Dirk P. van Asseldonk

Prolonged thioguanine therapy is well tolerated and safe in the treatment of ulcerative colitis

BACKGROUND Thioguanine has been used for the treatment of inflammatory bowel disease, in particular for patients who failed conventional thiopurine therapy. To date, thioguanine has been infrequently studied in ulcerative colitis. AIM To evaluate the tolerability, safety and efficacy of thioguanine in the treatment of ulcerative colitis. METHODS A database analysis was performed on inflammatory bowel disease patients who had failed conventional thiopurine therapy and were treated with thioguanine. Rates and reasons for treatment failure were assessed. Laboratory values, abdominal ultrasonography, liver biopsy and endoscopic remission rates were evaluated. RESULTS Forty-six patients were included and median treatment duration was 22 months (range 0.3-72.0). Nine patients failed thioguanine therapy: six due to adverse events, three due to therapy resistance. Concomitant treatment with aminosalicylates protected against thioguanine failure (hazard ratio (HR) 0.11, 95% CI 0.03-0.48). When performed, ultrasonography (n = 21) revealed no suspected therapy-related pathology in all but one patient, in whom hepatomegaly was observed. Liver histology (n = 12) predominantly revealed no abnormalities (n = 4) or non-specific regeneration (n = 4); none showed nodular regenerative hyperplasia. At follow-up, 40% of colonoscopies revealed endoscopic remission as compared with 10% at baseline (P = 0.180). CONCLUSIONS Long-term use of thioguanine appears to be well tolerated and relatively safe in ulcerative colitis patients who failed conventional thiopurine therapy.

On Therapeutic Drug Monitoring of Thiopurines in Inflammatory Bowel Disease; Pharmacology, Pharmacogenomics, Drug Intolerance and Clinical Relevance

Thiopurines such as azathioprine, 6-mercaptopurine and 6-thioguanine are antimetabolites that have been used for several decades in the treatment of several diseases including inflammatory bowel diseases. Additional anti-inflammatory properties of these thiopurines have been discovered in recent years. Thiopurine metabolism is complex due to the involvement of multiple enzymes, of which the activities are genetically determined and cell type dependent. Single nucleotide polymorphisms in the genes encoding these enzymes have been correlated with altered activities and drug intolerance. Detailed implications of these will be reviewed. Over the years several methods of therapeutic drug monitoring have been developed in an attempt to relate thiopurine drug availability with efficacy and intolerance. In this respect, monitoring pharmacologically active 6-thioguanine nucleotide concentrations is most widely used. So far, however, the clinical usefulness of these methods is hampered by methodological limitations. Some drug interactions may optimize the metabolization of thiopurines and consequently increase its efficacy and decrease drug intolerance. This review focuses on the clinical relevance and usefulness of therapeutic drug monitoring of thiopurines and provides suggestions to optimize thiopurine therapy in the treatment of inflammatory bowel diseases.

The Prevalence of Nodular Regenerative Hyperplasia in Inflammatory Bowel Disease Patients Treated with Thioguanine Is Not Associated with Clinically Significant Liver Disease.

Background:Nodular regenerative hyperplasia (NRH) of the liver is associated with inflammatory-mediated diseases and certain drugs. There is conflicting data on the prevalence of NRH and its clinical implications in inflammatory bowel disease (IBD) patients treated with thioguanine. Methods:A retrospective cohort study involving 7 Dutch centers comprised all IBD patients who were being treated with thioguanine and underwent a liver biopsy as part of the standard toxicity screening. Liver biopsy specimens were reviewed by 2 experienced liver pathologists. Clinical data as well as liver chemistry, blood counts, and abdominal imaging were collected. Results:One hundred eleven IBD patients who submitted to liver biopsy were treated with thioguanine in a daily dose of 0.3 mg/kg for a median duration of 20 (4–64) months. NRH was detected in 6% of patients (7; 95% confidence interval, 3–14 patients). Older age (P = 0.02), elevated gamma-glutamyl transferase (P = 0.01) and alkaline phosphatase (P = 0.01) levels, a higher mean corpuscular volume (P = 0.02), and a lower platelet or leukocyte count (P < 0.01 and P = 0.02, respectively) were associated with NRH. Three of the 7 patients with NRH did not have any associated clinical symptoms or signs. The other 4 had minor biochemical abnormalities only. Ultrasonography revealed splenomegaly in 3 of the 78 patients (4%; 95% confidence interval, 0%–9%), only one of whom had NRH. There was no clinically overt portal hypertension. Conclusions:The prevalence of NRH was 6% in liver biopsies obtained from IBD patients treated with thioguanine. Histopathological irregularities including NRH were not associated with clinically significant findings over the period of observation.

