurine levels <5700 pmol/8 × 10 erythrocytes. Nonadherence was defined as undetectable levels of 6-thioguanine and 6-methylmercaptopurine <240 pmol/8 × 10 erythrocytes. Data were divided into training and testing part. To construct the model predicting low 6-thioguanine levels, nonadherence, and the level of 6-thioguanine, the modification of random forest method with cross-validation and resampling was used.. The final models predicting low 6-thioguanine levels and nonadherence had area under the curve, 0.87 and 0.94; sensitivity, 0.81 and 0.82; specificity, 0.80 and 86; and distance, 0.31 and 0.21, respectively, when applied on the testing part of the dataset. When the final model for prediction of 6-thioguanine values was applied on testing dataset, a root-mean-square error of 110 was obtained.. Using easily obtained laboratory parameters, we constructed a model with sufficient accuracy to predict patients with low 6-thioguanine levels and a model for prediction of AZA treatment nonadherence (web applications: https://hradskyo.shinyapps.io/6TG_prediction/ and https://hradskyo.shinyapps.io/Non_adherence/).

Topics: Adolescent; Area Under Curve; Child; Drug Monitoring; Erythrocytes; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Medication Adherence; Mercaptopurine; Models, Biological; Predictive Value of Tests; Sensitivity and Specificity; Thioguanine

Topics: Adolescent; Adult; Aged; Azathioprine; Female; Humans; Hyperplasia; Inflammatory Bowel Diseases; Liver Diseases; Male; Mercaptopurine; Middle Aged; Thioguanine; Young Adult

Sperm DNA integrity, concentration, and motility are suspected to be altered by thiopurines (azathioprine [AZA] and 6-mercaptopurine [6-MP]). We investigated the impact of thiopurines on semen quality in men with inflammatory bowel disease [IBD], by a comprehensive panel of semen analyses.. Semen from 40 men with IBD, in remission on AZA/6-MP therapy, was prospectively collected and compared with samples from 40 healthy volunteers. Paired samples [off and on AZA/6-MP] were obtained from a subset of IBD patients, and blood and semen were collected to determine 6-MP transmission to the ejaculate. Sperm DNA fragmentation was evaluated via sperm chromatin structure assay [SCSA] and Comet analysis. Conventional World Health Organization [WHO] parameters, i.e. semen volume and sperm concentration, motility, and morphology, were assessed. Additionally, we measured thioguanine nucleotide [TGN] incorporation in sperm cell DNA.. Sperm DNA fragmentation levels did not differ between men with IBD on AZA/6-MP and healthy volunteers when evaluated by SCSA [p = 0.23] and Comet analysis [p = 0.72]. IBD patients on AZA/6-MP had significantly lower total and progressive sperm motility than healthy volunteers [48.5% versus 64.5%, p = 0.0003; 27.4% versus 43.3%, p = 0.0004; respectively], with no differences in concentration, volume, or morphology. The same trend was observed in the 10 paired samples. TGN incorporation was not detectable in sperm DNA, but 6-MP was detected in seminal plasma and correlated to blood levels [rs = 0.79, p = 0.02].. Thiopurines do not increase sperm DNA fragmentation but may impair sperm motility in this IBD cohort. Our findings support existing epidemiological data that thiopurine therapy is safe during preconception and should not be abandoned.

Topics: Adolescent; Adult; Azathioprine; Case-Control Studies; DNA; DNA Fragmentation; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Nucleotides; Prospective Studies; Semen; Semen Analysis; Spermatozoa; Thioguanine; Young Adult

Thiopurine metabolite monitoring to proactively dose optimize to achieve therapeutic levels has not been used consistently, and it is unclear if this would lead to better outcomes. We aimed to compare 6-month outcomes between standard and optimized dosing strategies and define long-term predictors of thiopurine durability.. Two hundred sixteen pediatric IBD patients with at least 2 6-thioguanine nucleotide (6-TGN) levels were grouped for analysis by start dose: >2.5 mg/kg/day AZA (group 1) or <2.5 mg/kg/day (group 2) and further subgrouped depending on whether dosing was optimized to achieve 6-TGN >235 pmol/8 × 108 RBC. The metabolites, 6TGN and 6MMP, were univariate and multivariate analyses tested associations among metabolite levels, laboratory data, and the primary outcome of 6-month steroid-free clinical remission (SFR) (HBI ≤4 for CD; partial Mayo Score [pMS] ≤2 for UC). Thiopurine durability was measured using Kaplan Maier survival analysis.. 6-MP, azathioprine, pediatrics, therapeutic drug monitoring, pediatrics were measured a median 59 (43-76) days after initiation of thiopurine. Both dosing strategies led to similar initial 6-TGN levels (group 1 = median 209 [IQR: 155-272] with 25% of patients >235; group 2 = 196 [139-274] with 29% >235). Steroid-free clinical remission was achieved in 74% of the 180 still on thiopurines at 6 months. Start dose was not associated with 6-month SFR-73% in group 1 and 77% in group 2 within those on thiopurines at 6 months (P = 0.61). Fixed- and optimized-dosing subgroups had similar 6-month 6-TGN levels, SFR rate, and percentage 6-TGN > 235. Only 6-TGN level >235 at 6 months predicted thiopurine durability (3 years [1.7-7.7] vs 2.5 years [0.83-5]; log-rank P < 0.001), and this did not retain significant in a multivariate model. Initial dosing strategy, first 6-TGN level, 6-month SFR, 6MMP:6TGN ratio, and delta-MCV did not predict durability. The rate of adverse events was 22%.. Steroid-free clinical remission and 6-TGN levels at 6 months were no different between a standardized, fixed dosing strategy and a metabolite-driven, optimized dosing strategy.

Topics: Adolescent; Azathioprine; Child; Drug Monitoring; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Prognosis; Retrospective Studies; Thioguanine

Cross-sectionally, more adherence barriers are associated with lower medication adherence. However, little is known about longitudinal associations between adherence barriers and adherence. Among adolescents with inflammatory bowel diseases (IBD), this study examined both (1) how time-varying self-reported adherence barriers affect daily thiopurine adherence and (2) how adherence barriers at baseline affect daily thiopurine adherence over a six-month period.. Eighty-one adolescents 11-18 years old prescribed a once-daily oral IBD maintenance medication participated in a six-month observational study. Adherence barriers were self-reported monthly via the Medication Adherence Measure (MAM): Medication Subscale. Daily adherence estimates were collected via Medication Event Monitoring System (MEMS) Track Caps.. Generalized linear mixed modeling indicated that time alone did not significantly predict whether one was more likely to be adherent (p = .602). However, increasing adherence barriers lowered the likelihood that a participant would be adherent on a given day, and the interaction between time and barriers predicted likelihood of adherence on a given day (p < .01). Specifically, when participants reported no adherence barriers at baseline, adherence did not significantly change over time (p = .369). However, when barriers were endorsed, adherence decreased over time (p < .01).. Fewer adherence barriers over time predicted greater likelihood of adherence on a given day, which is consistent with previous cross-sectional research. Routine assessment of barriers to adherence over the course of adolescence is critical in addressing suboptimal adherence behavior in youth with IBD.

Topics: Adolescent; Child; Cross-Sectional Studies; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Medication Adherence; Mercaptopurine; Self Report

Topics: DNA; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Spermatozoa

Thiopurines are key drugs in maintenance therapy for treating inflammatory bowel disease (IBD). Time-dependent 5-aminosalicylates (5-ASA) releasing preparations (time-dependent 5-ASA) increase 6-thioguanine nucleotide (6-TGN), an active metabolite of thiopurines. However, the effects of pH-dependent 5-ASA releasing preparations (pH-dependent 5-ASA) on thiopurine metabolism were not reported.. We conducted a retrospective study of 134 IBD patients who received thiopurine treatment. The 6-methylmercaptopurine (6-MMP)/6-TGN values after taking the same dose of thiopurine preparations for at least 28 days were included.. There was a significant decrease in the 6-MMP/6-TGN ratio in time-dependent 5-ASA compared with group without 5-ASA preparations and the pH-dependent 5-ASA group (p = 0.008 and < 0.001 respectively). Spearman's rank correlation coefficient indicated a negative relationship between the daily oral dose of time-dependent 5-ASA and the 6-MMP/6-TGN ratio (r = -0.362, p = 0.003). Multivariate logistic regression analysis was performed in the groups with 6-MMP/6-TGN ratios of 1 or more and less than 1. The use of time-dependent 5-ASA and concomitant allopurinol negatively affected the independent 6-MMP/6-TGN ratio (p = 0.006 and 0.007 respectively).. Our study revealed that time-dependent but not pH-dependent 5-ASA decreases the 6-MMP/6-TGN ratio. We also confirmed that concomitant allopurinol results in a low 6-MMP/6TGN ratio.

Topics: Administration, Oral; Adolescent; Adult; Aged; Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Drug Interactions; Drug Liberation; Female; Guanine Nucleotides; Humans; Hydrogen-Ion Concentration; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Mesalamine; Middle Aged; Retrospective Studies; Thionucleotides; Time Factors; Young Adult

The thiopurines azathioprine and 6-mercaptopurine are frequently used for remission maintenance in patients with inflammatory bowel diseases. However, there are therapy failures, and it is unclear whether clinical and laboratory parameters can be used to predict thiopurine metabolite concentrations (as a surrogate for adequate remission maintenance therapy) and clinical outcome in these patients.. In this retrospective analysis of clinical routine patient data, multivariate statistical models based on Linear Mixed Models regression and Generalized Estimating Equations logistic regression were developed. The adequacy of the models was assessed using Pearson's correlation and a receiver operating characteristic curve.. This study included 273 patients and 1158 thiopurine metabolite measurements as well as routine laboratory and clinical data. In the statistical models, thiopurine metabolite concentrations and the odds of non-remission based on different clinical and laboratory parameters were computed. Correlation (r. Although the models are not yet accurate enough to be used in clinical routine, model-based prediction of thiopurine metabolite concentrations and of outcome is feasible. Until more accurate models are developed and validated, traditional therapeutic drug monitoring of thiopurine metabolites in patients with inflammatory bowel diseases under thiopurine therapy stays the best tool to individualize therapy.

Topics: Adult; Area Under Curve; Azathioprine; Drug Monitoring; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Models, Statistical; Predictive Value of Tests; Retrospective Studies; Treatment Outcome

Thiopurine exposure throughout pregnancy in patients with inflammatory bowel diseases (IBD) is common and teratogenically safe. Late consequences of in utero exposure to thiopurines and its metabolite, 6-thioguanine nucleotides (6-TGN), such as neonatal and infant anemia are still disputed.. To evaluate whether 6-TGN exposure during pregnancy influences anemia in infants at 1 year of life.. A comparative observational study was performed between 2009 and 2015 at a multidisciplinary IBD clinic dedicated to pregnant women. The hemoglobin level and signs of anemia between 9 and 15 months after birth of infants born to women exposed to thiopurines throughout the entire pregnancy was compared to infants of women with no thiopurine exposure during pregnancy.. Altogether, 34 patients, 21 in the study group and 13 in the control group, were included. The median duration of maternal thiopurine exposure prior to pregnancy was 24 months (range 12-72 months), and median dosage was 100 mg (range 50-175 mg). Maternal IBD activity, infants' iron supplementation, and iron deficiency diagnoses were similar between both groups. The infants' mean hemoglobin level (gr/dL) in the thiopurine-exposed women versus the control group was 11.48 ± 0.8 versus 11.54 ± 0.6, respectively, p = 0.81. The composite risk of any sign of infant anemia was numerically higher in the thiopurine-exposed women, 10 (47%), compared to non-exposed women, 3 (23%), p = 0.17. The mean corpuscular volume, red cell distribution width, white blood cell, and platelet counts were similar among groups.. Thiopurine therapy during pregnancy in women with IBD is safe for long-term neonatal outcomes; still large-scale confirmatory studies are required.

Topics: Adult; Anemia; Anemia, Neonatal; Female; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Inflammatory Bowel Diseases; Mercaptopurine; Pregnancy; Pregnancy Complications; Pregnancy Outcome

Low-dose thiopurine-allopurinol (LDTA) combination therapy is a commonly applied optimisation strategy in IBD patients with a skewed thiopurine metabolism.. To assess continued LDTA maintenance treatment at annual intervals and explore risk factors for treatment cessation METHODS: Adult IBD patients treated with LDTA between 2009 and 2016 were retrospectively included. Data on the incidence of clinical and laboratory adverse events (AEs), including hepatotoxicity and myelotoxicity resulting in imposing LDTA therapy cessation and associated risk factors were collected.. In total, 221 IBD patients (46% male, median age 42 years) were included. Maintenance LDTA treatment was continued in 78% of patients at 1 year (n = 145), 66% at 2 years (n = 83), 57% at 3 years (n = 52) and 52% at 4 years (n = 33). Treatment in patients receiving LDTA therapy for AEs during thiopurine monotherapy was more often continued than in patients initiating LDTA for other indications (eg, ineffectiveness of thiopurine monotherapy, routinely discovered skewed metabolism) (P = 0.016). Myelotoxicity during thiopurine monotherapy resolved in 87% and hepatotoxicity in 86% after median of 1.2 and 1.4 months after LDTA initiation. Cumulative incidence of AEs during LDTA resulting in therapy cessation within total follow-up of 449 treatment-years was 7% for clinical AEs, 4% for myelotoxicity and 1% for hepatotoxicity.. LDTA therapy is a safe and beneficial optimisation strategy in IBD patients. Continued maintenance LDTA treatment is 52% after 4 years of treatment and most commonly affected by ineffectiveness of LDTA rather than LDTA-attributed toxicity. LDTA optimisation strategy is most advantageous in patients failing thiopurine monotherapy due to AEs.

Topics: Adult; Allopurinol; Bone Marrow Diseases; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Medication Adherence; Mercaptopurine; Middle Aged; Netherlands; Retrospective Studies; Withholding Treatment

New Zealand (NZ) has one of the highest rates of non-melanoma skin cancers (NMSCs) in the world. Thiopurine use in inflammatory bowel disease (IBD) patients has been shown to increase NMSC risk. This study aimed to investigate the possible increase of NMSC risk in thiopurine-treated IBD patients in NZ despite the high background rate.. Inflammatory bowel disease patients treated with thiopurines and healthy controls were recruited across two different latitude centers in NZ. Consented participants completed a questionnaire to identify additional risk factors and were examined for suspicious skin lesions. These were photographed, and the pictures were evaluated by a dermatologist. Data were compared between centers and between groups with NMSC incidence and thiopurine-associated relative risks estimated.. One hundred seventy-one thiopurine-exposed IBD patients and 201 controls were recruited. Twenty seven of 390 photographs (26 participants) showed suspicious lesions (17 exposed, 9 controls) as determined by the dermatologist. Estimated NMSC incidence was 24.7-34.3/1000 patient-years (thiopurine-exposed, depending on classification of unconfirmed suspicious lesions) and 7-14/1000 patient-years (control). The relative risk of NMSC among thiopurine exposed was 2.38-2.97 (P ≤ 0.014), which remained significant after individually adjusting for potential confounders. We estimated the NMSC risk to increase 5.4-6.6% per 6 months of thiopurine use (P < 0.001). Low compliance in avoiding NMSC risk factors in the exposed group was observed.. We found a twofold to threefold increase in NMSC incidence in IBD patients treated with thiopurines in NZ, despite the high background incidence rate.

Topics: Adolescent; Adult; Aged; Female; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; New Zealand; Risk; Risk Factors; Skin Neoplasms; Surveys and Questionnaires; Young Adult

Interactions between principal cytotoxic thiopurine metabolites, that is 6-thioguanine nucleotides [6-TGN], and infliximab [IFX] and anti-IFX antibodies [Abs] may contribute to higher effectiveness of IFX-thiopurine combination therapy than monotherapies in inflammatory bowel disease.. To examine if thiopurine metabolites influenced trough IFX and anti-IFX Abs, 89 patients previously assessed for anti-IFX Abs were included. To assess if IFX influenced thiopurine metabolites, eight patients who had responded to 12 weeks of intensified IFX at a constant thiopurine dosing were included.. In the first cohort, IFX-thiopurine combination therapy reduced anti-IFX Ab detection [8/40; 20%] as compared with IFX monotherapy [22/49; 45%], odds ratio [OR] 0.31 [0.12-0.80], p < 0.05. 6-TGN was significantly lower in anti-IFX Ab-positive patients (50 pmol/8 × 108 red blood cells [RBC] vs 105, p < 0.01). All anti-IFX Ab-positive patients had 6-TGN < 117 pmol/8 × 108 RBC (sensitivity 100% [63-100], specificity 47% [29-65], area under the curveROC = 0.82, p < 0.01). Trough IFX was similar between anti-IFX Ab-negative patients in IFX monotherapy and IFX-thiopurine combination therapy [5.1 μg/mL vs 4.9, p = 0.76]. 6-TGN and IFX did not correlate [rP = 0.04, p = 0.83; rS = 0.02, p = 0.89, respectively]. In the second cohort, trough IFX increased during IFX intensification [ΔIFX median 6.5 μg/mL, p = 0.02], but 6-TGN was stable [6-TGN at Weeks 0, 4, 8, 12: 90 pmol/8 × 108 RBC, 93, 101, 90; p > 0.05]. Methylated mercaptopurine metabolite associations were consistently negative.. Superior effect of IFX-thiopurine combination therapy over monotherapies partly relates to decrease in anti-IFX Abs, which associates with 6-TGN levels and has a lower therapeutic threshold than during thiopurine monotherapy. Additional benefit likely ascribes to synergy between different anti-inflammatory modes of action rather than direct drug interactions.

Topics: Adult; Antibodies; Drug Synergism; Drug Therapy, Combination; Erythrocytes; Female; Gastrointestinal Agents; Guanine Nucleotides; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Male; Mercaptopurine; Methyltransferases; Middle Aged; Retrospective Studies; Thionucleotides

Topics: Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine

Topics: Aging; Azathioprine; Genotype; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases

Topics: Aging; Azathioprine; Genotype; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases

The thiopurines azathioprine and mercaptopurine remain pivotal maintenance treatments in inflammatory bowel disease (IBD); however, up to 15%-20% of patients preferentially produce the hepatotoxic metabolite 6-methylmercaptopurine (6MMP) at the expense of the therapeutic 6-thioguanine nucleotides (6TGN). This metabolic shunting usually begins within 3 months of therapy. We noted patients developing shunting many months or years after starting treatment and aimed to determine how often this late shunting occurs and whether this could be explained by patient factors or concomitant medications.. The New Zealand database of thiopurine metabolite results from 2002 to 2016 (19085 6TGN/6MMP pairs from 7130 patients) was interrogated to identify patients developing a 6MMP/6TGN ratio >20 after at least 4 months treatment. Dosing history, concomitant therapy, and comorbidity data were assessed.. Fifteen percent of database patients developed preferential 6-MMP production, and of these, 29 patients had late-onset shunting with sufficient data available for validation. This extrapolates to 90 patients in total, representing 1.7% of IBD patients on thiopurines, or 10% of all those with preferential 6-MMP production. Time from starting therapy to shunting was 5 months to 10.4 years (median, 21 months). Eleven patients had abnormal liver function when shunting was recognized, all with 6MMP >5900 pmol/8 × 108 red blood cells. No common factors were found to explain the late onset.. Some IBD patients develop preferential 6MMP production many months or years after commencing therapy. This is important when considering frequency of metabolite monitoring, failure of therapy, or abnormal liver function. 10.1093/ibd/izx081_video1izx081.video15746667546001.

Topics: Adult; Aged; Aged, 80 and over; Azathioprine; Female; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; New Zealand; Thioguanine; Young Adult

Thiopurines are commonly used in the maintenance of remission for children with inflammatory bowel diseases (IBDs). Variation in drug metabolism may affect hepatotoxicity or therapeutic effect. We aimed to describe our center's experience with thiopurine optimization through the use of reduced thiopurine dosing in combination with allopurinol upon hepatotoxicity, drug metabolite levels, and clinical outcomes in children with IBD.. Patients aged 2 to 21 years with IBD treated with the combination of thiopurines/allopurinol between 2008 and 2015 were retrospectively reviewed. Patients previously treated with antitumor necrosis factor therapy were excluded. Demographic data, transaminase levels (aspartate transaminase, alanine transaminase), drug metabolites levels (6-thioguanine [6-TG], 6-methylmercaptopurine), physician global assessment, and corticosteroid use were recorded at baseline, 6, and 12 months.. Fifty-two patients (29 girls, 56%) met inclusion criteria. Thirty-two of 52 (62%) remained on the combination for 12 months. In those remaining on the thiopurine/allopurinol combination, median alanine transaminase and aspartate transaminase levels were reduced (P < 0.001) and median 6-TG levels were increased (P < 0.001) at both 6 and 12 months. Corticosteroid use was decreased at both 6 (P < 0.001) and 12 months (P < 0.001) compared to use at baseline. Remission rates also improved at both 6 (P = 0.013) and 12 months (P = 0.003). Twenty of the 52 patients (38%) had discontinued the thiopurine/allopurinol combination within 12 months of initiation with 17 of 52 (33%) initiating antitumor necrosis factor therapy.. Low-dose thiopurines in combination with allopurinol improved hepatotoxicity and increased 6-TG levels in children with IBD. Corticosteroid use was reduced and remission rates improved in those patients remaining on this combination for 1 year. However, approximately 40% of patients required a change in therapy within 12 months.

Topics: Adolescent; Adult; Allopurinol; Azathioprine; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Free Radical Scavengers; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Retrospective Studies; Treatment Outcome; Young Adult

The aim of this study was to evaluate the effect of combination therapy with methotrexate or 6-mercaptopurine on infliximab levels (IFXL) and antibodies to infliximab (ATI).. Infliximab (IFX) is a highly effective therapy for inflammatory bowel disease (IBD). Unfortunately, 25%-50% of patients will lose response to IFX. Loss of response is correlated with low IFXL and ATI formation which accelerates drug clearance. Combination therapy is thought to decrease ATI formation.. We performed a cross-sectional analysis of 223 pediatric and young adult patients with IBD on IFX. IFXL and ATI were measured and compared between subjects on current combination therapy, prior combination therapy, and IFX monotherapy.. Eighty-four (37.7%) patients were on combination therapy and 139 (62.3%) were on IFX monotherapy. Within the current monotherapy group, 112 (80.6%) had previously been on combination therapy, while 27 (19.4%) had never been on a concomitant immunomodulator. Patients currently on combination therapy had a higher IFXL (17.00 ± 1.33 μg/mL) than those currently on IFX monotherapy (13.18 ± 1.26 μg/mL), P < 0.01. IFXL was lowest in patients who had never been on combination therapy (11.53 ± 2.05 μg/mL) and highest in patients currently on combination therapy (17.00 ± 1.33 μg/mL). Patients currently on combination therapy had a lower rate of detectable ATI (9.5%) compared with those on monotherapy (20.0%) in multivariate analysis (odds ratio [OR]: 0.3; 95% confidence interval (CI), 0.1-0.7, P < 0.01).. Current or prior combination therapy is associated with higher IFXL and lower rates of ATI formation.

Topics: Adolescent; Boston; Cross-Sectional Studies; Drug Therapy, Combination; Female; Humans; Inflammatory Bowel Diseases; Infliximab; Logistic Models; Male; Mercaptopurine; Metabolic Clearance Rate; Methotrexate; Multivariate Analysis; Prospective Studies; Young Adult

Up to 20% of patients with inflammatory bowel disease (IBD) who are refractory to thiopurine therapy preferentially produce 6-methylmercaptopurine (6-MMP) at the expense of 6-thioguanine nucleotides (6-TGN), resulting in a high 6-MMP:6-TGN ratio (>20). The objective of this study was to evaluate whether genetic variability in guanine monophosphate synthetase (GMPS) contributes to preferential 6-MMP metabolizer phenotype.. Exome sequencing was performed in a cohort of IBD patients with 6-MMP:6-TGN ratios of >100 to identify nonsynonymous single nucleotide polymorphisms (nsSNPs). In vitro assays were performed to measure GMPS activity associated with these nsSNPs. Frequency of the nsSNPs was measured in a cohort of 530 Caucasian IBD patients.. Two nsSNPs in GMPS (rs747629729, rs61750370) were detected in 11 patients with very high 6-MMP:6-TGN ratios. The 2 nsSNPs were predicted to be damaging by in silico analysis. In vitro assays demonstrated that both nsSNPs resulted in a significant reduction in GMPS activity (P < 0.05). The SNP rs61750370 was significantly associated with 6-MMP:6-TGN ratios ≥100 (odds ratio, 5.64; 95% confidence interval, 1.01-25.12; P < 0.031) in a subset of 264 Caucasian IBD patients.. The GMPS SNP rs61750370 may be a reliable risk factor for extreme 6MMP preferential metabolism.

Topics: Adult; Azathioprine; Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor; Cohort Studies; Female; Guanine Nucleotides; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors; Thionucleotides; Young Adult

Topics: Allopurinol; Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine

Topics: Allopurinol; Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine

Despite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs.. Overall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation.. We confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E-63, 1.32E-69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E-04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r. Genotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD.

Topics: Alopecia; Antibodies, Monoclonal; Azathioprine; Biomarkers, Pharmacological; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomic Structural Variation; Haplotypes; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Japan; Leukopenia; Logistic Models; Mercaptopurine; Mesalamine; Pharmacogenetics; Pyrophosphatases; Retrospective Studies; Risk; ROC Curve; Sulfasalazine

Thiopurines (TP) represent an important therapeutic tool for the treatment of inflammatory bowel diseases (IBD) in the current situation of rising incidence and health care costs. The results of multiple clinical studies aimed at finding correlations between levels of TP metabolites and response of IBD patients to the treatment are, however, often controversial due to variability in analytical and sample preparation procedures among these studies. In this work, therefore, an updated analytical and sample preparation procedure for therapeutic drug monitoring (TDM) of TP metabolites in blood samples obtained from patients with IBD was proposed to establish a unified protocol. An advanced analytical method based on ion-exchange liquid chromatography hyphenated with tandem mass spectrometry (IEC-ESI-MS/MS) was used for the determination of the profiles of 12 individual TP metabolites in the particular steps of sample preparation procedure including blood collection, red blood cells (RBC) isolation, lysis, and storage. Favorable performance parameters of the IEC-ESI-MS/MS method (LLOQs 1⁻10 nmol/L, accuracy 95⁻105%, intra-day and inter-day precision < 10%, selectivity demonstrated via no sample matrix interferences) and acceptable stability (peak area fluctuations < 15%) of clinical samples under the proposed sample preparation conditions {(i) EDTA anticoagulant tube for the blood collection; (ii) 4 °C and 4 h between the sample collection and RBC isolation; (iii) phosphate-buffered saline for RBC washing and re-suspendation; (iv) -20 °C for RBC lysis and short-term storage; (v) 50 mmol/L phosphate buffer, pH 7.4, 10 mmol/L DTT as a stabilizing medium for TPN in RBC lysates} demonstrated the suitability of such protocol for a well-defined and reliable routine use in studies on thiopurines TDM.

Topics: Adult; Azathioprine; Drug Monitoring; Erythrocytes; Female; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Thioguanine

Thiopurine therapy can be optimised by determining the concentration of the drug's metabolites.. Retrospective analysis on a prospective database of 31 patients with inflammatory bowel disease who failed therapy with thiopurines. Thiopurine metabolites (6-thioguanine, 6-TGN and 6-methylmercaptopurine, 6-MMP) were measured by high-performance liquid chromatography (Laboratorios Cerba, Barcelona) and treatment was duly adjusted in accordance with the results. Clinical response was reassessed after six months.. Despite the appropriate theoretical dose of thiopurines being administered, the dose was insufficient in 45.6% of patients (nonadherence to treatment suspected in 6.45%) and 16.2% received an excessive dose or the drug was metabolised by other metabolic pathways. After treatment was optimised based on metabolite levels, only 25.8% (8/31) were prescribed a biological agent, while 74.2% of cases (23/31) were managed through dose optimisation alone.. Monitoring thiopurine metabolite levels may help clinicians to assess non-responsive patients before adding or switching to another drug (generally a biological agent), thereby avoiding any additional costs or potential toxicity. This strategy may also help to identify patients receiving an insufficient dose and those with an alternative metabolic pathway, who could be candidates for low-dose AZA with allopurinol, as well as patients who are suspected of being non-adherent. In three out of four patients, switching to a biological agent can be avoided.

Topics: Adult; Aged; Azathioprine; Biotransformation; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Thioguanine; Young Adult

Discontinuation of thiopurine analogues is common prior to live vaccines, during infection or when de-escalating therapy. Data regarding clearance of active metabolites and immune re-constitution is scant. We aimed to determine drug elimination and immune re-constitution following thiopurine cessation.. The elimination kinetics of 6-thioguanine nucleotides (6-TGN) were determined in nine inflammatory bowel disease [IBD] patients discontinuing thiopurines. Immune reconstitution was evaluated by toxic shock syndrome toxin 1 [TSST1] or anti-CD3 [OKT3]-induced CD4+ T-cell proliferation, following an initial exposure to TSST1 and 6-mercaptopurine [6MP], separately or combined.. All patients discontinuing thiopurines displayed first-order elimination kinetics of 6-TGN, with a median elimination half-life of 6.8 days [interquartile range 5.9-8.4]. Resting CD4+ T-cells exposed to 6MP preserved their response to subsequent polyclonal or Vβ2+-preferential stimulation. By contrast, exposure of TSST1-activated CD4+ T-cells to 6MP inhibited their subsequent Vβ2+clonal response to further stimulation [p = 0.008], whereas overall response to further non-Vβ2-selective stimulation with OKT3 was unaltered [p = 0.9].. Upon 6MP/azathioprine discontinuation, a 6-TGN elimination half-life of less than 10 days is expected in most patients. Immune reconstitution, however, may take longer for T-cell clones exposed to stimulation during thiopurine treatment. These findings may be useful when considering thiopurine cessation.

Topics: Adult; Azathioprine; Bacterial Toxins; Cell Proliferation; Enterotoxins; Female; Guanine Nucleotides; Humans; Immune Reconstitution; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Metabolic Clearance Rate; Muromonab-CD3; Superantigens; T-Lymphocytes; Thionucleotides; Withholding Treatment

Big data analytics leverage patterns in data to harvest valuable information, but are rarely implemented in clinical care. Optimising thiopurine therapy for inflammatory bowel disease [IBD] has proved difficult. Current methods using 6-thioguanine nucleotide [6-TGN] metabolites have failed in randomized controlled trials [RCTs], and have not been used to predict objective remission [OR]. Our aims were to: 1) develop machine learning algorithms [MLA] using laboratory values and age to identify patients in objective remission on thiopurines; and 2) determine whether achieving algorithm-predicted objective remission resulted in fewer clinical events per year.. Objective remission was defined as the absence of objective evidence of intestinal inflammation. MLAs were developed to predict three outcomes: objective remission, non-adherence, and preferential shunting to 6-methylmercaptopurine [6-MMP]. The performance of the algorithms was evaluated using the area under the receiver operating characteristic curve [AuROC]. Clinical event rates of new steroid prescriptions, hospitalisations, and abdominal surgeries were measured.. Retrospective review was performed on medical records of 1080 IBD patients on thiopurines. The AuROC for algorithm-predicted remission in the validation set was 0.79 vs 0.49 for 6-TGN. The mean number of clinical events per year in patients with sustained algorithm-predicted remission [APR] was 1.08 vs 3.95 in those that did not have sustained APR [p < 1 x 10-5]. Reductions in the individual endpoints of steroid prescriptions/year [-1.63, p < 1 x 10-5], hospitalisations/year [-1.05, p < 1 x 10-5], and surgeries/year [-0.19, p = 0.065] were seen with algorithm-predicted remission.. A machine learning algorithm was able to identify IBD patients on thiopurines with algorithm-predicted objective remission, a state associated with significant clinical benefits, including decreased steroid prescriptions, hospitalisations, and surgeries.

Topics: Adolescent; Adult; Algorithms; Area Under Curve; Azathioprine; Drug Prescriptions; Female; Hospitalization; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Machine Learning; Male; Medication Adherence; Mercaptopurine; Middle Aged; Remission Induction; Retrospective Studies; ROC Curve; Treatment Outcome; Young Adult

To determine if 6-mercaptopurine (MP) is better tolerated than azathioprine (AZA) as the initial thiopurine treatment in patients suffering from inflammatory bowel disease (IBD). Switching patients with IBD from AZA to MP is advocated in patients intolerant to AZA. However, no study has determined if MP is more suited than AZA as a first-line treatment for patients who are naïve to thiopurine treatment.. The tolerance of AZA and MP treatments in clinical practice was retrospectively evaluated from start to 12 months after initiating treatment in 113 patients with IBD who were all naïve to thiopurines (82 patients treated with AZA and 31 patients with MP).. 65% of the patients treated with AZA and 61% of the patients treated with MP tolerated their treatment during 12 months (i.e., no group difference, p = 0.742). No difference in reported side effects between the two treatments was observed. The mean equivalent initial dose (0.92 vs. 0.61 mg/kg; p < 0.001) and the mean equivalent dose at 12 months (1.98 vs. 1.65 mg/kg; p = 0.014) was significantly higher in the MP group vs. the AZA group. The proportion of patients with ΔMCV ≥ 7 at 12 months was numerically higher in the MP group than in the AZA group (53% vs. 31%; p = 0.090).. In this retrospective observational study, no differences in tolerance or adherence between AZA and MP were observed in patients naïve to thiopurines. However, MP treatment was at a higher equivalent thiopurine dose than AZA treatment, which tended to be associated with better treatment response.
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Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Female; Gastrointestinal Agents; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Time Factors; Treatment Outcome; Young Adult

Thiopurines are the prerequisite for immunomodulation in inflammatory bowel disease (IBD) therapy. When administered in high (oncological) dose, thiopurine metabolites act as purine antagonists, causing DNA-strand breakage and myelotoxicity. In lower IBD dosages, the mode of action is primarily restricted to anti-inflammatory effects. Then, myelosuppression and hepatotoxicity are the most common adverse events of thiopurines. The aim of this study was to assess the effect of thiopurine metabolites on hematologic and hepatic parameters and to determine which patient characteristics are related to generation of thiopurine metabolites.. The authors scrutinized the therapeutic drug monitoring database of the VU University medical center and subsequently merged this database with the Clinical Laboratory database of our hospital covering the same time period (2010-2015).. The authors included 940 laboratory findings of 424 unique patients in this study. Concentrations of 6-thioguanine nucleotides (6-TGN) correlated negatively with red blood cell count, white blood cell count, and neutrophil count in both azathioprine (AZA) and mercaptopurine users. There was a positive correlation with mean corpuscular volume. In patients using 6-thioguanine, 6-TGN concentrations correlated positively with white blood cell count. Furthermore, there was an inverse correlation between patient's age and 6-TGN concentrations in patients using AZA or 6-thioguanine, and we observed an inverse correlation between body mass index and 6-TGN concentrations in patients using AZA or mercaptopurine. No relations were observed with liver test abnormalities.. Thiopurine derivative therapy influenced bone marrow production and the size of red blood cells. Age and body mass index were important pharmacokinetic factors in the generation of 6-TGN.

Topics: Adult; Blood Cell Count; Databases, Factual; Drug Monitoring; Female; Guanine Nucleotides; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Thionucleotides; Time Factors; Treatment Outcome

The occurrence of thiopurine-related adverse events (AEs) may complicate the management of patients with inflammatory bowel disease (IBD). We aimed to evaluate the tolerability of thiopurines in a current IBD setting.. All consecutive patients who started a treatment with azathioprine (AZA) from January 2010 to March 2016 were entered in a prospectively maintained database, and the AEs which led to the permanent discontinuation of the drug were reported.. Two hundred and fifty three patients were included. Median total follow-up was 32 months (range: 0.2-75 months). At the end of the study, AZA was discontinued in 160 patients (63.2%). The main reason leading to drug withdrawal was the occurrence of AEs (109/160 patients [68.1%]; cumulative incidence among the entire cohort: 43.1%). Overall, the most frequent AEs leading to treatment withdrawal were nausea (31/253 patients, 12.3%) and subjective symptoms, i.e., poorly defined side effects such as fatigue, headache and muscle pain (20/253 patients, 7.9%). Among the 109 AZA-intolerant patients, a switch to 6-mercaptopurine (6-MP) was performed in 44 cases (40.4%). At the end of follow-up, 6-MP was discontinued in 35/44 patients (79.5%), mostly due to AEs (29/35 patients, 82.8%). Azathioprine-induced hepatic and pancreatic toxicity was associated with male gender (p = .01 and p = .03, respectively), and occurrence of nausea with Crohn's disease (p = .04).. Our real-life prospective cohort showed the higher cumulative incidence of thiopurine withdrawal due to AEs reported to date. Switching from AZA to 6-MP was often ineffective.

Topics: Adult; Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Italy; Kaplan-Meier Estimate; Male; Mercaptopurine; Middle Aged; Nausea; Prospective Studies

To identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use. The thiopurines azathioprine and 6-mercaptopurine have been a mainstay of inflammatory bowel disease (IBD) therapy for decades, but their mechanism of action. Complete blood counts revealed lower lymphocyte, but not monocyte or granulocyte, counts in IBD patients who were taking thiopurines at the time of sampling. This reduction was restricted to CD3-negative lymphocytes, wherein both natural killer (NK) and B cells were significantly reduced among thiopurine recipients. Among CD19+ B cells, the transitional B cells were particularly depleted, being nearly absent in both blood and colon biopsies of thiopurine recipients. No differences were associated with thiopurine use in CD8+ T cells, mucosa-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, gamma/delta T cells, Th1, Th17, regulatory T cells (Tregs) or naïve CD4+ T cells. However, patients with IBD had significantly more circulating FOXP3+, Helios+ Tregs and fewer iNKT and MAIT cells than healthy controls.. Thiopurine use is associated with reduced B and NK cell, but not T cell, subpopulations in the blood of IBD patients.

Topics: Antigens, CD19; Apoptosis; Azathioprine; B-Lymphocytes; Case-Control Studies; CD3 Complex; Colon; Humans; Inflammatory Bowel Diseases; Killer Cells, Natural; Mercaptopurine; Mucous Membrane; Natural Killer T-Cells; Risk; T-Lymphocytes, Regulatory

NUDT15 c.415C>T was a novel genetic marker confirmed in our center for thiopurine-induced leukopenia in Chinese inflammatory bowel disease (IBD). For validation, a large cohort study is needed. Meanwhile, the newly discovered NUDT15 coding variants (c.36_37insGGAGTC and c.52 G>A) have not been studied in patients with IBD. We aimed to further confirm the influence of 3 NUDT15 variants (c.415C>T, c.36_37insGGAGTC, and c.52G>A) on thiopurine-induced leukopenia in Chinese patients with IBD.. Patients prescribed on thiopurines for at least 2 weeks were recruited from 4 tertiary hospitals. Clinical data were collected. NUDT15 genotypes were determined with polymerase chain reaction-RFLP and sequencing. The interactions between variants and leukopenia were analyzed.. A total of 732 patients were included, 177 (24.3%) of whom developed leukopenia. There were strong associations of NUDT15 c.415C>T, c.36_37insGGAGTC, and c.52G>A with thiopurine-induced leukopenia (P = 1.81 × 10, P = 4.74 × 10 and P = 0.04, respectively), whereas there was no relevance for thiopurine S-methyltransferase genotypes (P = 0.25). The predictive sensitivity of NUDT15 c.415C>T was 49.2%, whereas it increased to 55.4% when combined analysis with c.36_37insGGAGTC and c.52G>A. Notably, not only the homozygotes with NUDT15 c.415C>T but also the heterozygotes both carrying c.415C>T and c.52G>A developed early leukopenia. The median dosage for NUDT15 c.415C>T carriers was significantly lower than that for wild-type (P < 0.001).. We confirmed that NUDT15 c.415C>T, c.36_37insGGAGTC, and c.52G>A variants were risk factors for thiopurine-induced leukopenia. Combined detection of the 3 variants could increase the predictive sensitivity of thiopurine-induced leukopenia and help to distinguish early leukopenia in heterozygote of c.415C>T in Chinese patients with IBD. Treatment monitoring by NUDT15 variants may be promising in individualized therapy.

