Berrie Meijer

Efficacy of thioguanine treatment in inflammatory bowel disease: A systematic review

AIM To critically assess the available literature regarding the efficacy of thioguanine treatment in inflammatory bowel disease (IBD) patients, irrespective of the (hepato-) toxicity profile. METHODS A systematic literature search of the MEDLINE database using PubMed was performed using the keywords “thioguanine”, “6-TG”, “thioguanine”, “inflammatory bowel disease”, “IBD”, “Crohn’s disease”, “Ulcerative colitis” and “effectiveness” in order to identify relevant articles published in English starting from 2000. Reference lists of the included articles were cross-checked for missing articles. Reviewed manuscripts concerning the effectiveness of thioguanine treatment in IBD were reviewed by the authors and the data were extracted. Data were subsequently analyzed with descriptive statistics. Due to the lack of standardized outcomes, a formal meta-analysis was not performed. RESULTS A total of 11 applicable studies were found that involved the effectiveness of thioguanine therapy in IBD. Eight studies were conducted in a prospective manner, in the remaining three studies, data was collected retrospectively. In total, 353 IBD-patients (225 patients with Crohn’s disease, 119 with ulcerative colitis and nine with unclassified IBD) with prior azathioprine/mercaptopurine resistance and/or intolerance (n = 321) or de novo thioguanine administration (n = 32) were included for analysis, of which 228 (65%) had clinical improvement on thioguanine therapy, based on standard IBD questionnaires, biochemical parameters or global physician assessments. Short-term results were based on 268 treatment years (median follow-up 9 mo, range 3-22 mo) with a median daily dose of 20 mg (range 10-80 mg). Discontinuation, mostly due to adverse events, was reported in 72 patients (20%). CONCLUSION The efficacy of thioguanine therapy in IBD patients intolerant to conventional thiopurine therapy is observed in 65%, with short term adverse events in 20% of patients.

6-methylmercaptopurine-induced leukocytopenia during thiopurine therapy in inflammatory bowel disease patients

Thiopurines have a favorable benefit–risk ratio in the treatment of inflammatory bowel disease. A feared adverse event of thiopurine therapy is myelotoxicity, mostly occurring due to toxic concentrations of the pharmacologically active metabolites 6‐thioguaninenucleotides. In oncology, myelosuppression has also been associated with elevated 6‐methylmercaptopurine (6‐MMP). In this case series, we provide a detailed overview of 6‐MMP‐induced myelotoxicity in inflammatory bowel disease patients.

6-methylmercaptopurine induced leukocytopenia during thiopurine therapy in IBD patients.

Thiopurines have a favorable benefit–risk ratio in the treatment of inflammatory bowel disease. A feared adverse event of thiopurine therapy is myelotoxicity, mostly occurring due to toxic concentrations of the pharmacologically active metabolites 6‐thioguaninenucleotides. In oncology, myelosuppression has also been associated with elevated 6‐methylmercaptopurine (6‐MMP). In this case series, we provide a detailed overview of 6‐MMP‐induced myelotoxicity in inflammatory bowel disease patients.

Finding hidden treasures in old drugs: the challenges and importance of licensing generics

Identifying new indications for existing drugs creates new therapeutic options while bypassing much of the costs and time involved with bringing a new drug to market. The rediscovery of a generic drug, however, is a challenging pursuit because there is no formal regulatory approach and a lack of economic interest by pharmaceutical companies. This played a part in the re-registration of thioguanine as a rescue drug for the treatment of patients with inflammatory bowel disease in The Netherlands. In this article, we aim to underline the importance of drug rediscovery, the difficulties of this procedure in Europe and we attempt to suggest conceivable solutions.

Optimizing Thiopurine Therapy in Inflammatory Bowel Disease Among 2 Real-life Intercept Cohorts: Effect of Allopurinol Comedication?

Background: 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. Methods: 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. Results: 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). Conclusions: 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.

Thiopurines in Inflammatory Bowel Disease: New Findings and Perspectives

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.