On the malignant potential of thiopurine therapy

With great interest we have read the paper by Schmiegelow and colleagues describing the increased risk of developing a second malignant neoplasm, especially acute myeloid leukemia and myelodysplastic syndromes, due to maintenance therapy with 6-mercaptopurine (6-MP) and methotrexate after childhood acute lymphoblastic leukemia.1 An impaired thiopurine S-methyltransferase (TPMT) activity, high 6-thioguaninenucleotides (6-TGN) and elevated 6-methylmercaptopurine-ribonucleosides (6-MMPR) levels were found to be risk factors. An increasing number of relatively young patients with different autoimmune diseases (eg, inflammatory bowel disease) or after organ transplantations are treated with a life-long thiopurine regime. The exact role of thiopurines in developing hematologic malignancies is unknown, but it has been postulated that the inactivation of the DNA mismatch repair system may lead to an increased rate of spontaneous mutations.2 Here we propose an additional theory from a more pharmacodynamic point of view. An intrinsic complication of thiopurine therapy is that this cytotoxic and apoptosis-inducing agent can target almost all human cells, particularly myeloid precursor cells, and may induce genetic alterations. Children with acute lymphocytic leukemia treated with chemotherapy, including 6-MP, developed a high number of mutations at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT)–reporter gene.3 In addition, azathioprine therapy in insulin-dependent diabetes mellitus patients resulted in an increase of HGPRT T cell–mutant frequencies that was statistically correlated with duration of therapy.4 All clinically used thiopurines have to be metabolized by the enzyme HGPRT to become pharmacologically active. Impaired HGPRT activity due to mutations may therefore lead to a relative failure of therapy. More importantly, mutated cells are thereby thiopurine refractory and thus positively selected and amplified, as all other cells will become apoptotic due to therapy. This process of selection of mutated cells due to thiopurine administration may give rise to an increased risk of developing hematologic malignancies such as leukemia or myelodysplastic syndromes. The risk factors diminished TPMT activity, high 6-TGN, and 6-MMPR levels that were observed by Schmiegelow and colleagues fit in with this theory. All these pharmacodynamic aspects indicate at an increased rate of elimination of nonmutated cells due to high levels of the pharmacologically active thiopurine metabolites, which eventually leads to an accelerated selection of HGPRT-mutated cells. These patients are probably at risk to develop a hematologic malignancy earlier than patients with a more common and more prevalent type of thiopurine metabolism, that is, those patients using usual, average TPMT activity. Studies are warranted to further explore the field of genotoxicity and mutagenicity of thiopurine therapy, as more and more patients are being treated with a lifelong regime.

Drug Rediscovery: Preventing Off-label Prescription and Reducing Health Care Costs: The Case of Thioguanine in the Netherlands

We have concerned ourselves at the gastroenterology unit of the VU University Medical Center with drug repositioning since 2001. Generic therapy, often successfully used off-label in daily practice and well described in literature in large observational studies, should be further developed for safe and economically viable use. To prevent off-label use legislative authoritiesshouldstimulate re-registration of these drugs.

Tolerability and Safety of Conventional Thiopurines Concomitantly With Allopurinol in IBD-Patients With a Skewed Thiopurine Metabolism