Topics: Adolescent; Adult; Aged; Asian People; Azathioprine; Child; Child, Preschool; China; Cohort Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Heterozygote; Homozygote; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Pyrophosphatases; Risk Factors; Young Adult

Thiopurines (azathioprine and mercaptopurine) are frequently used immunosuppressive drugs to maintain remission in patients with inflammatory bowel disease. Half of the conventional thiopurine-derivative users have to discontinue treatment within 5 years, mainly because of intolerable adverse events. Over recent years, different strategies to optimize thiopurine treatment were suggested, yet, studies describing the clinical effectiveness of these strategies remain scarce. The aims of this study were to compare tolerability and sustained clinical benefit of conventional thiopurine derivatives therapy among two 5-year real-life intercept cohorts and to assess the clinical value of specifically allopurinol cotherapy.. In this retrospective single-center cohort study, we analyzed data from patients in whom weight-based thiopurine monotherapy was initiated between 2005 and 2009 (cohort 1) or between 2010 and 2014 (cohort 2). The initiation of the second cohort was synchronic to the start of allopurinol-based optimization in our center. Optimization strategies were extracted from patient charts.. In total, 105 patients were included (60 in cohort 1, and 45 in cohort 2). Metabolite measurement was performed in 37% versus 84% of the patients (P < 0.001). Subsequent optimization strategies were applied in 33% versus 58% of the patients because of inadequate metabolite concentrations, intolerance, or ineffectiveness (P = 0.01). Allopurinol was coadministered to therapy in 18 patients (40%) in the second cohort. Therapy was switched to thioguanine in 11 versus 6 patients (P > 0.05). Overall, total duration was longer in the second cohort (10.8 versus 34.1 months, P < 0.001). The number of ongoing thiopurine users (20% versus 49%) and sustained clinical benefit (13% versus 38%) were higher in the second cohort (both P < 0.05). This was mainly because of a decrease in hepatotoxicity after optimization (P < 0.01).. Optimization of thiopurine therapy by the use of therapeutic drug monitoring with subsequent administration of allopurinol cotherapy successfully enhanced sustained clinical benefit and tolerability in patients with inflammatory bowel disease.

Topics: Adult; Allopurinol; Azathioprine; Drug Monitoring; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Thioguanine; Treatment Outcome; Young Adult

The effects of thiopurines on white cell count are well documented.. We compared the effects of infliximab 5 mg/kg monotherapy and combination of infliximab with thiopurines on the total and differential white cell count (WBC).. 13 IBD patients treated with infliximab monotherapy and 18 IBD patients treated with a combination of infliximab and thiopurines were included in the study. Using retrospective data, cell counts were examined prior to induction of infliximab, and at 6 weeks and 1 year post-induction.. The patients on combination therapy had an absolute WBC at 52 weeks of 5.7 whereas that of patients on Infliximab monotherapy at the same time point was 8.3 with comparable neutrophil count of 3.4 and 5.4. The results showed a significant reduction in white cell count and neutrophils at 6 weeks which persisted at 52 weeks in both groups (p < 0.05) with a greater drop in patients on combination infliximab and thiopurine (p < 0.05) as compared to Infliximab monotherapy. There was no significant change in the lymphocyte count.. Full blood counts should be closely monitored in all patients starting infliximab therapy, in particular patients receiving concomitant thiopurines.

Topics: Adolescent; Adult; Azathioprine; Drug Therapy, Combination; Female; Humans; Inflammatory Bowel Diseases; Infliximab; Male; Mercaptopurine; Middle Aged; Neutrophils; Retrospective Studies; Young Adult

Information on the safety of paternal use of azathioprine (AZA) and 6-mercaptopurine (6-MP) prior to conception is limited. Based on nationwide data from the Danish health registries, we examined the association between paternal use of AZA/6-MP within 3 months before conception and adverse birth outcomes.. This nationwide cohort study is based on data from all singletons born in Denmark from 1 January 1997 through 2013. Children fathered by men who used AZA/6-MP within 3 months before conception constituted the exposed cohort (N=699), and children fathered by men who did not use AZA/6-MP 3 months prior to conception constituted the unexposed cohort (N=1 012 624). The outcomes were congenital abnormalities (CAs), preterm birth and small for gestational age (SGA). We adjusted for multiple covariates and performed a restricted analysis of men with IBD.. There were no significantly increased risks of CAs, preterm birth or SGA in exposed versus unexposed cohorts of children. The adjusted ORs were 0.82 (95% CI 0.53 to 1.28) for CAs, 1.17 (95% CI 0.72 to 1.92) for preterm birth and 1.38 (95% CI 0.76 to 2.51) for SGA. Restricting our analysis to fathers with IBD showed similar results with no significantly increased risk of adverse birth outcomes.. This nationwide study is the largest to date, examining the effect of preconceptual paternal use of AZA/6-MP on birth outcomes in live born singletons. The results of no significantly increased risks of adverse birth outcomes are reassuring and support the continuation of paternal AZA/6-MP treatment during conception.

Topics: Adult; Azathioprine; Case-Control Studies; Cohort Studies; Congenital Abnormalities; Denmark; Female; Humans; Immunosuppressive Agents; Infant, Small for Gestational Age; Inflammatory Bowel Diseases; Male; Mercaptopurine; Paternal Exposure; Pregnancy; Pregnancy Outcome; Premature Birth; Young Adult

Myelosuppression is a life-threatening complication of thiopurine therapy, and the incidence of thiopurine-induced myelosuppression is higher in East Asians than in Europeans. We investigated genetic factors associated with thiopurine-induced leukopenia in patients with IBD.. A genome-wide association study (GWAS) was conducted in thiopurine-treated patients with IBD, followed by high-throughput sequencing of genes identified as significant in the GWAS or those involved in thiopurine metabolism (n=331). Significant loci associated with thiopurine-induced leukopenia were validated in two additional replication cohorts (n=437 and n=330). Functional consequences of. The GWAS identified two loci associated with thiopurine-induced leukopenia (rs16957920,. The results suggest that the hypomorphic

Topics: Adolescent; Adult; Aged; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Azathioprine; Case-Control Studies; Cohort Studies; Female; Genetic Markers; Genome-Wide Association Study; High-Throughput Nucleotide Sequencing; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Mice; Mice, Knockout; Middle Aged; Polymorphism, Single Nucleotide; Republic of Korea; Sequence Analysis, DNA; Young Adult

Topics: Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Microbiota

The objective of the study was to define the clinical, biochemical, and histologic features of liver injury from thiopurines.. Azathioprine (Aza) and 6-mercaptopurine (6-MP) can cause liver injury, but no large series exist.. Clinical and laboratory data and 6-month outcomes of patients with thiopurine hepatotoxicity from the Drug-Induced Liver Injury Network Prospective Study were analyzed.. Twenty-two patients were identified, 12 due to Aza and 10 due to 6-MP, with a median age of 55 years; the majority were female (68%). Inflammatory bowel disease was the indication in 55%, and the median thiopurine dose was 150 (range, 25 to 300) mg daily. The median latency to onset was 75 (range, 3 to 2584) days. Injury first arose after a dose escalation in 59% of patients, the median latency after dose increase being 44 (range, 3 to 254) days. At onset, the median alanine aminotransferase level was 210 U/L, alkaline phosphatase was 151 U/L, and bilirubin was 7.4 mg/dL (peak, 13.4 mg/dL). There were no major differences between Aza and 6-MP cases, but anicteric cases typically had nonspecific symptoms and a hepatocellular pattern of enzyme elevations, whereas icteric cases experienced cholestatic hepatitis with modest enzyme elevations in a mixed pattern. One patient with preexisting cirrhosis required liver transplantation; all others resolved clinically. One patient still had moderate alkaline phosphatase elevations 2 years after onset.. Nearly three-quarters of patients with thiopurine-induced liver injury present with self-limited, cholestatic hepatitis, typically within 3 months of starting or a dose increase. The prognosis is favorable except in patients with preexisting cirrhosis.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Alkaline Phosphatase; Azathioprine; Bilirubin; Chemical and Drug Induced Liver Injury; Child; Cholestasis; Databases, Factual; Female; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Prospective Studies; Time Factors; Young Adult

Data about use and effectiveness of mercaptopurine in inflammatory bowel disease are relatively limited.. To assess the possible therapeutic indications, efficacy and safety of mercaptopurine as an alternative to azathioprine in inflammatory bowel disease.. Retrospective observational study in patients treated with mercaptopurine in a total cohort of 1,574 patients with inflammatory bowel disease.. One hundred and fifty-two patients received mercaptopurine, 15.7% of these patients as an initial thiopurine, 5.3% after azathioprine failure, and 79% after azathioprine intolerance. In 52.6% of patients (n = 80), adverse effects of mercaptopurine occurred, resulting in withdrawal in 49 of them. Mercaptopurine was effective in 39% of cases (95% CI 31-48%). In the remaining patients, failure was due mainly to withdrawal due to side effects (55.1%) and therapeutic step-up (33.7%). The average total time of mercaptopurine exposure was 36 months (IQR: 2-60). Myelotoxicity with mercaptopurine was more common in patients with intermediate TPMT activity than in those with normal activity (p = 0.046).. In our setting, mercaptopurine is primarily used as a rescue therapy in patients with azathioprine adverse effects. This could explain its modest efficacy and the high rate of adverse effects. However, this drug is still an alternative in this group of patients, before a therapeutic step-up to biologics is considered.

Topics: Adult; Aged; Azathioprine; Cohort Studies; Crohn Disease; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Treatment Failure

Topics: Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine

Evidence that thiopurines impact on the risk of surgery in elderly onset inflammatory bowel disease (EO-IBD) is lacking. We aimed to compare the rates of surgery in EO-IBD (>60 years at diagnosis) with adult-onset IBD (18-59 yrs), and examine the impact of thiopurines on surgical risk in EO-IBD.. Using a U.K. database between 1990 and 2010, we compared rates of surgery between adult-onset IBD and EO-IBD using survival analysis. Ulcerative colitis (UC) and Crohn's disease (CD) were analyzed separately. Cox proportional hazard modeling was used to determine the adjusted relative risk of surgery. We further assessed the impact of duration of thiopurine treatment on risk of surgery.. We identified 2758 of 9515 patients with UC and 1349 of 6490 patients with CD, with EO-IBD. Cumulative 1, 5, and 10 years risk of colectomy was similar in EO-UC (2.2, 4.5, and 5.8%, respectively) and AO-UC (2.2, 5.0, and 7.3%, respectively; P = 0.15). Cumulative 1, 5, and 10 years risk of first intestinal surgery was lower in EO-CD (9.5, 14.6, and 17.9%, respectively) than AO-CD (12.2, 19.0, and 24.4%, respectively; P < 0.001). Early steroid use, steroid dependency, and thiopurine use was associated with higher risk of colectomy in EO-UC. Among EO-UC receiving thiopurines for >12 months, there was a 70% reduction in risk of colectomy (hazard ratio. 0.30; 95% confidence interval, 0.15-0.58). Thiopurines were not associated with a reduced risk of surgery in EO-CD.. Risk of colectomy in EO-UC does not differ from AO-UC, but the risk of surgery in EO-CD is significantly lower than in AO-CD. Sustained thiopurine use of 12 months or more duration in EO-UC reduces the risk colectomy, but does not impact on the risk of surgery in EO-CD. These findings are important given the greater risk of thiopurine-associated lymphoma in the elderly.

Topics: Adolescent; Adult; Age Factors; Aged; Azathioprine; Cohort Studies; Colectomy; Colitis, Ulcerative; Crohn Disease; Databases, Factual; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Proportional Hazards Models; Risk Factors; Survival Analysis; United Kingdom; Young Adult

Thiopurine therapy, particularly thioguanine, has been associated with nodular regenerative hyperplasia (NRH) of the liver. Combination therapy of allopurinol and an adapted low-dose thiopurine leads to a pharmacokinetic profile that has similarities to that of thioguanine. Therefore, allopurinol-thiopurine combination therapy may also be associated with NRH of the liver. We assessed the prevalence of NRH in patients with inflammatory bowel disease (IBD) treated with allopurinol-thiopurine combination therapy by liver biopsy specimen examination.. An observational, cross-sectional study was conducted in a Dutch IBD-referral center. Adult patients with IBD, treated for at least 1 year with allopurinol-thiopurine combination therapy were eligible. All patients underwent a liver biopsy, after standard laboratory and thiopurine metabolite concentration assessments. Histopathology was assessed by an experienced liver pathologist.. Twenty-two patients with IBD were included. The mean duration of combination therapy at the time of the liver biopsy was 24.7 months (SD 5.7). NRH was observed in one of the biopsies (4.8%), any grade of nodularity was observed in 3 biopsy specimens (14%). Other findings included phlebosclerosis (24%), perisinusoidal fibrosis (81%), sinusoidal dilatation (43%), perivenular fibrosis (14%), and periportal fibrosis (29%). Around the time of biopsy, the median 6-thioguanine nucleotide and 6-methylmercaptopurine ribonucleotide concentrations were 705 pmol × 10 red blood cells (RBC) (interquartile range 498-915) and 355 pmol × 10 RBC (interquartile range 225-670).. The prevalence of histologically assessed NRH in patients with IBD, who were treated with allopurinol-thiopurine combination therapy, was 5%. This percentage is in line with thiopurine-naive and thioguanine-using patients with IBD. None of the included patients had clinical symptoms or signs suggestive of (noncirrhotic) portal hypertension.

Topics: Adult; Allopurinol; Antimetabolites; Cross-Sectional Studies; Drug Therapy, Combination; Female; Focal Nodular Hyperplasia; Humans; Inflammatory Bowel Diseases; Liver; Male; Mercaptopurine; Middle Aged; Netherlands; Prevalence

Inflammatory bowel diseases are chronic conditions of unknown etiology, showing a growing incidence and prevalence in several countries, including Italy. Although the etiology of Crohn's disease and ulcerative colitis is unknown, due to the current knowledge regarding their pathogenesis, effective treatment strategies have been developed. Several guidelines are available regarding the efficacy and safety of available drug treatments for inflammatory bowel diseases. Nevertheless, national guidelines provide additional information adapted to local feasibility, costs and legal issues related to the use of the same drugs. These observations prompted the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) to establish Italian guidelines on the safety of currently available treatments for Crohn's disease and ulcerative colitis. These guidelines discuss the use of aminosalicylates, systemic and low bioavailability corticosteroids, antibiotics (metronidazole, ciprofloxacin, rifaximin), thiopurines, methotrexate, cyclosporine A, TNFα antagonists, vedolizumab, and combination therapies. These guidelines are based on current knowledge derived from evidence-based medicine coupled with clinical experience of a national working group.

Topics: Adrenal Cortex Hormones; Aminosalicylic Acid; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Cyclosporine; Drug Therapy, Combination; Evidence-Based Medicine; Female; Humans; Inflammatory Bowel Diseases; Italy; Mercaptopurine; Methotrexate; Pregnancy; Randomized Controlled Trials as Topic; Treatment Outcome; Tumor Necrosis Factor-alpha

Topics: Humans; Inflammatory Bowel Diseases; Mercaptopurine

Topics: Azathioprine; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases

Early-onset inflammatory bowel disease (IBD) is generally aggressive, with a high probability of complications and need of surgery. Despite the introduction of highly effective biological drugs, treatment with azathioprine continues to be important even for early-onset IBD; however, in these patients azathioprine response seems to be reduced. This study evaluated azathioprine doses, metabolite concentrations, and their associations with patients' age in children with IBD treated at 6 tertiary pediatric referral centers.. Azathioprine doses, metabolites, and clinical effects were assessed after at least 3 months of therapy in 17 early-onset (age < 6 yr, cases) and 51 nonearly-onset (aged > 12 and <18 yrs, controls) patients with IBD. Azathioprine dose was titrated on therapeutic efficacy (response and adverse effects). Azathioprine metabolites and thiopurine methyltransferase activity were determined by high-performance liquid chromatography with ultra violet-vis detection (HPLC-UV) methods.. Frequency of patients in remission was similar among early-onset and control groups, respectively (82% and 84%, P value = 0.72). Early-onset patients required higher doses of azathioprine (median 2.7 versus 2.0 mg·kg·d, P value = 1.1 × 10). Different doses resulted in comparable azathioprine active thioguanine nucleotide metabolite concentrations (median 263 versus 366 pmol/8 × 10 erythrocytes, P value = 0.41) and methylmercaptopurine nucleotide concentrations (median 1455 versus 1532 pmol/8 × 10 erythrocytes, P value = 0.60). Lower ratios between thioguanine nucleotide metabolites and azathioprine doses were found in early-onset patients (median 98 versus 184 pmol/8 × 10 erythrocytes·mg·kg·d, P value = 0.017). Interestingly, early-onset patients presented also higher thiopurine methyltransferase activity (median 476 versus 350 nmol methylmercaptopurine/mg hemoglobin/h, P-value = 0.046).. This study demonstrated that patients with early-onset IBD present increased inactivating azathioprine metabolism, likely because of elevated activity of the enzyme thiopurine methyltransferase.

Topics: Adolescent; Age of Onset; Antimetabolites; Azathioprine; Case-Control Studies; Child; Child, Preschool; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Erythrocytes; Female; Guanine Nucleotides; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Thioguanine

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Cyclosporine; Drug Eruptions; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Mesalamine; Methotrexate; Tumor Necrosis Factor-alpha

The thiopurine drugs, 6-mercaptopurine and azathioprine, remain the mainstay of immunomodulator therapy for inflammatory bowel disease (IBD). Optimal management depends on achieving therapeutic levels of 6-thioguanine (6-TGN), but measuring thiopurine metabolites is associated with significant cost. Thiopurines cause lymphopenia and an increase in mean corpuscular volume (MCV). It is unclear whether any clinically useful correlation exists between 6-TGN levels and lymphocyte count or MCV.. The aim of this study is to investigate the correlation between 6-TGN levels and lymphocyte count and MCV in thiopurine-treated patients with IBD.. We analysed a prospectively acquired database of 67 patients with IBD treated with thiopurine therapy. The data were analysed looking at the relationship between 6-TGN levels and both lymphocyte count and MCV by using the Spearman's rank correlation coefficient.. Twenty-seven (40%) patients had therapeutic 6-TGN levels. Thirty-three (49%) patients had sub-therapeutic 6-TGN levels. A weak positive correlation between 6-TGN levels and lymphocyte count was demonstrated, but this was not statistically significant (Spearman's R = 0.14, P = 0.23). Spearman's rank correlation coefficient between 6-TGN levels and MCV was statistically significant (R = 0.42, P = 0.0005). MCV >101 fL excluded a subtherapeutic 6-TGN level with positive predictive value of 92%.. There is no specific lymphopenia that can be assumed to indicate a therapeutic 6-TGN level. The relationship between 6-TGN levels and MCV is likely to be clinically relevant. If MCV is elevated, 6-TGN is unlikely to be sub-therapeutic. MCV is a potential surrogate marker which can rule out sub-therapeutic thiopurine metabolites in patients with IBD treated with azathioprine or 6-mercaptopurine.

Topics: Adult; Azathioprine; Biomarkers; Erythrocyte Indices; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Lymphopenia; Male; Mercaptopurine; Retrospective Studies; Thioguanine; Treatment Outcome

Thiopurine use in inflammatory bowel disease (IBD) is limited by drug toxicity and lack of therapeutic efficacy. We assessed the utility of thiopurine metabolite testing and the relationship between disease activity, dose, and metabolite levels in a real world setting.. Patients identified from pathology databases (2007-2012) at two tertiary IBD centers were included if they had thiopurines for at least four weeks. Demographics, dose, test indication, clinical status, action taken, and outcome were obtained by retrospective medical record review.. A total of 169 patients were included. 6-Thioguanine (TGN) levels were sub-therapeutic in 52%, therapeutic in 34%, and supratherapeutic in 14%. Test indication was active disease (79%), adverse effect (11%), or adherence assessment (7%). TGN trended lower in the active disease group compared to those with adverse effects (273 (+/- 23.2) versus 447 (+/- 117.7) pmol/8 × 10(8) RBC, P = 0.05). Weight-based dosing did not improve rates of therapeutic TGN levels (under-dosed 31.5% vs standard dose 35.4%), but was significantly associated with shunting toward 6-MMP (23.1% vs 6.8%, P = 0.008, OR = 4.1). Testing resulted in a change in patient treatment in 86% of patients with active disease and subtherapeutic levels and in 68% of tested patients overall.. Metabolite testing resulted in a change in management in most patients not responding to thiopurines or experiencing adverse events. Weight-based dosing did not increase rates of therapeutic levels but was associated with increased 6MMP shunting.

Topics: Azathioprine; Cohort Studies; Drug Monitoring; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Retrospective Studies; Thioguanine; Treatment Outcome

NUDT15 R139C (rs116855232) is a recently identified genetic factor responsible for thiopurine-induced leukocytopenia and hair loss. In this study, we investigated the association of NUDT15 R139C with 6-thioguanine nucleotide (6-TGN) levels and thiopurine-induced leukocytopenia in Japanese patients with inflammatory bowel disease (IBD).. Two hundred and sixty-four subjects (103 healthy volunteers and 161 IBD patients treated with thiopurines) were enrolled. Genotyping for NUDT15 R139C was performed using Custom TaqMan® SNP genotyping assays.. The NUDT15 C/C, C/T, and T/T genotypes were 80.7, 18.2, and 1.1 %, respectively. The allelic frequency was 10.2 %. Among 161 IBD patients, there was no significant difference in 6-TGN levels among the NUDT15 genotypes. Forty-five patients (27.9 %) developed leukocytopenia (WBC <3000/μl), and the C/T and T/T genotypes were significantly associated with the development of leukocytopenia (P = 1.7 × 10(-5)). In these patients, 6-TGN levels were not significantly different between NUDT15 genotypes. NUDT15 R139C was significantly associated with early (<8 weeks) (P = 1.03 × 10(-4)) and late (>8 weeks) leukocytopenia (P = 4.3 × 10(-4)). The decrease in WBC count at 2 and 4 weeks was significantly higher in patients with the C/T or T/T genotypes as compared to the patients with the C/C genotype. All patients with the T/T genotype (n = 2) developed early severe hair loss and severe leukocytopenia (<1000/μl). The logistic regression analysis revealed that NUDT15 R139C was the sole genetic factor responsible for the thiopurine-induced leukocytopenia (P = 0.001).. These results suggest that NUDT15 R139C-related thiopurine-induced leukocytopenia is mediated by a 6-TGN-independent mechanism.

Topics: Adult; Alopecia; Case-Control Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Guanine Nucleotides; Humans; Inflammatory Bowel Diseases; Leukocyte Count; Leukopenia; Male; Mercaptopurine; Middle Aged; Pyrophosphatases; Thionucleotides

Epstein Barr virus (EBV) is a human herpes virus that infects 90% of the world's population and has been linked to the development of lymphoproliferative disorders (LPDs) and immunosuppression. Primary EBV infection in patients with IBD on thiopurines is a risk factor for LPD, including lymphoma. We aimed to describe EBV status in a pediatric population with IBD with an emphasis on those initiating thiopurines.. Electronic medical records and EBV serologies were reviewed and categorized into asymptomatic screening versus suspicion for acute infection. EBV status before therapy was described by sex, age, and therapeutic regimen. Descriptive statistics and univariate analysis were employed.. Only 150 (22%) of our 688 pediatric patients with IBD had documented EBV status regardless of age or treatment regimen. Only 17% were assessed for suspicion of acute infection and 83% for screening. Sixty-four (52%) screened patients were checked before starting any treatment and only 40% were immunoglobulin (Ig)G positive. There was no difference in mean age between the seronegative and seropositive group. The majority (63%) of thiopurine-treated patients were IgG negative before starting therapy. Eighty percent of primary EBV infections occurred on thiopurines at a mean (SD) of 2 ± 1.5 years after initiating therapy.. The majority of our pediatric patients with IBD with documented EBV status were IgG negative at thiopurine initiation. Thiopurines were also associated with primary EBV infection. EBV status may be an important determinate of whether physicians prescribe thiopurines given the risk of primary EBV infections and lymphoproliferative diseases.

Topics: Adolescent; Child; Cross-Sectional Studies; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Lymphoma; Male; Mercaptopurine; New York City; Retrospective Studies; Viral Load; Young Adult

The possibility of developing idiopathic portal hypertension has been described with thiopurine treatment despite compromises the prognosis of these patients, the fact its true prevalence is unknown.. A cross-sectional study was conducted in a cohort of inflammatory bowel disease (IBD) patients followed at our unit, to determine the prevalence of diagnosis of idiopathic portal hypertension (IPH) and its relationship with thiopurine treatment.. At the time of the analysis, 927/1,419 patients were under treatment with thiopurine drugs (65%). A total of 4 patients with IBD type Crohn's disease with idiopathic portal hypertension probably related to the thiopurine treatment were identified (incidence of 4.3 cases per 1,000). Seventy-five percent of patients started with signs or symptoms of portal hypertension. Only one patient was asymptomatic but the diagnosis of IPH because of isolated thrombocytopenia is suspected. However, note that all patients had thrombocytopenia previously. Abdominal ultrasound with fibroscan, hepatic vein catheterization and liver biopsy were performed on all of them as part of the etiology of portal hypertension. In the abdominal ultrasound, indirect portal hypertension data were observed in all patients (as splenomegaly) cirrhosis was also ruled out. The fibroscan data showed significant liver fibrosis (F2-F3).. Idiopathic portal hypertension following thiopurine treatment in IBD patients is a rare occurrence, but it must be borne in mind in the differential diagnosis for early diagnosis, especially in patients undergoing thiopurine treatment over a long period. The presence of thrombocytopenia is often the only predictor of its development in the preclinical stage.

Topics: Adult; Aged; Azathioprine; Cross-Sectional Studies; Female; Humans; Hypertension, Portal; Idiopathic Noncirrhotic Portal Hypertension; Immunosuppressive Agents; Inflammatory Bowel Diseases; Liver Cirrhosis; Male; Mercaptopurine; Middle Aged; Pancytopenia; Splenomegaly; Treatment Outcome

Topics: Antibodies, Monoclonal, Humanized; Azathioprine; Biomarkers; C-Reactive Protein; Drug Therapy, Combination; Hemoglobins; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Remission Induction; Tumor Necrosis Factor-alpha

The clinical use of azathioprine and 6-mercaptopurine is limited by their delayed onset of action and potential side effects such as myelosuppression and hepatotoxicity. As these drugs specifically target the Vav1/Rac1 signalling pathway in T lamina propria lymphocytes via their metabolite 6-thio-GTP, we studied expression and optimised suppression of this pathway in inflammatory bowel diseases [IBD].. Rac1 and Vav1 expressions were analysed in mucosal immune cells in IBD patients. Targeted molecular modelling of the 6-thio-GTP molecule was performed to optimise Rac1 blockade; 44 modified designer thiopurine-analogues were tested for apoptosis induction, potential toxicity, and immunosuppression. Activation of the Vav1/Rac1 pathway in lymphocytes was studied in IBD patients and in lamina propria immune cells in the presence or absence of thiopurine-analogues.. Several thiopurine-analogues induced significantly higher T cell apoptosis than 6-mercaptopurine. We identified a compound, denoted B-0N, based on its capacity to mediate earlier and stronger induction of T cell apoptosis than 6-mercaptopurine. B-0N-treatment resulted in accelerated inhibition of Rac1 activity in primary peripheral blood T cells as well as in intestinal lamina propria immune cells. Compared with 6-thio-GTP and 6-mercaptopurine, B-0N-treatment was associated with decreased myelo- and hepatotoxicity.. The Vav1/Rac1 pathway is activated in mucosal immune cells in IBD. The designer thiopurine-analogue B-0N induces immunosuppression more potently than 6-mercaptopurine.

Topics: Apoptosis; Biomarkers; Case-Control Studies; Designer Drugs; Drug Design; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Intestinal Mucosa; Mercaptopurine; Proto-Oncogene Proteins c-vav; rac1 GTP-Binding Protein; Signal Transduction; T-Lymphocytes

Thiopurines have been widely accepted as immunosuppressive therapy in inflammatory bowel disease. However, many patients have to discontinue thiopurines due to intolerance or ineffectiveness. A therapeutically beneficial effect of switching from azathioprine (AZA) to mercaptopurine (MP) after developing adverse events (AEs) has been reported. The authors assessed the clinical value of MP therapy after AZA discontinuation due to intolerance and, secondary, due to ineffectiveness.. In this retrospective single-center study, the authors analyzed data from patients in whom AZA therapy had failed and who were subsequently treated with MP.. Thirty-eight patients initiated MP therapy after intolerance to AZA. Intolerance reoccurred in 22 (58%) patients and the remaining 16 (42%) tolerated MP. In 18 out of 48 patients (38%), the AEs that led to discontinuation of MP were similar to those of AZA. A longer duration of prior AZA use was more common in patients who were subsequently tolerant for MP (5.3 versus 1.2 months; P = 0.04). Twenty-two patients discontinued AZA due to ineffectiveness. Eight (36%) patients had clinical benefit from a switch to MP. Six out of these 8 (75%) patients used allopurinol alongside MP, due to ineffectiveness based on a skewed thiopurine metabolism. Patients were more likely to have clinical benefit if the interval between both thiopurines was longer (4.4 versus 0.01 months; P < 0.05).. The authors showed that a noteworthy number of patients benefitted therapeutically from a switch from AZA to MP when failing due to intolerance or ineffectiveness; however, the percentage was lower than previously reported in literature.

Topics: Adolescent; Adult; Allopurinol; Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Retrospective Studies; Young Adult

Breast cancer recurrence may be promoted by immunosuppression due to decreased immune surveillance. The aim of this study was to examine the rates of breast cancer recurrence in patients with immune-mediated disease and treated breast cancer who received therapy with methotrexate, thiopurines, or anti-tumor necrosis factor (anti-TNF).. Three retrospective cohort studies within Medicare (2000-2012) included women with rheumatoid arthritis (RA) or inflammatory bowel disease (IBD) who underwent surgery for primary breast cancer. Recurrent or second primary breast cancers occurring more than 365 days after the initial surgery were identified. Separate Cox regression models were used to examine the risk of cancer recurrence in patients treated with methotrexate, thiopurines, or anti-TNF agents after surgery, each compared with no use. Analyses were matched for type of breast surgery and receipt and type of adjuvant therapy.. Across all medication groups, 107 women experienced breast cancer recurrence during 5,196 person-years. The incidence rates were 20.3 and 19.6 per 1,000 person-years in methotrexate users and nonusers, respectively, 32.3 and 17.6 in thiopurine users and nonusers, respectively, and 22.3 and 19.5 in anti-TNF users and nonusers, respectively. There was no significantly increased risk of breast cancer recurrence with use of methotrexate (adjusted hazard ratio [HR] 1.07, 95% confidence interval [95% CI] 0.67-1.69), anti-TNF therapy (HR 1.13, 95% CI 0.65-1.97), or thiopurines (HR 2.10, 95% CI 0.62-7.14).. The risk of breast cancer recurrence in patients who received methotrexate, thiopurine, or anti-TNF therapy was not statistically significantly increased, although we cannot rule out a 2-fold or greater increased risk in those treated with thiopurines. These data provide reassurance to clinicians choosing to start methotrexate or anti-TNF therapy in RA or IBD patients with treated breast cancer.

Topics: Adalimumab; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Azathioprine; Breast Neoplasms; Cohort Studies; Etanercept; Female; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Infliximab; Medicare; Mercaptopurine; Methotrexate; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Proportional Hazards Models; Retrospective Studies; Risk Factors; Tumor Necrosis Factor-alpha; United States

Thiopurine methyltransferase (TPMT) and inosine triphosphatase (ITPA) are crucial enzymes involved in the metabolism of thiopurine drugs: azathioprine and 6-mercaptopurine, used in the treatment of leukemia or inflammatory bowel diseases (IBD). The activity in these enzymes correlates with the genetic polymorphism of the TPMT and ITPA genes, respectively, which determines an individual reaction and dosing of thiopurines. Three main TPMT alleles: TPMT*2 (c.238G>C), TPMT*3A (c.460G>A, c.719A>G) and TPMT*3C (c.719A>G) account for 80-95 % of inherited TPMT deficiency in different populations in the world. In the ITPA gene, a c.94C>A mutation is significantly associated with an adverse thiopurine reaction. The aim of this study was to develop a quick and highly sensitive method for determining major TPMT and ITPA alleles. Here we present the molecular test for genotyping c.238G>C, c.460G>A, c.719A>G and c.94C>A changes based on multiplex high resolution melting analysis (HRMA). We analyzed DNA samples from 100 clinically diagnosed IBD patients treated with thiopurine drugs, and a known genotype in the positions 238, 460 and 719 of the TPMT gene as well as in position 94 of the ITPA gene. Our results obtained with multiplex HRMA indicated 100 % accuracy in comparison with data from restriction fragments length polymorphism (RFLP) and standard DNA sequencing. We conclude, that multiplex HRMA can be used as a quick, sensitive and efficient alternative diagnostic method compared to conventional techniques for the determination of TPMT*2, TPMT*3A and TPMT*3C alleles and c.94C>A change in the ITPA gene.

Topics: Alleles; Azathioprine; Gene Frequency; Genotype; Genotyping Techniques; Humans; Inflammatory Bowel Diseases; Inosine Triphosphatase; Mercaptopurine; Methyltransferases; Nucleic Acid Amplification Techniques; Pharmacogenomic Testing; Pyrophosphatases

Topics: Anti-Inflammatory Agents; Azathioprine; Gastrointestinal Agents; Genotype; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Pharmacogenetics; Pharmacogenomic Variants; Phenotype; Pyrophosphatases

Previous data on inflammatory bowel disease (IBD) relapse during pregnancy mainly originate from retrospective studies. The aim of this study was therefore (i) to evaluate the effect of active disease at conception and IBD disease type on disease relapse during pregnancy and (ii) to study the effects of disease relapse during pregnancy on birth outcomes in a prospective cohort with adequate representation of current treatments.. From 2008 to 2014, IBD women were recruited from an ongoing prospective clinical cohort. All patients with confirmed IBD diagnosis with a pregnancy wish or pregnancy were prospectively followed-up until pregnancy and delivery. Disease relapse was measured at each visit. Birth outcomes were recorded from the obstetrician.. A total of 298 pregnancies were observed in 229 IBD patients (157 Crohn's disease (CD), 66 ulcerative colitis (UC), and 6 IBD unclassified), resulting in 226 live births. Active disease at conception was strongly associated with disease relapse during pregnancy (aOR=7.66, 95% confidence interval (CI): 3.77-15.54). UC patients experienced relapse during pregnancy more often than CD patients, independent of maternal age, smoking, periconceptional disease activity, previous IBD surgery, and the use of immunosuppressives or anti-tumor necrosis factor (TNF) (aOR=3.71, 95% CI:1.86-7.40). Disease relapse was not associated with adverse birth outcomes such as spontaneous abortion, low-birth weight, or preterm birth.. This study confirms that active disease around conception increases the risk of disease relapse during pregnancy. In addition, UC patients relapse more often during pregnancy than CD patients. Birth outcomes were excellent, reflecting the stringent follow-up and treatment of this group of patients.

Topics: Abortion, Spontaneous; Adult; Anti-Inflammatory Agents, Non-Steroidal; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Infant, Low Birth Weight; Infant, Newborn; Inflammatory Bowel Diseases; Maintenance Chemotherapy; Mercaptopurine; Mesalamine; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Premature Birth; Prospective Studies; Recurrence; Tumor Necrosis Factor-alpha

Adverse reactions and non-response are common in patients treated with thiopurine drugs. Current monitoring of drug metabolite levels for guiding treatment are limited to analysis of thioguanine nucleotides (TGNs) in erythrocytes after chemical derivatisation. Erythrocytes are not the target tissue and TGN levels show poor correlations with clinical response. We have developed a sensitive assay to quantify deoxythioguanosine (dTG) without derivatisation in the DNA of nucleated blood cells. Using liquid chromatography and detection by tandem mass spectrometry, an intra- and inter-assay variability below 7.8% and 17.0% respectively were achieved. The assay had a detection limit of 0.0003125ng (1.1 femtomoles) dTG and was quantified in DNA samples relative to endogenous deoxyadenosine (dA) in a small group of 20 patients with inflammatory bowel disease, all of whom had been established on azathioprine (AZA) therapy for more than 25 weeks. These patients had dTG levels of 20-1360mol dTG/10(6)mol dA; three patients who had not started therapy had no detectable dTG. This method, comparable to previous methods in sensitivity, enables the direct detection of a cytotoxic thiopurine metabolite without derivatisation in an easily obtainable, stable sample and will facilitate a better understanding of the mechanisms of action of these inexpensive yet effective drugs.

Topics: Blood Cells; Chromatography, Liquid; Deoxyguanosine; DNA; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Tandem Mass Spectrometry; Thionucleosides

Few studies exist on the frequency of thiopurine methyltransferase (TPMT) mutation in patients from Southern Europe. We aimed to evaluate the frequency of TPMT mutation in a homogeneous Sicilian cohort of patients with inflammatory bowel disease (IBD), autoimmune and hematological disorders, the rate of thiopurine-related adverse events, and its association with the TPMT genotype.. Among 105 patients with IBD, 45 with autoimmune disease, and 34 with hematologic diseases, the homozygous TPMT variant genotype was found in one patient only (0.5%), while the heterozygous TPMT genotype was identified in 8 patients (4.3%). In patients with IBD, leukopenia was observed in ten patients: one had the homozygous TPMT genotype, one the heterozygous genotype, and the remaining eight the wild type genotype.. The frequency of TPMT mutation in a Mediterranean area was low. TPMT genotyping is not a sensitive tool for predicting thiopurine-induced leukopenia.

Topics: Adult; Autoimmune Diseases; Azathioprine; Female; Hematologic Diseases; Heterozygote; Homozygote; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Italy; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Mutation; Phenotype; Polymorphism, Genetic

To analyze the cellular immune response towards microsatellite-instability (MSI)-induced frameshift-peptides (FSPs) in patients suffering from inflammatory bowel disease (IBD) with and without thiopurine-based immunosuppressive treatment.. Frequencies of peripheral blood T cell responses of IBD patients (n = 75) against FSPs derived from 14 microsatellite-containing candidate genes were quantified by interferon-γ enzyme-linked immunospot. T cells derived from 20 healthy individuals served as controls.. Significant T cell reactivities against MSI-induced FSPs were observed in 59 of 75 IBD patients (78.7%). This was significantly more as we could observe in 20 healthy controls (P = 0.001). Overall, the reactivity was significantly influenced by thiopurine treatment (P = 0.032) and duration of disease (P = 0.002) but not by duration or cumulative amount of thiopurine therapy (P = 0.476). Unexpected, 15 of 24 (62.5%) IBD patients without prior thiopurine treatment also showed increased FSP-specific immune responses (P = 0.001).. These findings propose FSPs as potential novel class of inflammation-associated antigens and this in turn may have implications for screening, diagnosis as well as clinical management of patients suffering from IBD and other inflammatory conditions.

Topics: Adult; Aged; Aged, 80 and over; Autoantigens; Case-Control Studies; Female; Frameshift Mutation; Genetic Markers; Genetic Predisposition to Disease; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Microsatellite Instability; Middle Aged; Phenotype; T-Lymphocytes; Time Factors; Treatment Outcome; Young Adult

Anti-tumor necrosis factor (anti-TNF) agents are widely used to treat patients with moderate-to-severe inflammatory bowel disease (IBD). We aimed to identify the risk factors for adverse skin lesions in patients with IBD receiving anti-TNF agents and assess the effect of concomitant use of azathioprine/6-mercaptopurine (AZA/6 MP).. A total of 500 patients (404 with Crohn's disease, 96 with ulcerative colitis) who received anti-TNF agents between June 2002 and July 2013 were identified and retrospectively investigated. We compared 47 patients with IBD with skin lesions with 443 patients with IBD without skin lesions to identify risk factors by univariate and multivariate analysis. The Kaplan-Meier method was used to estimate the cumulative incidence of adverse skin lesions in relation to the concomitant use of AZA/6 MP.. Eczematiform eruptions (n = 18, 38%) were the most common skin lesion type, followed by psoriasiform lesions (n = 13, 28%). A response to topical steroids was seen in 70% (33/47) of patients with skin lesions, and anti-TNF agents had to be discontinued in 9% (4/47). Concomitant use of AZA/6 MP decreased the risk of skin lesions in univariate (hazard ratio, 0.452; 95% CI, 0.251-0.814; P = 0.008) and multivariate (hazard ratio, 0.437; 95% CI, 0.242-0.790; P = 0.006) analysis. In addition, the cumulative incidence of adverse skin lesions was lower in patients on concomitant maintenance with AZA/6 MP (P = 0.009) than in those on anti-TNF monotherapy.. Concomitant use of AZA/6 MP may decrease the occurrence of adverse skin lesions in patients receiving anti-TNF therapy.

