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• W2169837631 abstract "Background & Aims: 6-Thioguanine nucleotide (6-TGN) levels have been proposed to correlate with inflammatory bowel disease (IBD) activity among patients treated with azathioprine or 6-mercaptopurine (6-MP). Previous studies, most with small sample sizes, yielded conflicting conclusions. Our aim was to pool the available data to provide a more precise estimate of the association between 6-TGN levels and IBD activity. Methods: We searched Medline and PubMed (from 1966 to November 2004) and reviewed the reference lists of selected articles. Fixed and random-effects models were used to test whether mean/median 6-TGN levels differed among patients with active disease vs remission and whether 6-TGN levels above a threshold of 230–260 pmol/8 × 108 red blood cells were associated with clinical remission. When studies reported multiple 6-TGN threshold values, we used the data for the lower value. Results: We identified 55 articles, 12 of which contained data sufficient for inclusion. The mean/median 6-TGN levels were higher among patients in remission than in those with active IBD (pooled difference, 66 pmol/8 × 108 red blood cells; 95% confidence interval, 18–113; P = .006), but with significant heterogeneity. Excluding the 1 outlier study eliminated this heterogeneity. Patients with 6-TGN levels above the threshold value were more likely to be in remission (62%) than those below the threshold value (36%) (pooled odds ratio, 3.3; 95% confidence interval, 1.7–6.3; P < .001), but with significant heterogeneity. Again, excluding the 1 outlier study eliminated this heterogeneity. Conclusions: Although prior studies yielded inconsistent conclusions, this analysis strongly supports that higher 6-TGN levels are associated with clinical remission. Background & Aims: 6-Thioguanine nucleotide (6-TGN) levels have been proposed to correlate with inflammatory bowel disease (IBD) activity among patients treated with azathioprine or 6-mercaptopurine (6-MP). Previous studies, most with small sample sizes, yielded conflicting conclusions. Our aim was to pool the available data to provide a more precise estimate of the association between 6-TGN levels and IBD activity. Methods: We searched Medline and PubMed (from 1966 to November 2004) and reviewed the reference lists of selected articles. Fixed and random-effects models were used to test whether mean/median 6-TGN levels differed among patients with active disease vs remission and whether 6-TGN levels above a threshold of 230–260 pmol/8 × 108 red blood cells were associated with clinical remission. When studies reported multiple 6-TGN threshold values, we used the data for the lower value. Results: We identified 55 articles, 12 of which contained data sufficient for inclusion. The mean/median 6-TGN levels were higher among patients in remission than in those with active IBD (pooled difference, 66 pmol/8 × 108 red blood cells; 95% confidence interval, 18–113; P = .006), but with significant heterogeneity. Excluding the 1 outlier study eliminated this heterogeneity. Patients with 6-TGN levels above the threshold value were more likely to be in remission (62%) than those below the threshold value (36%) (pooled odds ratio, 3.3; 95% confidence interval, 1.7–6.3; P < .001), but with significant heterogeneity. Again, excluding the 1 outlier study eliminated this heterogeneity. Conclusions: Although prior studies yielded inconsistent conclusions, this analysis strongly supports that higher 6-TGN levels are associated with clinical remission. 6-Mercaptopurine (6-MP) and azathioprine (AZA) are potent immunomodulators used to treat patients with inflammatory bowel disease (IBD) to induce and maintain remission, as steroid-sparing agents, and to limit loss of tolerance to biological agents. The mechanisms of action of 6-MP and AZA likely are multifactorial. At the molecular level, 6-thioguanine nucleotides (6-TGNs) have the ability to interfere with both DNA and RNA synthesis.1Lennard L. The clinical pharmacology of 6-mercaptopurine.Eur J Clin Pharmacol. 