was linked to the Dutch nationwide pathology archive (PALGA) to verify the IBD diagnosis and to determinewhether a patient had developed NMSC. Cox proportional hazard regression analysis was used to calculate the risk of NMSC in patients with and without thiopurine use, adjusted for type of IBD, gender, age and duration of IBD. Results: A total of 2887 patients with a confirmed IBD diagnosis were included in this study. Of these, 819 patients (28%) used thiopurines. No statistically significant differences were found for type of IBD, gender, age and extent of IBD between thiopurine users and non-users. Disease duration was significantly shorter in users compared to non-users (34 months (SD 45) versus 38 months (SD 48), p=0.03). Eighty-six patients (3%) developed NMSC during 18,727 person years of follow-up. Of these patients, 24 (28%) had used thiopurines. Mean age at NMSC diagnosis was 64 years (SD 12) in thiopurine users compared to 63 years (SD 13) in nonusers (p=0.68). Increasing age and duration of IBD were associated with a higher risk of developing NMSC (adjusted hazard ratio (HR) 1.06, 95% Confidence Interval (CI) 1.041.08 and adjusted HR 1.007, 95% CI 1.002-1.011, respectively). A diagnosis of ulcerative colitis and female gender were associated with a decreased risk of NMSC (adjusted HR 0.62, 95% CI 0.40-0.98) and adjusted HR 0.47, 95% CI 0.30-0.74). Thiopurine use was not associated with an increased risk of developing NMSC (adjusted HR 0.85, 95% CI 0.511.41). Conclusion: In contrast to transplant recipients, thiopurine use in IBD patients is not associated with an increased risk of developing NMSC.

W1110 6-Thioguanine Induces Remission and Mucosal Healing in IBD

INTRODUCTION: There is a paucity of data providing insight into the durability of Crohns disease treatment with infliximab for periods longer than 12 months. For patients who lose their initial response, consideration can be given to dose “intensification” to regain therapeutic benefit. AIM: To review how often infliximab loses its effect and dose intensification is required. METHODS: Bibliographical searches were performed in MEDLINE looking for the following words: infliximab AND “Crohns disease” AND (lose OR lost OR loss OR “dose escalation” OR intensification). We also conducted a manual search of abstracts from European (ECCO) and American (DDW) Congresses. Inclusion criteria: studies evaluating loss of efficacy and requirement of infliximab dose intensification (defined either as an increase of the infliximab dose generally from 5 mg/kg to 10 mg/kg or as a decrease in the frequency of infusion to as often as every 4 weeks) in Crohns disease patients. RESULTS: Sixteen studies evaluating the incidence of loss of response to infliximab in Crohns disease patients were found. A total of 2,236 patients were included (the majority of them receiving a 3dose induction regimen at weeks 0, 2, and 6, followed by maintenance therapy every 8 weeks), providing 6,284 patient-years of follow-up. The mean percentage of patients with loss of infliximab response was 37%. However, as the follow-up time markedly varied among studies, the risk of losing response to infliximab is better expressed as the incidence of this complication per patient-years of follow-up. Therefore, the annual risk for loss of infliximab response was calculated to be 13% per patient-year. CONCLUSION: A variable but relevant proportion of Crohns disease patients on long-term infliximab treatment lose response. This may be interpreted in two different but compatible ways: A positive view, highlighting that infliximab therapy is relatively durable, with the majority of patients predicted to continue infliximab treatment at least during the first year; or a negative view, interpreting that a significant proportion of Crohns disease patients −more than 10% per patient-year of infliximab treatment− on long-term will lose response and will require an increase in dose and/or decrease in infusion interval.

W1099 Adequately Dosed 6-Thioguanine Is a Well Tolerated and Safe Rescue Drug in Azathioprine or 6-Mercaptopurine Intolerant IBD Patients

G A A b st ra ct s end of follow-up. Fourteen experienced any complication, and 5 were infectious complications. These included 2 cases of shingles, and one each of PCP, EBV, and viral meningitis. No covariates predicted clinical success. Significant predictors of 6TGN levels included the dose of allopurinol, age, and BMI. Significant predictors of 6MMP levels included the doses of thiopurine and allopurinol, and BMI. Significant predictors of WBC included dosing, BMI, and age. Despite having only 5 events, there was a trend toward an association between infectious complications and low ALC (OR 7.4, p=0.14, 95% CI 0.51111). Conclusions: Adjunctive allopurinol therapy in shunting patients was successful in producing major clinical improvement in half of patients. However, in this small series, a surprising number of opportunistic infectious complications occurred. BMI has a significant modulating effect on metabolite levels and WBC levels. Low ALC may be an indicator of risk of opportunistic infections. Careful monitoring for infectious complications should be part of thiopurine plus allopurinol therapy for IBD.