Topics: Adolescent; Adult; Aged; Azathioprine; Body Mass Index; Colitis, Ulcerative; Crohn Disease; Drug Eruptions; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Psoriasis; Retrospective Studies; Risk Factors; Smoking; Th1 Cells; Th17 Cells; Tumor Necrosis Factor-alpha; Young Adult

Thiopurines are extensively used immunosuppressants for the treatment of inflammatory bowel disease (IBD). The polymorphism of thiopurine S-methyltransferase (TPMT) influences thiopurine metabolism and therapy outcome. We used a TPMT knockdown (kd) model of human Jurkat T-lymphocytes cells to study the effects of treatment with 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) on proteome and phosphoproteome. We identified thirteen proteins with altered expression and nine proteins with altered phosphorylation signals. Three proteins (THIO, TXD17, and GSTM3) with putative functions in cellular oxidative stress responses were altered by 6-TG treatment and another protein PRDX3 was differentially phosphorylated in TPMT kd cells. Furthermore, reactive oxygen species (ROS) assay results were consistent with a significant induction of oxidative stress by both TPMT knockdown and thiopurine treatments. Immunoblot analyses showed treatment altered expression of key antioxidant enzymes (i.e., SOD2 and catalase) in both wt and kd groups, while SOD1 was downregulated by 6-TG treatment and TPMT knockdown. Collectively, increased oxidative stress might be a mechanism involved in thiopurine induced cytotoxicity and adverse effects (i.e., hepatotoxicity) and an antioxidant cotherapy might help to combat this. Results highlight the significance of oxidative stress in thiopurines' actions and could have important implications for the treatment of IBD patients.

Topics: Humans; Inflammatory Bowel Diseases; Jurkat Cells; Mercaptopurine; Methyltransferases; Oxidative Stress; Phosphorylation; Proteomics; T-Lymphocytes; Thioguanine

Thiopurines are effective for maintenance of remission in inflammatory bowel disease (IBD) in only about half of patients. Predictors of response may assist in selecting the most appropriate patients for thiopurine therapy. Thiopurines inhibit Rac1, a GTPase that exerts an antiapoptotic effect on T-lymphocytes. A genetic association was recently demonstrated between a Rac1 single nucleotide polymorphism (SNP) and poorer response to thiopurines in adult patients with Crohn disease. We aimed to determine whether Rac1 SNPs are associated with response to thiopurines in children with IBD.. Children with IBD treated with thiopurines were prospectively followed for 1 year and were genotyped for 3 Rac1 SNPs previously found to be relevant to IBD: rs10951982, rs4720672, and rs34932801. The rate of sustained steroid-free remission (SSFR) without treatment escalation by 12 months was compared between wild types (WTs) and heterozygotes.. A total of 59 patients were studied (63% boys, 80% having Crohn disease, mean age 13 ± 4.1). Nineteen of the 41 WT (46%) and 9 of the 15 (60%) heterozygotes for rs10951982 were in SSFR (P = 0.55). Similarly, 21 of the 45 (47%) WT and 8 of the 12 (67%) heterozygotes for rs4720672 were in remission (P = 0.33). Finally, 21 of the 45 (47%) WT and 3 of the 5 (60%) heterozygotes for rs34932801 were in remission (P = 0.66). All of the 3 comparisons remained nonsignificant in a sensitivity analysis of only the patients with Crohn disease.. We did not find an association between 3 Rac1 SNPs and thiopurine effectiveness by 12 months in a prospective study of children with IBD. Other predictors of response should be sought to optimize patient selection for thiopurine therapy.

Topics: Adolescent; Azathioprine; Child; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Drug Resistance; Enzyme Inhibitors; Female; Genetic Association Studies; Heterozygote; Homozygote; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Israel; Longitudinal Studies; Male; Mercaptopurine; Polymorphism, Single Nucleotide; rac1 GTP-Binding Protein; Remission Induction

Thiopurines are an effective treatment for moderate to severe inflammatory bowel disease [IBD] and can be used safely in pregnancy. Combining allopurinol with a lower dose of thiopurine can improve clinical efficacy and bypass some adverse reactions associated with thiopurine monotherapy. Data on allopurinol in pregnancy are scarce. We report on a total of 13 cases where thiopurine and allopurinol co-therapy was used successfully to manage IBD during pregnancy without attributable adverse fetal effects.. Patients were retrospectively identified at our two hospitals, one in the UK and one in Australia, using local IBD databases. Data regarding pregnancy and fetal outcomes including in utero fetal ultrasound scans, APGAR scores, fetal birthweights and neonate checks were collected from patient notes.. We identified 12 women with a total of 13 pregnancies treated with co-therapy before conception and for the duration of pregnancy. There were no miscarriages or spontaneous pre-term deliveries. There were 14 live births [seven vaginal deliveries; six caesarean sections]. Except for a primagravid twin pregnancy complicated by pre-eclampsia and twin-to-twin transfusion syndrome requiring caesarean section at 25 weeks, there were no low birthweight [< 2.5 kg] babies born and the APGAR scores of all babies were normal. No congenital malformations were identified.. Adverse pregnancy outcomes attributable to thiopurine and allopurinol co-therapy were not detected in our case series. Our study provides reassurance for clinicians and patients who wish to continue the thiopurine-allopurinol co-therapy combination before conception and during pregnancy to maintain remission of IBD.

Topics: Adult; Allopurinol; Azathioprine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Retrospective Studies; Treatment Outcome

An association between inflammatory bowel disease (IBD) and cardiovascular diseases has been shown in multiple studies. However, little is known about the effect of IBD-related characteristics on cardiovascular events.. The authors conducted a retrospective, nested case-control study of IBD patients who presented to the institution from 2000 to 2004, allowing for a 10-year follow-up period. One hundred eleven patients who developed cardiovascular events (cases) and 222 patients who did not develop cardiovascular events (cases) were included in the study after matching for Framingham cardiovascular risk score (2008). Relationships between predictor variables and cardiovascular outcome were assessed by conditional logistic regression.. The cases and controls were similar in age, gender, smoking and cholesterol level. There was no difference in disease subtype (ulcerative colitis or Crohn's disease). On conditional logistic regression, thiopurine treatment (odds ratio [OR]: 0.42, 95% confidence interval [CI]: 0.19-0.87; P = 0.02) was associated with decreased cardiovascular events and tumor necrosis factor alpha antagonist use (OR: 2.63, 95% CI: 1.49-4.63; P = 0.001) was associated with increased cardiovascular events. Although not statistically significant, disease-related surgery (OR: 0.57, 95% CI: 0.32-1.02; P = 0.06) was associated with decreased cardiovascular events and disease-related hospitalization (OR: 1.58, 95% CI: 0.96-2.57; P = 0.07) was associated with increased incidence of cardiovascular disorders.. The authors observed decreased incidence of cardiovascular diseases in patients with IBD who were treated with thiopurines and increased incidence of cardiovascular outcomes among patients treated with tumor necrosis factor alpha antagonist.

Topics: Adult; Aged; Anti-Inflammatory Agents; Azathioprine; Cardiovascular Diseases; Case-Control Studies; Female; Humans; Incidence; Inflammatory Bowel Diseases; Logistic Models; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Risk Assessment; Tumor Necrosis Factor-alpha

Concerns persist about the risk of major congenital anomalies in children of women with inflammatory bowel disease (IBD), and whether medication use affects risk. We assessed these risks, and variations in use of medications by women with IBD before, during, and after pregnancy.. We accessed data on children born to women 15-45 y old from 1990 through 2010, using a mother-child linked dataset from an electronic database of primary care records containing medical diagnoses, events, and drug prescriptions from across the United Kingdom. We identified pregnant women with IBD, and all prescriptions for 5-aminosalicylates azathioprine/6-mercaptopurine, and corticosteroids were extracted from their primary care records. We calculated risks of major congenital anomaly in children of mothers with and without IBD, and in children exposed or not exposed to 5-aminosalicylates, azathioprine/6-mercaptopurine, or corticosteroids during their first trimester of fetal development. Logistic regression with a generalized estimating equation was used to provide risk estimates adjusted for confounders. We calculated proportions of women taking medications before, during, and after pregnancy and assessed whether cessation was associated with subsequent disease flares.. Risks of a major congenital anomaly in 1703 children of mothers with IBD and 384,811 children of mothers without IBD were 2.7% and 2.8%, respectively. This corresponded to an adjusted odds ratio of 0.98 (95% confidence interval [CI], 0.73-1.31). In children of women with IBD, the adjusted odds ratios of a major congenital anomaly associated with drug use were 0.82 (95% CI, 0.42-1.61) for 5-aminosalicylates 0.48 (95% CI, 0.15-1.50) for corticosteroids, and 1.27 (95% CI, 0.48-3.39) for azathioprine/6-mercaptopurine. No increases in heart, limb, or genital anomalies were found in children of women with IBD; 31.2% of women discontinued 5-aminosalicylates and 24.6% discontinued azathioprine/6-mercaptopurine in early pregnancy. The risk of flares later in pregnancy was not related to cessation of medication.. We found no evidence that IBD during pregnancy or medical therapy for IBD during pregnancy increases the risk of a major congenital anomaly in children. Patients should receive appropriate guidance on use of medication before and during pregnancy.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aminosalicylic Acids; Azathioprine; Congenital Abnormalities; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Logistic Models; Mercaptopurine; Mesalamine; Middle Aged; Odds Ratio; Pregnancy; Pregnancy Complications; Retrospective Studies; Risk Factors; Severity of Illness Index; United Kingdom; Young Adult

Individuals with decreased thiopurine methyltransferase (TPMT) activity are at risk of adverse effects of thiopurine administration whereas its increased activity may inactivate drugs faster. We evaluated genotype-phenotype correlations in patients with suspected hematological malignancies and inflammatory bowel disease from our region based on findings of nonlinear TPMT enzyme kinetics previously unreported.. The study group comprised 267 individuals. They were screened for the most common variants of low TPMT activity. TPMT activity was measured in erythrocytes using the HPLC rate-blanked method.. Thirty-three patients (12.4%) were heterozygous (26 were TPMT*1/*3A, 5 TPMT*1/*2, 2 TPMT *1/*3C) and 1 was a compound heterozygote (*2/*3A). Normal and low normal TPMT activities substantially overlapped in wild-type and heterozygous individuals, whereas high activities were found in 29 wild-type genotyped patients. Extreme and life-threatening toxicity was observed in the compound heterozygote patient.. Activity measurement performed at diagnosis provides clinicians with information on immediate pharmacokinetic-related adverse events and/or hypermetabolism, and genotyping may indicate the rate of pharmacodynamic thioguanine nucleotide accumulation due to slower overall thiopurine metabolism.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Chromatography, High Pressure Liquid; Cyclophosphamide; Cytarabine; Czech Republic; Daunorubicin; Erythrocyte Membrane; Female; Genetic Association Studies; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methotrexate; Methyltransferases; Polymerase Chain Reaction; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Slovakia; Vincristine

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

The aim of this study is to evaluate the cumulative probability of recurrence and admission rates in an inflammatory bowel disease (IBD) inception cohort diagnosed in 2003-2004.. Data on medications, phenotypes and surgery for 513 individuals with ulcerative colitis (UC, n=300) and Crohn's disease (CD, n=213) were obtained from medical records and linked to population-based health administrative database information. The admission rates and cumulative probability of recurrences were estimated, and the association with the baseline factors and medication was tested.. The cumulative risk of first recurrence after 1, 5 and 7 years was 40%, 63%, and 66% in CD patients and 51%, 75%, and 79% in UC patients, respectively. The cumulative risk of first surgical relapse was 6%, 18%, and 23% at 1, 5 and 7 years in CD respectively. One hundred and CD patients (66%) and 142 UC patients (47%) had at least one IBD-related hospitalisation. The hospitalisation rate decreased from 7.0 days/person-year in year one to 0.9 day at year 5 in CD, and from 4.7 days to 0.4 days for UC patients. Age above 40, current smoking, stricturing behaviour, and disease localisation (colonic, ileocolonic, and upper-GI) at diagnosis were predictors of recurrence in CD. In UC, age above 40 and former smoker status were predictors of recurrence and left-sided and extensive colitis were predictors of first-time hospitalisation.. In an era of improved treatment options, the recurrence rates, but not the surgery or hospitalisation rates, have decreased for CD but not for UC. The phenotypic characteristics at diagnosis predict the risk of recurrence and hospitalisation.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Azathioprine; Child; Child, Preschool; Cohort Studies; Colectomy; Constriction, Pathologic; Denmark; Female; Follow-Up Studies; Hospitalization; Humans; Immunosuppressive Agents; Infant; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Recurrence; Risk Factors; Smoking; Tumor Necrosis Factor-alpha; 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

The thiopurines are widely used in the treatment of inflammatory bowel disease, but are limited by poor dose-effect relationship. The objective was to assess the ability of a novel assay, determining the mono-, di-, and triphosphates, of thioguanine as well as methylthioinosine as individual metabolites in erythrocytes, to predict clinical outcome compared to a routine assay, determining metabolites as sums.. Samples from 79 patients with Crohn's disease or ulcerative colitis treated with azathioprine or mercaptopurine were analysed by both assays. Clinical status was determined by the Harvey-Bradshaw and Walmsley indices. The genotypes of thiopurine methyltransferase (TPMT) and inosine triphosphatase were determined.. TPMT wild-type patients with thioguanine nucleotide (TGN) levels below the cut-off level were more likely to have active disease when TGN was measured by the novel assay (p=0.02), and when thioguanosine triphosphate (TGTP) was measured separately (p=0.01). When TGN was measured by the routine assay the correlation was not evident (p=0.12). Neither TGN levels nor TGTP correlated to disease activity in TPMT deficient patients. Patients with methyl thioinosine nucleotide (meTIN) levels above 1500 pmol/8×10^8 RBCs were more likely to have active disease (p=0.07). We observed good correlations between the mono-, di-, and triphosphates and their respective sums (R(2)>0.88).. The novel TGN assay was better in predicting clinical outcome compared to the routine assay, while determination of TGTP had no clinical advantage and TGTP ratio was not correlated to disease activity.

Topics: Adolescent; Adult; Aged; Azathioprine; Cross-Sectional Studies; Drug Monitoring; Erythrocytes; Female; GTP Phosphohydrolases; Guanine Nucleotides; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methylthioinosine; Middle Aged; Thioguanine; Thioinosine; Thionucleotides; Young Adult

The drug-metabolizing enzyme thiopurine methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors' articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (G>A) from TPMT*24 to TPMT*30 and position 611 (T>C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged.

Topics: Alleles; Azathioprine; Genotype; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Pharmacogenetics; Polymorphism, Genetic; Thioguanine

Inflammatory bowel disease affects women in their peak reproductive years. Increased disease activity during pregnancy has been associated with adverse outcomes. Thus, it is recommended that immunosuppressant medications be continued during pregnancy. However, data regarding the safety of these medications during pregnancy are sparse and often conflicting. The study by Casanova et al. (1) adds to the growing evidence that the use of thiopurines and anti-TNFα agents during pregnancy does not increase the risk of birth defects. Results from prospective studies with longer follow-up are needed to fully understand the impact of thiopurines and anti-TNFα agents on child development and maturation of the immune system.

Topics: Antibodies, Monoclonal; Azathioprine; Female; Humans; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Pregnancy; Pregnancy Complications; Tumor Necrosis Factor-alpha

Previous studies have reported no or only a very poor correlation between 6-methylmercaptopurine/6-thioguanine nucleotide (6-MeMPN/6-TGN) and azathioprine (AZA) dose in the treatment of inflammatory bowel disease (IBD). However, metabolite levels are often repeatedly measured yielding a hierarchical data structure that requires more appropriate data analysis.. This study explored the relationship between the weight-based dosage of AZA and metabolites levels in 86 pediatric IBD patients using multilevel analysis. Other covariates related to patient characteristics and treatment were evaluated.. This is the first study to demonstrate positive correlations between AZA dose and 6-TGN and 6-MeMPN levels and 6-MeMPN/6-TGN ratio (P < 0.001) in IBD children. Other novel predictors of metabolites were reported. Younger children exhibited lower 6-TGN and 6-MeMPN levels, probably suggesting age-related differences in metabolism and/or absorption of thiopurines. Coadministration of infliximab resulted in a significant increase in 6-TGN levels (P = 0.023). Moreover, alanine aminotransferase values positively correlated with 6-MeMPN levels (P = 0.032). The duration of AZA therapy, gender, and thiopurine methyltransferase activity were associated with metabolite levels. The wide interindividual variability in metabolite levels that accounted for 67.7%, 48.6%, and 49.4% of variance in the 6-TGN and 6-MeMPN levels and the ratio, respectively, were confirmed.. The reliable AZA dose-metabolites relationship is useful for clinicians to guide the dosing regimen to maximize clinical response and minimize side effects or to consider alternative therapies when patients have preferential production of the toxic 6-MeMPN. These results may be of potential interest for optimizing thiopurine therapy to achieve safe and efficacious AZA use in pediatric IBD patients.

Topics: Adolescent; Age Factors; Azathioprine; Child; Dose-Response Relationship, Drug; Female; Guanine Nucleotides; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Multilevel Analysis; Retrospective Studies; Thionucleotides

Inflammatory bowel disease (IBD) affects a substantial number of female patients in their reproductive years. Therefore, many physicians face the dilemma whether thiopurines, prescribed to maintain remission, can be taken safely during pregnancy. Data on long-term development outcome of children exposed to maternal thiopurine therapy are very limited.. To assess the long-term effects of in utero exposure to thiopurines during pregnancy on infant health status.. A prospective multicentre follow-up study was performed in children exposed intrauterine to maternal thiopurine therapy. Physical, cognitive and social aspects of infant health status were assessed with the 43-item TNO-AZL Preschool Children Quality of Life Questionnaire (TAPQOL). Furthermore, information on visits to general practitioner and medical specialists, and physician's advice regarding lactation was evaluated. Data were compared with normative data from a control group consisting of 340 children.. Thirty children were included in this study [median 3.8 years (IQR 2.9-4.7)]. No differences on global medical and psychosocial health status were found between children exposed to intrauterine thiopurines and the reference group. Exposure to intrauterine thiopurines was not associated with increased susceptibility to infection or immunodeficiency in childhood. Twenty-one of 30 children were exclusively formula-fed based on a negative advice of medical specialists directed at thiopurine use during lactation.. Thiopurine use during pregnancy did not affect long-term development or immune function of children up to 6 years of age. Our results underscore the present notion that mothers, even those using thiopurines, should be encouraged to breastfeed their infants.

Topics: Adult; Breast Feeding; Case-Control Studies; Child; Child, Preschool; Female; Follow-Up Studies; Health Status; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Pregnancy; Prenatal Exposure Delayed Effects; Prospective Studies; Quality of Life; Surveys and Questionnaires; Time Factors

Up to 1/5 of patients with wildtype thiopurine-S-methyltransferase (TPMT) activity prescribed azathioprine (AZA) or mercaptopurine (MP) demonstrate a skewed drug metabolism in which MP is preferentially methylated to yield methylmercaptopurine (MeMP). This is known as thiopurine hypermethylation and is associated with drug toxicity and treatment non-response. Co-prescription of allopurinol with low dose AZA/MP (25-33%) circumvents this phenotype and leads to a dramatic reduction in methylated metabolites; however, the biochemical mechanism remains unclear. Using intact and lysate red cell models we propose a novel pathway of allopurinol mediated TPMT inhibition, through the production of thioxanthine (TX, 2-hydroxymercaptopurine). In red blood cells pre-incubated with 250 μM MP for 2h prior to the addition of 250 μM TX or an equivalent volume of Earle's balanced salt solution, there was a significant reduction in the concentration of MeMP detected at 4h and 6h in cells exposed to TX (4 h, 1.68, p=0.0005, t-test). TX acts as a direct TPMT inhibitor with an apparent Ki of 0.329 mM. In addition we have confirmed that the mechanism is relevant to in vivo metabolism by demonstrating raised urinary TX levels in patients receiving combination therapy. We conclude that the formation of TX in patients receiving combination therapy with AZA/MP and allopurinol, likely explains the significant reduction of methylated metabolites due to direct TPMT inhibition.

Topics: Adult; Allopurinol; Azathioprine; Case-Control Studies; Drug Therapy, Combination; Erythrocytes; Female; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Oxypurinol; Prospective Studies; Xanthines

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

Few data on azathioprine (AZA) therapy for inflammatory bowel disease (IBD) exist for children. We evaluated whether the 6-thioguanine nucleotides (6-TGN) level predicts AZA refractoriness in children with IBD and whether children benefit an AZA dose escalation. Seventy-eight children with IBD initially treated with an AZA dose of 1.5-2.5 mg/kg/day were retrospectively included. The dose was adjusted based on the clinical status. The receiver operating characteristic curve and logistic regression were used to determine predictors for AZA resistance. Initially, 18 of 40 (45%) patients receiving a dose of <2 mg/kg/day and 11 of 38 (28.9%) patients receiving a dose of 2-2.5 mg/kg/day achieved remission. The 6-TGN level above 250 pmol/8.10(8) RBCs was associated with a higher remission rate, though non-significant. Among 35 patients with a dose escalation due to treatment failure, 12 (34.3%) achieved remission (the median 6-TGN level increased from 260 to 394 pmol/8.10(8) RBCs [P = .002]), 23 (67.6%) were AZA refractory. A 6-TGN level above 405 pmol/8.10(8) RBCs was the only predictor for AZA resistance (sensitivity 78.3%, specificity 75%, OR 10.8 [95% CI: 2.1-55.7, P = .004]). Serial metabolite monitoring is useful to identify children with IBD resistant to AZA. Children who cannot achieve remission despite a 6-TGN level above 405 pmol/8.10(8) RBCs should receive alternative therapies than dose increase.

Topics: Adolescent; Antimetabolites; Azathioprine; Child; Child, Preschool; Drug Resistance; Female; Humans; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Thioguanine

We aimed to determine the prevalence of chronic and past hepatitis B virus (HBV) infection in Chinese patients with inflammatory bowel disease (IBD), and to determine the risk factors associated with having received no vaccination for HBV and abnormal liver function among our patients.. The prevalence of chronic or past infection with HBV infection and effective HBV vaccination were determined in patients with IBD who attended the IBD Clinic of the Queen Mary Hospital in Hong Kong, China. Risk factors associated with the absence of HBV vaccination and abnormal liver function were identified.. A total of 267 Chinese IBD patients (166 ulcerative colitis and 101 Crohn's disease) were enrolled. The mean follow-up period was 10.5 years. Chronic and past HBV infection was detected in 6.7% and 28.5% patients, respectively. Altogether 102 patients lacked effective HBV vaccination. Multivariate analysis found that elder age at diagnosis of IBD (OR 1.02, 95% CI 1.00-0.94) and the absence of using thiopurine (OR 0.53, 95% CI 0.29-0.94) were associated with the presence of anti-HBs. Abnormal liver function was detected in 27 (10.1%) patients. The use of anti-tumor necrosis factor agents (OR 4.6, 95% CI 1.3-16.0), previous bowel resection (OR 3.7, 95% CI 1.5-9.2) and male gender (OR 4.4, 95% CI 1.4-13.7) were significant risk factors for abnormal liver function.. The use of thiopurine and younger age at diagnosis were associated with no vaccination against HBV in Chinese IBD patients. Chronic or past HBV infection was, however, not associated with abnormal liver function in these patients.

Topics: Adult; Age Factors; Aged; Alanine Transaminase; Female; Follow-Up Studies; Hepatitis B Antibodies; Hepatitis B Surface Antigens; Hepatitis B Vaccines; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Liver; Male; Mercaptopurine; Middle Aged; Risk Factors; Vaccination

Adherence of the patients with inflammatory bowel diseases is important to maintain the remission. However, the patients do not always keep their appointments for treatment. The aim of this study was to investigate the clinical factors associated with adherence of patients in terms of appointment keeping.. A total of 73 subjects were retrospectively investigated from September 2005 to January 2012 at Dongguk University Ilsan Hospital (Goyang, Korea). We reviewed medical records including the age, sex, residence, medications, the disease activity, and the rate of keeping the date. A punctual visit was defined as outpatient visit on the scheduled date ±7 days. Punctual patients for the visit were defined as their punctual visit rates exceed 90%.. Male to female ratio was 2.4:1. Mean age was 41.5±15.4 years (range, 20 to 78 years). Ulcerative colitis was 53 cases (72.6%) and Crohn's disease was 20 cases (27.4%). Mean duration of disease was 42.0±41.6 months (range, 4 to 226 months). Mean puntual visit rate was 86.7±16.0% (range, 27 to 100). Thirty-eight patients (52.1%) were punctual patients for the visit. Azathioprine/6-mercaptopurine treatment was associated with punctual patients for the visit (odd ratio, 3.19; 95% confidence interval, 1.12 to 9.09; p=0.03). However, other clinical factors did not influence the punctual visit rates.. Our study demonstrated that the use of azathioprine/6-mercaptopurine was associated with keeping the appointment for meeting the doctor. Further prospective study would be necessary.

Topics: Adult; Age Factors; Aged; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Demography; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Male; Mercaptopurine; Middle Aged; Patient Compliance; Retrospective Studies; Severity of Illness Index; Sex Factors

To investigate the incidence of neoplasms in inflammatory bowel disease (IBD) patients and the potential causative role of thiopurines.. We performed an observational descriptive study comparing the incidence of malignancies in IBD patients treated with thiopurines and patients not treated with these drugs. We included 812 patients which were divided in two groups depending on whether they have received thiopurines or not. We have studied basal characteristics of both groups (age when the disease was diagnosed, sex, type of IBD, etc.) and treatments received (Azathioprine, mercaptopurine, infliximab, adalimumab or other immunomodulators), as well as neoplasms incidence. Univariate analysis was performed with the student t test, χ(2) test or Wilcoxon exact test as appropriate. A logistic regression analysis was performed as multivariate analysis. Statistical significance was establish at P values of less than 0.05, and 95%CI were used for the odds ratios.. Among 812 patients included, 429 (52.83%) have received thiopurines: 79.5% azathioprine, 14% mercaptopurine and 6.5% both drugs. 44.76% of patients treated with thiopurines and 46, 48% of patients who did not receive this treatment were women (P > 0.05). The proportion of ulcerative colitis patients treated with thiopurines was 30.3% compare to 66. 67% of patients not treated (P < 0.001). Mean azathioprine dose was 123.79 ± 36.5 mg/d (range: 50-250 mg/d), mean usage time was 72.16 ± 55.7 mo (range: 1-300 mo) and the accumulated dose along this time was 274.32 ± 233.5 g (1.5-1350 g). With respect to mercaptopurine, mean dose was 74.7 ± 23.9 mg/d (range: 25-150 mg/d), mean usage time of 23.37 ± 27.6 mo (range: 1-118 mo), and the accumulated dose along this time was 52.2 ± 63.5 g (range: 1.5-243 g). Thiopurine S-methyltransferase activity was tested in 66% of patients treated with thiopurines, among which 98.2% had an intermediate or high activity. Among the patients treated with thiopurines, 27.27% (112 patients) and 11.66% (50 patients) received treatment with Infliximab and Adalimumab respectively, but only 1.83% (7 patients) and 0.78% (3 patients) received these drugs in the group of patients who did not received thiopurines (P < 0.001 and P < 0.001 respectively). Finally, 6.8% (29 patients) among those treated with thiopurines have received other immunosuppressants (Methotrexate, Tacrolimus, Cyclosporin), compare to 1% (4 patients) of patients not treated with thiopurines (P < 0.001). Among patients treated with thiopurines, 3.97% developed a malignancy, and among those not treated neoplasms presented in 8.1% (P = 0.013). The most frequent neoplasms were colorectal ones (12 cases in patients not treated with thiopurines but none in treated, P < 0.001) followed by non-melanoma skin cancer (8 patients in treated with thiopurines and 6 in not treated, P > 0.05).. In our experience, thiopurine therapy did not increase malignancies development in IBD patients, and was an effective and safe treatment for these diseases.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Azathioprine; Chi-Square Distribution; Child; Child, Preschool; Drug Therapy, Combination; Female; Gastrointestinal Agents; Hospitals, University; Humans; Incidence; Inflammatory Bowel Diseases; Logistic Models; Male; Mercaptopurine; Middle Aged; Multivariate Analysis; Neoplasms; Odds Ratio; Retrospective Studies; Risk Assessment; Risk Factors; Spain; Young Adult

Topics: Anti-Inflammatory Agents; Azathioprine; Female; Fetus; Gastrointestinal Agents; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Pregnancy; Pregnancy Complications; Purines; Remission Induction; Risk Assessment; Risk Factors; Treatment Outcome

The setting of chronic immunosuppression in inflammatory bowel disease (IBD) may promote the proliferation of Epstein-Barr virus-positive neoplastic clones. We report two rare cases of Epstein-Barr virus-associated lymphoproliferative disorder in IBD patients: one resembled lymphomatoid granulomatosis, and the other was a lymphoma resembling Hodgkin lymphoma. There are currently no guidelines for the prevention of lymphoproliferative disorder in IBD patients on immunosuppressive therapy.

Topics: Adult; Chronic Disease; Epstein-Barr Virus Infections; Fatal Outcome; Female; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Lymphoproliferative Disorders; Male; Mercaptopurine

The thiopurines azathioprine and 6-mercaptopurine are recommended for maintenance of remission in inflammatory bowel disease (IBD). Measurement of concentrations of the metabolites 6-thioguanine nucleotide and 6-methylmercaptopurine helps delineate interindividual variation in metabolism that may underlie variability in efficacy and toxicity.. We aimed to perform a retrospective observational study to determine the utility of thiopurine metabolite testing following its introduction into South Australia.. All patients having thiopurine metabolite tests done at Flinders Medical Centre between November 2008 and January 2010 were identified. Case notes of patients with testing done in the context of treatment for IBD were interrogated to determine the reason for testing, clinical context and outcome.. One hundred and fifty-one patients were identified with thiopurine metabolite testing for IBD with 157 testing episodes. Eighty (51.0%) had testing done for flare or inefficacy, 18 (11.5%) for adverse effects, 5 (3.2%) for a combination of inefficacy and adverse effects, and 54 (34.4%) for routine or other reasons. Testing was followed by improved outcomes of increased efficacy, reduced toxicity or change to alternative therapy in 55.0% of the inefficacy/flare group, 27.8% of the suspected adverse reaction group, 60.0% of the combination group, and 13.0% of the routine/other group. Allopurinol was used as cotherapy in 16 patients and led to marked improvements in metabolite concentrations.. Thiopurine metabolite testing has quickly become established in South Australia. When used for inefficacy or adverse effects, it often leads to improved outcomes. Prospective studies are needed to determine whether routine testing to guide dosing is of benefit.

Topics: Adult; Biomarkers; Disease Management; Female; Guanine Nucleotides; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Thionucleotides

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder. Systemic inflammation increases the risk of atherosclerosis and ischaemic heart disease (IHD).. To examine the impact of IBD, including its duration and treatment, on the risk of IHD.. In a nationwide population-based cohort of 4.6 million Danes aged ≥ 15 years, we compared people diagnosed with IBD during 1997-2009 (n=28 833) with IBD-free individuals. Subjects with IHD were identified in the National Patient Register. Using Poisson regression, we estimated the incidence rate ratios (IRRs) for IHD with 95% CI with adjustment for age, gender, socioeconomic status, calendar year and use of drugs for comorbidities.. A markedly increased risk of IHD was seen within the first year after IBD diagnosis (IRR=2.13 95% CI 1.91 to 2.38). During 1-13 years of follow-up after IBD diagnosis, the risk of IHD was 1.22 (95% CI 1.14 to 1.30). The risk of IHD was lower among patients with IBD using 5-aminosalicylic acids (IRR=1.16; 95% CI 1.06 to 1.26) than among non-users (IRR=1.36; 95% CI 1.22 to 1.51) (p=0.02), in particular among oral corticosteroid users, used as a proxy for disease severity. Likewise patients treated surgically or with thiopurines and tumour necrosis factor α antagonists tended to have reduced IRRs for IHD.. The risk of IHD was highest in the first year after IBD diagnosis, possibly owing to ascertainment bias. The increased long-term risk of IHD in IBD may be related to chronic inflammation, and interventions reducing the inflammatory burden may attenuate this risk.

Topics: Adolescent; Adult; Aged; Atherosclerosis; Case-Control Studies; Cohort Studies; Denmark; Female; Follow-Up Studies; Glucocorticoids; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Male; Mercaptopurine; Mesalamine; Middle Aged; Myocardial Ischemia; Registries; Risk; Severity of Illness Index; Tumor Necrosis Factor-alpha

Testing for LTBI is recommended prior to anti-TNFα agents. This includes an assessment of TB risk factors, chest radiograph, and interferon-gamma release assay alone or with concurrent Tuberculin skin testing. Here we review our experience and cost-effectiveness of using T-SPOT.TB IGRA to detect mycobacterial infection in patients with IBD suitable for anti-TNFα therapy.. This was a single-centre, retrospective review and economic evaluation (compared to British Thoracic Society guidance) of 125 adult IBD patients (90 anti-TNFα naïve, 35 established on anti-TNFα) tested for LTBI using T-SPOT.TB IGRA.. All subjects had normal chest radiographs and no clinical evidence for TB. 109 (87%) were BCG vaccinated. 27 (22%) of all patients tested were not using immunomodulation at the time of testing. 66 (53%) were taking thiopurines, 22 (18%)corticosteroids, and 35 (28%) anti-TNFα agents. One hundred twenty two (98%) had a negative IGRA result, two (2%) had positive results, and one (1%) had an indeterminate IGRA. A strategy using IGRA to guide TB preventative treatment produced cost savings of £10.79 per person compared to the BTS guidance. Eighty eight percent of the anti-TNFα naïve group have subsequently received treatment with either infliximab or adalimumab (median follow-up of 24 months, IQR 18-30) with no cases of TB disease occurring.. The use of a simple screening protocol for LTBI incorporating T-SPOT.TB IGRA in place of TST in a largely BCG vaccinated population, many using immunomodulatory agents, appears to work well and is a cost-effective strategy in our IBD service.

Topics: Adalimumab; Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Cost-Benefit Analysis; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Interferon-gamma Release Tests; Latent Tuberculosis; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Tumor Necrosis Factor-alpha; United Kingdom

The risk of non-Hodgkin's lymphoma (NHL) with tumor necrosis factor alpha (TNF-α) inhibitors is unclear, whether related to concomitant thiopurines usage or due to the underlying inflammatory disease. We sought to review all cases of T-cell NHL reported to the Food and Drug Administration (FDA) in patients receiving TNF-α inhibitors for all approved indications and examine the risk of T-cell NHL with TNF-α inhibitors in comparison with the use of thiopurines in inflammatory bowel disease (IBD).. The FDA Adverse Event Reporting System (AERS) was queried for all lymphomas following treatment with the following TNF-α inhibitors: infliximab, adalimumab, certolizumab, etanercept, and their trade names. Full reports for T-cell NHL cases were identified using the Freedom of Information Act. In addition, T-cell NHL reported in patients IBD with the use of the thiopurines-azathioprine, 6-mercaptopurine, and their trade names were also collected. A search of MEDLINE was performed for additional T-cell NHL with TNF-α inhibitors or thiopurines, not reported to the FDA but available in published literature. The histological subtypes of T-cell NHL reported with TNF-α inhibitors were compared with reported subtypes in Surveillance Epidemiology and End Results (SEER) -17 registry. Reported risk of T-cell NHL in IBD with TNF-α inhibitors, thiopurines, or concomitant use was calculated using Fisher's exact test using 5-aminosalicylates as control drugs.. A total of 3,130,267 reports were downloaded from the FDA AERS (2003-2010). Ninety-one cases of T-cell NHL with TNF-α inhibitors were identified in the FDA AERS and nine additional cases were identified on MEDLINE search. A total of 38 patients had rheumatoid arthritis, 36 cases had Crohn's disease, 11 had psoriasis, 9 had ulcerative colitis, and 6 had ankylosing spondylitis. Sixty-eight of the cases (68%) involved exposure to both a TNF-α inhibitor and an immunomodulator (azathioprine, 6-mercaptopurine, methotrexate, leflunomide, or cyclosporine). Hepatosplenic T-cell lymphoma (HSTCL) was the most common reported subtype, whereas mycosis fungoides/Sezary syndrome and HSTCL were identified as more common with TNF-α-inhibitor exposure compared with SEER-17 registry. Nineteen cases of T-cell NHL with thiopurines were identified in the FDA AERS and one additional case on MEDLINE. Reported risk of T-cell NHL was higher with TNF-α inhibitor use in combination with thiopurines (95% confidence interval (CI) 4.98-354.09; P<0.0001) and thiopurines alone (95% CI 8.32-945.38; P<0.0001) but not with TNF-α inhibitor use alone (95% CI 0.13-10.61; P=1.00).. Risk of T-cell NHL is increased with TNF-α inhibitor use in combination with thiopurines but not with TNF-α inhibitors alone.

Topics: Adalimumab; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid; Azathioprine; Certolizumab Pegol; Drug Therapy, Combination; Etanercept; Female; Humans; Immunoglobulin Fab Fragments; Immunoglobulin G; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Lymphoma, T-Cell; Male; MEDLINE; Mercaptopurine; Middle Aged; Odds Ratio; Polyethylene Glycols; Psoriasis; Receptors, Tumor Necrosis Factor; Risk Factors; SEER Program; Spondylitis, Ankylosing; Tumor Necrosis Factor-alpha; United States; United States Food and Drug Administration

There are few therapeutic options for patients with inflammatory bowel disease who lose response to infliximab because they produced antibodies against the drug. We performed a retrospective analysis to investigate whether administration of immune modulators to 5 patients who developed antibodies to infliximab (ATI) restored response to this drug; 3 patients were given azathioprine/6-mercaptopurine and 2 patients were given methotrexate. Concentrations of infliximab and ATIs, and antitumor necrosis factor (TNF) activity, were analyzed using enzyme-linked immunosorbent assay-based competition assays of serum samples collected before and after patients were given the immunomodulator. In all patients, levels of ATIs gradually decreased and trough levels of infliximab increased; clinical responses were restored to all patients. In competition assays, immunomodulator-induced elimination of ATIs was associated with increased anti-TNF activity in serum. The addition of immunomodulators to therapy might be helpful to patients who have lost response to anti-TNF agents owing to formation of antidrug antibodies.

Topics: Adolescent; Adult; Antibodies; Antibodies, Monoclonal; Azathioprine; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunologic Factors; Inflammatory Bowel Diseases; Infliximab; Male; Mercaptopurine; Methotrexate; Retrospective Studies; Treatment Outcome; Tumor Necrosis Factor-alpha; Young Adult

Topics: Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine

Topics: Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine

Patients with inflammatory bowel disease (IBD) on certain immunosuppressants have increased herpes zoster (HZ) risk.. To determine the risk of HZ in IBD and how antitumour necrosis factor-alpha (anti-TNF) agents affect this risk.. We performed a retrospective cohort and nested case-control study using administrative data from IMS LifeLink(®) Information Assets-Health Plan Claims Database. In the cohort, we identified IBD patients

Topics: Adult; Case-Control Studies; Cohort Studies; Female; Herpes Zoster; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Risk Factors; Tumor Necrosis Factor-alpha

Thioguanine nucleotides (TGNs) are the active product of thiopurine metabolism. Levels have been correlated with effective clinical response. Nonetheless, the value of TGN monitoring in clinical practice is debated. We report the influence of introducing TGN monitoring into a large adult inflammatory bowel disease (IBD) clinic.. Patients with IBD undergoing TGN monitoring were identified from Purine Research Laboratory records. Whole blood TGNs and methylated mercaptopurine nucleotides were hydrolysed to the base and measured using HPLC. Clinical and laboratory data were obtained retrospectively.. One hundred and eighty-nine patients with 608 available TGN results were identified. In non-responders, TGNs directed treatment change in 39/53 patients. When treatment was changed as directed by TGN, 18/20 (90%) improved vs. 7/21 (33%) where the treatment decision was not TGN-directed, p < 0.001. Where treatment change was directed at optimisation of thiopurine therapy, 14/20 achieved steroid-free remission at 6 months vs. 3/10 where the TGN was ignored, (p = 0.037). Six per cent of patients were non-adherent, 25% under-dosed and 29% over-dosed by TGN. Twelve per cent of patients predominantly methylated thiopurines, this group had low TGN levels and high risk of hepatotoxicity. In responders, adherence and dosing issues were identified and TGN-guided dose-reduction was possible without precipitating relapse. Mean cell volume (MCV), white blood cell count (WBC) and lymphocyte counts were not adequate surrogate markers. MCV/WBC ratio correlated with clinical response, but was less useful than TGN for guiding clinical decisions.. Monitoring TGNs enables thiopurine therapy to be optimised and individualised, guiding effective treatment decisions and improving clinical outcomes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azathioprine; Biomarkers, Pharmacological; Child; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Medication Adherence; Mercaptopurine; Methyltransferases; Middle Aged; Treatment Outcome; Young Adult

Thiopurine therapy is often discontinued in inflammatory bowel disease (IBD) patients. The xanthine oxidase (XO) inhibitor allopurinol has previously shown to enhance thiopurine efficacy and to prevent adverse reactions, the mechanism of this beneficial interaction is not completely clarified. The aim of this study is to observe possible effects of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes.. A prospective study of IBD patients failing thiopurine therapy due to a skewed thiopurine metabolism was performed. Patients were treated with allopurinol and azathioprine or mercaptopurine. Xanthine oxidase, hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and thiopurine S-methyl transferase (TPMT) activities, and thiopurine metabolites concentrations were measured during thiopurine monotherapy, and after 4 and 12 weeks of combination therapy.. Of fifteen IBD patients, XO activity decreased from 0.18 (IQR 0.08-0.3) during thiopurine monotherapy to 0.14 (IQR 0.06-0.2) and 0.11 (IQR 0.06-0.2; p=0.008) mU/hour/ml at 4 and 12 weeks, respectively. HGPRT activity increased from 150 (IQR 114-176) to 180 (IQR 135-213) and 204 nmol/(h×mg protein) (IQR 173-213; p=0.013). TPMT activity seemed not to be affected. 6-Thioguanine nucleotide concentrations increased from 138 (IQR 119-188) to 235 (223-304) and to 265 pmol/8×10^8 (IQR 188-344), whereas 6-methyl mercaptopurine ribonucleotides concentrations decreased from 13230 (IQR 7130-17420) to 690 (IQR 378-1325) and 540 (IQR 240-790) pmol/8×10^8 at 4 and 12 weeks of combination therapy (both p<0.001).. Allopurinol and thiopurine combination-therapy seems to increase HGPRT and decrease XO activity in IBD patients, which at least in part may explain the observed changes in thiopurine metabolite concentrations.