1992; 43: 329-339Crossref PubMed Scopus (536) Google Scholar AZA and 6-MP also are believed to work at the cellular level by inhibiting the proliferation of both T and B lymphocytes, decreasing suppressor T-lymphocyte function and cellular immunity, inducing apoptosis of T lymphocytes, and interfering with the cytotoxic ability of natural killer cells.1Lennard L. The clinical pharmacology of 6-mercaptopurine.Eur J Clin Pharmacol. 1992; 43: 329-339Crossref PubMed Scopus (536) Google Scholar, 2Brogan M. Hiserodt J. Oliver M. et al.The effect of 6-mercaptopurine on natural killer-cell activities in Crohn’s disease.J Clin Immunol. 1985; 5: 204-211Crossref PubMed Scopus (31) Google Scholar, 3Tiede I. Fritz G. Strand S. et al.CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes.J Clin Invest. 2003; 111: 1133-1145Crossref PubMed Scopus (705) Google Scholar About 30% of patients with Crohn’s disease fail to respond to the standard doses used in most published series.4Pearson D.C. May G.R. Fick G.H. et al.Azathioprine and 6-mercaptopurine in Crohn’s disease a meta-analysis.Ann Intern Med. 1995; 123: 132-142Crossref PubMed Scopus (925) Google Scholar Concerns regarding both short- and long-term toxicity are the most common explanation for their restricted use.5Markowitz J. Grancher K. Kohn N. et al.A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease.Gastroenterology. 2000; 119: 895-902Abstract Full Text Full Text PDF PubMed Scopus (660) Google ScholarSee editorial on page 1352; CME Quiz on page 1348. See editorial on page 1352; CME Quiz on page 1348. 6-MP and its nitroimidazole derivative, AZA, are members of the thiopurine class of medications. They are both inactive prodrugs that require extensive chemical alteration by a number of different enzymes to achieve their active forms (Figure 1). On oral administration, AZA is absorbed into the plasma and cleaved rapidly to 6-MP and glutathionyl imidazole by a nonenzymatic reaction occurring within erythrocytes. Three major pathways then ensue to convert 6-MP into its various metabolites.1Lennard L. The clinical pharmacology of 6-mercaptopurine.Eur J Clin Pharmacol. 1992; 43: 329-339Crossref PubMed Scopus (536) Google Scholar The 3 critical enzymes corresponding to these pathways are xanthine oxidase, thiopurine methyltransferase (TPMT), and hypoxanthine phosphoribosyltransferase. Xanthine oxidase, which is present in high concentrations within enterocytes and hepatocytes, rapidly and extensively metabolizes 6-MP into the inactive compound 6-thiouric acid. As a result, the absolute oral bioavailability of 6-MP is only 5%–37%.6Zimm S. Collins J.M. Riccardi R. et al.Variable bioavailability of oral mercaptopurine is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered?.N Engl J Med. 1983; 308: 1005-1009Crossref PubMed Scopus (237) Google Scholar The anabolic conversion of 6-MP into its active metabolites occurs along 2 competing pathways via the enzymes TPMT and hypoxanthine phosphoribosyltransferase. TPMT catalyzes 2 reactions, resulting in the formation of 6-methylmercaptopurine and 6-methylmercaptopurine ribonucleotides (6-MMPR). 6-methylmercaptopurine and 6-methylmercaptopurine ribonucleotides are thought to be responsible for some of the toxic effects (particularly hepatotoxicity) of 6-MP and AZA. Hypoxanthine phosphoribosyltransferase begins the process of converting 6-MP into its therapeutically active metabolites, the 6-TGNs, which helps quell the inflammatory response in IBD but may lead to the untoward effect of myelosuppression, which can affect all 3 bone marrow cell lines. The TPMT gene, located on chromosome 6, is inherited as an autosomal-codominant trait. An apparent genetic polymorphism has been observed in TPMT activity, resulting in a trimodal distribution. Approximately 0.3% of the general population shows low to absent activity as a result of inheritance of 2 mutant copies of the TPMT gene (TPMTL/TPMTL). Roughly 11% of the population is heterozygous for the mutation (TMPTH/TPMTL), and therefore has intermediate enzyme activity. These 2 groups of individuals are particularly susceptible to myelosuppression after administration of 6-MP or AZA. Fortunately, however, the vast majority of the population (89%) is homozygous for the wild-type of TPMT (TPMTH/TPMTH), with normal to high activity.7Weinshilboum R.M. Sladek S.L. Mercaptopurine pharmacogenetics monogenic inheritance of erythrocyte thiopurine methyltransferase activity.Am J Hum Genet. 