Methotrexate and Thioguanine Rescue Therapy for Conventional Thiopurine Failing Ulcerative Colitis Patients: A Multi-center Database Study on Tolerability and Effectiveness

Background Patients with active ulcerative colitis (UC) failing conventional therapies are in need of rescue strategies. Due to the fact that accepted step-up therapy with biologicals is expensive and sometimes unavailable, alternative therapies are warranted. Methotrexate (MTX) and thioguanine (TG) have both been suggested as alternative maintenance strategies in conventional thiopurine failing UC patients. In this multicenter database study, we compared safety and effectiveness (drug-survival) of MTX and TG in UC patients. Methods We collected data from the Parelsnoer database, a prospective Dutch national database consisting of inflammatory bowel disease patients from all university hospitals in The Netherlands. Additional data were collected from detailed chart review. Results In total, 99 UC patients were included, of which 48 used TG, 43 used MTX, and 8 patients had a history of both TG and MTX use. In 12% of the patients, biological therapy had failed. Roughly 70% of the patients in both groups were able to continue therapy for over 1 year. Adverse events were noted in 33% of all the patients and were mainly elevated liver enzymes or gastrointestinal complaints. Twenty-eight patients (28%) continued therapy (15 TG, 13 MTX) without the need of escalation therapy (eg, corticosteroids, biologicals, or surgery). Drug survival curves of both drugs were comparable, just as the number of patients with sustained clinical benefit of therapy (P > 0.05). Conclusion Both MTX and TG may be used and maintained as rescue therapy with sustained clinical benefit in one-third of the UC patients failing conventional therapies.

Letter: thiopurines - is less really more?

EDITORS, With much interest, we read the original study by Roblin et al about reducing the daily azathioprine (AZA) dose in patients with inflammatory bowel disease (IBD) receiving combination therapy with infliximab. After thoroughly reading the manuscript, we wonder which scientific data formed the basis or rationale of the trial design. To our knowledge, the statement that lower dosages of immunosuppressants (such as AZA) lead to less side effects (e.g. cancer, lymphoma or infection) is not backed by scientific data, at least not in a population of IBD patients. Although it has been observed that ongoing exposure to thiopurines increased the risk of lymphoma over 5-fold, and that this risk reduces to baseline after discontinuation of thiopurines, there is no evidence that reduction of the daily dose has the same protective potential. This also holds true for the increased risk of (viral) infections. There are no reports that less inhibition of the small GTPase Rac1 in T-lymphocytes, by administering less AZA (thus lower 6-thioguaninenucleotide levels), leads to less infections. We do know that thiopurines are effective as maintenance immunosuppressive monotherapy in IBD. As determined in a metaanalysis, 6-thioguaninenucleotide levels above 230-260 pmol/ 8 9 10 red blood cells were associated with clinical remission. It has been observed that these concentrations are generally reached when AZA is administered when dosed as 2.0-2.5 mg/kg body weight. Moreover, the SONIC-trial demonstrated that combination therapy with regularly dosed AZA is the optimal strategy. Patients in need of combination therapy are in general patients with more severe or complex disease. To us, it is unclear why this “winning team” has to be changed. It is very unlikely that more efficacy will be induced by administering less AZA next to infliximab, but one may assume that additional immunosuppressive effect of AZA itself decreases. More importantly, it is unknown whether the lowering of AZA decreases the susceptibility to infections and development of cancer. In other words, is less really more?

Analytical Pitfalls of Therapeutic Drug Monitoring of Thiopurines in Inflammatory Bowel Disease Patients

Abstract: 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.

How I treat my inflammatory bowel disease-patients with thiopurines?

Thiopurines are essential drugs to maintain remission in patients with inflammatory bowel disease (IBD). Thiopurines used in IBD are azathioprine (2.0-2.5 mg/kg), mercaptopurine (1.0-1.5 mg/kg) and thioguanine (0.2-0.3 mg/kg). However, mainly due to numerous adverse events associated with thiopurine use, almost 50% of the patients have to discontinue conventional thiopurine treatment. Extensive monitoring and the application of several treatment strategies, such as split-dose administration, co-administration with allopurinol or dose reduction/increase, may increase the chance of successful therapy. With this review, we provide practical information on how thiopurines are initiated and maintained in two thiopurine research centers in The Netherlands. We provide clinical information concerning safety issues, indications and management of therapy that may serve as a guide for the administration of thiopurines in IBD patients in daily practice.