Topics: Adult; Allopurinol; Azathioprine; Drug Therapy, Combination; Enzyme Activation; Enzyme Inhibitors; Fatigue; Female; Guanine Nucleotides; Humans; Hypoxanthine Phosphoribosyltransferase; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Middle Aged; Nausea; Prospective Studies; Thioinosine; Thionucleotides; Xanthine Oxidase

The safety of thiopurines and anti-tumor necrosis factor-α (TNF-α) drugs during pregnancy remains controversial, as the experience with these drugs in this situation is limited. Our aim is to assess the safety of thiopurines and anti-TNF-α drugs for the treatment of inflammatory bowel disease (IBD) during pregnancy.. Retrospective, multicenter study in IBD patients. Pregnancies were classified according to the therapeutic regimens during pregnancy or during the 3 months before the conception: non-exposed group, pregnancies exposed to thiopurines alone (group A), and pregnancies exposed to anti-TNF-α drugs (group B). An unfavorable Global Pregnancy Outcome (GPO) was considered if pregnancy developed with obstetric complications in the mother and in the newborn.. A total of 187 pregnancies in the group A, 66 pregnancies in the group B, and 318 pregnancies in the non-exposed group were included. The rate of unfavorable GPO was different among the three groups (31.8% in non-exposed group, 21.9% in group A, and 34.8% in group B), being lower in pregnancies under thiopurines than among non-exposed (P = 0.01). The rate of pregnancy complications was similar among the three groups (27.7% in non-exposed, 20.9% in group A, and 30.3% in group B). The rate of neonatal complications was different among the three groups (23.3% in non-exposed group, 13.9% in group A, and 21.2% in group B), being lower in pregnancies under thiopurines than among non-exposed (P = 0.01). In the multivariate analysis, the treatment with thiopurines (odds ratio = 0.6; 95% confidence interval = 0.4-0.9, P = 0.02) was the only predictor of favorable GPO, whereas maternal age >35 years at conception was the only predictor of unfavorable GPO. The treatment with anti-TNF-α drugs was not associated with an unfavorable GPO.. The treatment with thiopurines and anti-TNF-α drugs does not seem to increase the risk of complications during pregnancy and does seem to be safe for the newborn.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Azathioprine; Female; Humans; Infant, Newborn; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Retrospective Studies; Tumor Necrosis Factor-alpha

Previous studies have suggested a chemopreventive effect of 5-aminosalicylic acid (5-ASA) therapy in patients with inflammatory bowel disease (IBD). This effect has not been reported in IBD patients using thiopurines. We investigated the association between thiopurine or 5-ASA use and the risk of advanced neoplasia (AN), including high-grade dysplasia and colorectal cancer, in a large cohort of patients with IBD in the Netherlands.. PALGA, the nationwide network and registry of histo- and cytopathology in The Netherlands was linked to an anonymised computerised database of a Dutch health insurance company to identify patients with IBD with or without AN. Pharmaceutical data, including type and duration of medication use, were collected between January 2001 and December 2009. Cox proportional hazard regression analysis was used to calculate risk of AN in patients with and without thiopurine or 5-ASA use.. A total of 2578 patients with IBD were included. Of these, 973 patients (38%) used 5-ASA, 314 (12%) thiopurines, 456 (18%) both 5-ASA and thiopurines and 835 (32%) none of these drugs. Twenty-eight patients (1%) developed AN during 16,289 person-years of follow-up. Of these, 11 patients (39%) had used 5-ASA, two (7%) thiopurines and one (4%) both drugs. Thiopurine use was associated with a significantly decreased risk of developing AN (adjusted HR 0.10, 95% CI 0.01 to 0.75). 5-ASA therapy also had a protective effect on developing AN, but this was not statistically significant (adjusted HR 0.56, 95% CI 0.22 to 1.40).. Thiopurine use protects IBD patients against the development of AN. The effect of 5-ASA appeared to be less pronounced.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Cohort Studies; Colorectal Neoplasms; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Mesalamine; Middle Aged; Proportional Hazards Models; Risk

The thiopurines azathioprine and 6-mercaptopurine are effective in the management of patients with inflammatory bowel disease (IBD) in whom aminosalicylates, antibiotics and corticosteroids have failed to induce or maintain remission. Long-term use of these agents has been linked to a greatly increased risk of non-melanoma skin cancer and lymphatic cancer in organ transplant recipients. There is some evidence to suggest that IBD patients receiving thiopurines might be at increased risk of cancer. Our aim was to determine the incidence of cancer in a cohort of patients with IBD managed in our clinic, and to relate this to thiopurine exposure.. We conducted a retrospective study based on the clinical and pathology records of patients attending a specialist IBD clinic at Groote Schuur Hospital, Cape Town, South Africa between 1960 and 2007.. We analyzed the records of 1084 patients. A total of 123 subjects (11.5%) had received thiopurine therapy. Cancer was identified in 51 patients (4.7%), including colorectal cancer (15 patients), melanoma (two patients), non-melanoma skin cancer (seven patients) and non-Hodgkin's lymphoma (five patients). A diagnosis of non-melanoma skin cancer was significantly associated with thiopurine exposure (odds ratio 5.0, 95% confidence interval 1.1-22.8). Six of seven non-melanoma skin cancers occurred in Caucasian patients, with a highly significant association with thiopurine use (odds ratio 12.4, 95% confidence interval 2.3-67.4).. Patients with IBD who receive thiopurines are at increased risk of non-melanoma skin cancer. The risk is highest in Caucasian patients, and is negligible in other groups.

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Female; Gastrointestinal Agents; Humans; Incidence; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Odds Ratio; Retrospective Studies; Risk Assessment; Risk Factors; Skin Neoplasms; Skin Pigmentation; South Africa; Sunlight; Time Factors; White People; Young Adult

Topics: Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases

  6-mercaptopurine (6-MP) is efficacious in the treatment of inflammatory bowel disease (IBD). However, about one-third of patients respond poorly to therapy. This study aimed to characterize the inherent differences in 6-MP transport that may cotribute to the differences in treatment responses..   Intracellular 6-MP accumulation was assayed in Epstein-Barr virus (EBV)-transformed lymphocytes from IBD patients, using (14) C-radiolabeled 6-MP. Cell proliferation was determined by methyl thiazolyl tetrazolium (MTT) assay. Apoptosis was assayed based on the activation of caspase 3. The expressions of 15 potential 6-MP transporters were evaluated by reverse transcription-polymerase chain reaction (RT-PCR)..   Intracellular 6-MP accumulation, varying significantly among patients, was carrier-dependent and partially sodium-dependent. 6-MP cytotoxicity was, at least in part, due to apoptosis and correlated with intracellular drug accumulation. The efflux transporters did not appear to contribute to the variability of intracellular drug accumulation between patients, since none correlated with drug accumulation or cytotoxicity. Rather, differential expression of five influx/uptake transporters might be a key contributor to the difference in the accumulation of and susceptibility to the drug..   The heterogeneity of the drug transporters may be the reason for the therapeutic sensitivity of 6-MP in IBD patients. As the 6-MP uptake is a carrier-mediated and partially sodium-dependent process, future studies are necessary to evaluate the role of the putative transporters and their correlation with drug sensitivity in patients.

Topics: Adolescent; Adult; Aged; Apoptosis; Binding, Competitive; Carbon Radioisotopes; Carrier Proteins; Caspase 3; Cell Line, Transformed; Cell Survival; Cytotoxins; Drug Resistance; Female; Gene Expression; Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Lymphocytes; Male; Mercaptopurine; Middle Aged; Sodium; Young Adult

Topics: Anti-Inflammatory Agents; Azathioprine; Female; Gastrointestinal Agents; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Skin Neoplasms

High concentrations of methylated thiopurine metabolites, such as 6-methyl mercaptopurine, are associated with hepatotoxicity during administration of the conventional thiopurines azathioprine or 6-mercaptopurine in IBD patients. Metabolization of the non-conventional thiopurine 6-thioguanine does not generate 6-methyl mercaptopurine. Hence, the aim of our study was to evaluate hepatotoxicity during 6-thioguanine in IBD patients who previously failed conventional thiopurines due to 6-methyl mercaptopurine associated hepatotoxicity.. A retrospective single center intercept cohort study was performed of IBD patients using 6-thioguanine between January 2006 and July 2010 after failing conventional thiopurine therapy due to 6-methyl mercaptopurine associated hepatotoxicity. The primary outcome was the occurrence of 6-thioguanine induced hepatotoxicity, scaled according to the Common Terminology Criteria for Adverse Events.. Nineteen patients were included. Median duration of 6-thioguanine therapy (median daily dosage 21 mg (9-24)) was 23 weeks (6-96). Hepatotoxicity did not reoccur in 15 out of 19, whereas grade 1 toxicity persisted in 4 patients (p<0.001). Median aspartate aminotransferase and alanine aminotransferase concentrations decreased from 34 U/l (20-59) and 64 U/l (15-175) to 23 U/l (18-40; p=0.003) and 20 U/l (14-48; p=0.019), respectively.. Hepatotoxicity does not reoccur during 6-thioguanine treatment in most IBD patients who failed conventional thiopurines due to 6-methyl mercaptopurine associated hepatotoxicity. Hence, at least at short-term, 6-thioguanine appears a justifiable alternative thiopurine for these IBD patients.

Topics: Antimetabolites, Antineoplastic; Azathioprine; Chemical and Drug Induced Liver Injury; Female; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Retrospective Studies; Thioguanine; Treatment Outcome

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

A pre-treatment determination of the thiopurine S-methyltransferase (TPMT) genotype or phenotype can identify patients at risk of developing severe adverse reactions from thiopurine treatment. The risk of misclassifying a patient might be dependent on the method used. The aim of this study was to investigate the concordance between TPMT genotyping and phenotyping.. The data consist of 7195 unselected and consecutive TPMT genotype and phenotype determinations sent to the division of Clinical Pharmacology, Linköping, Sweden. TPMT activity was measured in red blood cells (RBC) and the genotype determined by pyrosequencing for the three most common TPMT variants (TPMT *2, *3A, *3C).. TPMT genotyping identified 89% as TPMT wild type (*1/*1), 10% as TPMT heterozygous and 0.5% as TMPT defective. The overall concordance between genotyping and phenotyping was 95%, while it was 96% among IBD patients (n=4024). Genotyping would have misclassified 8% of the TPMT defectives as heterozygous as compared to 11% if only TPMT activity had been measured. 11% of the heterozygous patients had a normal TPMT activity (>8.9 U/ml RBC) and 3% of the TPMT wild-type patients had an intermediate TPMT activity (2.5-8.9 U/ml RBC).. There is a risk for TPMT misclassification when only genotyping or phenotyping is used, but it is not reasonable to check both in all patients. Since TPMT genotyping is the more reliable test, especially in TPMT heterozygotes, we suggest that genotyping should be considered the primary choice for the pre-treatment evaluation of TPMT function before initiation of thiopurine therapy.

Topics: Azathioprine; Biomarkers; Cohort Studies; Genetic Markers; Genotype; Genotyping Techniques; Humans; Immunosuppressive Agents; Inactivation, Metabolic; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Phenotype; Retrospective Studies; Sweden

Thiopurines represent the mainstay of immunosuppressive therapy in inflammatory bowel diseases. Since it is likely that response to therapy and adverse events depends on the genetic background of patients our study aimed to evaluate retrospectively response to therapy and safety in a mixed IBD population in Southern Europe.. We evaluated demographic and clinical data of our patients treated with thiopurines. after 6 months in responders and non-responders to therapy. Moreover the likelihood to remain in thiopurine monotherapy was evaluated in responders, whereas adverse events were investigated in all patients.. Among disease- and patient-related parameters a shorter disease duration, female gender and ileal disease in Crohn's patients were associated with better response. By ROC analysis, the best predictors of response were decreasing values of C-reactive protein and erythrocyte sedimentation rate. In the long-term more than half of IBD patients who responded at 6 months remained on monotherapy at 42 months. Flu-like syndrome represented the most frequent adverse event followed by abnormalities of liver function tests and myelotoxicity. Adverse events did occur at any time and were frequently impredictable.. In this retrospective study, thiopurines showed a good clinical efficacy, especially in patients with short duration of disease. Normalization of markers of systemic inflammation represents the most useful tool to assess response. Careful monitoring of patients is required during the whole duration of treatment although it may not prevent all severe complications.

Topics: Adolescent; Adult; Aged; Azathioprine; Child; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Patient Compliance; Patient Safety; Retrospective Studies; ROC Curve; Treatment Outcome; Young Adult

Evidence supporting the importance of assessment of mucosal healing in inflammatory bowel disease has increased in the last years. Mucosal healing has been integrated in the assessment of treatment efficacy in ulcerative colitis, but in Crohn's disease this thought has arised after biological agents have been evaluated in clinical trials. Although a validated definition of mucosal healing still does not exist, its use is also assuming an increasingly important role in the follow-up of individual patients in clinical practice. Corticosteroids induce mucosal healing in a small proportion of patients with Crohn's disease and are of no benefit to maintain it. By contrast, mucosal healing in Crohn's disease can be achieved and maintained, with varying degrees of evidence and success, with thiopurines and biological agents. In ulcerative colitis, the ability of corticosteroids to induce mucosal healing is well recognized. 5-aminosalicylates, thiopurines and biological agents are also able to induce mucosal healing and, additionally, to maintain it. Mucosal healing assessment should be considered in clinical practice when symptoms persist despite therapy or when treatment discontinuation is being considered. Conversely, in patients whose clinical remission is not associated with mucosal healing, intensification of treatment is not currently recommended because of lack of evidence.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Endoscopy, Gastrointestinal; Humans; Inflammatory Bowel Diseases; Infliximab; Intestinal Mucosa; Mercaptopurine; Mesalamine; Methotrexate; Treatment Outcome

Up to 20% of patients on thiopurine therapy fail to achieve adequate drug response. Many of these patients preferentially produce the toxic 6-methylmercaptopurine metabolites (6-MMP) rather than the active 6-thioguanine nucleotides (6-TGN) resulting in a high 6-MMP/6-TGN ratio (>20) and increased risk of hepatotoxicity.. To determine the prevalence of preferential 6-MMP producers and define the relationships between 6-TGN, 6-MMP and thiopurine methyltransferase (TPMT).. The database of 6-TGN, 6-MMP and TPMT measurements from patients throughout New Zealand was used to calculate patients' 6-MMP/6-TGN ratios and identify those with high (>20) or normal ratio (≤20).The TPMT enzyme activity was compared amongst the groups.. Of 1879 patients with TPMT, 6-TGN and 6-MMP results, 349 (19%) had a 6-MMP/6-TGN ratio >20. The mean TPMT enzyme activity was slightly lower for those with a 6-MMP/6-TGN ratio ≤20 vs. >20, which achieved statistical significance (12.2 vs. 13.2; P < 0.001). However, the distributions of TPMT enzyme activity were similar, with 97% of TPMT results falling between 5.0 and 17.6 IU/mL for both groups. In all, 17% of those with 6-MMP/6-TGN ratio ≤20 were intermediate TPMT metabolisers (TPMT 5.0-9.2 IU/mL) vs. 7% in those with a ratio >20.. In this patient population with measured 6-MMP/6-TGN ratios, 19% of patients were preferential 6-MMP producers. The results show that high TPMT enzyme activity is not the major reason for preferential 6-MMP production in most patients with a high metabolite ratio. This suggests that there are one or more important alternative mechanisms for preferentially producing 6-MMP.

Topics: Antimetabolites, Antineoplastic; Azathioprine; Chromatography, High Pressure Liquid; Drug Resistance; Erythrocyte Membrane; Female; Genotype; Guanine Nucleotides; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Statistics as Topic; Thioguanine; Thionucleotides

Infliximab-induced hepatotoxicity is reported in several case studies involving patients with inflammatory bowel disease (IBD) and a direct hepatotoxic effect has been proposed.. The aim of this study was to determine the direct in vitro toxicity of infliximab. As a proof of principle the in vitro toxicity of thiopurines and methotrexate was also determined.. Cell survival curves and the half maximal inhibitory concentrations (IC(50)) were obtained after 24, 48 and 72 h of incubation in HepG2 cells with the IBD drugs azathioprine, 6-mercaptopurine, 6-thioguanine, methotrexate or infliximab by using the WST-1 cytotoxicity assay.. No in vitro hepatotoxicity in HepG2 cells was seen with infliximab, while concentration-dependent cytotoxicity was observed when HepG2 cells were incubated with increasing concentrations of azathioprine, 6-mercaptopurine and 6-thioguanine.. Infliximab alone or given in combination with azathioprine showed no direct hepatotoxic effect in vitro, indicating that the postulated direct hepatotoxicity of infliximab is unlikely.

Topics: Analysis of Variance; Antibodies, Monoclonal; Azathioprine; Cell Survival; Dose-Response Relationship, Drug; Hep G2 Cells; Hepatoblastoma; Humans; In Vitro Techniques; Inflammatory Bowel Diseases; Infliximab; Liver Neoplasms; Mercaptopurine; Methotrexate; Sensitivity and Specificity; Thioguanine

Topics: Azathioprine; Genotype; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Phenotype

Patients with inflammatory bowel disease (IBD) are at risk for certain malignancies. We aimed to determine the risk of melanoma and nonmelanoma skin cancer (NMSC) in patients with IBD and how medications affect these risks.. We performed retrospective cohort and nested case-control studies using administrative data from the LifeLink Health Plan Claims Database from 1997 to 2009. The cohort comprised 108,579 patients with IBD, and each was matched to 4 individuals without IBD. The risk of melanoma and NMSC was evaluated by incidence rate ratio (IRR) and by adjusted Cox proportional hazard ratio (HR) modeling. In nested case-control studies, patients with melanoma or NMSC were matched to 4 patients with IBD without melanoma or NMSC. Conditional logistic regression was used to determine associations between medications and both skin cancers.. In the cohort, IBD was associated with an increased incidence of melanoma (IRR, 1.29; 95% confidence interval [CI], 1.09-1.53). Risk was greatest among individuals with Crohn's disease (IRR, 1.45; 95% CI, 1.13-1.85; adjusted HR, 1.28; 95% CI, 1.00-1.64). The incidence of NMSC also increased among patients with IBD (IRR, 1.46; 95% CI, 1.40-1.53) and was greatest among those with CD (IRR, 1.64; 95% CI, 1.54-1.74). In the nested case-control studies, therapy with biologics increased the risk of melanoma (odds ratio [OR], 1.88; 95% CI, 1.08-3.29). Patients who had been treated with thiopurines had an increased risk of NMSC (OR, 1.85; 95% CI, 1.66-2.05).. Immunosuppression increases the risk of melanoma and NMSC among patients with IBD. The risk of melanoma is increased by use of biologics, and the risk of NMSC is increased by use of thiopurines. Patients with IBD should be counseled and monitored for skin cancer.

Topics: Adult; Antibodies, Monoclonal, Humanized; Case-Control Studies; Cohort Studies; Female; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Logistic Models; Male; Melanoma; Mercaptopurine; Middle Aged; Proportional Hazards Models; Retrospective Studies; Risk; Skin Neoplasms; Tumor Necrosis Factor-alpha; United States

Hepatotoxicity is an important side effect of thiopurine analog treatment for inflammatory bowel disease. A variety of histopathologic findings have been observed in patients with inflammatory bowel disease with thiopurine-induced hepatotoxicity, including nodular regenerative hyperplasia, vascular injury, and cholestasis.. To describe the histologic features shared by 3 cases of thiopurine-induced hepatotoxicity in patients with inflammatory bowel disease.. We identified 3 patients with inflammatory bowel disease who developed hepatotoxicity due to 6-mercaptopurine from the educational files of the Department of Pathology at Massachusetts General Hospital (Boston). Histology slides (stained with hematoxylin-eosin, trichrome, periodic-acid Schiff with diastase digestion, and iron stains) and patients' medical records were reviewed retrospectively.. All 3 patients were receiving 6-mercaptopurine monotherapy at therapeutic doses, had normal thiopurine metabolite levels, and presented with elevated aminotransferase levels. Biopsies from all 3 cases exhibited a pattern of centrilobular hepatocyte injury characterized by ceroid-laden macrophages, hepatocyte anisonucleosis, and increased lipofuscin pigment, as well as centrilobular steatosis. Aminotransferase levels trended downward and either normalized or remained at borderline elevated levels after 6-mercaptopurine dose was reduced (in 1 patient) or discontinued (in 2 patients).. Recognition of a pattern of centrilobular injury enables pathologists to suggest thiopurine-induced liver injury as the cause of elevated aminotransferases in patients with inflammatory bowel disease.

Topics: Adult; Chemical and Drug Induced Liver Injury; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Liver; Male; Mercaptopurine; Middle Aged; Retrospective Studies

To investigate the potential influence of 5-aminosalicylic acid (5-ASA) on the induction of myelotoxicity during thiopurine therapy in inflammatory bowel disease patients.. (a) The retrospective study included inflammatory bowel disease patients treated with azathioprine (AZA)/6-mercaptopurine (6-MP). Thiopurine methyltransferase (TPMT) activity and 6-thioguanine nucleotide (6-TGN) levels were detected at stable medication points. (b) The prospective study was performed in active disease patients: 4 weeks of AZA 50 mg/day followed by concomitant 5-ASA 3 g/day for another 4 weeks. 6-TGN was analyzed at weeks 4 and 8.. (a) Of the 139 retrospective study patients, 45 were on AZA/6-MP+5-ASA and 94 on AZA/6-MP alone. The myelotoxicity rates were 47 and 16%, respectively. Multivariates regression analysis indicated that the administration of concomitant 5-ASA was the only risk factor associated with myelotoxicity (odds ratio=3.45, 95% confidence interval 1.31-9.04, P=0.01). (b) Thiopurine methyltransferase activity was not significantly different between patients on AZA/6-MP+5-ASA and patients on AZA/6-MP alone (P=0.78). (c) 6-TGN levels were significantly higher in samples on AZA/6-MP+5-ASA than those on AZA/6-MP (P=0.003) alone. (d) Sixteen patients completed the prospective study. After 4 weeks on AZA 50 mg/day, 6-TGN levels of 13 patients were less than 230 pmol/8×10 RBC. After another 4 weeks' cotreatment with mesalazine 3 g/day, 12 patients had 6-TGN levels at least 230 pmol/8×10 RBC, five patients had 6-TGN levels at least 420 pmol/8×10 RBC, and two of these five patients developed myelotoxicity.. The risk of thiopurine-induced myelotoxicity markedly increases in patients treated with combined 5-ASA and 2 mg/kg/day AZA therapy, which may be correlated to the increase in 6-TGN. 50 mg daily AZA when concomitant 5-ASA might help maintain an effective 6-TGN level without increasing the risk of myelotoxicity.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Asian People; Azathioprine; Bone Marrow; Child; Child, Preschool; Cohort Studies; Drug Therapy, Combination; Female; Guanine Nucleotides; Humans; Immunosuppressive Agents; Infant; Inflammatory Bowel Diseases; Male; Mercaptopurine; Mesalamine; Methyltransferases; Middle Aged; Prospective Studies; Retrospective Studies; Thionucleotides; Young Adult

To examine the validity of patient self-report of thiopurine adherence in pediatric inflammatory bowel disease (IBD) against an objective electronic monitoring adherence measure, and to investigate the role of youth and maternal involvement in remembering to take daily medications as predictors of medication adherence.. Fifty-one youths with IBD, ages 11-18 years, participated. Youths completed questionnaire assessments of their own and their maternal caregiver's involvement in remembering to take daily medications at baseline, completed monthly interviews assessing thiopurine adherence over the past week for a period of 6 months, and utilized a Medication Events Monitoring System (MEMS) electronic monitor for their thiopurine medication for 6 months. Participants were grouped into adherent (at least 80% of doses taken based on objective MEMS caps) or nonadherent for analyses.. Youths who were nonadherent based on electronic monitoring overestimated their adherence by 23%, whereas adherent youths overestimated their adherence by only 2%, and as such patient self-report offered little utility in identifying youths who were nonadherent. Youths who reported high levels of involvement in remembering to take their medications were nearly eight times less likely to be nonadherent.. The current findings provide evidence that clinicians who work with children and adolescents with IBD may benefit from modifying their approach to nonadherence screening. Asking about youth involvement in remembering daily medications may be more informative than asking them to recall their medication-taking behavior over the last week in identifying those at highest risk for nonadherence.

Topics: Adolescent; Caregivers; Child; Databases, Factual; Drug Monitoring; Family; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Medication Adherence; Mercaptopurine; Patient Compliance; Practice Guidelines as Topic; Prognosis; Self Report; Surveys and Questionnaires

Topics: Antimetabolites, Antineoplastic; Azathioprine; Female; Guanine Nucleotides; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Thioguanine; Thionucleotides

Mercaptopurine and azathioprine (AZA) are efficacious in treating IBD. 6-tioguanine (6-TGN) levels correlate with therapeutic efficacy, whereas high 6-methylmercaptopurine (6-MMP) levels are associated with hepatotoxicity and myelotoxicity. Some IBD patients exhibit dose-limiting preferential 6-MMP production, which may lead to undesired side effects and impact efficacy.. To review the outcomes of thiopurine split-dosing in patients with preferential 6-MMP metabolism.. A retrospective chart review of 179 IBD patients treated at the Cedars-Sinai IBD Center with AZA or mercaptopurine was performed. Preferential 6-MMP metabolisers with 6-MMP levels greater than 7000 pmol/8 × 10(8) erythrocytes who underwent split-dosing were identified and assessed for biochemical and clinical responses to these dose modifications.. A total of 20 of 179 patients met the criteria for preferential 6-MMP metabolism and underwent thiopurine split-dosing. Dividing the total daily thiopurine dose led to a reduction in 6-MMP levels (11785 vs. 5324 pmol/8 × 10(8) erythrocytes; P < 0.0001) without negatively affecting clinical disease activity or 6-TGN levels (239 vs. 216 pmol/8 × 10(8) erythrocytes; P = N.S.) and led to resolution of 6-MMP associated side effects (elevated transaminases, leucopenia and flu-like symptoms) in all but two patients. After mean follow-up of 36 months, 12 patients remained in clinical remission on split-dose mercaptopurine. Five of the remaining eight patients escalated to anti-TNF therapy, two progressed to surgery, and one switched to tioguanine therapy.. Split-dose administration of mercaptopurine/AZA represents an alternative option in IBD patients with preferential 6-MMP metabolism who might otherwise require steroid exposure or escalation of therapy.

Topics: Adolescent; Adult; Azathioprine; Dose-Response Relationship, Drug; Erythrocytes; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Treatment Outcome; Young Adult

Topics: Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Melanoma; Mercaptopurine; Prospective Studies; Skin Neoplasms

Immunomodulator medications (IMM) play a vital role in the care of patients with inflammatory bowel disease (IBD). IBD practice guidelines recommend myelosuppression monitoring after initiation of IMM.. To identify adherence rates and predictors of myelosuppression monitoring after IMM initiation in a large practice setting.. We identified a national cohort of VA users with IBD for the fiscal years 2003-2009 using the Veterans Affairs administrative datasets. Subjects with filled prescriptions for IMM were included. The primary endpoint was the proportion of subjects who had a white blood cell (WBC) test completed within 90 days of the IMM index date. Determinants of myelosuppression monitoring were identified by univariate and multivariate analyses.. A total of 6045 unique IBD patients were identified with filled IMM prescriptions. Overall, only 57% of subjects completed a WBC test within 90 days of IMM index date. Monitoring rates increased over time, from 48% in 2003 to 75% in 2009. There was variability of monitoring rates by facility, ranging from 0 to 83%. In multivariate analyses, older age at IMM index date was associated with a lower rate of monitoring. Frequency of VA encounters and IMM index date were associated with increased rates of myelosuppression monitoring.. Monitoring for myelosuppression among veterans with inflammatory bowel disease after immunomodulator medications initiation is low with wide variability based on facility. This may reflect a low quality of care among veterans with IBD. Provider- and system-wide interventions are needed to improve adherence and reduce variability of immunomodulator medications monitoring across facilities.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Azathioprine; Delivery of Health Care; Drug Monitoring; Drug Prescriptions; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukocyte Count; Leukopenia; Male; Medical Audit; Mercaptopurine; Methotrexate; Middle Aged; Practice Guidelines as Topic; Treatment Outcome; United States; United States Department of Veterans Affairs; Veterans

Topics: Azathioprine; Female; Humans; Immunologic Factors; Inflammatory Bowel Diseases; Mercaptopurine; Pregnancy; Remission Induction

Topics: Azathioprine; Colorectal Neoplasms; Crohn Disease; Folic Acid; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Mesalamine

Not all of the adverse effects to thiopurine therapy can be explained by thiopurine methyltransferase (TPMT) polymorphisms. This study was intended to evaluate the value of TPMT genotype and phenotype measurement during the first year of thiopurine therapy.. Consecutive patients with inflammatory bowel disease (IBD) who were receiving azathioprine or 6-mercaptopurine were followed up for 12 months. TPMT genotypes and phenotypes were examined in patients with IBD before thiopurine therapy and in unrelated healthy volunteers by polymerase chain reaction and high-performance liquid chromatography.. A total of 199 patients and 300 healthy volunteers were included at 2 centers. Forty-seven of the 199 patients (23.62%) exhibited adverse effects during the entire course of thiopurine therapy. Two (1%) patients carrying TPMT*3C developed leucopenia at week 4 of azathioprine treatment. The TPMT*3C had a specificity of 100% (163/163) but a sensitivity of 5.56% (2/36) for predicting leucopenia. The calculated optimal cutoff activity for high TPMT activity and decreased TPMT activity was 4.75 U/mL red blood cells. The risk of leucopenia increased in the decreased TPMT group (odds ratio: 20.25; 95% confidence interval: 2.19-187.17; P = 0.004) and increased more during the initial 3 months of thiopurine therapy (odds ratio: 34.80; 95% confidence interval: 3.71-326.77; P = 0.001). Leucopenia occurred more frequently in the patients cotreated with 5-aminosalicylates than in those not cotreated (32.81% versus 11.11%, respectively, P < 0.001).. The results of this study suggest that the value of TPMT genotyping before thiopurine therapy is limited in Chinese patients with IBD, considering the low sensitivity of predicting leucopenia, and that phenotyping is a more cost-effective tool that can be successfully used in patients. The coadministration of 5-aminosalicylates results in a high frequency of leucopenia in patients receiving azathioprine or 6-mercaptopurine.

Topics: Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; China; Drug Interactions; Drug Monitoring; Female; Follow-Up Studies; Genetic Association Studies; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Mesalamine; Methyltransferases; Middle Aged; Mutation; Prospective Studies; Young Adult

Circulating concentrations of 6-thioguanine nucleotide (6-TGN) and 6-methyl mercaptopurine (6-MMP) are associated with thiopurine efficacy and may predict toxicity. This study aimed to examine retrospectively the utility of measuring metabolite concentrations in patients with inflammatory bowel disease (IBD) who had continuing symptoms despite stable thiopurine treatment.. Concentrations of 6-TGN and 6-MMP were measured in lysates of washed red cells by high-performance liquid chromatography in peripheral blood drawn from 63 symptomatic patients with IBD (63% men, mean age 37, range 14-74 years, 67% Crohn's disease, 33% ulcerative colitis) treated with azathioprine or 6-mercaptopurine. Short-term clinical outcomes were examined.. 6-TGN concentrations weakly correlated with the thiopurine dose (r = 0.28, P = 0.08). On weight-based criteria, 50% of patients were underdosed. However, metabolite patterns suggested 7 (11%) patients were noncompliant, 18 (29%) were being underdosed, 33 (52%) were refractory to treatment with either appropriate (41%) or elevated (11%) metabolite concentrations, and 6 (10%) had a raised 6-MMP:6-TGN ratio consistent with aberrant thiopurine metabolism. The clinical outcome improved in 40 of 46 (87%) of patients in whom the course of action taken was as recommended by a metabolite-directed algorithm, while 3 of 17 patients (18%) improved where discordant actions were taken (P = 0.0001; Fisher's exact test). Fifteen patients (24%) avoided inappropriate escalation of therapy.. Dose-optimization or toxicity-avoidance strategies frequently result from metabolite testing in patients with inadequate efficacy from thiopurines, with evidence of better outcomes. Thiopurine metabolite testing is a potentially powerful tool for optimizing thiopurine usage in IBD.

Topics: Adolescent; Adult; Aged; Azathioprine; Chromatography, High Pressure Liquid; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Thioguanine; Treatment Failure; Young Adult

Few studies have been conducted addressing the safety of thiopurine treatment in pregnant women with inflammatory bowel disease (IBD). The aim of this study was to evaluate the pregnancy outcome of women with IBD who have been exposed to thiopurines.. 215 pregnancies in 204 women were registered and documented in the CESAME cohort between May 2004 and October 2007. Physicians documented the following information from the women: last menstrual date, delivery term, details of pregnancy outcome, prematurity, birth weight and height, congenital abnormalities, medication history during each trimester, smoking history and alcohol ingestion. Data were compared between three groups: women exposed to thiopurines (group A), women receiving a drug other than thiopurines (group B) and women not receiving any medication (group C).. Mean age at pregnancy was 28.3 years. 75.7% of the women had Crohn's disease and 21.8% had ulcerative colitis, with a mean disease duration of 6.8 years at inclusion. Of the 215 pregnancies, there were 138 births (142 newborns), and the mean birth weight was 3135 g. There were 86 pregnancies in group A, 84 in group B and 45 in group C. Interrupted pregnancies occurred in 36% of patients enrolled in group A, 33% of patients enrolled in group B, and 40% of patients enrolled in group C; congenital abnormalities arose in 3.6% of group A cases and 7.1% of group B cases. No significant differences were found between the three groups in overall pregnancy outcome.. The results obtained from this cohort indicate that thiopurine use during pregnancy is not associated with increased risks, including congenital abnormalities.

Topics: Abnormalities, Drug-Induced; Adult; Birth Weight; Cohort Studies; Female; France; Humans; Immunosuppressive Agents; Infant, Newborn; Inflammatory Bowel Diseases; Maternal-Fetal Exchange; Mercaptopurine; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Treatment Outcome; Young Adult

Allopurinol potentiates azathioprine and 6-mercaptopurine (6-MP) by increasing 6-thioguanine nucleotide (6-TGN) metabolite concentrations. The outcome might also be improved by adding allopurinol in individuals who preferentially produce 6-methylmercaptopurine nucleotides (6-MMPN), rather than 6-TGN. The aim of the present study was to investigate the effect of allopurinol on concentrations of 6-MMPN and 6-TGN in individuals with a high ratio of these metabolites (>20), which is indicative of a poor thiopurine response.. Sixteen individuals were identified who were taking azathioprine or 6-MP, and were commenced on allopurinol to improve a high 6-MMPN:TGN ratio. Metabolite concentrations were compared before and after commencing allopurinol, and markers of disease control were compared.. The addition of 100-300 mg allopurinol daily and thiopurine dose reduction (17-50% of the original dose) resulted in a reduction of the median (and range) 6-MMPN concentration, from 11,643 (3,365-27,832) to 221 (55-844) pmol/8×10(8) red blood cells (RBC; P=0.0005), increased 6-TGN from 162 (125-300) to 332 (135-923) pmol/8×10(8) RBC (P=0.0005), and reduced the 6-MMPN:6-TGN ratio from 63 (12-199) to 1 (0.1-4.5) (P=0.0005). There was a significant reduction in steroid dose requirements at 12 months (P=0.04) and trends for improvement in other markers of disease control. One patient developed red cell aplasia that resolved upon stopping azathioprine and allopurinol.. In those with a high 6-MMPN:6-TGN ratio (>20), response to thiopurine treatment might be improved by the addition of allopurinol, together with a reduced thiopurine dose and close hematological monitoring.

Topics: Adult; Allopurinol; Anti-Inflammatory Agents; Azathioprine; Biotransformation; Drug Therapy, Combination; Enzyme Inhibitors; Erythrocyte Count; Female; Gastrointestinal Agents; Guanine Nucleotides; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; New Zealand; Red-Cell Aplasia, Pure; Retrospective Studies; Steroids; Thionucleotides; Time Factors; Treatment Outcome; Xanthine Oxidase

Topics: Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Risk Assessment; Skin Neoplasms

We performed a worldwide survey to evaluate the extent to which gastroenterologists who are experts in the field of inflammatory bowel diseases (IBDs) are utilizing thiopurine metabolism in practice.. This was a Web-based cross-sectional survey consisting of 12 multiple-choice and open-ended questions.. Between December 2009 and April 2010, 175 questionnaires were received. The proportion of practitioners with access and reimbursement for thiopurine S-methyltransferase (TPMT) genotype, TPMT phenotype, 6-thioguanine nucleotides (6-TGN) levels, and 6-methylmercaptopurine ribonucleotides (6-MMP) levels was 48%, 54%, 44%, and 35%, respectively. Before azathioprine initiation, TPMT genotype and phenotype were performed by only 30% and 43% of responders, respectively. In patients on thiopurine therapy, 6-TGN and 6-MMP levels were determined by 54% and 44% of responders, respectively. Only 27% of physicians always wait for TMPT activity/genotype results before initiating azathioprine and 81% do not routinely recheck metabolite levels after dose escalation or reduction. In cases of very high or low TPMT activity, 75% and 74% of practitioners take into account TMPT activity result, respectively. If access to all azathioprine metabolite measurements was available and if all these tests were reimbursed by public health insurance, 47% of responders would use these tests more often in their practice. The availability and reimbursement of TPMT status and azathioprine metabolites strongly influenced experts' attitudes.. Thiopurine testing is relatively underutilized by IBD gastroenterologists. The availability and reimbursement of TPMT status and azathioprine metabolites strongly influence the management of IBD patients treated with thiopurines.