1980; 32: 651-662PubMed Google Scholar Several prior studies have suggested that higher levels of 6-TGN are associated with both clinical response and toxicity (myelosuppression, primarily leukopenia) in IBD (Figure 2). However, the majority of these studies were underpowered to detect small differences, and the studies frequently came to different conclusions. The aim of our meta-analysis was to examine the relationship between 6-TGN levels and clinical response in IBD by pooling the results of studies reporting data on 6-TGN levels and disease activity. Inclusion and exclusion criteria were delineated before the commencement of the literature search. Studies were included in this meta-analysis if they presented data on 6-TGN levels in IBD patients taking 6-MP or AZA. Studies also were required to measure disease activity and to specify how remission and active disease states were ascertained. Both pediatric and adult data were included. Only studies published in English were included. Studies not meeting the aforementioned criteria were excluded. In addition, studies published only in abstract form were excluded from the primary analysis but were examined in a secondary analysis. Medline and PubMed Plus from 1966 through November 2004 were used to identify potential studies for inclusion. Multiple search strategies were used; keywords were used in preference to MeSH terms to increase the sensitivity of our search. The following key words were used alone and in multiple combinations: 6-thioguanine, 6-thioguanine level(s), 6-thioguanine nucleoside(s), 6-thioguanine nucleoside level(s), 6-TG, 6-TG level(s), 6-TG nucleoside(s), 6-TG nucleoside level(s), 6-TGN, 6-TGN level(s), azathioprine, azathioprine metabolite(s), 6-mercaptopurine, 6-mercaptopurine metabolite(s), 6-MP, 6-MP metabolite(s), inflammatory bowel disease, ulcerative colitis, and Crohn’s disease. Reference lists of all studies identified were reviewed comprehensively to ensure completeness of the search. Data were abstracted independently from all included studies by 2 investigators (M.T.O. and R.K.). Discrepancies in data interpretation were resolved by discussion and re-review of the studies and consultation with the senior author (J.D.L.) when necessary. We conducted 3 primary analyses to address our aim. First, we explored differences in mean or median 6-TGN levels between patients in clinical remission and those with active disease. For the sake of pooling means and medians of 6-TGN levels and calculating 95% confidence intervals (CIs) for the analysis, medians with ranges were considered to approximate means ± 1.96 SDs. Fixed and random-effects models were used to test whether pooled mean/median 6-TGN levels differed between patients with active and inactive disease, executed by the metan command in STATA (Stata Corp, College Station, TX). We decided a priori that patients labeled as partial responders were considered to have active disease for this meta-analysis. The studies by Achkar et al8Achkar J.P. Stevens T. Easley K. et al.Indicators of clinical response to treatment with six-mercaptopurine or azathioprine in patients with inflammatory bowel disease.Inflamm Bowel Dis. 2004; 10: 339-345Crossref PubMed Scopus (43) Google Scholar and Belaiche et al9Belaiche J. Desager J.P. Horsmans Y. et al.Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn’s disease.Scand J Gastroenterol. 2001; 36: 71-76Crossref PubMed Scopus (112) Google Scholar included patients who were partial responders. However, in the Achkar et al8Achkar J.P. Stevens T. Easley K. et al.Indicators of clinical response to treatment with six-mercaptopurine or azathioprine in patients with inflammatory bowel disease.Inflamm Bowel Dis. 2004; 10: 339-345Crossref PubMed Scopus (43) Google Scholar study, insufficient data were provided to calculate a grouped SD, and in the Belaiche et al9Belaiche J. Desager J.P. Horsmans Y. et al.Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn’s disease.Scand J Gastroenterol. 2001; 36: 71-76Crossref PubMed Scopus (112) Google Scholar study, insufficient data were provided to calculate a grouped median 6-TGN level. For these reasons, only complete responders and complete nonresponders were used to compare mean/median 6-TGN levels in these studies, which led to the exclusion of 7 patients from the Achkar et al8Achkar J.P. Stevens T. Easley K. et al.Indicators of clinical response to treatment with six-mercaptopurine or azathioprine in patients with inflammatory bowel disease.Inflamm Bowel Dis. 2004; 10: 339-345Crossref PubMed Scopus (43) Google Scholar study and 6 patients from the Belaiche et al9Belaiche J. Desager J.P. Horsmans Y. et al.Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn’s disease.Scand J Gastroenterol. 2001; 36: 71-76Crossref PubMed Scopus (112) Google Scholar study. The study by Wright et al10Wright S. Sanders D.S. Lobo A.J. et al.Clinical significance of azathioprine active metabolite concentrations in inflammatory bowel disease.Gut. 2004; 53: 1123-1128Crossref PubMed Scopus (120) Google Scholar provided data on mean/median 6-TGN levels on only the 131 patients who had achieved steady-state concentration, thus excluding 28 patients. Therefore, we were limited to including the data on only these 131 patients in our analysis. The study by Dubinsky et al11Dubinsky M.C. Lamothe S. Yang H.Y. et al.Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease.Gastroenterology. 2000; 118: 705-713Abstract Full Text Full Text PDF PubMed Scopus (894) Google Scholar from 2000 did not provide independent data on 6-TGN levels for all patients and instead used 1 sample for 46 patients and roughly 3 samples from each of the other 46 patients, thus yielding 173 samples that were not independent. We included these results in our analysis because the investigators stated in their publication that nearly identical results were observed in analyses using the nonindependent and independent samples. A second set of analyses were performed to determine whether certain threshold values of 6-TGN levels were associated with clinical remission. Odds ratios (ORs) with 95% CIs for remission were calculated using Mantel–Haenszel methods for all studies in which sufficient data were provided. When studies reported more than one 6-TGN threshold value8Achkar J.P. Stevens T. Easley K. et al.Indicators of clinical response to treatment with six-mercaptopurine or azathioprine in patients with inflammatory bowel disease.Inflamm Bowel Dis. 2004; 10: 339-345Crossref PubMed Scopus (43) Google Scholar, 9Belaiche J. Desager J.P. Horsmans Y. et al.Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn’s disease.Scand J Gastroenterol. 2001; 36: 71-76Crossref PubMed Scopus (112) Google Scholar, we calculated ORs based on each value. Separate pooled ORs were generated based on the lowest and highest threshold values for each study using pooled Mantel–Haenszel methods with the metan command in STATA. However, because the pooled results based on the lowest and highest threshold values were nearly identical, only results based on the lowest threshold values are reported here. Both fixed and random-effects models were used. For each study that reported threshold values of the 6-TGN level, we calculated the proportion of patients above and below the threshold values who were in remission. We pooled these results separately for the lowest and highest threshold values using fixed and random-effects models. Again, because the results were nearly identical, only results based on the lowest threshold values are reported. In every pooled analysis, the weight assigned to each study in the pooling process was inversely proportional to the variance of the particular study. In all cases, fixed and random-effects models yielded nearly identical results, with the random-effects models showing more conservative estimates. For this reason, only random-effects results are reported. We examined the studies for evidence of heterogeneity using a χ2 test for heterogeneity. A P value of less than .05 was considered indicative of statistically significant heterogeneity. We