Topics: Azathioprine; Biomarkers; Cross-Sectional Studies; Gastroenterology; Genetic Testing; Genotype; Global Health; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Phenotype; Practice Patterns, Physicians'; Surveys and Questionnaires

To investigate the effects of azathioprine/6-mercaptopurine (AZA/6-MP) on birth outcomes in women with inflammatory bowel disease (IBD).. Details of pregnant women with IBD were obtained through an ObstetriX Database in 3 major teaching hospitals in Sydney from 1996 to 2006. Medical records were reviewed. Birth outcomes of interest were single live births, low birth weight (LBW) at term (<2500 g), preterm births (<37 weeks gestation), neonatal adverse outcomes, and congenital anomaly. Placental blood flow during third trimester of pregnancy was measured using arterial Doppler ultrasonography, where available.. All women had IBD diagnosed before pregnancy. 19 births were exposed to AZA/6-MP. 74 births that were never exposed to AZA/6-MP were selected as controls. Preterm birth was seen in 26.3% of the exposed group as compared to 13.5% of controls (p<0.001). However, in univariate analysis, preterm birth was not associated with AZA/6-MP (OR=2.28; CI: 0.67-7.73). There was 1 neonatal adverse outcome in the exposed group as compared to 4 in controls (5.3% vs 5.4%, p=0.97). One congenital anomaly was seen in each group (p=0.27). No LBW at term was seen in either group. Placental blood flow in 4 women exposed to AZA/6-MP was normal.. The use of AZA/6-MP during pregnancy in IBD women was not associated with an increased risk of preterm birth, LBW at term, neonatal adverse outcomes and congenital anomalies.

Topics: Adult; Azathioprine; Female; Gestational Age; Humans; Immunosuppressive Agents; Infant, Low Birth Weight; Infant, Newborn; Inflammatory Bowel Diseases; Live Birth; Mercaptopurine; Placental Circulation; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Premature Birth

Prospective follow-up for a median of 35 months of a French cohort of 19 486 patients with inflammatory bowel disease showed a nearly 4-fold increase in the risk of lymphoma in patients exposed to azathioprine or mercaptopurine (relative risk 3.75; 95% confidence interval 1.59 to 8.85). This risk should be taken into account when weighing the likely benefits of these drugs in treatment of patients with severe chronic inflammatory bowel disease no longer responding to first-line treatment.

Topics: Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Lymphoma; Mercaptopurine

Low thiopurine-methyl-transferase (TPMT) activity and high 6-thioguanine-nucleotide (6TGN) concentrations have been linked to therapeutic success in inflammatory bowel disease patients treated with thiopurines; however, this has not been implemented in clinical practice.. To identify a therapeutic threshold value for TPMT or 6TGN concentrations, and their capability to predict treatment safety and efficacy.. Prospective multicentre study including steroid-resistant/dependent patients starting thiopurines. The TPMT activity was determined at inclusion (>5 U/mL required). Azathioprine metabolites [6TGN, 6-methyl-mercaptopurine ribonucleotides (6MMP), and 6TGN/6MMP and 6TGN/TPMT ratios] were periodically monitored during steroid tapering and after withdrawal for 6 months or until a new flare occurred.. A total of 113 patients were analysed (62% clinical response). Areas under the receiver operating characteristic (ROC) curve (AUC) relating clinical response and metabolite levels at 2, 4 and 6 months after steroid withdrawal were less than 0.7. The AUCs relating final response and initial TPMT activity or metabolite concentrations at 2, 4, 8 and 16 weeks after starting thiopurines were less than 0.7. No cut-off point with worthwhile sensitivity/specificity was found. Eight (7%) patients developed thiopurine-related toxicity that could not be linked to TPMT activity or 6TGN levels.. Our results do not support determination of TPMT activity or 6TGN concentrations to predict treatment outcome, and no useful serum metabolites threshold value to adjust the drug's dose was identified.

Topics: Adolescent; Adult; Aged; Area Under Curve; Azathioprine; Biomarkers; Dose-Response Relationship, Drug; Female; Guanine Nucleotides; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Middle Aged; Prospective Studies; ROC Curve; Thionucleotides; Treatment Outcome; Young Adult

Immune suppressant medications such as thiopurines and anti-tumor necrosis factor agents are important for maintaining disease control in most patients with inflammatory bowel diseases (IBDs); however, their use has been associated with the development of malignant lymphoma. The purpose of this Dutch nationwide study was to estimate the relative risk of malignant lymphoma in IBD patients.. IBD patients who developed a lymphoma between 1997 and 2004 were identified using the Dutch National Database of PALGA. Data from confirmed cases were collected from individual hospitals, including data on Epstein-Barr virus (EBV). The age-adjusted 8-year incidence of malignant lymphoma in the Netherlands was retrieved from the Central Bureau of Statistics.. Forty-two hospitals were visited and 285 matches evaluated in the total cohort of 17,834 IBD patients. Forty-four lymphomas were observed, resulting in a relative risk of 1.27 (95% confidence interval [CI]: 0.92-1.68). Only 19 of 44 patients (43%) were exposed to azathioprine/6-mercaptopurine (AZA/6-MP). Remarkably, 92% of patients (11/12) with EBV-positive lymphoma used AZA/6-MP, in contrast to only 19% patients (4/21) with EBV-negative lymphoma, suggesting a strong relation between EBV-positive lymphoma and thiopurine use.. This nationwide study does not suggest a significant overall increased risk for lymphoma in IBD patients. A distinct correlation between EBV-positive lymphoma and AZA/6-MP use was observed.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azathioprine; Case-Control Studies; Child; Child, Preschool; Cohort Studies; Epstein-Barr Virus Infections; Female; Follow-Up Studies; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Incidence; Infant; Infant, Newborn; Inflammatory Bowel Diseases; Lymphoma; Male; Mercaptopurine; Middle Aged; Netherlands; Prognosis; Risk Factors; Survival Rate; Young Adult

Mesenchymal stromal cells (MSC) have both multilineage differentiation capacity and immunosuppressive properties. Promising results with MSC administration have been obtained in experimental colitis. Clinical application of MSC for the treatment of inflammatory bowel disease (IBD) is currently under investigation in phase I-III trials in patients with past or concurrent immunomodulating therapy. However, little is known about MSC interactions with these immunosuppressive drugs. To address this issue we studied the combined effect of MSC and IBD drugs in in vitro functionality assays.. The effects of azathioprine, methotrexate, 6-mercaptopurine and anti-tumor necrosis factor (TNF)-α on MSC phenotype, survival, differentiation capacity and immunosuppressive capacity were studied.. MSC exposed to physiologically relevant concentrations of IBD drugs displayed a normal morphology and fulfilled phenotypic and functional criteria for MSC. Differentiation into adipocyte and osteocyte lineages was not affected and cells exhibited normal survival after exposure to the various drugs. MSC suppression of peripheral blood mononuclear cell (PBMC) proliferation in vitro was not hampered by IBD drugs. In fact, in the presence of 6-mercaptopurine and anti-TNF-α antibodies, the inhibitory effect of this drug alone was enhanced, suggesting an additive effect of pharmacotherapy and MSC treatment.. This study demonstrates that, in vitro, MSC phenotype and function are not affected by therapeutic concentrations of drugs commonly used in the treatment of IBD. These findings are important for the potential clinical use of MSC in combination with immunomodulating drugs and anti-TNF-α therapy.

Topics: Adipogenesis; Antibodies, Monoclonal; Azathioprine; Cell Differentiation; Cell Survival; Cells, Cultured; Combined Modality Therapy; Humans; Immune Tolerance; Immunosuppression Therapy; Inflammatory Bowel Diseases; Mercaptopurine; Mesenchymal Stem Cells; Methotrexate; Osteogenesis; Pluripotent Stem Cells; Tumor Necrosis Factor-alpha

Clinical response to thiopurine medication is related to the concentration of its metabolites. Proxy measures are traditionally used to assess dose adequacy. We present our experience of using tioguanine (previously known/formerly referred to as thioguanine) metabolite measurements in paediatric patients and evaluate their effect on clinical practice.. To report our experience of using tioguanine metabolite measurements in paediatric patients and to evaluate their effects on clinical practice.. The 6-tioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) were measured in children prescribed thiopurine medication for at least 3 months. Data were collected on thiopurine methyl transferase (TPMT) genotype, drug dose, laboratory indices and management changes. Therapeutic 6-TGN levels were defined as 235-400 pmol/8 × 10(8) RBCs. Seventy individuals (30 males) with a median age of 15 years. Underlying diagnoses were 'IBD' (68/70) and two cases of eosinophilic colitis. Sixty-three were treated with azathioprine and seven with mercaptopurine. A total of 103 separate measurements were made.. On initial measurement, 68% of patients had 6-TGN levels outside therapeutic levels despite standard thiopurine dosing. Initial 6-TGN levels were significantly higher in patients with TPMT mutations. Toxicity occurred in seven cases. The 6-TGN levels were significantly higher in those with signs of marrow toxicity. The 6-TGN level correlated with WBC, leukocyte count, mean corpuscular volume (MCV) and ΔMCV; however, the ability of each of these to predict therapeutic 6-TGN levels was poor. After initial measurement, management was changed in 25/70 cases (36%).. 6-TGN levels were therapeutic in a minority of those patients who were tested. Proxy measures perform poorly in predicting therapeutic 6-TGN levels. Measuring thiopurine metabolites is useful for dosage adjustment in children, and for the detection of potential toxicity.

Topics: Adolescent; Azathioprine; Biomarkers; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Female; Guanine Nucleotides; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Retrospective Studies; Thionucleotides; Time Factors; Treatment Outcome

Topics: Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases

Misconceptions are common in the care of patients with inflammatory bowel disease (IBD). In this paper, we state the most commonly found misconceptions in clinical practice and deal with the use of 5-aminosalicylates and thiopurines, to review the related scientific evidence, and make appropriate recommendations. Prevention of errors needs knowledge to avoid making such errors through ignorance. However, the amount of knowledge is increasing so quickly that one new danger is an overabundance of information. IBD is a model of a very complex disease and our goal with this review is to summarize the key evidence for the most common daily clinical problems. With regard to the use of 5-aminosalicylates, the best practice may to be consider abandoning the use of these drugs in patients with small bowel Crohn' s disease. The combined approach with oral plus topical 5-aminosalicylates should be the first-line therapy in patients with active ulcerative colitis; once-daily treatment should be offered as a first choice regimen due to its better compliance and higher efficacy. With regard to thiopurines, they seem to be as effective in ulcerative colitis as in Crohn' s disease. Underdosing of thiopurines is a form of undertreatment. Thiopurines should probably be continued indefinitely because their withdrawal is associated with a high risk of relapse. Mercaptopurine is a safe alternative in patients with digestive intolerance or hepatotoxicity due to azathioprine. Finally, thiopurine methyltransferase (TPMT) screening cannot substitute for regular monitoring because the majority of cases of myelotoxicity are not TPMT-related.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Mesalamine

Topics: Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases

The objective of this study was to assess inflammatory bowel disease (IBD) medications in relation to lymphoma risk.. Information on IBD and relevant medications and other utilization was obtained from the Kaiser Permanente IBD Registry, 1996-2009. Lymphoma cases were ascertained from the Kaiser Permanente Cancer Registry. Lymphoma incidence was compared between the IBD cohort and the general Kaiser Permanente population.. Of the 16,023 IBD patients without human immunodeficiency virus followed an average 5.8 years, 43 developed lymphoma. IBD patients with and without lymphoma did not differ with respect to past IBD-related visits, procedures, or tests. The standardized incidence rate ratio (SIRR) for lymphoma among IBD patients with no dispensing of thiopurine or anti-tumor necrosis factor (TNF) was 1.0 (95% confidence interval (CI): 0.96-1.1). Of the 21,282 person-years involving exposure to thiopurine or anti-TNF, 81% involved thiopurine alone; 3%, anti-TNF alone; and 16%, combination therapy. Among patients with thiopurine but not anti-TNF dispensings, the SIRR was 0.3 (95% CI: 0.2-0.4) for past use and 1.4 for current use (95% CI: 1.2-2.7). Among patients with dispensing of anti-TNF (with and without thiopurine), the SIRR was 5.5 for past use (95% CI: 4.5-6.6) and 4.4 for current use (95% CI: 3.4-5.4). The most common lymphoma subtypes were diffuse large B-cell lymphoma (44%), follicular lymphoma (14%), and Hodgkin's disease (12%).. Our study provides evidence that IBD alone is not associated with the risk of lymphoma. Use of anti-TNF with thiopurine and current use of thiopurine alone were associated with increased risk, although the effect of disease severity merits further evaluation.

Topics: Adalimumab; Adolescent; Adult; Aged; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Child; Child, Preschool; Cohort Studies; Drug Therapy, Combination; Female; Humans; Incidence; Infant; Infant, Newborn; Inflammatory Bowel Diseases; Infliximab; Lymphoma; Male; Mercaptopurine; Middle Aged; Risk Factors; Tumor Necrosis Factor-alpha; Young Adult

Levels of the thiopurine metabolites 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine commonly are monitored during thiopurine therapy for inflammatory bowel disease despite this test's high cost and poor prediction of clinical response (sensitivity, 62%; specificity, 72%). We investigated whether patterns in common laboratory parameters might be used to identify appropriate immunologic responses to thiopurine and whether they are more accurate than measurements of thiopurine metabolites in identifying patients who respond to therapy.. We identified 774 patients with inflammatory bowel disease on thiopurine therapy using metabolite and standard laboratory tests over a 24-hour time period. Machine learning algorithms were developed using laboratory values and age in a random training set of 70% of the cases; these algorithms were tested in the remaining 30% of the cases.. A random forest algorithm was developed based on laboratory and age data; it differentiated clinical responders from nonresponders in the test set with an area under the receiver operating characteristic (AUROC) curve of 0.856. In contrast, 6-TGN levels differentiated clinical responders from nonresponders with an AUROC of 0.594 (P < .001). Algorithms developed to identify thiopurine nonadherence (AUROC, 0.813) and thiopurine shunters (AUROC, 0.797) were accurate.. Algorithms that use age and laboratory values can differentiate clinical response, nonadherence, and shunting of thiopurine metabolism among patients who take thiopurines. This approach was less costly and more accurate than 6-TGN metabolite measurements in predicting clinical response. If validated, this approach would provide a low-cost, rapid alternative to metabolite measurements for monitoring thiopurine use.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Algorithms; Artificial Intelligence; Child; Child, Preschool; Drug Monitoring; Female; Guanine Nucleotides; Humans; Immunologic Factors; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Thionucleotides; Young Adult

There is a lack of research describing the associations between thiopurine methyltransferase (TPMT)/inosine triphosphate pyrophosphatase (ITPA) genotypes and long-term clinical outcomes. We investigated whether TPMT/ITPA genotypes predicted long-term clinical response in Korean patients with inflammatory bowel diseases (IBDs) undergoing thiopurine treatment. A total of 204 patients with IBD in whom thiopurine treatment was indicated were enrolled and categorized by TPMT and ITPA genotypes. Long-term follow-up clinical data for these patients were analyzed with specific focus on disease relapse. Of the 204 patients, 162 (79.4%) patients using thiopurines achieved remission and were included in an analysis of long-term clinical outcomes. There were no significant differences in disease relapse-free survival between wild and mutant types of TPMT (P=0.903) or ITPA (P=0.392), according to the results of the log-rank analysis. Our study suggests that TPMT and ITPA genotypes may not affect the rates of disease relapse in IBD patients treated with thiopurines. Further studies are indicated to confirm the utility of TPMT/ITPA genotyping to guide clinicians formulating individualized treatments for IBD patients requiring thiopurine therapy.

Topics: Asian People; Azathioprine; Gene Frequency; Genotype; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Pyrophosphatases; Recurrence; Treatment Outcome

This study compared youth and parent-proxy reports of health-related quality of life (HRQoL) among youth with inflammatory bowel disease (IBD) to published comparison group data and examined concordance between youth and parent-proxy reports of HRQoL.. One hundred thirty-six youth and parent-proxy reports on the PedsQL 4.0 Generic Core Scales were compared to published data from chronically ill, acutely ill, and healthy comparison groups using independent samples t-tests. Reporter agreement was examined using paired samples t-tests and intraclass correlations (ICCs).. Youth with IBD reported lower psychosocial functioning than the healthy comparison group, higher physical and social functioning than the chronically ill group, and lower school functioning than all published comparison groups. Parent-proxy reports of youth HRQoL were higher than the chronically ill group, but lower than the healthy group on all scales except psychosocial functioning. Youth with active IBD reported lower physical health domain scores than youth with inactive disease. Concordance between youth and parent-proxy reports was moderate, with the lowest agreement in school and social functioning.. Youth with IBD and their parents rate HRQoL as lower than healthy youth but do not perceive the impact of IBD to be as limiting as in other chronic conditions. Youth report suggests that IBD may be particularly detrimental to HRQoL in the school functioning domain. Moderate agreement between parent and youth reports substantiates continued use of multiple informants in studies of pediatric HRQoL.

Topics: Adolescent; Adult; Child; Female; Humans; Inflammatory Bowel Diseases; Interpersonal Relations; Male; Mercaptopurine; Mesalamine; Methylthioinosine; Middle Aged; Parents; Quality of Life; Self Concept; Severity of Illness Index; Sickness Impact Profile; Social Adjustment; Thioguanine

The thiopurine drugs, azathioprine and mercaptopurine (MP), are established treatments for IBD. However, therapeutic failure caused by adverse drug reactions occurs frequently.. To study combination of allopurinol with reduced-dose thiopurine in an attempt to avoid adverse drug reactions in the treatment of IBD.. Patients with drug reactions to full-dose thiopurines were recruited for combination therapy in two IBD centres in this retrospective study. Dosing was guided by measuring thiopurine methyltransferase (for UK patients) or thioguanine nucleotides and methyl-6MP (Australian patients). Response was monitored by clinical activity indices.. Of 41 patients, 25 had non-hepatic and 16 had hepatitic reactions. Clinical remission was achieved in 32 patients (78%) with a median follow-up of 41 weeks (range 0.5-400). Patients who did not respond to combination therapy tended to fail early with the same adverse reaction. The relative risk of having an adverse reaction with methyl-6MP in the top interquartile range was 2.7 (1.3-28) times that with methyl-6MP in the lower three quartiles (95% confidence interval).. The combined experience from our centres is the largest reported experience of this combination therapy strategy in IBD, and the first to provide evidence for benefit in thiopurine and allopurinol co-therapy to avoid non-hepatitic adverse drug reactions.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Allopurinol; Azathioprine; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; London; Male; Mercaptopurine; Middle Aged; Queensland; Retrospective Studies; Treatment Outcome

To examine perceived barriers to medication adherence in inflammatory bowel disease (IBD) treatment and their relationship with adherence using a combined forced choice and semi-structured interview assessment approach.. Sixteen adolescents with IBD and their parents participated in an open-ended interview regarding adherence barriers and completed quantitative measures of adherence, barriers to treatment, and disease severity.. The most commonly identified barriers to adherence were forgetting, interference with other activities, difficulty swallowing pills, and not being at home. Number of reported barriers was positively correlated with objective nonadherence for 6-MP/azathioprine. Nonadherence frequency was 42% for 6-MP/azathoprine and 50% for 5-ASA medications.. Using a combined assessment approach, patients and parents reported several barriers to treatment adherence that are appropriate for clinical intervention. This is critical given the significant medication nonadherence observed in this sample and the relationship between total number of barriers and disease management problems.

Topics: Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Interviews as Topic; Male; Medication Adherence; Mercaptopurine; Mesalamine; Severity of Illness Index; Social Environment

Thiopurines have proven efficacy in long-term maintenance therapy of inflammatory bowel disease (IBD). Limited data are available with regard to factors predicting effectiveness and failure of long-term thiopurine use in IBD patients.. The data in this retrospective study are based on an 8-year intercept cohort of previous or present thiopurine-using IBD patients. Both cohorts are assessed by descriptive and statistical analysis aimed at determining thiopurine effectiveness and the variables that are predictive for failure of thiopurine therapy.. In all, 363 IBD patients were included (60% female), 63% with Crohn's disease and 33% with ulcerative colitis. Overall, thiopurines were continued in 145/363 (40%) and discontinued in 208/363 (57%) patients. The proportion of patients still using thiopurines at 3, 6, 12, 24, and 60 months was 73%, 69%, 63%, 51%, and 42%, respectively. Patients discontinued thiopurines due to adverse events (39%), refractoriness (16%), and ongoing remission / patient's request (4%). 6-methylmercaptopurine (6-MMP) concentration and 6-MMP/6-thioguanine nucleotides (6-TGN) ratio were significant higher in the failure group. Prolonged continuation of thiopurines was associated with a decreased risk of discontinuation.. Azathioprine and 6-mercaptopurine were considered effective in approximately 40% of IBD patients after 5 years of treatment. A quarter of the patients discontinued thiopurines within 3 months, mostly due to adverse events. A high 6-MMP concentration or 6-MMP/6-TGN ratio was associated with therapeutic failure. If thiopurine use was successfully initiated in the first months, its use was usually extended over many years, as long-term use was associated with continuation of therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Azathioprine; Child; Cohort Studies; Female; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Survival Rate; Time Factors; Young Adult

The monitoring of 6-thioguanine nucleotides (6-TGN) levels is warranted during thiopurine therapy for patients with inflammatory bowel diseases.. The aim of this study was to elucidate the parameters that can predict the 6-TGN levels among Japanese patients with inflammatory bowel diseases undergoing thiopurine therapy.. The 6-TGN levels were measured in 54 patients with inflammatory bowel diseases (32 with ulcerative colitis and 22 with Crohn's disease), who had been administered azathioprine or 6-mercaptopurine for more than 90 days. Possible correlations between the hematologic parameters and 6-TGN levels were investigated. The clinical and hematologic variables were evaluated to determine the 6-TGN levels of less than or over 235 pmol/8 x 10(8) RBCs.. The 6-TGN levels correlated significantly with changes in the mean corpuscular volume (R = 0.423, p = 0.001) and the lymphocyte counts (R = -0.280, p = 0.04). A multivariate analysis revealed changes in the mean corpuscular volume (OR: 1.22, 95% CI: 1.07-1.40) and hemoglobin levels (OR: 0.59, 95% CI: 0.35-0.99) to be factors predictive of the 6-TGN levels. An increase in the mean corpuscular volume of 3.5 fl was determined to be the most preferable cut-off value to distinguish patients with 6-TGN >or= 235 pmol/8 x 10(8) RBCs from those with a lower concentration.. Changes in the mean corpuscular volume are considered to be predictive of the 6-TGN levels in patients with inflammatory bowel diseases receiving thiopurine therapy.

Topics: Adult; Azathioprine; Biomarkers, Pharmacological; Chi-Square Distribution; Erythrocyte Volume; Female; Humans; Inflammatory Bowel Diseases; Japan; Logistic Models; Male; Mercaptopurine; Nucleotides; Predictive Value of Tests; Retrospective Studies; Statistics, Nonparametric; Thioguanine

Azathioprine (AZA) and 6-mercaptopurine (6MP) are used in the treatment of paediatric inflammatory bowel disease (IBD). Genetic variations in thiopurine S-methyltranfarase (TPMT) gene have been correlated with enzyme activity and with the occurrence of adverse events to AZA and 6MP. The aim of the present study was to investigate the frequency of the functional TPMT polymorphisms and their association with the occurrence of adverse events during azathioprine therapy in a paediatric IBD cohort.. Ninety-seven thiopurine-treated paediatric IBD patients (41.24% boys and 58.76% girls) with a mean age 11.25 years (range 3-16), were assessed for TPMT polymorphisms and adverse events.. Of the 97 patients enrolled in the study, 18 (18.56%) were heterozygous mutated; two (2.06%) were homozygous for a mutated TPMT gene. Ten patients (10.31%) developed adverse effects, and four of them (40%) had one of the variant alleles.. In this small cohort of subjects, no association was found between TPMT polymorphisms and the occurrence of thiopurines-related adverse events.

Topics: Adolescent; Alleles; Azathioprine; Child; Child, Preschool; Female; Genetic Association Studies; Greece; Heterozygote; Homozygote; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length

Crohn's disease and ulcerative colitis are chronic, immune-mediated inflammatory bowel diseases (IBDs) of unknown etiology with high morbidity in patients who are not receiving adequate medical treatment. A variety of medical therapies are currently available, and much progress has been made to alleviate symptoms and restore quality of life. The mainstay of treatment in those with moderate to severe disease consists of medications that alter or suppress the body's immunologic attack on its own gastrointestinal tract. The medications currently in use are highly effective when given in the appropriate clinical context, but side effects are not uncommon and must be treated expeditiously when they occur. One class of immunosuppressive medication, 6-mercaptopurine and its prodrug azathioprine, is effective at inducing remission and improving the lives of patients with IBD. The most common side effects of these drugs are allergic reactions and rarely can they be severe and life threatening. These reactions can sometimes be overcome by desensitizing the immune system to the drug. This review emphasizes allergy to 6-mercaptopurine and azathioprine and the process of desensitization when these allergic reactions occur in order to continue use of this important class of medication in the total treatment of IBD.

Topics: Azathioprine; Desensitization, Immunologic; Drug Hypersensitivity; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine

Monitoring of thiopurine metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP) is used to assess compliance and explain adverse reactions in IBD-patients. Correlations between dosage, metabolite concentrations and therapeutic efficacy or toxicity are contradictive. Research is complicated by analytical problems as matrices analyzed and analytical procedures vary widely. Moreover, stability of thiopurine metabolites is not well documented, yet pivotal for interpretation of analytical outcomes. Therefore, we prospectively investigated metabolite stability in blood samples under standard storage conditions.. Stability at room temperature and refrigeration (22 degrees C, 4 degrees C) was investigated during 1 week and frozen samples (-20 degrees C, -80 degrees C) were analyzed during 6 months storage. Ten patient samples were analyzed for each study period.. Median 6-TGN concentrations on day 7 decreased significantly to 53% and 90% during storage at ambient temperature or refrigeration. Median 6-MMP concentrations on day 7 decreased significantly to 55% and 86%, respectively. Samples stored at -20 degrees C also showed significant decreases in both 6-TGN and 6-MMP in comparison with baseline values. At -80 degrees C, only 6-MMP showed a significant decrease in values compared to baseline.. The stability of thiopurine metabolites is clearly a limiting factor in studies investigating utilisation of TDM and correlations with therapeutic outcome in IBD-patients. This has to be accounted for in clinical practice and (multi-center) trials investigating thiopurine drugs.

Topics: Chromatography, High Pressure Liquid; Drug Stability; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Reproducibility of Results; Specimen Handling; Statistics, Nonparametric; Thioguanine

Monitoring of thiopurine metabolites is important due to a complex metabolism with large interindividual variation, but the suitability of currently used methods has been questioned. The drawbacks include poor reproducibility, the inability to differentiate between the different analytes, as well as the use of a nontarget matrix. Further research should be directed toward measuring thiopurine metabolites in mononuclear cells, measuring the different nucleotides specifically, as well as measuring the incorporation of thioguanine into DNA. The studies should not be limited to thioguanosine nucleotides but include methylthioinosine nucleotides as well.

Topics: Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Purines; Thioguanine

Topics: Allopurinol; Antimetabolites; Azathioprine; Drug Therapy, Combination; Humans; Inflammatory Bowel Diseases; Mercaptopurine

Immunomodulators are used as maintenance treatment of inflammatory bowel disease (IBD). Data regarding their possible effects in the course of pregnancy when the father is exposed at the time of conception are limited.. To evaluate the outcomes of pregnancies of which the fathers were exposed to thiopurines at the time of conception. A series of male patients followed in seven IBD clinics in Madrid, Spain, was studied. Any exposure to thiopurines during the 3 months preceding conception was considered significant. Controls were pregnancies fathered by patients who either had never been treated with thiopurines or had interrupted them >3 months before conception. Statistical comparisons and multivariate analysis were carried out with the generalized estimating equations model.. There were 46 conceptions in the exposed group (mercaptopurine 9, azathioprine 37) and 84 in the control group. In the exposed group, there were more Crohn's patients (82.6% vs. 53.6%), the duration of the disease was longer (median: 8 vs. 5 years), fathers were slightly older (mean: 34.2 vs. 32.7 years), and there were fewer patients on mesalamine (15.2% vs. 47.6%). Otherwise, baseline characteristics were similar in both groups. There were no significant differences regarding unsuccessful pregnancies-namely, spontaneous abortions, ectopic pregnancies, anembryonic pregnancies, or fetal deaths (10.9% exposed group vs. 13.1% control group; odds ratio (OR): 0.79, confidence interval (CI): 0.22-2.85), preterm births (4.3% vs. 2.4%; OR: 1.3, CI: 0.22-7.61), low birth weight (6.5% vs. 6%; OR: 1.06, CI: 0.25-4.54), or congenital malformations (2.2% vs. 2.4%; OR: 0.82, CI: 0.08-9). No infant neoplasms were detected. The proportion of conceptions that needed >1 year to be achieved was higher in the exposed group, but this was not statistically significant (15.2% vs. 8.3%; OR: 1.92, CI: 0.54-6.88). Multivariate analysis was carried out for unsuccessful pregnancies and fertility impairment, and it showed that, although mesalamine exposure confounded the effect of the exposure to thiopurines on these outcomes, this effect was still nonsignificant (respectively, OR: 0.49, CI: 0.17-1.44; OR: 2.82, CI: 0.7-11.38).. Our data do not support the practice of routinely recommending to male patients that they interrupt thiopurines when wanting to conceive.

Topics: Azathioprine; Fathers; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Odds Ratio; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Spain; Treatment Outcome

6-Mercaptopurine (6-MP) and azathioprine (AZA) are widely used as maintenance therapy in children with inflammatory bowel disease (IBD). However, proper 6-thioguanine nucleotide (6-TGN) concentrations in Japanese children with IBD have not been reported.. This retrospective review examines 32 ulcerative colitis (UC) patients and 19 Crohn's disease (CD) patients (12.87 ± 3.56 years) who required 6-MP or AZA to maintain disease remission. All patients were treated with 6-MP or AZA for at least 3 weeks prior to this study in addition to previous treatment. 6-MP dose, 6-TGN levels, assayed by high-performance liquid chromatography, as well as laboratory data were evaluated.. Thirty-five children were successfully kept in remission with 6-MP and AZA therapy after weaning off corticosteroids. Overall, 123 measurements (59 active disease, 64 in remission) were analyzed. The mean 6-TGN concentration of the entire study population was 499.61 ± 249.35 pmol/8 × 10(8) red blood cell. The mean 6-MP dose in patients with active disease (0.910 ± 0.326 mg/kg per day) was significantly higher than for patients in remission (0.749 ± 0.225) (P = 0.0016). A significant inverse correlation was found between white blood cell counts and 6-TGN concentrations (r = 0.275, P < 0.002). Two patients experienced leukopenia with alopecia, and four transiently experienced increased serum levels of pancreatic enzymes, although no thiopurine S-methyl transferase mutations were confirmed.. The doses of 6-MP or AZA needed to maintain remission in Japanese children with IBD are lower than those reported in Western countries. However, 6-TGN concentrations in this population are higher than previously reported.

Topics: Adolescent; Azathioprine; Biomarkers, Pharmacological; Child; Chromatography, High Pressure Liquid; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Drug Monitoring; Female; Follow-Up Studies; Guanine Nucleotides; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Japan; Male; Mercaptopurine; Remission Induction; Retrospective Studies; Thionucleotides; Treatment Outcome

Topics: Allopurinol; Azathioprine; Biotransformation; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Polymorphism, Genetic; Xanthine Oxidase

Allopurinol has been presented as a safe and effective adjunct to thiopurine therapy in inflammatory bowel disease (IBD). We aimed to determine the rate of infectious complications and clinical successes with a combination of thiopurine/allopurinol in IBD, and to identify which variables predict 6-thioguanine, 6-methylmercaptopurine, and white blood cell levels. Additionally we aimed to identify which variables predict complications.. A retrospective database search identified patients with inflammatory bowel disease on both thiopurines and allopurinol. Regression modeling was used to identify which variables predicted metabolite levels, white blood cell levels, and complications.. Twenty-seven subjects were found, with 20 treated intentionally and 7 inadvertently after a concurrent gout diagnosis. Thirteen of 20 patients had a major clinical improvement and 7 of 16 stopped steroids. Five infectious complications occurred. These included 2 cases of shingles, and one each of PCP, EBV, and viral meningitis. Significant predictors of metabolite levels included the dose of thiopurine and allopurinol, age, and BMI. Low white blood cell count levels were associated with increased doses, high BMI, and older age. Despite having only 5 events, there was a difference in absolute lymphocyte count between patients with and without infection (median 200 per mm³ vs 850 per mm³ respectively, p=0.0503).. Adjunctive allopurinol therapy in shunting patients produced major clinical improvement in 48% of patients. However, a surprising number of opportunistic infections have occurred. Low absolute lymphocyte count may be a previously unrecognized indicator of risk of opportunistic infections.

Topics: Adult; Allopurinol; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Opportunistic Infections; Retrospective Studies; Young Adult

6-mercaptopurine (6-MP) is used for the induction and maintenance of remission of inflammatory bowel disease (IBD). 6-MP is converted into 6-methylmercaptopurine (6-MMP) or 6-thioguanine nucleotides (6-TGN) intracellularly. Treatment response in IBD patients correlates with 6-TGN levels. This study prospectively evaluated the effect of allopurinol on 6-MP metabolites in adult and pediatric IBD patients. Additionally, we quantified the prevalence of preferential metabolism towards 6-MMP through a retrospective analysis of IBD patients.. Twenty patients (10 adult; 10 pediatric) with evidence of preferential metabolism towards 6-MMP, (6-TGN<250 pmol/8×10⁸ RBCs and 6-MMP>5000 pmol/8×10⁸ RBCs) were prospectively treated with allopurinol 100 mg daily and up to 100 mg of 6-MP. 6-MP dose was adjusted after a 3-week metabolite measurement.. The median dose of 6-MP for adults decreased from 100mg daily (range: 37.5-150 mg) to 25mg daily (range: 12.5-50 mg). The median dose of 6-MP for pediatric patients decreased from 50 mg (range: 25-50 mg) to 10.7 mg (range: 10.7 to 21.4 mg). Mean 6-TGN levels in all subjects increased from 197.4 (± 59) to 284.8 (± 107) pmol/8×10⁸ RBCs (p=0.0005). Mean 6-MMP levels in all subjects decreased from a mean of 7719.8 (± 4716) to 404.8 (± 332) pmol/8×10⁸ RBCs (p=0.0004). There were no complications associated with allopurinol therapy. Eighty-eight (30.9%) of 285 IBD patients had evidence of preferential metabolism towards 6-MMP. The proportion of preferential metabolism was equal in adults and pediatric patients.. Our results indicate that the addition of allopurinol safely shifts metabolite production in both adult and pediatric IBD patients and that there is a high prevalence of preferential metabolism towards 6-MMP among IBD patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Allopurinol; Child; Child, Preschool; Drug Administration Schedule; Enzyme Inhibitors; Female; Guanine Nucleotides; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Middle Aged; Phenotype; Prevalence; Prospective Studies; Thionucleotides; Young Adult

Azathioprine is a thiopurine immunosuppressive antimetabolite used to chronically treat inflammatory bowel disease and autoimmune hepatitis. Azathioprine treatment is a long-term therapy and therefore it is at risk for non-adherence, which is considered an important determinant of treatment inefficacy. Measurement of 6-thioguanine and 6-methylmercaptopurine nucleotides has been recently suggested as a screener for non-adherence detection. We describe four young patients in which non-adherence to azathioprine therapy was detected only through the measurement of drug metabolite concentrations, and the criterion for non-adherence was undetectable metabolite levels. After the identification of non-adherence, patients and their families were approached and the importance of a correct drug administration was thoroughly enlightened and discussed; this allowed obtaining a full remission in all subjects. Our observations support the use of undetectable metabolite levels as indicators of non-adherence to therapy in azathioprine treated patients. The additional level of medical supervision given by this assay allows getting a better adherence to medical treatment, which results in an improvement in the response to therapy; these benefits may justify the costs associated with the assay.

Topics: Adolescent; Azathioprine; Child; Child, Preschool; Female; Guanine Nucleotides; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Medication Adherence; Mercaptopurine; Thionucleotides; Young Adult

Azathioprine (AZA) has a slow onset of action in treatment of pediatric inflammatory bowel disease (IBD). It is anticipated, that this delay correlates to the kinetics of 6-thioguanine nucleotides (6-TGN) accumulation. The aim of this study was to evaluate the time to steady state of 6-TGN concentration in red blood cells.. The inclusion criteria were: a) age 0-19 years b) IBD diagnosis c) AZA treatment initiation. High performance liquid chromatography was used for the 6-TGN analysis. Concentrations of metabolites were studied in weeks 0, 1, 2, 5, and 8 after beginning of treatment.. The inclusion criteria were matched to 18 patients with IBD. The median time to steady state of 6-TGN was 55.3 days. The mean 6-TGN concentration at the steady state achieved 326 (SD 154) pmol/8.108 erythrocytes. High erythrocyte TPMT activity corresponds to the low steady state 6-TGN concentration and vice versa. This correlation reached statistical significance (p<0.01) for the dose expressed in mg per square meter of body surface area.. The time to steady state of 6-TGN erythrocyte concentration is significantly shorter than would expected according to clinical observation describe earlier.

Topics: Adolescent; Azathioprine; Child; Child, Preschool; Female; Genotype; Guanine Nucleotides; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Prospective Studies; Severity of Illness Index; Thionucleotides; Treatment Outcome

Adverse drug reactions are a significant reason for therapeutic failure during thiopurine treatment of inflammatory bowel disease. Some smaller series in this patient population have shown that a switch to mercaptopurine may be successful in many cases of azathioprine intolerance.. To assess the long-term outcome of mercaptopurine treatment in a large patient population with azathioprine intolerance.. We identified 135 patients (74 women; median age 40 years) with Crohn's disease (n = 88) or ulcerative colitis (n = 47) and reviewed their medical records.. A total of 70 patients (52%) tolerated mercaptopurine and were followed up for 736 (362-1080) days; 65 patients discontinued mercaptopurine due to adverse events after 25 (8-92) days. Mercaptopurine was tolerated in 71% (12/17) with hepatotoxicity and in 68% (13/19) with arthralgia/myalgia during azathioprine treatment. Previous abdominal surgery was more common in mercaptopurine intolerant patients [39/65 (60%) vs. 27/70 (39%); P = 0.02] and thiopurine methyltransferase activity was higher in mercaptopurine tolerant patients than in mercaptopurine intolerant patients [13.2 (11.4-15.3) vs. 11.8 (9.6-14.2) U/mL red blood cells; P = 0.04; n = 81].. A trial of mercaptopurine should be considered in azathioprine intolerance, as half of the patients tolerate a switch to mercaptopurine. Patients with hepatotoxicity or arthralgia/myalgia during azathioprine treatment might benefit more often than those with other types of adverse events.

Topics: Adult; Azathioprine; Dose-Response Relationship, Drug; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Treatment Outcome

Individualised doses of azathioprine (AZA) may be prescribed by monitoring the levels of the enzyme thiopurine methyltransferase (TPMT). The measurements of thiopurine metabolites of AZA, 6-thioguanine (6-TGN) and 6-methylmercaptopurine (6-MMP), have also been reported as new markers of AZA activity.. To describe TPMT phenotype in our population and to establish a relationship between thiopurine metabolites,and therapeutic activity and adverse effects.. Data on TPMT were retrospectively collected from 107 patients, and 6-TGN and 6-MMP levels in 18 patients currently on treatment with AZA (Crohn's disease 5, ulcerative colitis 5, autoimmune hepatitis 5).. Mean value of TPMT was 20.19U/ml. None of the patients had a TPMT activity<5U/ml. Of the 18 patients on treatment, 13 showed sub-therapeutic levels of 6-TGN (<235pmol/8x10(8) red blood cells). Clinical remission was maintained in 45% of patients. Mean levels of 6-TGN in patients with clinical remission were 259pmol/8x10(8) red blood cells versus 209pmol/8x10(8) red blood cells in non-responders (p=0.37). There was an inverse relationship (r=-0.28) between TPMT and 6-TGN levels. Toxic effects occurred in 6 of 18 patients, with leukopenia in 5 and hyperamylasemia in 1.. Determination of TPMT and monitoring of thiopurine metabolites allows AZA treatment to be optimised, although further studies are necessary to establish therapeutic effectiveness and toxicity ranges.

Topics: Adolescent; Azathioprine; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Retrospective Studies; Thioguanine

Azathioprine and 6-mercaptopurine are often used in the treatment of patients with inflammatory bowel disease (IBD). They are prodrugs and undergo a complex metabolism to active and inactive metabolites. Thiopurine treatment is monitored in many laboratories by measuring metabolite concentrations in erythrocytes (red blood cells). The metabolites of interest are not measured directly but as hydrolysis products, which can be produced from several metabolites. The aim of this study was to examine which metabolites are actually measured during routine monitoring. Samples from 18 patients treated with a thiopurine were analyzed by a typical routine high-performance liquid chromatography method for therapeutic drug monitoring and by a newly developed specific method measuring thioguanosine monophosphate (TGMP), thioguanosine diphosphate (TGDP), and thioguanosine triphosphate (TGTP), as well as methylthioinosine monophosphate (meTIMP), and the results were compared. 6-Thioguanine nucleotide (TGN) values detected by the routine method were 69% (range 40%-90%) of the sum of TGMP, TGDP, and TGTP measured by the specific method. TGTP and TGDP contributed 85% (range 78%-90%) and 14% (range 10%-21%) of the TGN total, respectively. Thioguanosine was not found in any patient sample. The concentration of meTIMP obtained by the routine method was 548% of the value obtained by the specific method (range 340%-718%). The difference in TGN measurements between the routine and specific methods can be explained by low hydrolysis efficiency in the routine method, although the most likely explanation for the difference in meTIMP values is that not yet identified metabolites are codetermined in the routine high-performance liquid chromatography method. Concentrations reported as TGN during therapeutic drug monitoring of thiopurine metabolites consist of TGDP and TGTP with a minor contribution of the TGMP. Concentrations reported as meTIMP or methyl mercaptopurine consist in part of meTIMP, but other not yet identified metabolites are codetermined.

Topics: Adult; Aged; Aged, 80 and over; Azathioprine; Drug Monitoring; Female; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Young Adult

Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Clinical Trials as Topic; Glucocorticoids; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Mesalamine; Methotrexate; Natalizumab; Probiotics; Sulfasalazine; Treatment Outcome; Tumor Necrosis Factor-alpha

Despite the wide use of azathioprine/mercaptopurine (AZA/MP) therapy in the management of both Crohn's disease (CD) and ulcerative colitis (UC), approximately 20% of patients cannot tolerate the drugs and 30% do not respond.. To examine the efficacy and safety profile of methotrexate (MTX) in patients with CD or UC who are either intolerant or non-responsive to AZA/MP.. A total of 131 patients with IBD treated with MTX were identified. Retrospective data were obtained by case note review. Clinical response (defined as steroid withdrawal, normalization of previously raised CRP or physician's clinical assessment of improvement) was assessed at 6 months.. Clinical response in Crohn's disease occurred in 18 of 29 patients (62%) refractory to AZA/MP and 42 of 70 patients (60%) intolerant to AZA/MP, with no difference between the groups (P = 1.0). In UC, clinical response was seen in 7 of 9 (78%) patients refractory to AZA/MP and 15 of 23 (65%) intolerant to thiopurines. MTX was well tolerated in a majority of individuals.. Methotrexate appears effective in both CD and UC patients who fail to respond to or are intolerant to AZA/MP therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azathioprine; Drug Hypersensitivity; Drug Resistance; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methotrexate; Middle Aged; Treatment Outcome; Young Adult

Thiopurine methyltransferase genotyping and thiopurine metabolite testing has been established as an adjunct to monitoring patients taking thiopurine drugs. This special report describes the clinical implications for this type of testing for patients with inflammatory bowel disease who are taking thiopurine drugs. A total of 10% of patients were found to be intermediate metabolizers and the mean dosage (in mg/kg equivalent) was lower in intermediate metabolizers than extensive metabolizers. The metabolite levels did not correlate with scores measuring clinical severity but levels of 6-methylmercaptopurine were related to the dosage of the drugs. Despite considerable study of thiopurine methyltransferase testing in the literature, it is still not widely used in many geographical areas. This study adds to the evidence about using such testing as well as expanding the role of simultaneously measuring thiopurine metabolites. Further work is planned to evaluate the uptake when such testing becomes available locally as a clinical service.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cross-Sectional Studies; Genetic Testing; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Middle Aged; Young Adult

Thiopurines (azathioprine and 6-mercaptopurine) can induce life-threatening myelosuppression. This study determined the frequency, timing, and outcomes of mild and severe myelosuppression after initiation of thiopurine therapy.. This retrospective cohort study included patients with inflammatory bowel disease who were new users of thiopurines; those tested for thiopurine methyltransferase levels before therapy were excluded. Patients were followed from their first thiopurine prescription until the earliest of severe leukopenia (white blood cell count, <1.0 x 10(9)/L), severe thrombocytopenia (platelet level, <20 x 10(9)/L), the end of therapy, the first gap in therapy, disenrollment, or December 31, 2006.. Among 1997 new users, the incidence of severe leukopenia per 100 person-months was 0.16 (95% confidence interval [CI], 0.03-0.29; n = 6) in weeks 0 to 8, 0.00 in weeks 9 to 24, and 0.01 (95% CI, 0-0.03; n = 3) after week 26 of therapy. The incidence of severe neutropenia and severe thrombocytopenia per 100 person-months during the first 8 weeks of therapy was 0.51 (95% CI, 0.31-0.80; n = 19) and 0.08 (95% CI, 0.02-0.23; n = 3), respectively. During the first 8 weeks, the median duration from a normal white blood cell count to severe leukopenia was 13 days (range, 8-26 d) and to severe neutropenia was 14 days (range, 7-23 d).. The high incidence of severe myelosuppression justifies frequent monitoring during the first 8 weeks of therapy. Subsequently, the rate of severe myelosuppression and the proportion of patients who progress from mild to severe myelosuppression decrease, justifying less-frequent monitoring.

Topics: Adult; Aged; Antimetabolites; Azathioprine; Bone Marrow; Cohort Studies; Drug Monitoring; Female; Humans; Inflammatory Bowel Diseases; Leukopenia; Longitudinal Studies; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Thrombocytopenia; Time Factors; Treatment Outcome

Thiopurines are increasingly used in the treatment of inflammatory bowel disease (IBD), being the most common immunosuppressive therapy; however, potentially harmful interactions between thiopurines and other drugs (especially 5-aminosalicylic acid, 5-ASA) were described.. To explore potential interactions between thiopurines and concomitant medications.. A total of 183 consecutive IBD patients were enrolled. Clinical characteristics and concomitant medications were recorded. Thiopurine metabolism was analysed with thiopurine S-methyl transferase (TPMT) genetic variants and enzyme activity assays. Comparisons were carried out with stratification of patients according to clinical characteristics and active treatments.. Based on TPMT genetics, 95% IBD patients were wild-type homozygous, the remaining being heterozygous. Median TPMT activity was 24.9 U/Hgb g (IQR 20.7-29.5). No difference in TPMT activity was noted according to 5-ASA exposure. IBD patients on thiopurines had higher TPMT activity levels, but no dose-effect was evident. No difference in TPMT activity was observed in 41 (63%) patients co-treated with 5-ASA. In patients on active thiopurines also, 6-TGN and 6-MMP levels were evaluated and no significant difference was observed based on co-medication. TPMT activity was independently associated only with thiopurines dose (P = 0.016).. Our data suggest the absence of significant interactions between thiopurines and 5-ASA.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; DNA; Drug Interactions; Female; Genotype; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Mesalamine; Middle Aged; Multivariate Analysis; Polymerase Chain Reaction; Prospective Studies; Young Adult

Thiopurines (such as azathioprine and 6-mercaptopurine) are widely used for the treatment of patients suffering from malignancies, rheumatic disease, inflammatory bowel disease and solid organ transplant rejection. These drugs are activated and eliminated by a number of enzymes in the human body. This analyzes all the exons and exon-intron junctions of 5 enzyme genes (hypoxanthine-guanine phosphoribosyltransferase, HGPRT; inosine triphosphate pyrophosphatase, ITPA; inosine monophosphate dehydrogenases 1 and 2, IMPDH1 and IMPDH2 and guanosine monophosphate synthetase, GMPS) involved in the metabolism of thiopurine drugs. Twelve novel single nucleotide polymorphisms (SNPs) (HGPRT: IVS6-12C>A (frequency:0.003); ITPA: 569T>C (Phe189Phe, 0.003); IMPDH1: IVS8-15C>A (0.003), IVS9+227A>G (0.003), IVS17+115C>T (0.003), and 930C>T (Thr310Thr, 0.005); IMPDH2: IVS1+50G>T (0.003), IVS2+15G>A (0.010), IVS3-20G>A (0.003), 609C>T (Arg203Arg, 0.003), and 1534C>T (Arg512Trp, 0.003); and GMPS: 1563T>C (Gly521Gly, 0.003)) and 7 known SNPs (ITPA: 94C>A (Pro32Thr, 0.005), 138G>A (Gln46Gln, 0.586), and 563G>A (Glu187Glu, 0.433); IMPDH1: 987G>C (Leu329Leu, 0.113) and 1575A>G (Ala525Ala, 0.620) and GMPS: IVS5-7T>C (0.153), 993A>G (Thr331Thr, 0.153)) were identified in 200 Japanese subjects. These data should provide useful information for thiopurine therapy in the Japanese and as well as other Asian populations.

Topics: Asian People; Azathioprine; Carbon-Nitrogen Ligases; Exons; Gene Frequency; Genes, Recessive; Genetic Variation; Genotype; Guanosine Monophosphate; Humans; Hypoxanthine Phosphoribosyltransferase; Inflammatory Bowel Diseases; Inosine Triphosphatase; Introns; Mercaptopurine; Methyltransferases; Molecular Sequence Data; Mutation; Myeloid-Lymphoid Leukemia Protein; Oncogene Proteins, Fusion; Pharmacogenetics; Phenotype; Polymorphism, Single Nucleotide; Pyrophosphatases; Thionucleotides

This study was to evaluate the frequency and the course of the adverse effects of AZA/6-MP in Korean patients with inflammatory bowel disease (IBD).. Medical records of the patients with IBD treated with AZA/6-MP at Severance hospital from June 1996 to September 2006 were retrospectively analyzed.. A total of 133 patients were studied. Male to female ratio was 1.3:1. The mean age was 31.7+/-10.9 year. Adverse effects included leukopenia occurred in 75 cases (56.4%), nausea/vomiting in 32 cases (24.1%), arthralgia in 6 cases (4.5%), hepatitis in 6 cases (4.5%), skin rash in 4 cases (3.0%), herpes zoster in 3 cases (2.3%), and headache in 1 case (0.8%). Most of leucopenia (58.7%) developed within 3 months after maximal tolerated dose of AZA/6-MP and nausea/vomiting frequently occurred within 3 months after start of AZA/6-MP treatment. Thirty-eight patients (28.6%) required the discontinuation of medication due to adverse effects.. Leukopenia was the most common adverse effect of AZA/6-MP treatment. Leukopenia and nausea/vomiting developed frequently in the early period of treatment of AZA/6-MP in patients with IBD. AZA/6-MP should be used cautiously to scrutinize bone marrow suppression.

Topics: Adolescent; Adult; Azathioprine; Behcet Syndrome; Cohort Studies; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Time Factors

Topics: Antimetabolites, Antineoplastic; Azathioprine; Cohort Studies; Drug Therapy, Combination; Humans; Inflammatory Bowel Diseases; Leukopenia; Mercaptopurine

I have several patients with inflammatory bowel disease (IBD) who are pregnant or planning pregnancies. What information can I give them regarding the possible effects of IBD on pregnancy and the medications used to treat IBD during pregnancy?. Women with IBD appear to be at increased risk of giving birth prematurely, having low-birth-weight infants, and having cesarean sections. Neither 5-aminosalicylic acid nor sulfasalazine has been found to increase the rate of major malformations, fetal mortality, or morbidity. There is conflicting evidence regarding the use of corticosteroids and azathioprine and 6-mercaptopurine. There are limited data on the use of infliximab during pregnancy, although no pattern of defects or complications has been reported to date.

Topics: Abnormalities, Drug-Induced; Adrenal Cortex Hormones; Adult; Aminosalicylic Acids; Anti-Infective Agents; Anti-Inflammatory Agents; Antibodies, Monoclonal; Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Risk; Sulfasalazine

To examine the allelic variation of three enzymes involved in 6-mercaptopurine/azathioprine (6-MP/AZA) metabolism and evaluate the influence of these polymorphisms on toxicity, haematological parameters and metabolite levels in patients with acute lymphoblastic leukaemia (ALL) or inflammatory bowel disease (IBD).. Clinical data and blood samples were collected from 19 ALL paediatric patients and 35 IBD patients who were receiving 6-MP/AZA therapy. All patients were screened for seven genetic polymorphisms in three enzymes involved in mercaptopurine metabolism [xanthine oxidase, inosine triphosphatase (C94-->A and IVS2+21A-->C) and thiopurine methyltransferase]. Erythrocyte and plasma metabolite concentrations were also determined. The associations between the various genotypes and myelotoxicity, haematological parameters and metabolite concentrations were determined.. Thiopurine methyltransferase variant alleles were associated with a preferential metabolism away from 6-methylmercaptopurine nucleotides (P = 0.008 in ALL patients, P = 0.038 in IBD patients) favouring 6-thioguanine nucleotides (6-TGNs) (P = 0.021 in ALL patients). Interestingly, carriers of inosine triphosphatase IVS2+21A-->C variants among ALL and IBD patients had significantly higher concentrations of the active cytotoxic metabolites, 6-TGNs (P = 0.008 in ALL patients, P = 0.047 in IBD patients). The study confirmed the association of thiopurine methyltransferase heterozygosity with leucopenia and neutropenia in ALL patients and reported a significant association between inosine triphosphatase IVS2+21A-->C variants with thrombocytopenia (P = 0.012). CONCLUSIONS; Pharmacogenetic polymorphisms in the 6-MP pathway may help identify patients at risk for associated toxicities and may serve as a guide for dose individualization.

Topics: Adolescent; Antimetabolites, Antineoplastic; Azathioprine; Child; Child, Preschool; Female; Gene Frequency; Genotype; Guanine Nucleotides; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Pharmacogenetics; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thionucleotides; Treatment Outcome

To investigate the efficacy of 6-mercaptopurine (6-MP) in cases of azathioprine (AZA) hypersensitivity in patients with inflammatory bowel disease.. Twenty nine previously confirmed Crohn's disease (CD) (n = 14) and ulcerative colitis (UC) (n = 15) patients with a known previous (AZA) hypersensitivity reaction were studied prospectively. The 6-MP doses were gradually increased from 0.5 up to 1.0-1.5 mg/kg per day. Clinical activity indicies (CDAI/CAI), laboratory variables and daily doses of oral 5-ASA, corticosteroids, and 6-MP were assessed before and in the first, sixth and twelfth months of treatment.. In 9 patients, 6-MP was withdrawn in the first 2 wk due to an early hypersensitivity reaction. Medication was ineffective within 6 mo in 6 CD patients, and myelotoxic reaction was observed in two. Data were evaluated at the end of the sixth month in 12 (8 UC, 4 CD) patients, and after the first year in 9 (6 UC, 3 CD) patients. CDAI decreased transiently at the end of the sixth month, but no significant changes were observed in the CDAI or the CAI values at the end of the year. Leukocyte counts (P = 0.01), CRP (P = 0.02), and serum iron (P = 0.05) values indicated decreased inflammatory reactions, especially in the UC patients at the end of the year, making the possibility to taper oral steroid doses.. About one-third of the previously AZA-intolerant patients showed adverse effects on taking 6MP. In our series, 20 patients tolerated 6MP, but it was ineffective in 8 CD cases, and valuable mainly in ulcerative colitis patients.

Topics: Adrenal Cortex Hormones; Adult; Aged; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Steroids

Topics: Azathioprine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine

Topics: Administration, Oral; Azathioprine; Biomarkers, Pharmacological; Drug Monitoring; Erythrocyte Count; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Japan; Leukocyte Count; Mercaptopurine; Methyltransferases; Mutation; Remission Induction; Thioguanine; Treatment Outcome

Hepatotoxicity results in the withdrawal of thiopurines drugs, azathioprine (AZA) and mercaptopurine (MP), in up to 10% of patients with inflammatory bowel disease. Our group previously demonstrated that allopurinol with AZA/ciclosporin/steroid 'triple therapy' improved renal graft survival.. To confirm the hypothesis that allopurinol may alleviate thiopurine hepatotoxicity by similar mechanisms as proposed in our renal study.. Unselected patients with acute thiopurine hepatotoxicity were offered allopurinol co-therapy with low-dose AZA or MP. The starting AZA/MP dose was determined by thiopurine methyltransferase (TPMT) activity (two patients were intermediate TPMT); then this dose was reduced to 25% for allopurinol co-therapy. Response to treatment was assessed by clinical severity indices, endoscopy and blood tests.. Of 11 patients (three Crohn's disease, eight ulcerative colitis) treated, nine (82%) remain in long-term remission (median 42 months) with normal liver tests. One patient also successfully bypassed flu-like symptoms. Two stopped: one nausea, one abnormal liver function (stealosis on biopsy). Leucopenia occurred in two cases and resolved with minor dose reductions.. Allopurinol co-therapy with low-dose AZA/MP can alleviate thiopurine hepatotoxicity. It appears safe and effective for long-term use, but requires monitoring for myelotoxicity. Assessing the TPMT activity helps tailor the AZA/MP doses.

Topics: Adult; Aged; Allopurinol; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Enzyme Inhibitors; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Middle Aged; Retrospective Studies; Treatment Outcome

Azathioprine and 6-mercaptopurine are steroid-sparing drugs used in inflammatory bowel disease (IBD). The polymorphic enzyme thiopurine S-methyltransferase (TPMT) is of importance for thiopurine metabolism and occurrence of adverse events. The role of other thiopurine-metabolizing enzymes is less well known. This study investigated the role of inosine-5'-monophosphate dehydrogenase (IMPDH), which is a key enzyme in the de novo synthesis of guanine nucleotides and also strategically positioned in the metabolic pathway of thiopurines.. IMPDH was measured in 100 healthy blood donors. IMPDH, TPMT and metabolite concentrations were studied in 50 patients with IBD on stable thiopurine therapy. IMPDH activity was measured in peripheral blood mononuclear cells. TPMT activity, 6-methylthioinosine 5'-monophosphate (meTIMP) and 6-thioguanine nucleotide (6-TGN) concentrations were measured in red blood cells, which is the current practice in clinical monitoring of thiopurines. Enzyme activities were related to metabolite concentrations and clinical characteristics.. A wide range of IMPDH activity was observed both in healthy blood donors (median 13.1, range 4.7-24.2 nmol mg(-1) protein h(-1)) and IBD patients (median 14.0, range 7.0-21.7). There was a negative correlation between IMPDH activity and dose-normalized meTIMP concentrations (r(s) = -0.31, P = 0.03), but no evident correlation to 6-TGN concentration or the meTIMP/6-TGN ratio. There were no significant correlations between TPMT activity and metabolite concentrations.. Even though the meTIMP concentrations correlated inversely to the IMPDH activity, the role of IMPDH in balancing the formation of methylated and phosphorylated metabolites was not evident. Taken together, the results give cause to question established opinions about thiopurine metabolism.

Topics: Adult; Aged; Aged, 80 and over; Azathioprine; Biomarkers; Female; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Middle Aged; Polymorphism, Genetic

Studies examining the treatment reality of IBD patients in Germany have been limited, as networking among deliverers of care and reliable documentation of medical, demographic, and economic data are lacking. The aim of the present study was to establish an internet-based treatment registry in order to evaluate treatment of IBD patients in Germany.. Between November 1(st), 2005, and January 31, 2007, 1024 outpatients with prevalent IBD from 10 gastroenterological private practices and 3 hospitals (UC = 439, CD = 567, ID = 18) were enrolled in the study. An internet-based registry was established that included data about medical history, disease status, diagnostic procedures, laboratory test results, and medical treatment. Data for private practices and hospitals were pooled in order to compare treatment habits between these types of medical facilities. The cost of medication was determined according to medications prescribed.. There was no significant difference between the 2 patient groups in demographic and clinical characteristics. Marked differences were observed in medical treatment. The most frequently prescribed medications in the private practices for patients in remission and those with active disease were aminosalicylates and corticosteroids. Immunomodulators played a marginal role. In contrast, in the hospitals azathioprine/6-MP was predominantly used for the maintenance of remission. Patients with fistulizing CD were treated with infliximab. The mean annual cost of medications was 1826 +/- 1331euro/patient (median 1353euro) in the private practices and 1849euro +/- 2897euro/patient (median 960euro) at the University Hospital.. The registry provides the first detailed data about the reality of treatment of IBD patients in Germany and reveals the necessity for networking among attending physicians in order to implement guidelines-conformed treatment.

Topics: Adrenal Cortex Hormones; Adult; Aminosalicylic Acids; Anti-Inflammatory Agents; Antibodies, Monoclonal; Azathioprine; Cost of Illness; Female; Germany; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Inpatients; Internet; Male; Mercaptopurine; Middle Aged; Outpatients; Prospective Studies; Registries

Azathioprine intolerance is a common clinical problem, requiring drug withdrawal in up to 30% of patients. The successful use of mercaptopurine is described, but data to support this strategy are needed.. To assess the tolerability of mercaptopurine in inflammatory bowel disease patients previously intolerant of azathioprine, and identify predictive factors.. Sixty-one azathioprine-intolerant patients (31 males, median age at diagnosis 32 years, 31 with Crohn's disease, 30 with ulcerative colitis) who had been treated with mercaptopurine were identified. Intolerances included nausea and vomiting, flu-like illness, neutropenia, hepatotoxicity and pancreatitis.. Mercaptopurine was tolerated by 59% (36 of 61) of azathioprine-intolerant patients (median dose 1.0 mg/kg), 61% (17 of 28) in patients with azathioprine-related nausea and vomiting, 61% (11 of 18) with flu-like illness, 33% (three of nine) with hepatotoxicity, 100% (one of one) with neutropenia, 100% (three of three) with rash and 0% (zero of one) with pancreatitis. Mercaptopurine intolerance was frequently for a different adverse event. Those intolerant of mercaptopurine were younger (28.4 years vs. 37.0 years; P = 0.014) and more frequently female (14/30 vs. 2/29, P = 0.027). Mercaptopurine tolerability was not affected by diagnosis, location, behaviour, surgery, smoking, family history or extra-intestinal manifestations.. Mercaptopurine may be tolerated in up to 60% of azathioprine-intolerant patients, and treatment should be considered, particularly if intolerance was due to nausea, vomiting, flu-like illness or rash.

Topics: Adult; Age Distribution; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Administration Schedule; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Sex Distribution; Statistics, Nonparametric

Topics: Bias; Guanine Nucleotides; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Prospective Studies; Thionucleotides

6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are effective for the induction and maintenance of remission and reduction of corticosteroid exposure for pediatric inflammatory bowel disease (IBD). The standard dose of 6-MP is 1.0-1.5 mg/kg/day and for AZA is 2.0-2.5 mg/kg/day. The aim of this study was to determine whether IBD patients 6 years of age and younger require higher than standard doses of 6-MP/AZA to achieve clinical remission.. Clinical data was collected retrospectively for all IBD patients 6 years of age or younger treated with 6-MP/AZA at The Children's Hospital of Philadelphia.. Thirty patients met the inclusion criteria. IBD was diagnosed at a median age of 3.3 years (25-75th %ile 2.3-4.6 years) and 6-MP/AZA was initiated at a median age of 3.9 years (range 0.8-6.8 years). After dose escalation, the median AZA-equivalent dose was 3.1 mg/kg/day (25-75th %ile 2.5-3.5, max. dose 5.1 mg/kg/day). At the final recorded dose, 8/13 (62%) patients receiving AZA >3.0 mg/kg/day achieved clinical remission, compared to 2/12 (17%) receiving 2-3 mg/kg/day (P = 0.02). The risk of having active disease was on average 85% lower if the AZA-equivalent dose was >3.0 mg/kg/day (95% confidence interval [CI] 72%-93%). Adverse events were experienced by 4/30 patients (hepatitis, n = 2; leukopenia, n = 2). No patients had to discontinue 6-MP/AZA, and all laboratory abnormalities improved spontaneously or with dose reduction.. The standard dose of 6-MP/AZA may not be adequate for IBD patients 6 years of age and younger. Closely monitored dose escalation beyond the standard dosing range is effective and well-tolerated.

Topics: Age Factors; Azathioprine; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Infant; Inflammatory Bowel Diseases; Male; Mercaptopurine; Remission Induction; Retrospective Studies

Topics: Adult; Azathioprine; Factor V; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine

Nodular regenerative hyperplasia (NRH) and sinusoidal dilatation have been described in relation to thiopurine use in patients with inflammatory bowel disease (IBD). However, there is a dearth of data on the prevalence of these histological abnormalities in general. The aim of our study was to describe the prevalence of these histological liver changes in a thiopurine-naïve IBD cohort.. Liver biopsy specimens were obtained from patients who were treated in a referral center and who underwent gastrointestinal surgery for IBD. Patients were excluded if thiopurines were ever used. The liver specimens were pathohistologically assessed with special attention to NRH.. A total of 83, properly stained, liver specimens (Crohn's disease 61%) were evaluated. NRH was observed in 6% compared to sinusoidal dilatation of varying degree in 34% of specimens. An older age at biopsy was correlated with NRH (p=0.015). Fibrosis and steatosis of varying degrees were detected in 31% and 36% of liver biopsies, respectively. No cases of liver cirrhosis were observed.. Pathohistological hepatic abnormalities are common in non-thiopurine using IBD patients. The association between thiopurine use, NRH and sinusoidal dilatation may be weaker than as reported in recent literature, as there is relatively high background prevalence in selected series.

Topics: Adolescent; Adult; Aged; Azathioprine; Biopsy, Needle; Female; Humans; Hyperplasia; Immunosuppressive Agents; Inflammatory Bowel Diseases; Liver; Male; Mercaptopurine; Middle Aged

6-Thioguanine nucleotides (6-TGN) are active metabolites of azathioprine (AZA) and 6-mercaptopurine (6MP). Higher remission rates have been observed in patients with higher 6-TGN levels. However, many physicians prescribe AZA/6MP using milligrams per kilogram (mg/kg) dosing regimens without measuring 6-TGN levels. The aim of this study was to examine the association between 6MP dose and 6-TGN levels.. We conducted a cross-sectional study of patients treated for inflammatory bowel disease (IBD) with AZA or 6MP, whose 6-TGN levels were measured. Patients with low or intermediate thiopurine methyl transferase (TPMT) activity were excluded. AZA dose was converted to 6MP equivalents. The relationship between dose and 6-TGN levels was assessed with the Spearman correlation coefficient. We used logistic regression to assess the relationship between dose and 6-TGN levels of >230 pmol/8 x 10(8).. In this study, 155 patients met our inclusion criteria (median dose, 1.01 +/- 0.40; range, 0.61-1.41 mg/kg). There was a weak correlation between 6-TGN levels and the absolute dose (rho = 0.18, P = 0.04) and the dose in mg/kg (rho = 0.19, P = 0.03). The correlation between mg/kg dosage and 6-TGN levels was slightly stronger in those using concomitant 5-aminosalicylate (5-ASA) medications (rho = 0.24, P = 0.02). Compared with <1.0 mg/kg per day, doses of > or =1.5 mg/kg per day were strongly associated with 6-TGN levels of >230 pmol/8 x 10(8) RBC (adjusted odds ratio [OR] = 3.7, 95% confidence interval [CI] = 1.1-11.8). However, only 37% of patients receiving > or =1.0 mg/kg per day had 6-TGN levels of >230 pmol/8 x 10(8) RBC.. 6MP dose is weakly associated with 6-TGN levels. The use of standard mg/kg dosing regimens will result in low 6-TGN levels in most patients.

Topics: Adult; Biological Availability; Cross-Sectional Studies; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Thioguanine

Clinical improvement in inflammatory bowel disease (IBD) treated with methotrexate and 6-mercaptopurine (6-MP) is associated with a decrease in pro-inflammatory cytokines. This has been presumed to indicate the mechanism of action of methotrexate and 6-MP. Although controversial, there are increasingly compelling data that Mycobacterium avium subspecies paratuberculosis (MAP) may be an etiological agent in some or all of IBD. We hypothesized that the clinical efficacy of methotrexate and 6-MP in IBD may be to simply inhibit the growth of MAP.. The effect on MAP growth kinetics by methotrexate and 6-MP were evaluated in cell culture of two strains each of MAP and M. avium using a radiometric ((14)CO(2) BACTEC detection system that quantifies mycobacterial growth as arbitrary "growth index units" (GI). Efficacy data are presented as "percent decrease in cumulative GI" (% -DeltacGI).. The positive control antibiotic (clarithromycin) has >or=85% -DeltacGI at a concentration of 0.5 microg/ml. The negative control (ampicillin) has minimal inhibition at 64 microg/ml. MAP ATCC 19698 shows >or=80% -DeltacGI for both agents by 4 microg/ml. With the other three isolates, although more effective than ampicillin, 6-MP is consistently less effective than methotrexate.. We show that methotrexate and 6-MP inhibit MAP growth in vitro. Each of the four isolates manifests different % -DeltacGI. These data are compatible with the hypothesis that the clinical improvement in patients with IBD treated with methotrexate and 6-MP could be due to treating a MAP infection. The decrease in pro-inflammatory cytokines, thought to be the primary mechanism of action, may simply be a normal, secondary, physiological response. We conclude that henceforth, in clinical studies that evaluate the effect of anti-MAP agents in IBD, the use of methotrexate and 6-MP should be excluded from any control groups.

Topics: Ampicillin; Animals; Anti-Bacterial Agents; Cattle; Cytokines; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate; Microbial Sensitivity Tests; Mycobacterium avium subsp. paratuberculosis

Topics: Allopurinol; Azathioprine; Drug Synergism; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine

Many IBD patients not responding to azathioprine (AZA) or 6-mercaptopurine (6-MP) preferentially metabolize 6-MP to 6-methylmercaptopurine (6-MMP). We describe the use of allopurinol in AZA/6-MP nonresponders to deliberately shunt metabolism of 6-MP toward 6-thioguanine (6-TGN) and improve clinical responses.. Twenty outpatients who were AZA/6-MP nonresponders and had high 6-MMP metabolite levels were included. Subjects were commenced on allopurinol 100 mg daily, and the dose of 6-MP/AZA was reduced to 25%-50% of the original dose.. After allopurinol was started, mean 6-TGN levels increased from 191.3 (+/- standard error of the mean) +/- 17.1 to 400.3 +/- 36.9 pmol/8 x 10(8) red blood cells (P < .001), whereas mean 6-MMP levels decreased from 10,604.7 +/- 1278.2 to 2000.6 +/- 437.1 pmol/8 x 10(8) red blood cells (P < .001). The addition of allopurinol led to a reduction in the mean partial Harvey Bradshaw Index in Crohn's disease patients from 4.9 +/- 1.0 to 1.5 +/- 0.3 points (P = .001), and in ulcerative colitis patients mean Mayo Scores decreased from 4.1 +/- 0.7 to 2.9 +/- 0.7 points (P = .13). The addition of allopurinol enabled a reduction in mean daily prednisone dosage from 17.6 +/- 3.9 to 1.8 +/- 0.7 mg (P < .001) and led to normalization of transaminase levels, with mean AST levels reducing from 42.5 +/- 8.1 to 23.5 +/- 1.6 IU (P = .12) and mean ALT levels reducing from 101.6 +/- 26.9 to 33.9 +/- 5.2 IU (P = .01).. The addition of allopurinol to thiopurine nonresponders with high 6-MMP metabolite levels is an effective and safe means of optimizing 6-TGN production, leading to improved disease activity scores, reduced corticosteroid requirements, and normalization of liver enzymes.

Topics: Allopurinol; Azathioprine; Drug Synergism; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine; Treatment Outcome

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

Myelosuppression occurs in 2-7% of inflammatory bowel disease (IBD) patients treated with azathioprine, and can be associated with reduced activity of thiopurine methyltransferase (TPMT) in some patients. It has been proposed that pretreatment assessment of TPMT status reduces the incidence of toxicity and is cost-effective.. To determine if screening for TPMT status predicts side-effects to azathioprine in patients with IBD and to ascertain whether screening by TPMT enzyme activity or genotype is superior.. Sequential IBD patients were identified and azathioprine tolerance recorded. Blood was collected for measurement of TPMT activity and TPMT*3C, TPMT*3A and TPMT*2 genotypes.. Of 130 patients, 25% stopped azathioprine because of toxicity. Four patients experienced severe myelosuppression (WCC < 2). Eleven of 17 patients with reduced TPMT activity were heterozygotes, including one patient with marked TPMT deficiency who experienced severe myelosuppression. There was no association between intermediate TPMT deficiency and any side-effect.. Moderate reduction of TPMT activity in heterozygotes was not associated with toxicity, but very low TPMT activity caused severe myelosuppression in one patient. This would have been predicted by measuring TPMT activity but not by genotyping. Measurement of TPMT activity may therefore be superior to genotype in predicting severe myelosuppression.

Topics: Clinical Enzyme Tests; Cost-Benefit Analysis; Female; Gastrointestinal Agents; Genetic Techniques; Genotype; Humans; Inflammatory Bowel Diseases; Lymphopenia; Male; Mass Spectrometry; Mercaptopurine; Methyltransferases; Polymerase Chain Reaction; Sensitivity and Specificity

The aim of the study was to evaluate the incidence of abnormality of liver tests (LTs) or hepatotoxicity in a large group of inflammatory bowel disease (IBD) patients and, specifically, to assess the incidence of azathioprine (AZA)/mercaptopurine (MP)-induced liver injury in a long-term follow-up study.. All consecutive IBD patients followed for at least 5 years were included in this retrospective study. LTs including alanine transaminase, aspartate transaminase, alkaline phosphatase, gamma-glutamyl transferase, and bilirubin were periodically monitored. "Abnormality-of-LTs" was defined as LTs between N (upper limit of the normal range) and 2 N, and "liver injury/hepatotoxicity" as LTs>2 N.. A total of 786 patients were included, and 138 received AZA/MP; 120 patients (15%) and 39 (5%) presented abnormality of LTs or hepatotoxicity, respectively, during follow-up. The most frequent explanations were AZA/MP treatment and fatty liver disease. Among AZA/MP-treated patients (690 patient-years follow-up) the incidence of abnormal LTs and hepatotoxicity was, respectively, 7.1% and 2.6% per patient-year. Most patients spontaneously normalized LTs despite maintaining AZA/MP. These drugs were withdrawn due to hepatotoxicity (LTs>5 N and lack of decrease despite 50% dose reduction) in 3.6% of the patients and all of them normalized LTs.. In IBD patients, AZA or MP treatment induces abnormality of LTs in a relatively high proportion of the cases, but the development of true hepatotoxicity/liver injury is exceptional. Moreover, most of the cases of thiopurine-induced hepatotoxicity in IBD patients are mild, and the abnormalities in LTs spontaneously return to normal values despite AZA/MP being maintained, therapy withdrawal being necessary in only approximately 4% of the patients.

Topics: Adult; Algorithms; Azathioprine; Chemical and Drug Induced Liver Injury; Colitis, Ulcerative; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Inflammation; Inflammatory Bowel Diseases; Liver; Male; Mercaptopurine; Middle Aged; Time Factors

The aim of this study was to explore the service for patients with inflammatory bowel disease taking or having taken azathioprine or 6-mercaptopurine in the last three years, at two District General Hospitals within the same Trust.. Published data confirm that the use of azathioprine and 6-mercaptopurine is effective in the control of inflammatory bowel disease. However, there are inconsistencies in dosing regimes, blood monitoring and duration of therapy. Regimes used have been largely based on clinicians' personal preference leading to inconsistencies in practice.. A questionnaire, designed to elicit the experience of treatment regimes, blood monitoring and access to information was sent to 130 patients taking or having taken azathioprine or 6-mercaptopurine in the last three years. A further questionnaire was sent to 94 general practitioners and interviews were conducted with 10 hospital doctors initiating treatment.. The study demonstrated lack of clarity in the prescribing methods, the monitoring regimes being offered, variation in information given to patients and consequent patient knowledge.. Azathioprine and 6-mercaptopurine are increasingly being used successfully in inflammatory bowel disease, sparing the use of steroids and maintaining remission over a longer period. A review of the current literature has informed and made possible a suggested blood-monitoring regime.. The adoption of a protocol-led service, managed by the nurse specialist, incorporating guided self-management by patients should be considered. A shared-care approach with the patient and general practitioner with rapid access to secondary care would provide a robust system.

Topics: Adult; Attitude of Health Personnel; Attitude to Health; Azathioprine; Clinical Protocols; Drug Administration Schedule; Drug Monitoring; Drug Utilization Review; England; Health Knowledge, Attitudes, Practice; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Medical Staff, Hospital; Mercaptopurine; Nurse Clinicians; Nursing Methodology Research; Patient Education as Topic; Patient Selection; Physicians, Family; Practice Guidelines as Topic; Practice Patterns, Physicians'; Qualitative Research; Surveys and Questionnaires; Treatment Outcome

Topics: Adult; Antimetabolites; Breast Feeding; Dose-Response Relationship, Drug; Female; Humans; Infant; Infant, Newborn; Inflammatory Bowel Diseases; Mercaptopurine; Milk, Human

6-Mercaptopurine (6-MP) and azathioprine (AZA) are effective in the treatment of IBD; however, drug-induced hepatotoxicity has been reported in 10-15% of pediatric patients and has been associated with the 6-MP metabolite 6-methylmercaptopurine ribonucleotide (6-MMPR) at levels >5,700 pmol/8 x 10(8) RBC. The aim of this study was to assess the prevalence of 6-MP/AZA hepatotoxicity and its correlation with serum 6-MMPR levels in adult IBD patients.. Aminotransferases, bilirubin, and 6-MP metabolite levels were measured in 173 adult IBD patients treated with 6-MP or AZA from November 2002 to December 2003. Hepatotoxicity was defined as AST and/or ALT >2x upper limit of normal or cholestasis.. Eight patients (4.6%) met criteria for a diagnosis of 6-MP/AZA-induced hepatotoxicity. The mean 6-MMPR level in these 8 patients was 10,537 pmol/8 x 10(8) RBC versus 3,452 pmol/8 x 10(8) RBC in the nonhepatotoxic group (P < 0.001). Risk of hepatotoxicity above the third quartile (6-MMPR > 5,300) was 5 times that below the third quartile (11.4%vs 2.3%, P < 0.05); however, nearly 90% of all patients with 6-MMPR > 5,300 pmol/8 x 10(8) RBC had no hepatotoxicity, while almost 40% of subjects with hepatotoxicity had 6-MMPR levels below this cutoff.. 6-MP/AZA-induced hepatotoxicity is uncommon in the adult population. Although hepatotoxicity is associated with higher mean 6-MMPR levels, the sensitivity and specificity of 6-MMPR for drug-induced hepatotoxicity was poor. Monitoring liver tests in patients on 6-MP/AZA is suggested, and dose reduction or cessation of 6-MP/AZA, even with high 6-MMPR levels, should be reserved for patients with elevated aminotransferases.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites; Azathioprine; Chemical and Drug Induced Liver Injury; Female; Humans; Inflammatory Bowel Diseases; Liver Function Tests; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Sensitivity and Specificity; Statistics, Nonparametric

Topics: Azathioprine; Biopsy; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Tolerance; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Liver; Liver Diseases; Mercaptopurine; Thioguanine

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Azathioprine; Cyclosporine; Humans; Immunologic Factors; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Methotrexate; Mycophenolic Acid

Topics: Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Lymphoma; Mercaptopurine; Risk Factors

Small uncontrolled trials have suggested that 5-aminosalicylate (5-ASA) medications increase 6-thioguanine nucleotide (6-TGn) levels in adults with Crohn's disease (CD) on azathioprine (AZA) or 6-mercaptopurine (6-MP), presumably through the inhibition of thiopurine methyltransferase (TPMT). We tested the theory that coadministration of 5-ASA agents with AZA/6-MP results in higher 6-TGn levels in a large cohort of children and adults with CD or ulcerative colitis (UC).. A retrospective cohort study identified all children and adults treated for IBD with AZA/6-MP at 2 tertiary medical centers. Patients were included if their TPMT genotype was known and 6-TGn and 6-methymercaptopurine (6-MMP) levels had been obtained after 3 months of clinical remission at a stable dose of AZA/6-MP. 6-TGn and 6-MMP levels were compared between patients taking and those not taking 5-ASA medications through the use of linear regression models to identify and adjust for potentially confounding variables.. Of the 126 patients included, 88 were taking 5-ASA medications. Patients on 5-ASA agents had higher mean 6-TGn levels after adjustment for confounding variables (Delta6-TGn, 47.6 +/- 21.8 pmol/8 x 10 red blood cells; P = 0.03). CD and TPMT heterozygosity was independently associated with higher 6-TGn levels (P = 0.01 and P = 0.03, respectively). 5-ASA exposure was not associated with a change in 6-MMP levels.. We found that 5-ASA therapy is associated with higher 6-TGn levels in children and adults with IBD on 6-MP/AZA. TPMT inhibition may not explain this effect because 5-ASA exposure did not affect 6-MMP levels. The observed association of CD with higher 6-TGn levels is novel and needs to be verified in prospective studies.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Biomarkers; Child; Cross-Sectional Studies; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Mesalamine; Middle Aged; Remission Induction; Retrospective Studies; Severity of Illness Index; Thioguanine; Treatment Outcome

Studies to date have not confirmed an association between neoplasms and inflammatory bowel disease (IBD) treated with 6-mercaptopurine (6-MP). We have observed the occurrence of some neoplasms in IBD patients who developed sustained leukopenia as a result of treatment with 6-MP. As a result, we sought to compare the incidence of neoplasms in patients who developed sustained leukopenia after taking 6-MP compared with patients treated with 6-MP without sustained leukopenia.. A database containing the medical records of more than 600 patients treated with 6-MP for IBD at 1 center between 1965 and 2002 was searched. The patients were divided into 2 groups. The study group consisted of patients who developed sustained leukopenia, defined as a white blood cell count of less than 4000 for 20 or more days. The control group patients matched those in the study group for age and sex. There were 3 matched controls for each patient in the study group.. Eighteen patients developed sustained leukopenia and, of these, 4 developed neoplasms (22%)-2 leukemias, 1 non-Hodgkin's lymphoma, and 1 breast cancer. Of the 54 patients in the control group, 4 developed neoplasms (7%) (P = .10). Post hoc analysis revealed a statistically significant difference in the number of hematologic malignancies in the group with sustained leukopenia (P = .014). There was no significant difference between the 2 groups for all confounding variables examined.. There was a trend toward a greater number of total malignancies in the sustained leukopenic patients. The data suggest that it is those patients who develop sustained leukopenia while taking 6-MP/azathioprine who are most at risk.