performed sensitivity analyses in which we excluded each study individually to determine the effect on the test of heterogeneity and the overall pooled estimates. In additional sensitivity analyses, we included studies published only as abstracts. The likelihood of publication bias was assessed via the Begg and Egger tests. All statistical analyses were performed using STATA version 8.0. We identified 55 studies, 12 of which contained data sufficient for inclusion (Table 1).8Achkar J.P. Stevens T. Easley K. et al.Indicators of clinical response to treatment with six-mercaptopurine or azathioprine in patients with inflammatory bowel disease.Inflamm Bowel Dis. 2004; 10: 339-345Crossref PubMed Scopus (43) Google Scholar, 9Belaiche J. Desager J.P. Horsmans Y. et al.Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn’s disease.Scand J Gastroenterol. 2001; 36: 71-76Crossref PubMed Scopus (112) Google Scholar, 10Wright S. Sanders D.S. Lobo A.J. et al.Clinical significance of azathioprine active metabolite concentrations in inflammatory bowel disease.Gut. 2004; 53: 1123-1128Crossref PubMed Scopus (120) Google Scholar, 11Dubinsky M.C. Lamothe S. Yang H.Y. et al.Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease.Gastroenterology. 2000; 118: 705-713Abstract Full Text Full Text PDF PubMed Scopus (894) Google Scholar, 12Goldenberg B.A. Rawsthorne P. Bernstein C.N. The utility of 6-thioguanine metabolite levels in managing patients with inflammatory bowel disease.Am J Gastroenterol. 2004; 99: 1744-1748Crossref PubMed Scopus (89) Google Scholar, 13Hindorf U. Lyrenas E. Nilsson A. et al.Monitoring of long-term thiopurine therapy among adults with inflammatory bowel disease.Scand J Gastroenterol. 2004; 39: 1105-1112Crossref PubMed Scopus (55) Google Scholar, 14Mardini H.E. Arnold G.L. Utility of measuring 6-methylmercaptopurine and 6-thioguanine nucleotide levels in managing inflammatory bowel disease patients treated with 6-mercaptopurine in a clinical setting.J Clin Gastroenterol. 2003; 36: 390-395Crossref PubMed Scopus (28) Google Scholar, 15Dubinsky M.C. Yang H.Y. Hassard P.V. et al.6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease.Gastroenterology. 2002; 122: 904-915Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar, 16Cuffari C. Hunt S. Bayless T. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise therapy in patients with inflammatory bowel disease.Gut. 2001; 48: 642-646Crossref PubMed Scopus (284) Google Scholar, 17Gupta P. Gokhale R. Kirschner B. 6-Mercaptopurine metabolite levels in children with inflammatory bowel disease.J Pediatr Gastroenterol Nutr. 2001; 33: 450-454Crossref PubMed Scopus (84) Google Scholar, 18Lowry P.W. Franklin C.L. Weaver A.L. et al.Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease.Gut. 2001; 49: 665-670Crossref PubMed Scopus (216) Google Scholar, 19Cuffari C. Theoret Y. Latour S. et al.6-Mercaptopurine metabolism in Crohn’s disease correlation with efficacy and toxicity.Gut. 1996; 39: 401-406Crossref PubMed Scopus (305) Google Scholar The 12 studies varied widely in sample size, in the proportion of patients who were in remission, their duration of disease, their duration of 6-MP or AZA use, and by the indices used to assess disease activity. The studies appeared less heterogeneous in other aspects because the majority of patients in each study were adults with Crohn’s disease who had been using 6-MP or AZA at the target dose for at least 10 weeks. In addition, assays for 6-TGN levels were performed in a uniform fashion in 10 of the 12 studies8Achkar J.P. Stevens T. Easley K. et al.Indicators of clinical response to treatment with six-mercaptopurine or azathioprine in patients with inflammatory bowel disease.Inflamm Bowel Dis. 2004; 10: 339-345Crossref PubMed Scopus (43) Google Scholar, 9Belaiche J. Desager J.P. Horsmans Y. et al.Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn’s disease.Scand J Gastroenterol. 2001; 36: 71-76Crossref PubMed Scopus (112) Google Scholar, 10Wright S. Sanders D.S. Lobo A.J. et al.Clinical significance of azathioprine active metabolite concentrations in inflammatory bowel disease.Gut. 2004; 53: 1123-1128Crossref PubMed Scopus (120) Google Scholar, 11Dubinsky M.C. Lamothe S. Yang H.Y. et al.Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease.Gastroenterology. 2000; 118: 705-713Abstract Full Text Full Text PDF PubMed Scopus (894) Google Scholar, 12Goldenberg B.A. Rawsthorne P. Bernstein C.N. The utility of 6-thioguanine metabolite levels in managing patients with inflammatory bowel disease.Am J Gastroenterol. 2004; 99: 1744-1748Crossref PubMed Scopus (89) Google Scholar, 14Mardini H.E. Arnold G.L. Utility of measuring 6-methylmercaptopurine and 6-thioguanine nucleotide levels in managing inflammatory bowel disease patients treated with 6-mercaptopurine in a clinical setting.J Clin Gastroenterol. 2003; 36: 390-395Crossref PubMed Scopus (28) Google Scholar, 15Dubinsky M.C. Yang H.Y. Hassard P.V. et al.6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease.Gastroenterology. 2002; 122: 904-915Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar, 16Cuffari C. Hunt S. Bayless T. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise therapy in patients with inflammatory bowel disease.Gut. 2001; 48: 642-646Crossref PubMed Scopus (284) Google Scholar, 17Gupta P. Gokhale R. Kirschner B. 6-Mercaptopurine metabolite levels in children with inflammatory bowel disease.J Pediatr Gastroenterol Nutr. 2001; 33: 450-454Crossref PubMed Scopus (84) Google Scholar, 19Cuffari C. Theoret Y. Latour S. et al.6-Mercaptopurine metabolism in Crohn’s disease correlation with efficacy and toxicity.Gut. 1996; 39: 401-406Crossref PubMed Scopus (305) Google Scholar via a modification of the high-performance liquid chromatography assay developed initially by Lennard and Singleton20Lennard L. Singleton H.J. High-performance liquid chromatographic assay of the methyl and nucleotide metabolites of 6-mercaptopurine quantitation of red blood cell 6-thioguanine nucleotide, 6-thioinosinic acid and 6-methylmercaptopurine metabolites in a single sample.J Chromatogr B Biomed Sci Appl. 1992; 83: 83-90Crossref Scopus (179) Google Scholar; in 5 of these studies the assays were performed at Prometheus Laboratories in San Diego, CA.8Achkar J.P. Stevens T. Easley K. et al.Indicators of clinical response to treatment with six-mercaptopurine or azathioprine in patients with inflammatory bowel disease.Inflamm Bowel Dis. 2004; 10: 339-345Crossref PubMed Scopus (43) Google Scholar, 12Goldenberg B.A. Rawsthorne P. Bernstein C.N. The utility of 6-thioguanine metabolite levels in managing patients with inflammatory bowel disease.Am J Gastroenterol. 2004; 99: 1744-1748Crossref PubMed Scopus (89) Google Scholar, 14Mardini H.E. Arnold G.L. Utility of measuring 6-methylmercaptopurine and 6-thioguanine nucleotide levels in managing inflammatory bowel disease patients treated with 6-mercaptopurine in a clinical setting.J Clin Gastroenterol. 2003; 36: 390-395Crossref PubMed Scopus (28) Google Scholar, 15Dubinsky M.C. Yang H.Y. Hassard P.V. et al.6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease.Gastroenterology. 2002; 122: 904-915Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar, 17Gupta P. Gokhale R. Kirschner B. 6-Mercaptopurine metabolite levels in children with inflammatory bowel disease.J Pediatr Gastroenterol Nutr. 2001; 33: 450-454Crossref PubMed Scopus (84) Google Scholar The study by Lowry et al18Lowry P.W. Franklin C.L. Weaver A.L. et al.Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease.Gut. 2001; 49: 665-670Crossref PubMed Scopus (216) Google Scholar used the Erdmann method, which required a conversion factor of 1.6 to convert Erdmann assay results into Lennard assay results. The study by Hindorf et al13Hindorf U. Lyrenas E. Nilsson A. et al.Monitoring of long-term thiopurine therapy among adults with inflammatory bowel disease.Scand J Gastroenterol. 