Topics: Adult; Aged; Case-Control Studies; Databases as Topic; Female; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Middle Aged; Neoplasms; Retrospective Studies

We evaluated how our use of thiopurines was altered by determination of thiopurine methyltransferase (TPMT) level and drug dose adjustment guided by a 6-mercaptopurine metabolite assay. We further examined whether these resulted in better selection of the drug dose, improved control of disease, and decreased corticosteroid use in pediatric inflammatory bowel disease (IBD).. This is a retrospective review of 101 pediatric patients with IBD receiving a stable dose of azathioprine (AZA) for 4 months or longer. The study group (n = 64) consisted of patients who received AZA and had metabolite levels measured. The comparison group (n = 37) consisted of patients who were receiving AZA before the availability of metabolite measurement. The TPMT level was measured in study group patients before starting AZA.. Patients with normal TPMT level received a higher starting dose of AZA than in patients who were heterozygous for TPMT deficiency (1.7 vs 0.9 mg/[kg x d], P < 0.0001). Study group patients received a higher starting dose (1.6 vs 1.2 mg/[kg x d], P = 0.001) and a higher final dose of AZA (2.4 vs 1.7 mg/[kg x d], P < 0.0001) compared with patients in the comparison group. These patients also had more dose adjustments (0.8 vs 0.4 mg/kg, P < 0.002). The number of disease exacerbations per patient per year was 55% less in the study group (95% CI, 17%-76%, P < 0.0001). The study group patients received less prednisone (P < 0.0001) and had lower disease activity scores (P < 0.05). There was no difference between groups in infliximab use or surgery rate.. Azathioprine dose adjustment using a 6-mercaptopurine metabolite assay was associated with use of higher doses, improved control of disease and decreased corticosteroid use in pediatric patients with IBD.

Topics: Adolescent; Adult; Azathioprine; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Erythrocytes; Female; Guanine Nucleotides; Heterozygote; Humans; Infant; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Prednisone; Remission Induction; Retrospective Studies; Thionucleotides

The aim of this study was to follow, during standardized initiation of thiopurine treatment, thiopurine methyltransferase (TPMT) gene expression and enzyme activity and thiopurine metabolite concentrations, and to study the role of TPMT and ITPA 94C > A polymorphisms for the development of adverse drug reactions. Sixty patients with ulcerative colitis or Crohn's disease were included in this open and prospective multi-center study. Thiopurine naïve patients were prescribed azathioprine (AZA), patients previously intolerant to AZA received 6-mercaptopurine (6-MP). The patients followed a predetermined dose escalation schedule, reaching target dose at Week 3; 2.5 and 1.25 mg/kg body weight for AZA and 6-MP, respectively. The patients were followed every week during Weeks 1-8 from baseline and then every 4 weeks until 20 weeks. TPMT activity and thiopurine metabolites were determined in erythrocytes, TPMT and ITPA genotypes, and TPMT gene expression were determined in whole blood. One homozygous TPMT-deficient patient was excluded. Five non compliant patients were withdrawn during the first weeks. Twenty-seven patients completed the study per protocol; 27 patients were withdrawn because of adverse events. Sixty-seven percent of the withdrawn patients tolerated thiopurines at a lower dose at Week 20. There was no difference in baseline TPMT enzyme activity between individuals completing the study and those withdrawn for adverse events (p = 0.45). A significant decrease in TPMT gene expression (TPMT/huCYC ratio, p = 0.02) was found, however TPMT enzyme activity did not change. TPMT heterozygous individuals had a lower probability of remaining in the study on the predetermined dose (p = 0.039). The ITPA 94C > A polymorphism was not predictive of adverse events (p = 0.35).

Topics: Alleles; Antimetabolites; Dose-Response Relationship, Drug; Gene Expression Regulation, Enzymologic; Genotype; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Prospective Studies; Purines; Pyrophosphatases; Time Factors

To report the 10-year experience of a single center in treating patients with refractory inflammatory bowel disease (IBD) with relatively lower dose of 6-mercaptopurine (6-MP).. The charts of 285 patients with IBD (Crohn's disease 160 and ulcerative colitis 125) receiving 6-MP were reviewed. Clinical response, subsequent breakthrough while taking 6-MP, and relapse rates when 6-MP was discontinued and side effects were assessed.. Ninety-three percent of the patients were taking 50 to 75 mg/day of 6-MP. Complete remission was achieved in 62%, partial remission in 14.5%, and failure to achieve remission in 23.5% of the patients. Of complete responders, 27.5% had breakthrough while continuing 6-MP. Nine percent of those that achieved a complete remission experienced a relapse after 6-MP was discontinued. Side effects included leukopenia (11.2%), abnormal liver function tests (3.8%), various infections, including pneumonia (3.1%), pancreatitis (2.5%), nausea (2.1%), headache (2.8%), fever (1.4%), hair loss (1%), and rash (0.7%). Two cancers occurred while taking 6-MP: melanoma on the finger and a fatal colonic lymphoma. Four patients continued 6-MP throughout pregnancies and had normal outcomes.. In our experience 6-MP is relatively safe and appears to be as effective at a lower dosage (0.84 mg/kg per day) compared with the recommended higher dosage (1-1.5 mg/kg per day), when leukopenia was more frequent. Serious side effects, although rare, need to be monitored.

Topics: Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Recurrence; Time Factors

Azathioprine and 6-mercaptopurine are useful therapies in inflammatory bowel diseases. Despite their efficacy, their use is limited owing to treatment intolerance or toxicity in 10-15% of patients. It has been suggested that both drugs could be interchangeable.. All patients treated with 6-mercaptopurine because of previous digestive intolerance of azathioprine in four Spanish hospitals were reviewed. Tolerance of 6-mercaptopurine therapy was assessed.. Fifteen patients (11 Crohn's disease, 4 ulcerative colitis) were included. Immunosuppressant therapy was prescribed for steroid-dependent disease in 13 cases, and for perianal disease in 2. Main symptoms of digestive intolerance were epigastric pain, nausea and vomiting, which developed within the first weeks of treatment. Acute pancreatitis was ruled out in all the cases. Five patients commenced 6-mercaptopurine immediately after azathioprine discontinuation and 7 patients within the first month. Eleven patients (73.3%) tolerated 6-mercaptopurine and reached the therapeutic goals; only two patients had to discontinue 6-mercaptopurine because of adverse effects.. Treatment with 6-mercaptopurine is a safe alternative in patients with inflammatory bowel diseases and previous digestive intolerance of azathioprine.

Topics: Adult; Azathioprine; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Maximum Tolerated Dose; Mercaptopurine; Middle Aged; Retrospective Studies; Spain; Treatment Outcome

Topics: Adult; Age of Onset; Antimetabolites; Child; Growth Disorders; Humans; Immune System Diseases; Inflammatory Bowel Diseases; Mercaptopurine

The present study was undertaken to investigate the possible effects of various agents on thiopurine methyltransferase (TPMT) activity in red blood cells (RBCs) from patients with chronic inflammatory bowel disease (IBD).. In three groups of patients with very high, normal and intermediate TPMT activity (each n=6), the inhibitory potential of furosemide, piretanide, azathioprine (AZA) and testosterone was assessed by ex vivo measurements of TPMT activity in RBCs. From individual concentration-response curves, IC50 values have been determined.. Independent of the basal TPMT activity, lowest IC50 values were calculated for furosemide (15-19 microM), followed by testosterone (30-72 microM), piretanide (300-313 microM) and AZA (430-532 microM). Compared with reported plasma concentration achieved during treatment, only furosemide would have the potential to inhibit TPMT also in vivo, whereas the IC50 values of the other agents are far above the corresponding plasma levels.. Our ex vivo study revealed that only furosemide has the potential to inhibit TPMT activity in patients with IBD. This possibility should be taken into consideration if the diuretic and AZA or 6-mercaptopurine are coadministered. However, the extrapolation to the clinical setting remains open.

Topics: Adolescent; Adult; Aged; Azathioprine; Child; Diuretics; Dose-Response Relationship, Drug; Drug Interactions; Erythrocytes; Female; Furosemide; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Inhibitory Concentration 50; Male; Mercaptopurine; Methyltransferases; Middle Aged

Topics: Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine

Based on adherence to intestinal mucosa, intralumenally administered liposomal formulations of 5-aminosalicylate (5-ASA) and 6-mercaptopurine (6-MP) were studied for their potential to enhance local drug delivery to intestinal tissue for the treatment of inflammatory bowel disease.. 5-ASA was encapsulated in standard phospholipid liposomes while 6-MP required encapsulation in nonphospholipid liposomes to obtain equivalent drug loading. Encapsulation efficiency was measured by size-exclusion chromatography/high-performance liquid chromatogtaphy (HPLC). Liposomal formulations or solution of the drugs were injected into unligated jejunum to compare pharmacokinetics and into ligated loops of rat ileum and colon to evaluate local delivery. Dextran sulfate and acetic acid induced colitis were used as models of lower intestinal inflammation. Plasma, tissue and luminal drug and metabolite levels were measured by liquid scintillation counting or HPLC.. Encapsulation efficiency of 6-MP was dependent on lipid content and composition. While liposomal encapsulation significantly reduced systemic absorption of 5-ASA this was not the case for 6-MP. Liposomal adherence to intestinal tissue resulted in increased tissue levels for 5-ASA; however, 6-MP local tissue levels were not improved compared to solution drug.. Nonphospholipid liposomes optimize encapsulation of 6-MP. While liposomal formulations show potential for local drug delivery to diseased bowel, drug physicochemical properties, absorption, and metabolic profiles dictate tissue-targeting potential. Liposomes reduce systemic availability from paracellular absorption of hydrophilic 5-ASA, but fail to improve local tissue delivery of 6-MP, a molecule absorbed by passive membrane permeation that undergoes extensive first- pass metabolism.

Topics: Algorithms; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Transport, Active; Caco-2 Cells; Chemical Phenomena; Chemistry, Pharmaceutical; Chemistry, Physical; Colitis; Drug Carriers; Drug Compounding; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Intestinal Absorption; Liposomes; Male; Mercaptopurine; Mesalamine; Rats; Rats, Sprague-Dawley

Many non-responders to azathioprine or mercaptopurine (6-mercaptopurine) have high normal thiopurine methyltransferase activity and preferentially metabolize mercaptopurine to produce 6-methylmercaptopurine instead of the active 6-tioguanine (6-tioguanine) metabolites.. To describe the use of allopurinol in mercaptopurine/azathioprine non-responders to deliberately shunt metabolism of mercaptopurine towards 6-tioguanine.. Fifteen thiopurine non-responders whose metabolites demonstrated preferential metabolism towards 6-methylmercaptopurine are described. Subjects were commenced on allopurinol 100 mg po daily and mercaptopurine/azathioprine was reduced to 25-50% of the original dose. Patients were followed clinically and with serial 6-tioguanine and 6-methylmercaptopurine metabolite measurements.. After initiating allopurinol, 6-tioguanine levels increased from a mean of 185.73 +/- 17.7 to 385.4 +/- 41.5 pmol/8 x 10(8) red blood cells (P < 0.001), while 6-methylmercaptopurine decreased from a mean of 10 380 +/- 1245 to 1732 +/- 502 pmol/8 x 10(8) RBCs (P < 0.001). Allopurinol led to a decrease in white blood cell from a mean of 8.28 +/- 0.95 to 6.1 +/- 0.82 x 10(8)/L (P = 0.01).. The addition of allopurinol to thiopurine non-responders with preferential shunting to 6-methylmercaptopurine metabolites appears to be an effective means to shift metabolism towards 6-tioguanine.

Topics: Allopurinol; Antimetabolites; Azathioprine; Drug Combinations; Drug Resistance; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine

Our objective was to assess the activity of thiopurine methyltransferase (TPMT) in a very large number of Spanish patients with inflammatory bowel disease (IBD), to evaluate the influence of several variables (including azathioprine or 6-mercaptopurine) on that activity, and to know the proportion of patients with low TPMT activity and therefore high risk of myelotoxicity when treated with these drugs.. TPMT activity in red blood cells (RBCs) was measured by a radiochemical method. The association between several variables and TPMT values was assessed by multiple lineal regression.. 7046 patients were included (mean age: 37 years; 53% males): 70% with Crohn's disease, 22% with ulcerative colitis, and 8% with indeterminate colitis. Mean TPMT value was 20 (6) U/ml RBCs (minimum 0 and maximum 46). TPMT activity distribution was as follows: low levels (< 5 U/ml), 0.5%; intermediate (5-13.7), 11.1%; and high (> or = 13.8), 88.4%. TPMT values did not follow a normal distribution (p < 0.001). In the univariate study, statistically significant differences (p < 0.001), yet of doubtly clinical significance because its minimal magnitude, were demonstrated in TPMT values depending on age, sex, type of disease, and treatment with azathioprine/6-mercaptopurine. In the multivariate study, the variables associated with TPMT activity were: sex, treatment with 5-aminosalicylates, steroids and azathioprine/6-mercaptopurine.. This study shows that 0.5% of the Spanish patients with IBD have low TPMT activity (< 5 U/ml RBCs), a figure similar to that reported in other countries, these patients being at higher risk of myelotoxicity when treated with azathioprine or 6-mercaptopurine. The drugs usually prescribed for the treatment of IBD, including 5-aminosalicylates and azathioprine/6-mercaptopurine, do not seem to modify in a clinically relevant manner TPMT activity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Middle Aged

Topics: Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases

Polymorphic thiopurine S-methyltransferase (TPMT) is a major determinant of thiopurine toxicity.. We extracted 6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-MMPNs) from erythrocytes with perchloric acid and converted them to 6-thioguanine (6-TG) and a 6-methylmercaptopurine (6-MMP) derivative during a 60-min acid hydrolysis step. The liquid chromatography system consisted of a C(18) column with an ammonium acetate-formic acid-acetonitrile buffer. 8-Bromoadenine was the internal standard. Analytes were measured with positive ionization and multiple reaction monitoring mode. With PCR-restriction fragment length polymorphism analysis and TaqMan allelic discrimination, common TPMT alleles (*1, *2, *3A, *3B, *3C) were determined in 31 792 individuals. We used perchloric acid extraction, acid hydrolysis, and HPLC with ultraviolet detection to measure erythrocyte 6-TG and 6-MMP nucleotide concentrations in 6189 patients with inflammatory bowel disease receiving azathioprine/6-mercaptopurine therapy.. Intra- and interday imprecision were <10% at low and high analyte concentrations. The conversion of 6-TG and 6-MMP nucleoside mono-, di-, and triphosphates was complete after hydrolysis. Allelic frequency for TPMT variant alleles ranged from 0.0063% (*3B) to 3.61% (*3A). Compared with wild types, TPMT heterozygotes had an 8.3-fold higher risk for 6-TGNs >450 pmol/8 x 10(8) erythrocytes (concentration associated with increased risk for leukopenia), but an 8.2-fold lower risk for 6-MMPNs >5700 pmol/8 x 10(8) erythrocytes (concentration associated with increased risk for hepatotoxicity).. The liquid chromatography-tandem mass spectrometry method can be applied to the routine monitoring of thiopurine therapy. The association between TPMT genotype and metabolite concentrations illustrates the utility of pharmacogenetics in the management of patients undergoing treatment with thiopurines.

Topics: Adult; Azathioprine; Chromatography, Liquid; Cohort Studies; Drug Therapy, Combination; Erythrocytes; Female; Genetic Variation; Guanine Nucleotides; Humans; Hydrolysis; Inflammatory Bowel Diseases; Male; Mass Spectrometry; Mercaptopurine; Methyltransferases; Purine Nucleotides; Thionucleotides

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

Azathioprine and 6-mercaptopurine (6-MP) are well established for the treatment of inflammatory bowel disease (IBD). Assessing thiopurine methyltransferase (TPMT) status has been recommended to reduce the risk of serious toxicity. Measuring red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) concentrations has been recommended for dose adjustment.. To describe the results of measuring TPMT activity and genotype, and 6-TGN concentration in New Zealand.. Canterbury Health Laboratories provided these analyses for New Zealand. Those with low TPMT activity also underwent genotyping. All results were collated and analysed descriptively. 6-TGN concentrations were correlated with the dose of thiopurine when known.. TPMT enzyme activity (range 1-22 U/mL) from 574 patients showed a trimodal distribution. Genotyping results matched this distribution with only mild overlap between (*1/*1) homozygote and (*1/*3) heterozygote groups. One patient without TPMT measurement before therapy had life-threatening neutropenia and was later found to have (*3/*3) genotype. TPMT analysis probably prevented two further such cases. Of 884 6-TGN concentrations (range 0-1434 pmol/10(8) RBC), 41, 39 and 20% were within, below, and above the therapeutic range of 235-450 pmol/10(8) RBC, respectively. Leucopenia was seen in some patients with high 6-TGN. 6-MMP concentrations in 177 patients with low 6-TGN suggested non-compliance in 31, underdosing in 130, and preferential metabolism of 6-MP to 6-methylmercaptopurine in 16. There was poor correlation between azathioprine dose and 6-TGN concentration (r(2) = 0.002), supporting 6-TGN monitoring.. Measurement of TPMT enzyme activity and 6-TGN concentration has been well-integrated into clinical practice. These tests should reduce the risk of toxicity and improve efficacy with thiopurines in patients with IBD.

Topics: Azathioprine; Biomarkers; Erythrocytes; Genotype; Guanine Nucleotides; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Thionucleotides

To determine the tolerability and safety profile of a low-dose maintenance therapy with 6-TG in azathioprine (AZA) or 6-mercaptopurine (6-MP) intolerant inflammatory bowel disease (IBD) patients over a treatment period of at least 1 year.. Database analysis.. Twenty out of ninety-five (21%) patients discontinued 6-TG (mean dose 24.6 mg; mean 6-TGN level 540 pmol/8 x 10(8) RBC) within 1 year. Reasons for discontinuation were GI complaints (31%), malaise (15%) and hepatotoxicity (15%). Hematological events occurred in three patients, one discontinued treatment. In the 6-TG-tolerant group, 9% (7/75) could be classified as hepatotoxicity. An abdominal ultrasound was performed in 54% of patients, one patient had splenomegaly.. The majority of AZA or 6-MP-intolerant IBD patients (79%) is able to tolerate maintenance treatment with 6-TG (dosages between 0.3 and 0.4 mg/kg per d). 6-TG may still be considered as an escape maintenance immunosuppressant in this difficult to treat group of patients, taking into account potential toxicity and efficacy of other alternatives. The recently reported hepatotoxicity is worrisome and 6-TG should therefore be administered only in prospective trials.

Topics: Adult; Aged; Azathioprine; Drug Tolerance; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Safety; Thioguanine

The incidence of thiopurine-induced hepatotoxicity in patients with inflammatory bowel disease varies in different studies.. To assess the rate of thiopurine-induced liver toxicity in patients with inflammatory bowel disease; to determine the predictive factors and to characterize its clinical course and management.. A cohort of 161 patients was prospectively followed for a median of 271 days. Hepatotoxicity was established when alanine transaminase or alkaline phosphatase plasma levels were greater than twice the upper normal limit.. Abnormal liver function was detected in 21 patients (13%; 95% CI: 7-18). Hepatotoxicity occurred in 16 patients (10%; 95% CI: 6-16) after a median of 85 days. In five cases, treatment was withdrawn due to hepatotoxicity. Use of corticosteroids was associated with hepatotoxicity (OR: 4.94; 95% CI: 1.01-23.98) with antitumour necrosis factor concomitant therapy showing a protective role (OR: 0.3; 95% CI: 0.1-3.1). gamma-Glutamyl transferase plasma levels at the onset of hepatotoxicity showed the best predictive value for treatment withdrawal (area under the receiver operating characteristic curve: 0.95).. The incidence of hepatotoxicity in inflammatory bowel disease patients receiving thiopurines is relevant, mainly in patients co-treated with corticosteroids. gamma-Glutamyl transferase plasma level is a useful biomarker in therapy withdrawal prediction.

Topics: Adolescent; Adult; Aged; Azathioprine; Biomarkers; Chemical and Drug Induced Liver Injury; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Liver; Liver Diseases; Liver Function Tests; Male; Mercaptopurine; Middle Aged; Prospective Studies; Risk Factors

Topics: Azathioprine; Humans; Inflammatory Bowel Diseases; Lymphoma; Mercaptopurine; Risk Factors

Topics: Allopurinol; Antimetabolites; Azathioprine; Drug Combinations; Drug Synergism; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine

Topics: Female; Humans; Infant, Newborn; Inflammatory Bowel Diseases; Male; Mercaptopurine; Pregnancy; Pregnancy Complications

Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs that are commonly used to treat a wide range of conditions. It is now well established that interpatient variation in sensitivity to these drugs is due to point mutations in the TPMT gene. The mutant alleles TPMT*2 (238G>C), TPMT*3A (460G>A, 719A>G), TPMT*3B (460G>A), and TPMT*3C (719A>G) account for 80-95% of TPMT deficiency observed in Caucasian populations. In this paper, we describe a novel, multiplex, allele-specific polymerase chain reaction (PCR) method that detects the 238G>C, 460G>A, and 719A>G mutations, allowing for the simultaneous identification of TPMT*2 and TPMT*3 alleles. The assay is internally controlled, robust, and does not require the use of restriction endonucleases. Therefore, the assay is not prone to erroneous readings due to incomplete restriction digestion, as documented for existing PCR restriction fragment length polymorphism (RFLP) assays of TPMT.

Topics: Alleles; Azathioprine; DNA; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Mutation; Oligonucleotide Probes; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Reproducibility of Results

Inflammatory bowel disease (IBD) is characterized by periods of relapse and remission. Treatment is aimed at reducing symptoms during relapse and prolonging the duration of remissions. 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are commonly used to prolong clinical remissions. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are two widely used laboratory markers of inflammation. The authors observed an unexplained discordance between ESR and CRP in children with asymptomatic IBD who were being treated with AZA or 6-MP.. To characterize children with IBD in remission treated with 6-MP or AZA who have persistently elevated ESR but normal CRP.. All patients seen in Pediatric Gastroenterology Clinic between January 1, 1995, and December 31, 2002, with Crohn disease or ulcerative colitis who received AZA or 6-MP continuously for at least 6 months were identified and their medical records reviewed.. One hundred twenty patients met the eligibility criteria. Twelve had an ESR >18 mm/hour on at least three occasions during at least 12 consecutive months with a simultaneous CRP <0.8 mg/dL. Eleven of these 12 had no signs or symptoms of active disease and had Pediatric Crohn Disease Activity Index scores <10 for at least 12 consecutive months while the ESR was elevated. Disease duration was similar in the 11 children with asymptomatic disease and with discordant ESR and CRP and in 108 children with concordant ESR and CRP (69.2 + 22.5 months v 54.3 +/- 40.1 months, P = 0.0709). Duration of AZA or 6-MP therapy was greater in the 11 children with asymptomatic disease and discordant ESR and CRP than in those with or without symptoms and with concordant ESR and CRP (58.1 +/- 16.4 months v 36.6 +/- 24.1 months, P = 0.0043). There were no differences between the groups with respect to diagnosis, location of disease, or age at onset of symptoms. The mean corpuscular volume (MCV) was somewhat larger in the children with discordant ESR and CRP than in the children with concordant ESR and CRP (91.4 +/- 6.97 fL v 87.0 +/-7.07 fL, respectively, P = 0.0373); however, in both groups, the MCV was in the normal range. There were no significant differences in hematocrit, white blood cell count, serum albumin, total serum protein, or estimated serum globulin between the groups.. The results suggest that among children treated with AZA or 6-MP, CRP may be a more reliable indirect indicator of inflammation than ESR. This report alerts clinicians that some children taking AZA or 6-MP may have persistent elevation of the ESR with a normal CRP and have no clinical evidence of active disease.

Topics: Adolescent; Azathioprine; Biomarkers; Blood Sedimentation; C-Reactive Protein; Child; Female; Humans; Immunosuppressive Agents; Inflammation; Inflammatory Bowel Diseases; Male; Mercaptopurine; Predictive Value of Tests

Topics: Cohort Studies; Female; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Pregnancy; Retrospective Studies

The thiopurines azathioprine and 6-mercaptopurine (6-MP) are effective drugs in steroid-dependent and refractory inflammatory bowel disease patients. Therapeutic drug monitoring (TDM) is a new concept to improve drug efficacy and prevent toxic adverse events. As thiopurine metabolism is influenced by genetic polymorphisms of methylating enzymes, metabolite levels may vary considerably, enabling significant adverse effects. In the present paper five patients are described to demonstrate the clinical usefulness of TDM when applying thiopurines for inflammatory bowel disease. Emphasized are patients with liver function test abnormalities and myelosuppression due to inappropriate 6-MP metabolite levels, and subsequently the treatment of these events. In addition, sophisticated 6-MP metabolite level-guided therapy, including non-compliance, is demonstrated. These cases demonstrate that TDM may improve effectivity and safety of thiopurine treatment.

Topics: Adult; Azathioprine; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Treatment Refusal

There are conflicting reports on the role of azathioprine (AZA) thioguanine nucleotide (TGN) metabolites in optimising therapy for inflammatory bowel disease (IBD). The aim of this study was to investigate TGN intrapatient variation, and the relationship between TGN concentrations and disease activity in IBD patients taking long term constant dose AZA.. TGN and methylmercaptopurine nucleotide (MeMPN) concentrations were measured at intervals over a two year period. Disease activity was assessed at each clinic visit using the Crohn's disease activity index or Walmsley simple index for ulcerative colitis.. Serial TGNs were measured in 159 patients (3-14 TGN assays, median 6). Intrapatient variation in TGN concentrations was 1-5-fold (median 1.6); the incidence of non-compliance was 13%. At the end of two years, 131 patients were evaluable at TGN steady state. Of this group, patients who remained in remission had significantly higher mean TGN concentrations than those patients who developed active disease (median TGNs 236 v 175, respectively; median difference 44 pmol (95% confidence interval 1-92); p = 0.04). MeMPN concentrations were not related to AZA efficacy or toxicity.. This study has shown that lower TGN concentrations were linked to the development of active disease, and that TGNs may act as useful markers of compliance. However, it is clear that repeat TGN measurements are required for an unambiguous index of active metabolite exposure. In view of the high intrapatient variability in TGN production over time, TGN measurements may not be currently advocated for routine clinical use.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Antimetabolites, Antineoplastic; Azathioprine; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Erythrocytes; Female; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Patient Compliance; Thioguanine; Treatment Outcome

The thiopurine drugs, azathioprine and 6-mercaptopurine are effective in the treatment of inflammatory bowel disease (IBD). However, their use is limited by serious adverse effects that can lead to cessation of therapy. The incidence of these adverse effects has been reported to be approximately 9% but in Christchurch it was felt that the incidence was higher.. We searched our letter database to identify all patients with IBD who had received a thiopurine drug between 1996 and 2002. The case notes were then reviewed to identify those patients who had suffered an adverse effect that required cessation of the drug.. From a total of 216 patients with IBD taking a thiopurine drug, 56 (25.9%) had an adverse reaction requiring cessation of the drug. Adverse effects included allergic-type (25%), liver test abnormalities (34%), nausea/vomiting (6%), bone marrow suppression (7%), pancreatitis (7%) and other (9%). Males were significantly more likely than females to have an allergic-type reaction (p = 0.003). All adverse effects resolved with cessation of the drug, with a median of 7 days to resolution. Of the patients with liver test abnormalities on azathioprine, most were able to tolerate 6-mercaptopurine, however challenge with 6-mercaptopurine was not successful for most other patients.. In Canterbury, New Zealand, patients with IBD have a high rate of therapy-limiting adverse effects to thiopurine drugs. There is a significant gender bias for allergic-type adverse effects. Mechanisms for both these observations are not clear.

Topics: Adolescent; Adult; Aged; Azathioprine; Female; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; New Zealand; Pharmacoepidemiology; Sex Distribution

We aimed at determining the utility of measuring 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) in inflammatory bowel disease (IBD) patients on azathioprine (AZA) or 6-mercaptopurine (6-MP), whether the described therapeutic range for 6-TG (235-400 pmol/8 x 10(8) red blood cells, RBC) correlated with clinical remission or leukopenia, and if 6-MMP level was a marker for hepatotoxicity (>5,700 pmol/8 x 10(8) RBC).. Study eligibility included an IBD diagnosis of >6 months and either active disease or disease remission of <6 months and the use of AZA/6-MP for >10 wk consecutively. Metabolite levels were evaluated against clinical status, CBC, and hepatic parameters.. Seventy-four of 166 AZA/6-MP users were eligible. 6-TG levels >235 pmol/8 x 10(8) RBC were found in 22/59 (38%) with active disease and in 7/15 with remission (47%, p= 0.16). There was a trend of higher 6-TG levels among those in remission versus those with active disease (mean 325 +/- 284 vs 223 +/- 159 pmol/8 x 10(8) RBC, p= 0.2). No hepatotoxicity was observed, although 12.2% had 6-MMP levels > 5,700 pmol/8 x 10(8) RBC. The correlation between 6-MP dose and 6-TG levels was weak (r = 0.22, p= 0.08). The 6-TG level did not correlate with WBC. There were five instances, each of markedly low levels of both 6-TG and 6-MMP, suggesting noncompliance and of marked 6-MMP levels versus 6-TG.. There was a poor correlation between 6-TG levels and remission. Nonetheless, the measurements of these levels are helpful when patients are on high doses but not achieving remission since noncompliance or metabolism favoring 6-MMP can be established.

Topics: Adult; Azathioprine; Biomarkers; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Inflammatory Bowel Diseases; Male; Maximum Tolerated Dose; Mercaptopurine; Middle Aged; Predictive Value of Tests; Prognosis; Prospective Studies; Risk Assessment; Severity of Illness Index; Thioguanine; Treatment Outcome

Recent studies have suggested that mercaptopurine metabolism is influenced by drug formulation (mercaptopurine vs. azathioprine) and concomitant use of 5-aminosalicylic acid medications.. To determine the influence of dose, formulation and 5-aminosalicylic acid use on mercaptopurine metabolism.. Metabolites from 131 inflammatory bowel disease patients were analysed. Logistic regression was used to analyse correlations between dose and metabolite levels. Multivariate analysis was used to determine the effects of drug formulation and 5-aminosalicylic acid use.. A positive correlation was detected between dose and 6-tioguanine nucleotides levels for azathioprine/Imuran formulation (P = 0.005) but not for mercaptopurine formulation. Adjusted mean 6-tioguanine nucleotides levels were similar for both formulations. Adjusted mean 6-methylmercaptopurine levels were higher for mercaptopurine formulation than for azathioprine formulation (1950 vs. 1056, P = 0.04). 5-Aminosalicylic acid use: 6-tioguanine nucleotides levels did not differ based on concomitant 5-aminosalicylic acid use. However, 5-aminosalicylic acid use did result in higher adjusted mean 6-methylmercaptopurine levels: 2078 on 5-aminosalicylic acid vs. 991 off 5-aminosalicylic acid (P = 0.004).. (i) Azathioprine may have metabolic benefits by achieving a correlation of dose with 6-tioguanine nucleotides levels and by leading to lower mean 6-methylmercaptopurine levels. (ii) 5-aminosalicylic acid use does not significantly impact 6-tioguanine levels and may lead to higher 6-methylmercaptopurine levels.

Topics: Adolescent; Adult; Aged; Aminosalicylic Acids; Antimetabolites; Azathioprine; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Female; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Regression Analysis

Azathioprine (AZA) or 6-mercaptopurine (6-MP) are the immunosuppressive drugs of choice in the treatment of inflammatory bowel disorders (IBD). Optimal dosage for AZA is around 2.5 mg/kg body weight and induction of remission by these drugs may take 6 - 7 months. Intramuscularly applied Methotrexate (MTX) is the second choice, while its efficacy starts earlier than that of AZA; studies assessing oral low-dose MTX treatment are lacking. Cyclosporin is the standard treatment in case of steroid-refractory severe ulcerative colitis. This drug may also be used in patients with severe extraintestinal manifestations of IBD. Regarding other immunosuppressive drugs such as mycophenolic acid or 6-thioguanine respective controlled clinical study data are not available. The risk of malignancy using immunosuppressive drugs such as AZA is low and furthermore, especially AZA and 6-MP can be used rather safely during pregnancy.

Topics: Administration, Oral; Azathioprine; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Injections, Intramuscular; Male; Mercaptopurine; Methotrexate; Placebos; Pregnancy; Randomized Controlled Trials as Topic; Remission Induction; Retrospective Studies; Safety; Time Factors

Topics: Abnormalities, Drug-Induced; Azathioprine; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Paternal Exposure; Spermatozoa

The immunosuppressive effects of thiopurine drugs are mainly mediated through their intracellular metabolism into active 6-thioguanine nucleotide (6-TGN) metabolites, which are incorporated into DNA. Erythrocyte 6-TGN (E-6TGN) levels have been proposed as an instrument for monitoring treatment. The aim of the study was to use erythrocyte E-6TGN, methylated mercaptopurine (MeMP) metabolites, and thiopurine methyltransferase (TPMT) measurements in a clinical setting to determine the clinical outcome in relation to thiopurine metabolism.. Fifty-five adult patients with inflammatory bowel disease were included in a prospective study and followed for 6 months. Metabolite levels were measured and correlated to outcome and AZA/6-MP dose.. The E-6TGN level was significantly related to the TPMT genotype (P = 0.008). Patients in disease remission had higher E-6TGN levels than patients with disease activity both at baseline (P < 0.05) and after 6 months (P = 0.02). Active disease was more frequent among subjects with E-6TGN < or = 125 nmol/mmol Hb at baseline (P = 0.04), but not at 6 months. AZA/6-MP drug dose was positively correlated to E-MeMP levels (r = 0.48; P < 0.001) and E-MeMP/E-6TGN ratio (r = 0.41; P = 0.002). Dose changes were positively correlated with the changes in E-MeMP levels (P = 0.01) and E-MeMP/E-6TGN ratio (P = 0.03).. E-6TGN level was the only factor in this study related to disease activity, while there was no relationship between AZA/6-MP dose and E-6TGN levels. This finding illustrates the clinical usefulness of E-6TGN monitoring in the evaluation of treatment intensity.

Topics: Adolescent; Adult; Azathioprine; Drug Monitoring; Erythrocytes; Female; Genotype; Guanine Nucleotides; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Middle Aged; Sulfasalazine; Thionucleotides

Thiopurine drugs are commonly used immunosuppressants in the treatment of inflammatory bowel disease (IBD) as well as in autoimmune hepatitis (AIH), rheumatic diseases and in transplantation medicine. The relatively narrow therapeutic range requires useful therapy control. Therefore, the purpose of this study was to further investigate the rationale and usefulness of therapeutic drug monitoring in the surveillance of thiopurine drug therapy in Crohn's disease, ulcerative colitis and autoimmune hepatitis.. 6-Thioguanine nucleotide (TGN) and 6-methylmercaptopurine nucleotide (MMPN) levels were measured in 182 IBD patients and 18 AIH patients using HPLC-UV.. In our cohort of IBD patients, 18% had TGN levels < 235 pmol/8 x 10 red blood cells (RBC) (recommended range, 235-450 pmol/8 x 10 RBC), 41% of these patients were sent for drug failure. Twenty-four per cent of the IBD patients had TGN levels > 450 pmol/8 x 10 RBC, but only 27% of these experienced adverse effects. Fifty-nine per cent of the patients having drug failure had TGN levels in the recommended range and could therefore be classified as non-responders. In the AIH cohort 33% of the patients had TGN levels below the recommended range but showed clinical response to therapy. MMPN levels increased with the duration of treatment and could be useful for controlling compliance. There was 8.8% of IBD patients who were heterozygous for non-functional TPMT alleles.. TGN monitoring did not identify significant differences between patient groups but allowed the identification of non-responders from non-compliant patients and allowed the differentiation of mild side effects, such as malaise, from genuine toxicity caused by highly increased TGN levels.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Chromatography, High Pressure Liquid; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Drug Monitoring; Female; Guanine Nucleotides; Hepatitis, Autoimmune; Heterozygote; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Purines; Thioguanine; Thionucleotides

Azathioprine (AZA) and its active metabolite mercaptopurine (MP) are frequently used in the management of inflammatory bowel disease. Measurement of the AZA/MP metabolites, thioguanine (TG) and methylmercaptopurine (MMP), has been suggested as a means to optimize therapy with AZA/MP in inflammatory bowel disease.. To evaluate the results of initial AZA/MP metabolite panels sent by gastroenterologists during the first year of its widespread availability.. Initial AZA/MP metabolite panels sent by gastroenterologists to a single laboratory were reviewed and the metabolite panels were interpreted.. Initial metabolite levels were reviewed for 9187 patients. Noncompliance was detected in 263 patients (3%) and under-dosing in 4260 patients (46%). 534 patients (6%) had levels that were consistent with preferential metabolism via the TPMT pathway. The therapeutic goal was achieved in 2444 patients (27%) and an additional 552 patients (6%) had appropriate TG levels but potential hepatotoxicity. 936 patients (10%) had potential TPMT deficiency, and 58 patients (1%) had potential TPMT absence and were at risk for leukopenia. 140 patients (2%) had too high a dose.. Measurement of AZA/MP metabolites can be used by practising gastroenterologists to identify potential reasons for nonresponse to AZA or MP, and to identify patients at risk for certain drug-related toxicities.

Topics: Azathioprine; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Patient Compliance; Risk Factors; Thioguanine

6-mercaptopurine/azathioprine is effective in IBD patients. However, data regarding toxicity associated with pregnancy are lacking, raising both patients' and physicians' concerns and sometimes resulting in elective abortion.. To evaluate potential toxicity of 6-mercaptopurine (6-MP), we reviewed the records of 485 patients who had received the drug. We contacted 462, of whom 155 had conceived at least 1 pregnancy after developing IBD. Pregnancies were analyzed as to whether the patient had taken 6-MP before, or at the time of, conception. These were compared with IBD patients who had their pregnancies before taking 6-MP. We collected data on live births, spontaneous abortions, prematurity, abortions secondary to birth defects, major and minor congenital birth defects, infections, and neoplasia. Outcomes were analyzed comparing pregnancies from men and women who had taken or were currently taking 6-MP to controls.. There was no statistical difference in conception failures (defined as a spontaneous abortion), abortion secondary to a birth defect, major congenital malformations, neoplasia, or increased infections among male or female patients taking 6-MP compared with controls (RR = 0.85 [0.47-1.55], P = 0.59).. 6-MP use before or at conception or during pregnancy appears to be safe. Discontinuation of the drug before and during pregnancy is not indicated.

Topics: Control Groups; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Medical Records; Mercaptopurine; Pregnancy; Pregnancy Complications; Retrospective Studies; Safety

6-Mercaptopurine (6-MP) has proven efficacy in the therapy of inflammatory bowel disease. Its teratogenicity is demonstrated in animal studies when used at very high doses, whereas human data suggest that 6-MP at maintenance doses is safe. We report the outcome of 72 pregnancies in patients with inflammatory bowel disease who were previously treated with 6-MP with three different doses of 50, 75, and 100 mg/d, for a median duration of 18 months, along with long-term follow-up of the children.. We have compared the outcome of pregnancies and development of the offspring in the following two groups: group 1, patients with inflammatory bowel disease who conceived 6 months to 22 years after stopping 6-MP (median 72 months); and group 2, patients with inflammatory bowel disease who never received 6-MP prior to conception. All pregnancies were evaluated in terms of outcome: live full-term birth, premature delivery, stillbirth, spontaneous abortion, ectopic pregnancy, and therapeutic dilatation and curettage. Data on children were obtained regarding birth weight, congenital anomalies, and development.. Group 1 included 72 pregnancies carried by 29 women. There were 51 live births (4 premature), 16 spontaneous abortions, 1 stillbirth, 2 therapeutic abortions due to abnormal amniocentesis, and 2 ectopic pregnancies. The total incidence of fetal loss was 29.2%. In group 2, 75 women had 140 pregnancies resulting in 120 live births (8 premature), 18 spontaneous abortions, and 2 stillbirths. There were no cases of ectopic pregnancies or abnormal amniocentesis. The total incidence of fetal loss was 14.3%. There was no increase in the incidence of developmental defects when the mothers had been treated with 6-MP prior to pregnancy.. The incidence of fetal loss is higher in women with inflammatory bowel disease who had been previously treated with 6-MP compared with those who had not. Whether this was related to the older age at conception in 6-MP group, longer duration of disease, initially more severe disease, or use of 6-MP we cannot tell.

Topics: Abortion, Spontaneous; Adult; Case-Control Studies; Child Development; Child, Preschool; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Embryonic and Fetal Development; Female; Fetal Death; Humans; Infant, Newborn; Infant, Premature; Inflammatory Bowel Diseases; Mercaptopurine; Obstetric Labor, Premature; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prevalence; Probability; Reference Values; Risk Assessment

6-mercaptopurine (6-MP) and its parent drug azathioprine (AZA) have been proven to be effective for both steroid-dependent and chronically active, or steroid-resistant inflammatory bowel disease, as well as for the prevention of relapse. Concerns about toxicity, delayed onset of action, and therapeutic failure (1 out of 3 patients) have restricted their use. Recent pharmacogenetic advances have led to the development of novel strategies to optimize and individualize therapy with AZA and 6-MP, maximizing efficacy while minimizing toxicity. We have defined a range of optimal therapeutic 6-MP metabolite levels, as well as an association of metabolite levels with medication-induced toxicity and the genotype of the main catabolic enzyme, thiopurine methyltransferase (TPMT). Measurement of 6-MP metabolite levels and TPMT molecular analysis provide clinicians with useful tools for optimizing therapeutic response to 6-MP/AZA, as well as for identifying individuals at increased risk for drug-induced toxicity.

Topics: Antimetabolites; Azathioprine; Evidence-Based Medicine; Genotype; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Liver; Mercaptopurine; Methyltransferases; Pharmacogenetics; Polymorphism, Genetic; Remission Induction

Topics: Adjuvants, Immunologic; Azathioprine; Clinical Trials as Topic; Contraindications; Cyclosporine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate; Safety; Tumor Necrosis Factor-alpha

Topics: Genotype; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Phenotype; Polymorphism, Genetic

There is a general lack of information on the care of inflammatory bowel disease (IBD) in a broad, geographically diverse, non-clinic population. The purposes of this study were (1) to compare a sample drawn from the membership of a national Crohn's and Colitis Foundation to published clinic-based and population-based IBD samples, (2) to describe current patterns of health care use, and (3) to determine if unexpected variations exist in how and by whom IBD is treated.. Mailed survey of 4453 members of the Crohn's and Colitis Foundation of Canada. The questionnaire, in members stated language of preference, included items on demographic and disease characteristics, general health behaviors and current and past IBD treatment. Each member received an initial and one reminder mailing.. Questionnaires were returned by 1787, 913, and 128 people with Crohn's disease, ulcerative colitis and indeterminate colitis, respectively. At least one operation had been performed on 1159 Crohn's disease patients, with risk increasing with duration of disease. Regional variation in surgical rates in ulcerative colitis patients was identified. 6-mercaptopurine/azathioprine was used by 24% of patients with Crohn's disease and 12% of patients with ulcerative colitis (95% CI for the difference: 8.9%-15%). In patients with Crohn's disease, use was not associated with gender, income or region of residence but was associated with age and markers of disease activity. Infliximab was used by 112 respondents (4%), the majority of whom had Crohn's disease. Variations in infliximab use based on region of residence and income were not seen. Sixty-eight percent of respondents indicated that they depended most on a gastroenterologist for their IBD care. There was significant regional variation in this. However, satisfaction with primary physician did not depend on physician type (for example, gastroenterologist versus general practitioner).. This study achieved the goal of obtaining a large, geographically diverse sample that is more representative of the general IBD population than a clinic sample would have been. We could find no evidence of significant regional variation in medical treatments due to gender, region of residence or income level. Differences were noted between different age groups, which deserves further attention.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Azathioprine; Canada; Colitis; Colitis, Ulcerative; Crohn Disease; Digestive System Surgical Procedures; Female; Gastroenterology; Health Services; Humans; Incidence; Inflammatory Bowel Diseases; Infliximab; Male; Mercaptopurine; Middle Aged; Patient Satisfaction; Population Surveillance

Approximately 10% of inflammatory bowel disease (IBD) patients receiving 6-mercaptopurine (6-MP) or azathioprine (AZA) develop drug hypersensitivity reactions necessitating early discontinuation of these traditional thiopurines. These allergic reactions typically reoccur upon rechallenge. Our recently published pilot study suggested that thioguanine (6-TG), a closely related thiopurine, was efficacious and well tolerated in IBD patients resistant to 6-MP/AZA. The aim of this study was to determine if hypersensitivity reactions to 6-MP/AZA reoccur with 6-TG therapy.. IBD patients allergic to 6-MP and/or AZA were treated with 6-TG as an alternate thiopurine. Hypersensitivity reactions to 6-MP/AZA must have been documented within 6 wk of 6-MP/AZA initiation.. 6-TG was initiated in 21 IBD patients at a median (range) dose of 20 (10-40) mg/day. 6-TG hypersensitivity reaction occurred in only four of 21 (19%) patients after a median time interval of 9 days. Pancreatitis did not reoccur with 6-TG. Eighty-two percent of 6-TG tolerant patients were assessed as improved at last follow-up.. These results suggest that 6-TG may be considered as a possible alternate thiopurine in patients allergic to traditional 6-MP/AZA. Despite these favorable results, candidates for 6-TG should be selected with caution, and its use should be reserved for IBD patients well informed about potential toxicities.

Topics: Adult; Azathioprine; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Intestinal Mucosa; Male; Mercaptopurine; Middle Aged; Pilot Projects; Prospective Studies; Safety; Thioguanine; Treatment Outcome

We aimed at assessing whether there exists a relationship between thiopurine methyltransferase (TPMT) activity and the incidence of adverse events, especially myelotoxicity, in patients with inflammatory bowel disease treated with azathioprine (AZA) or 6-mercaptopurine (6-MP).. By means of a radiochemical method, we determined the TPMT activity in erythrocytes of patients with inflammatory bowel disease who had received previously or at the time of the study AZA or 6-MP (n = 97). A group of 37 patients who had never been treated with these drugs was included. We studied the relationship between several variables and TPMT values as well as their correlation with adverse events.. Mean (SD) TPMT value was 20.8 (5) U/ml erythrocytes (from 7.8 to 32.7). There was no patient with low TPMT levels (< 5); 9% patients had intermediate levels (from 5 to 13.7 U/ml), while 91% displayed high levels (>= 13.8 U/ml). There were no differences when comparing TPMT values according to several variables such as age, gender, tobacco consumption, weight, type of inflammatory bowel disease, and treatment with 5-aminosalicylates, steroids or AZA/6-MP. Side effects were seen in 13 out of 97 (13%) patients administered AZA/6-MP. None patient with side effects exhibited low TPMT levels (< 5 U/ml), nor even intermediate levels (5-13.7 U/ml). There were no differences when comparing mean TPMT values in patients with side effects and in those without side effects.. In this study, the usefulness of the determination of the TPMT activity to identify patients with inflammatory bowel disease at risk of myelotoxicity due to AZA or 6-MP has not been confirmed. Therefore, even when the TPMT enzymatic activity is normal, it is necessary to continue performing the periodic laboratory analysis.

Topics: Adult; Azathioprine; Bone Marrow; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Linear Models; Male; Mercaptopurine; Methyltransferases

Many patients with inflammatory bowel disease receive corticosteroids and 6-mercaptopurine/azathioprine during elective bowel surgery. We investigated the postoperative infection risk for patients undergoing elective bowel surgery who were receiving corticosteroids and/or 6-mercaptopurine/azathioprine before surgery compared with patients not receiving these medications.. A retrospective cohort study was conducted on 159 patients with inflammatory bowel disease who underwent elective bowel surgery. There were 56 patients receiving corticosteroids alone, 52 patients receiving 6-mercaptopurine/azathioprine alone or with corticosteroids, and 51 patients receiving neither corticosteroids nor 6-mercaptopurine/azathioprine. Postoperative infectious complications to time of discharge were categorized into major and minor complications.. Patients receiving corticosteroids had an adjusted odds ratio for any and major infectious complications of 3.69 (95% confidence interval [CI], 1.24-10.97) and 5.54 (95% CI, 1.12-27.26), respectively. The adjusted odds ratio for patients receiving 6-mercaptopurine/azathioprine for any and major infectious complications was 1.68 (95% CI, 0.65-4.27) and 1.20 (95% CI, 0.37-3.94), respectively.. Preoperative use of corticosteroids in patients with inflammatory bowel disease who are undergoing elective bowel surgery is associated with an increased risk of postoperative infectious complications. 6-Mercaptopurine/azathioprine alone and the addition of 6-mercaptopurine/azathioprine for patients receiving corticosteroids was not found to significantly increase the risk of postoperative infectious complications.

Topics: Adjuvants, Immunologic; Adolescent; Adrenal Cortex Hormones; Adult; Aged; Azathioprine; Cohort Studies; Female; Humans; Infections; Inflammatory Bowel Diseases; Length of Stay; Male; Mercaptopurine; Middle Aged; Postoperative Complications; Retrospective Studies; Risk

Topics: Adjuvants, Immunologic; Azathioprine; Humans; Infections; Inflammatory Bowel Diseases; Mercaptopurine; Postoperative Complications

Topics: Cohort Studies; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Retrospective Studies

Topics: Azathioprine; Child; Drug Monitoring; Guanine Nucleotides; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methylthioinosine; Methyltransferases; Polymorphism, Genetic; Thionucleotides

Topics: Azathioprine; Child; Drug Monitoring; Guanine Nucleotides; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methylthioinosine; Methyltransferases; Polymorphism, Genetic; Thionucleotides

Topics: Azathioprine; Drug Hypersensitivity; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine

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

Topics: Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Pharmacogenetics

The use of azathioprine and 6-mercaptopurine for inflammatory bowel disease increased in the early 1990s. We sought to determine the effect of this change in therapy on the risk of lymphoma in patients with inflammatory bowel disease.. All patients with inflammatory bowel disease at a single tertiary care medical center who developed lymphoma between 1985-2000 were identified and the pathologic features of the lymphoma including presence of Epstein- Barr virus were determined. The patients were divided into two 8-year periods (1985-1992, 1993-2000) corresponding with the introduction of azathioprine and 6-mercaptopurine in 1993.. Eighteen patients with lymphoma were identified, 6 between 1985-1992 and 12 between 1993-2000. Six of 18 lymphomas occurred in patients treated with azathioprine or 6-mercaptopurine, all between 1993-2000. Seven patients developed Epstein-Barr virus-positive lymphoma (1 from 1985-1992, 6 from 1993-2000). Five of 7 Epstein-Barr virus-positive lymphomas occurred in patients treated with azathioprine or 6-mercaptopurine compared with 1 of 11 Epstein-Barr virus-negative lymphomas (P = 0.01). Approximately 1200 patients with inflammatory bowel disease were treated with these agents between 1993-2000.. Treatment of inflammatory bowel disease with azathioprine or 6-mercaptopurine appears to be associated with a small increased risk of Epstein-Barr virus-positive lymphoma.

Topics: Adult; Aged; Aged, 80 and over; Azathioprine; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Lymphoma; Male; Mercaptopurine; Middle Aged; Risk Factors

Topics: Adult; Azathioprine; Dose-Response Relationship, Drug; Female; Forecasting; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases

Topics: Adult; Amniocentesis; Congenital Abnormalities; Fathers; Female; Humans; Immunosuppressive Agents; Infant, Newborn; Inflammatory Bowel Diseases; Male; Mercaptopurine; Paternal Exposure; Pregnancy; Risk Assessment

Pyoderma gangrenosum complicates inflammatory bowel disease in 2-3% of patients and often fails to respond to antibiotics, steroids, surgical debridement or even colectomy.. We performed a retrospective chart analysis of 11 consecutive steroid-refractory pyoderma patients (5 ulcerative colitis, 6 Crohn's disease) referred to our practice and then treated with intravenous cyclosporine. Pyoderma gangrenosum was present on the extremities in 10 patients, the face in 2, and stomas in 21. At initiation of intravenous cyclosporine, bowel activity was moderate in 3 patients, mild in 4, and inactive in 4. All patients received intravenous cyclosporine at a dose of 4 mg/kg/d for 7-22 days. They were discharged on oral cyclosporine at a dose of 4-7 mg/kg/d.. All 11 patients had closure of their pyoderma with a mean time to response of 4.5 days and a mean time to closure of 1.4 months. All seven patients with bowel activity went into remission. Nine patients were able to discontinue steroids, and nine were maintained on 6-mercaptopurine or azathioprine. One patient who could not tolerate 6-mercaptopurine had a recurrence of pyoderma. No patient experienced significant toxicity.. Intravenous cyclosporine is the treatment of choice for pyoderma gangrenosum refractory to steroids and 6-mercaptopurine should be used as maintenance therapy.

Topics: Adrenal Cortex Hormones; Adult; Aged; Cyclosporine; Drug Resistance; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infusions, Intravenous; Male; Mercaptopurine; Middle Aged; Pyoderma Gangrenosum; Retrospective Studies; Treatment Outcome

The conversion of the cytotoxic and immunosuppressive 6-mercaptopurine (6MP) to the active 6-thioguanine nucleotides (6TGN) is necessary for clinical efficacy of 6MP and its prodrug azathioprine. Another metabolite, 6-methylmercaptopurine nucleotide (6MMPN), is formed via a competing pathway by thiopurine methyl transferase. The concentrations of 6TGN and 6MMPN are measured in washed erythrocytes as a surrogate to the intracellular levels of these metabolites in the target tissues. Analysis of 6TGN and 6MMPN in multi-center clinical studies is more complicated because of the requirement to wash erythrocytes. In this investigation, we found no differences in the concentrations of 6TGN and 6MMPN in blood versus washed erythrocytes in samples obtained from patients taking therapeutic doses of oral 6MP or azathioprine for inflammatory bowel disease. We concluded that whole blood could be used for the analysis of these analytes, thus saving sample preparation time. We also found that the erythrocyte 6TGN concentration in blood at ambient temperature declined 2-4% per day, a loss that can be avoided by shipping blood samples frozen. The loss of 6TGN in blood stored at approximately -80 degrees C was 1% after 1 week and 12% after 24 weeks, indicating the analyte was moderately stable. 6MMPN in blood did not significantly change after 24 weeks of storage at approximately -80 degrees C. In addition, the sensitivity of the 6TGN assay was improved by modifying the HPLC conditions, which made the method more suitable for quantifying low levels of 6TGN in human intestinal biopsy samples and blood.

Topics: Chromatography, High Pressure Liquid; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Reproducibility of Results; Spectrometry, Fluorescence; Thioguanine

Topics: Antimetabolites; Azathioprine; Humans; Inflammatory Bowel Diseases; Mercaptopurine

Enhanced MAdCAM-1 (mucosal addressin cell adhesion molecule-1) expression is associated with the aetiology of inflammatory bowel disease, but little is known about MAdCAM-1: regulation, or how inflammatory bowel disease therapies modulate MAdCAM-1.. To examine how agents currently used to treat inflammatory bowel disease affect MAdCAM-1: induced by tnf-alpha in an in vitro model of inflammatory bowel disease.. Endothelial monolayers were pretreated with dexamethasone (DEX): 5-aminosalicylic acid (5-ASA), 6-mercaptopurine (6-MP), sulfasalazine or interleukin-10: (IL-10: prior to TNF-alpha (20 ng/mL), and MAdCAM-1: measured by Western blotting, RT-PCR, EMSA and lymphocyte adhesion assays.. MAdCAM-1: was induced dose- and time-dependently by TNF-alpha on endothelial cells. Either dexamethasone or IL-10: reduced TNF-alpha-induced MAdCAM-1: protein, mRNA and lymphocyte adhesion. However, neither 5-ASA, sulfasalazine nor 6-MP blocked MAdCAM-1 induction.. Our data indicate that dexamethasone or IL-10 can exert therapeutic activity in inflammatory bowel disease through MAdCAM-1 inhibition. 5-ASA, sulfasalazine and 6-MP, while beneficial in inflammatory bowel disease, do not directly control MAdCAM-1, and are beneficial through inhibition of other inflammatory processes.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Adhesion Molecules; Cells, Cultured; Dexamethasone; Endothelium; Glucocorticoids; Immunoglobulins; Immunosuppressive Agents; Inflammatory Bowel Diseases; Interleukin-10; Lymphocytes; Mercaptopurine; Mesalamine; Mice; Mucoproteins; Reverse Transcriptase Polymerase Chain Reaction; Sulfasalazine; Thymidine Kinase; Tumor Necrosis Factor-alpha

Measurement of 6-thioguanine nucleotide concentrations may be useful for optimising treatment with azathioprine and 6-mercaptopurine.. We conducted a study of 170 patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine to determine the relationship between 6-thioguanine nucleotide concentrations and both disease activity, as measured by the inflammatory bowel disease questionnaire (active disease < 170, remission > or = 170) and leucopenia. Blood was submitted for whole blood 6-thioguanine nucleotide concentration and leucocyte count.. Mean (SD) inflammatory bowel disease questionnaire score was 176 (32). There was no correlation between inflammatory bowel disease questionnaire scores and 6-thioguanine nucleotide concentrations (r(s) = -0.09, p = 0.24). Median 6-thioguanine nucleotide concentrations in 56 patients with active disease and 114 patients in remission were similar (139 v 131 pmol/8 x 10(8) red blood cells; p = 0.26). There was no correlation between 6-thioguanine nucleotide concentrations and leucocyte counts.. In patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine, 6-thioguanine nucleotide concentrations did not correlate with disease activity, as measured by the inflammatory bowel disease questionnaire, or leucocyte count. These findings are discrepant with most previous studies, possibly due to selection of responding patients who tolerated the medications. A prospective, randomised, dose optimisation trial using 6-thioguanine nucleotide concentrations is warranted.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Severity of Illness Index; Statistics, Nonparametric

Some authors suggest that efficacy of 6-mercaptopurine (6-MP) in patients with inflammatory bowel disease correlates with circulating 6-thioguanine (6-TG) levels more than 235 pmol/8 x 10(8) red blood cells. The authors evaluated the relation between 6-MP metabolite levels and disease activity in children and adolescents with inflammatory bowel disease.. Clinical status and hematologic and hepatic parameters were determined in 101 children with inflammatory bowel disease from a single center and compared with 6-MP metabolite levels.. There was a trend for higher 6-TG levels among patients in remission than among those with active disease (217 vs. 173); however the difference was not statistically significant ( P = 0.09). The likelihood of therapeutic response did not increase significantly at 6-TG levels greater than 235 pmol/8 x 10(8) red blood cells (odds ratio 1.7; P = 0.1). In the current study, 58% of patients in remission had 6-TG levels less than 235. However, serial measurements of 6-MP metabolite levels in 50 patients with active disease showed that increasing 6-TG levels correlated significantly with disease remission in patients followed up longitudinally ( P = 0.04). Leukopenia was significantly associated with high 6-TG levels ( P = 0.03) but not with clinical response ( P = 0.2).. These data suggest that the target range of 6-TG levels previously described by others did not apply to 58% of the pediatric patients with IBD in remission. However, serial monitoring of 6-MP metabolite levels in individual patients with active disease should allow dose escalation and induction of remission while minimizing the risk of toxicity.

Topics: Adolescent; Antimetabolites, Antineoplastic; Azathioprine; Child; Cross-Sectional Studies; Erythrocytes; Humans; Inflammatory Bowel Diseases; Leukocyte Count; Leukopenia; Liver; Male; Mercaptopurine; Odds Ratio; Retrospective Studies; Thioguanine; Treatment Outcome

At this time, standard therapy for treatment of inflammatory bowel disease includes the use of glucocorticoids for moderate to severe Crohn's disease, severe ulcerative colitis, and moderate ulcerative colitis failing mesalamine. Although the majority of patients will have clinical improvement with glucocorticoids, a substantial minority of patients will later flare with attempts to withdraw therapy. Given the numerous potential side effects associated with glucocorticoids, every effort should be made to switch these patients to a less toxic medication. Historically, the most reliable agents have been azathioprine or 6-mercaptopurine. Infliximab is a relatively new medication but would be expected to be beneficial for weaning glucocorticoids for Crohn's disease patients. Methotrexate is another alternative for Crohn's disease. Budesonide and CDP571 are still in developmental phases but likely will be helpful in managing this patient population. Mesalamine, cyclosporine, mycofenalate mofetil, and thalidomide have less data available to support their use but may be helpful for some patients. 6-Thioguanine may be an alternative to patients who do not tolerate 6-mercaptopurine or azathioprine.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antimetabolites; Gastrointestinal Agents; Glucocorticoids; Humans; Inflammatory Bowel Diseases; Infliximab; Male; Mercaptopurine; Middle Aged; Prednisone; Sulfasalazine

Topics: Antimetabolites, Antineoplastic; Azathioprine; Biomarkers; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Pilot Projects; Prospective Studies; Thioguanine

To obtain information on the clinical experience with azathioprine (AZA), 6-mercaptopurine (6-MP), cyclosporin A (CyA) and methotrexate (MTX) in the treatment of patients with inflammatory bowel disease (IBD) by gastroenterologists and internists in different countries.. A questionnaire designed by the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) was mailed to 300 gastroenterologists, living in North America (n = 76) and Europe (n = 224) (12 countries), to obtain information on clinical experience.. More than half of the respondents (168/298; 56.4%) worked in university hospitals and 58/298 (19.5%) in general (non-university) hospitals. Two-thirds (65%) had more than 10 years' experience in gastroenterology.. The respondents had personal experience with AZA (88.4%), 6-MP (33.3%), CyA (48.7%) and MTX (36.3%). AZA was prescribed more frequently in Europe (92.6%) than in North America (74.2%) (P = 0.0002), 6-MP less frequently by the European than the North American respondents (23.8 and 53.3% respectively, P = 0.0001). Two-thirds (69.7%) usually prescribed AZA together with steroids to Crohn's disease patients; 62.4% of the respondents prescribed AZA for periods longer than 24 months. For ulcerative colitis, 77.9% had experience with AZA (Europe > North America, P = 0.0001). AZA had been prescribed by 69 respondents to pregnant patients, without apparent toxicity. Acute pancreatitis had been observed after AZA by 56.7% respondents; 25 malignancies were mentioned (six lymphoma, three leukaemia, three colon cancer, four renal carcinoma, nine others). CyA had been prescribed in acute ulcerative colitis by 140/291 respondents (North America 45.1%, Europe 49.1 %); of all respondents 63.9% treated < 5 patients with CyA, 36.1% 6-20 cases. CyA results were considered good in 29.5%, acceptable but with recurrences in 58.6%, and poor in 14.3%. MTX was prescribed in North America by 47.8% of the respondents, and by 33.9% in Europe (not significant). Several significant differences were observed between the prescription behaviour of respondents working at university hospitals and non-university hospitals, in particular in relation to participation in clinical trials.. Considerable experience exists in the use of immunosuppressive therapy in IBD; however, differential prescription behaviour exists in the choice of immunosuppressives between North America and Europe. These IOIBD study results may contribute to a better insight in the daily use of immunosuppressive agents in IBD by gastroenterologists and other specialists.

Topics: Azathioprine; Cyclosporine; Europe; Female; Gastroenterology; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Internal Medicine; Male; Mercaptopurine; Methotrexate; North America; Practice Patterns, Physicians'; Pregnancy; Pregnancy Complications; Surveys and Questionnaires

Topics: Antibodies, Monoclonal; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Treatment Outcome

Topics: Abnormalities, Drug-Induced; Fathers; Female; Humans; Immunosuppressive Agents; Infant, Newborn; Inflammatory Bowel Diseases; Mercaptopurine; Pregnancy; Risk Factors

The outcomes of pregnancies after maternal use of 6-mercaptopurine (6-MP) for inflammatory bowel disease (IBD) during pregnancy have been reported, but data are lacking for outcomes when the fathers use this drug.. Subjects were male patients with IBD seen at one center between 1970 and 1997. Patients and their wives were interviewed. Group 1 comprised pregnancies fathered by men who were taking 6-MP. This group was further subdivided into those conceived within 3 months of 6-MP use and those conceived at least 3 months after 6-MP was stopped. Group 2 comprised pregnancies fathered by men with IBD, similar in characteristics to group 1, who had not taken 6-MP before fertilization. Information was collected regarding the fathers, the mothers, and the pregnancies, as well as the health of the children, in a historical cohort study.. There were 50 pregnancies in group 1 (13 in 1A and 37 in 1B) and 90 pregnancies in group 2. Four of the 13 pregnancies in group 1A were associated with complications. There were two spontaneous abortions, and two congenital anomalies including a missing thumb in one and acrania with multiple digital and limb abnormalities in the other. Risk of complications was significantly increased when compared with group 1B (p < 0.013) and group 2 (p < 0.002).. The incidence of pregnancy-related complications was significantly increased when the fathers used 6-MP within 3 months of conception.

Topics: Abnormalities, Drug-Induced; Adult; Drug Administration Schedule; Fathers; Female; Humans; Immunosuppressive Agents; Infant, Newborn; Inflammatory Bowel Diseases; Male; Mercaptopurine; Pregnancy; Pregnancy Outcome

Topics: Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Drug Interactions; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Mesalamine

Topics: Abnormalities, Drug-Induced; Female; Fertilization; Humans; Immunosuppressive Agents; Incidence; Infant, Newborn; Inflammatory Bowel Diseases; Male; Mercaptopurine; Paternal Exposure; Pregnancy; Pregnancy Outcome; Risk Factors

Both azathioprine and its active metabolite, 6-mercaptopurine, are of benefit in the treatment of inflammatory bowel disease, either in resistant cases, or for their steroid-sparing effect. Azathioprine treatment is limited in some patients by hypersensitivity reactions or other side effects. We report our experience in 11 patients previously unable to tolerate azathioprine for a variety of reasons, who were switched to 6-mercaptopurine. Of seven patients with ulcerative colitis and four patients with Crohn's disease who were treated with 6-mercaptopurine following failed azathioprine therapy, six were able to successfully tolerate the substitute medication, with good response. Where patients have previously been intolerant of azathioprine yet ongoing indications for immunosuppressive therapy remain, a trial of 6-mercatopurine may be warranted. Given the similar efficacies of the two drugs in inflammatory bowel disease, these findings also favor the use of 6-mercaptopurine rather than the parent compound as initial therapy.

Topics: Adult; Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged

Hypersensitivity reactions to 6-mercaptopurine (6-MP) or azathioprine occur during the treatment of inflammatory bowel disease (IBD), raising significant diagnostic and therapeutic challenges. Charts of 591 patient with IBD treated with 6-MP in a single center were retrospectively reviewed. All allergic reactions were recorded along with results of rechallenge, desensitization, and subsequent course of IBD. Sixteen (2.7%) allergic reactions to 6-MP were noted, with fever being the most common (14 cases). Nine of these were rechallenged with 6-MP with recurrence of the same symptoms. Azathioprine was tried in six patients and in five the same symptoms recurred. Four patients underwent successful desensitization to either 6-MP or azathioprine; all four plus another patient who tolerated direct switch to azathioprine entered long-term remission. Among the remaining 11, 5 required surgery, 2 are well on methotrexate, and 4 have chronic symptoms while being treated with other medications. If an allergic reaction to 6-MP occurs during the treatment of IBD, direct switching to azathioprine is probably not justified. Instead, desensitization to either 6-MP or azathioprine should be attempted. Patients who can tolerate these medications after previous allergic reactions have improved outcomes compared with patients who resort to other forms of treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azathioprine; Desensitization, Immunologic; Female; Humans; Hypersensitivity; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Retrospective Studies

Topics: Aminosalicylic Acids; Anti-Ulcer Agents; Antirheumatic Agents; Azathioprine; Drug Interactions; Drug Therapy, Combination; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Mesalamine; Phenylhydrazines

Most complications of 6-mercaptopurine (6MP) used in the treatment of inflammatory bowel disease (IBD) occur early, whereas neoplasms occur late in the course. Concern persists that the risk is increased when 6MP is used. We report our experience with malignant tumors developing over 27 yr of treating IBD patients with 6MP.. A total of 591 patients with IBD treated with 6MP between 1969 and 1997 were followed or traced until present to identify all malignant tumors and blood dyscrasias that had developed to determine the type, distribution, and duration of the IBD, the dose and duration of 6MP therapy, the concurrent versus previous use of 6MP, the incidence and probable relationship of 6MP to specific neoplasms, and whether the 6MP had been effective in treatment.. A total of 550 patients (93%) fulfilled the criteria for follow-up; these included 380 with Crohn's disease (CD) and 170 with ulcerative colitis (UC). Twenty-five patients had developed neoplasms (16 of 380 CD and nine of 170 UC) (p = 0.66). In half of the cases, the goal of therapy had been achieved with 6MP. In 10 patients, the neoplasm was diagnosed while the patients were taking 6MP (40%) and in 15, many years after the 6MP had been terminated (60%). The incidence of neoplasms (25 of 550) was 2.7/1000 patient-years of follow-up. The most common neoplasms were found in the bowel (eight of 550, 1.6%; five CD, and three UC), and breast (three, 0.5%; two CD, and one UC). Non-Hodgkins lymphomas occurred in two patients with CD; one was cerebral and the other abdominal. One patient with CD developed leukemia. The duration of 6MP therapy ranged from 5 months to 22 yr, with a mean of 5 yr. The dose of 6MP ranged from a quarter of a tablet/day (12.5 mg) to 100 mg/day, with the majority in a range from 50 to 75 mg/day.. In no instance could a neoplasm be attributed to the use of 6MP. The incidence of colon cancer is not greater than that with long standing colitis. Suspicion of a relationship between 6MP and leukemia/lymphoma persists, but the incidence is low. This must be weighed against the improved quality of life due to 6MP for patients with IBD.

Topics: Abdominal Neoplasms; Adult; Aged; Aged, 80 and over; Brain Neoplasms; Breast Neoplasms; Colitis, Ulcerative; Crohn Disease; Drug Administration Schedule; Female; Follow-Up Studies; Hematologic Diseases; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Intestinal Neoplasms; Leukemia; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Middle Aged; Neoplasms; Risk Factors; Time Factors

Topics: Antibodies, Antineutrophil Cytoplasmic; Azathioprine; Child; Clinical Trials as Topic; Drug Therapy, Combination; Factor V; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Risk Factors

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

Azathioprine (AZA) and 6-mercaptopurine (6-MP) are used in pediatric patients with ulcerative colitis and Crohn's disease to reduce disease activity, maintain remission, prevent relapse, and lower corticosteroid dosage, but their long-term side effects remain to be studied. The aim of this study was to analyze the safety of AZA and 6-MP and steroid reduction in this age group.. The investigators' database identified 118 patients who received either drug; 23 were excluded (single visit, noncompliance, or therapy < 1 week), leaving 95 patients, with a mean (+/-SD) age of 14.2 +/- 4.4 years. Medical files were reviewed for adverse side effects: fever, pancreatitis, infections, gastrointestinal intolerance, aminotransferase level increase, leukopenia, and thrombocytopenia. Prednisone doses before and after immunomodulatory therapy were compared.. AZA or 6-MP was tolerated in 51 of 95 patients (54%) without adverse reaction; 27 of 95 (28%) experienced side effects that responded to dose reduction (23 patients) or spontaneously (4 patients), most commonly increased aminotransferase level (13.7%). Cessation of therapy was needed in 17 of 95 patients (18%), including recurrent fever (4), pancreatitis (4), gastrointestinal intolerance (4), and recurrent infections (3). Mean prednisone dose decreased from 24.3 to 8.6 mg/day.. AZA and 6-MP were well tolerated in 82% of patients; of these, prednisone reduction occurred in 87%. However, 18% required discontinuation because of hypersensitivity or infectious side effects.

Topics: Adolescent; Adult; Azathioprine; Child; Child, Preschool; Databases as Topic; Drug Hypersensitivity; Humans; Immunosuppressive Agents; Infections; Inflammatory Bowel Diseases; Medical Records; Mercaptopurine; Prednisone

Topics: Humans; Inflammatory Bowel Diseases; Liver; Liver Function Tests; Mercaptopurine

Topics: Adult; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukocytes; Leukopenia; Male; Mercaptopurine; Middle Aged

Topics: Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine

After failure of medical therapy, children with refractory inflammatory bowel disease may require surgical intervention. In this article the authors describe one child in whom, after traditional therapies for refractory ulcerative colitis failed, full remission of the disease occurred after the addition of 6-mercaptopurine and cyclosporine A to her medical regimen. 6-Mercaptopurine has been used with increasing frequency in refractory inflammatory bowel disease; the use of cyclosporine A for this condition is still under investigation.

Topics: Child; Colitis, Ulcerative; Combined Modality Therapy; Cyclosporine; Drug Therapy, Combination; Female; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methylprednisolone; Parenteral Nutrition, Total; Sulfasalazine

Topics: Aged; Aged, 80 and over; Azathioprine; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Neoplasms; Risk Factors

A feared complication of therapy with 6-mercaptopurine (6-MP) is myelosuppression. To evaluate whether rigorous blood count monitoring is necessary, we prospectively followed the hematologic profiles of 57 patients with inflammatory bowel disease who were treated with low-dose 6-MP. Most patients (97%) were treated initially with a single dose of 50 mg/day and 79% never used more than 50 mg/day. Blood counts were obtained at weekly intervals over the first month, every two weeks for the second month, and monthly thereafter in the first year. Sixteen (28%) developed mild leukopenia (white blood count < 4.5 x 10(3)/mm3). No patient had a white blood cell count < 2.8 x 10(3)/mm3 and no patient developed leukopenia prior to three months of treatment. In only five patients did the leukopenia prompt a change in 6-mercaptopurine dose. Very mild thrombocytopenia (platelet count of < 145 x 10(3)/mm3) developed in three (5%) and macrocytosis (mean cell volume > 101 fl) was seen in nine (16%). In conclusion, leukopenia was not uncommon in patients treated with low-dose 6-MP, but was not clinically significant. Leukopenia occurred no earlier than three months and as late as 42 months into therapy. Thrombocytopenia was uncommon, mild, and was not associated with apparent bleeding. Macrocytosis may occur in the absence of vitamin B12 and folate deficiencies. Patients can be spared from weekly blood count monitoring when using low-dose 6-mercaptopurine treatment.

Topics: Anemia, Macrocytic; Humans; Inflammatory Bowel Diseases; Leukopenia; Mercaptopurine; Monitoring, Physiologic; Prospective Studies; Thrombocytopenia

Topics: Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Digestive System; Female; Gastroenterology; Hepacivirus; Hepatitis A; Hepatitis B; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Sulfasalazine

We report the results of a survey of the membership of the North American Society for Pediatric Gastroenterology and Nutrition designed to determine pediatric gastroenterologists' attitudes toward the use of immunosuppressive therapy for inflammatory bowel disease (IBD), and to assess how these medications are actually being used in the treatment of children with IBD. One hundred five physicians (27% of surveys) responded. Eighty-eight (84%) had prescribed 6-mercaptopurine and/or azathioprine for IBD, and 66 believed that they were effective. Only 12 had used cyclosporine and four methotrexate. All physicians who had used immunosuppressives in IBD had prescribed them for patients with Crohn's disease, but only 50% had prescribed them for ulcerative colitis. The predominant indications for use included intractable symptoms despite traditional medical therapy (92%) and for corticosteroid-sparing effects (86%). Potential toxicities of greatest concern included marrow and immune suppression and malignancy. The vast majority of responders were not certain what to recommend with respect to the use of immunosuppressive agents prior to and during pregnancy. A clinical database was compiled from 165 retrospective case reports submitted by 45 physicians (33 medical facilities). At the start of immunosuppressive therapy, patients were 15.3 +/- 4.0 yr of age, and 52% were Tanner IV-V. Eighty-one percent had Crohn's disease, 8% ulcerative colitis, and 11% indeterminant colitis. One hundred twenty-two were treated with 6-mercaptopurine, and 43 with azathioprine. Five also received cyclosporine concomitantly. Overall, 68% of patients treated with an immunosuppressive improved. Complications requiring discontinuation of immunosuppressive therapy occurred in 6% of patients. It appears that immunosuppressives are commonly used to treat children with IBD despite a paucity of data regarding their safety and efficacy in this age group. Controlled, prospective trials are warranted to better define the role of immunosuppressive therapy in pediatric IBD.

Topics: Adolescent; Adult; Attitude of Health Personnel; Azathioprine; Child; Colitis; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Female; Gastroenterology; Health Surveys; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methotrexate; Pediatrics; Remission Induction; Retrospective Studies; Societies, Medical; Surveys and Questionnaires

Topics: Adult; Chemical and Drug Induced Liver Injury; Crohn Disease; Humans; Inflammatory Bowel Diseases; Liver Function Tests; Male; Mercaptopurine

As outlined, scanty data exist with regard to immunologic therapy in children with IBD despite the fact that the pediatric population affords a unique opportunity for clinical evaluation. Children are less affected by modifying conditions such as smoking, alcohol ingestion, and the long-term use of medications, and because of their specific needs for ponderal and linear growth, children might benefit most from immunological therapy that has been proven to be steroid sparing. Therefore, clinical trials to evaluate the efficacy of 6-MP and/or azathioprine in growing children with Crohn's disease would appear to provide a fruitful avenue for collaborative research. Efforts to organize a multicenter evaluation of these agents have been initiated. The studies are crucial in evaluating the efficacy and safety of immunosuppressive therapy in the pediatric population with IBD.

Topics: Aminosalicylic Acids; Anti-Inflammatory Agents; Humans; Immunologic Factors; Immunosuppressive Agents; Inflammatory Bowel Diseases; Lipoxygenase Inhibitors; Mercaptopurine; Mesalamine; Methotrexate; Metronidazole; Steroids

Topics: Colitis, Ulcerative; Crohn Disease; Female; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Pregnancy; Pregnancy Complications; Radiography

This study was undertaken to determine if asymptomatic children and adolescents with inflammatory bowel disease and moderate to severe anorectosigmoid inflammation might remain symptom-free for at least 12 months without specific intrarectal therapy. We prospectively studied 13 asymptomatic patients 6-21 years of age (four with Crohn's disease and nine with nonspecific colitis) with previously documented anorectosigmoid inflammation. Of these 13, four had moderate to severe anorectosigmoid inflammation both endoscopically and histologically. These four patients (two with Crohn's disease and two with nonspecific colitis) were entered into the second phase of the study. Three were receiving sulfasalazine, and one received methylprednisolone, 4 mg/day, and 6-mercaptopurine, 50 mg/day. None received intrarectal therapy. Clinical evaluation revealed that all four remained asymptomatic for 12 months despite the continued presence of moderate to severe anorectosigmoid inflammation. These results indicate that in children and adolescents with inflammatory bowel disease, the presence of inflammation of the anorectosigmoid does not necessarily correlate with or presage the onset of symptoms of proctosigmoiditis. Therefore, active inflammation of the anorectosigmoid is not the sole prerequisite for intrarectal therapy. The clinician should be guided by the symptoms of the patient, not by the presence or absence of active anorectosigmoid inflammation.

Topics: Adolescent; Child; Child, Preschool; Colitis; Crohn Disease; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methylprednisolone; Proctocolitis; Prospective Studies; Sulfasalazine