2004; 39: 1105-1112Crossref PubMed Scopus (55) Google Scholar used an assay developed by Bruunshuus and Schmeigelow, which required a conversion factor of 2.0 to convert into Lennard assay results.Table 1Descriptive StatisticsStudyNAdult/pediatric% Remission% Crohn’s diseaseaSome patients in the studies had ulcerative colitis, some of the patients with Crohn’s disease had fistulizing disease, and others had luminal disease.Disease activity index usedAchkar et al, 20048Achkar J.P. Stevens T. Easley K. et al.Indicators of clinical response to treatment with six-mercaptopurine or azathioprine in patients with inflammatory bowel disease.Inflamm Bowel Dis. 2004; 10: 339-345Crossref PubMed Scopus (43) Google Scholar60Adult4082Global assessmentGoldenberg et al, 200412Goldenberg B.A. Rawsthorne P. Bernstein C.N. The utility of 6-thioguanine metabolite levels in managing patients with inflammatory bowel disease.Am J Gastroenterol. 2004; 99: 1744-1748Crossref PubMed Scopus (89) Google Scholar74Adult2076HBI, Powell–TuckHindorf et al, 200413Hindorf U. Lyrenas E. Nilsson A. et al.Monitoring of long-term thiopurine therapy among adults with inflammatory bowel disease.Scand J Gastroenterol. 2004; 39: 1105-1112Crossref PubMed Scopus (55) Google Scholar55Adult7869CDAI, SeoWright et al, 200410Wright S. Sanders D.S. Lobo A.J. et al.Clinical significance of azathioprine active metabolite concentrations in inflammatory bowel disease.Gut. 2004; 53: 1123-1128Crossref PubMed Scopus (120) Google Scholar159Adult7966CDAI, WBIMardini et al, 200314Mardini H.E. Arnold G.L. Utility of measuring 6-methylmercaptopurine and 6-thioguanine nucleotide levels in managing inflammatory bowel disease patients treated with 6-mercaptopurine in a clinical setting.J Clin Gastroenterol. 2003; 36: 390-395Crossref PubMed Scopus (28) Google Scholar44Adult3066Global assessmentDubinsky et al, 200215Dubinsky M.C. Yang H.Y. Hassard P.V. et al.6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease.Gastroenterology. 2002; 122: 904-915Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar51Adult2769HBI, UCDAIBelaiche et al, 20019Belaiche J. Desager J.P. Horsmans Y. et al.Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn’s disease.Scand J Gastroenterol. 2001; 36: 71-76Crossref PubMed Scopus (112) Google Scholar28Adult68100CDAICuffari et al, 200116Cuffari C. Hunt S. Bayless T. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise therapy in patients with inflammatory bowel disease.Gut. 2001; 48: 642-646Crossref PubMed Scopus (284) Google Scholar82Adult5777HBI, LichtigerGupta et al, 200117Gupta P. Gokhale R. Kirschner B. 6-Mercaptopurine metabolite levels in children with inflammatory bowel disease.J Pediatr Gastroenterol Nutr. 2001; 33: 450-454Crossref PubMed Scopus (84) Google Scholar101Pediatric4771PCDAI, TWLowry et al, 200118Lowry P.W. Franklin C.L. Weaver A.L. et al.Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease.Gut. 2001; 49: 665-670Crossref PubMed Scopus (216) Google Scholar170Adult6776IBDQDubinsky et al, 200011Dubinsky M.C. Lamothe S. Yang H.Y. et al.Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease.Gastroenterology. 2000; 118: 705-713Abstract Full Text Full Text PDF PubMed Scopus (894) Google Scholar92Pediatric5186HBI, TWCuffari et al, 199619Cuffari C. Theoret Y. Latour S. et al.6-Mercaptopurine metabolism in Crohn’s disease correlation with efficacy and toxicity.Gut. 1996; 39: 401-406Crossref PubMed Scopus (305) Google Scholar25Pediatric72100HBIHBI, Harvey–Bradshaw Index; CDAI, Crohn’s Disease Activity Index; WBI, Walmsley Simple Index; UCDAI, Ulcerative Colitis Disease Activity Index; PCDAI, Pediatric Crohn’s Disease Activity Index; TW, Truelove and Witts; IBDQ, Inflammatory Bowel Disease Questionnaire.a Some patients in the studies had ulcerative colitis, some of the patients with Crohn’s disease had fistulizing disease, and others had luminal disease. Open table in a new tab HBI, Harvey–Bradshaw Index; CDAI, Crohn’s Disease Activity Index; WBI, Walmsley Simple Index; UCDAI, Ulcerative Colitis Disease Activity Index; PCDAI, Pediatric Crohn’s Disease Activity Index; TW, Truelove and Witts; IBDQ, Inflammatory Bowel Disease Questionnaire. Eig" @default.
• W2169837631 created "2016-06-24" @default.
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• W2169837631 date "2006-04-01" @default.
• W2169837631 modified "2023-10-10" @default.
• W2169837631 title "Association of 6-Thioguanine Nucleotide Levels and Inflammatory Bowel Disease Activity: A Meta-Analysis" @default.
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