Azathioprine, 6-mercaptopurine in inflammatory bowel disease: Pharmacology, efficacy, and safety
2004; Elsevier BV; Volume: 2; Issue: 9 Linguagem: Inglês
10.1016/s1542-3565(04)00344-1
ISSN1542-7714
Autores Tópico(s)Adolescent and Pediatric Healthcare
Resumo6-Mercaptopurine and its prodrug azathioprine remain the mainstay of immunomodulator therapy for the maintenance of a steroid-free remission in patients with IBD. Recent evidence suggests that the cytotoxic and immunosuppressive effects of azathioprine might be mediated via the induction of lymphocyte apoptosis by its active metabolites, 6-thioguanine nucleotides. The therapeutic benefits of thiopurines have been shown to correlate with the concentration of 6-thioguanine nucleotides. Inherited differences in drug metabolism and disposition can significantly impact the safety and efficacy of these drugs. The thiopurine methyltransferase enzyme plays an important role in the metabolism of 6-mercaptopurine and azathioprine and in the determination of thiopurine cytotoxicity. By gaining an understanding of the pharmacology and metabolism of thiopurine therapy and putting it into the clinical context, clinicians will be able to optimize thiopurine therapy in IBD. 6-Mercaptopurine and its prodrug azathioprine remain the mainstay of immunomodulator therapy for the maintenance of a steroid-free remission in patients with IBD. Recent evidence suggests that the cytotoxic and immunosuppressive effects of azathioprine might be mediated via the induction of lymphocyte apoptosis by its active metabolites, 6-thioguanine nucleotides. The therapeutic benefits of thiopurines have been shown to correlate with the concentration of 6-thioguanine nucleotides. Inherited differences in drug metabolism and disposition can significantly impact the safety and efficacy of these drugs. The thiopurine methyltransferase enzyme plays an important role in the metabolism of 6-mercaptopurine and azathioprine and in the determination of thiopurine cytotoxicity. By gaining an understanding of the pharmacology and metabolism of thiopurine therapy and putting it into the clinical context, clinicians will be able to optimize thiopurine therapy in IBD. As the arsenal of inflammatory bowel disease (IBD) therapies becomes more powerful, choosing a therapy that is appropriate for an individual patient requires an understanding of the goals of IBD therapy. Maximizing the efficacy of IBD-directed therapies while minimizing their toxicity remains the principal objective in developing management strategies for IBD patients. Immunomodulator therapy has become an integral part of these management strategies. The most commonly used immunomodulators, 6-mercaptopurine (6-MP) and its prodrug azathioprine (AZA), belong to the family of drugs known as the thiopurines. Although the use of these drugs in IBD has significantly increased during the last 5–10 years, there still remains a discrepancy between need and use among IBD patients. Safety concerns, bone marrow suppression in particular, and delayed onset of action most likely drive this incongruity. The advent of pharmacogenetics and therapeutic drug monitoring in IBD has addressed some of these concerns; however, an understanding of the pharmacology and metabolism of thiopurines is critical to optimizing the effects of thiopurines in IBD patients. This review will highlight the pharmacology of thiopurines and discuss the safety and efficacy of these therapies in the management of IBD. Although both AZA and 6-MP are often used interchangeably as thiopurines, it is important to understand the pharmacologic differences between the 2 compounds. Studies have shown that the bioavailability of AZA might be superior to that of 6-MP with a range of 27%–83%.1Van Os E.C. Zins B.J. Sandborn W.J. Mays D.C. Tremaine W.J. Mahoney D.W. Zinsmeister A.R. Lipsky J.J. Azathioprine pharmacokinetics after intravenous, oral, delayed release oral and rectal foam administration.Gut. 1996; 39: 63-68Crossref PubMed Scopus (92) Google Scholar, 2Ding T.L. Benet L.Z. Comparative bioavailability and pharmacokinetic study of azathioprine and 6-mercaptopurine in the rhesus monkey.Drug Metab Dispos. 1979; 7: 373-377PubMed Google Scholar Once absorbed, AZA is rapidly converted via a nonenzymatic process to 6-MP and S-methyl-4-nitro-5-thioimidazole. AZA is 55% of 6-MP by molecular weight, and 88% of AZA is converted to 6-MP, such that a conversion factor of 2.08 must be taken into account when calculating equivalent doses of 6-MP and AZA. 6-MP (or AZA converted to 6-MP) undergoes a complex biotransformation to its inactive and active metabolites via competing catabolic and anabolic metabolic pathways (Figure 1). 6-MP undergoes extensive “first pass” catabolism by xanthine oxidase, which is present in both the intestinal mucosa and liver, limiting the systemic bioavailability of thiopurines. 6-MP also serves as a substrate for the thiopurine methyltransferase (TPMT) enzyme, which methylates 6-MP to the inactive methylated-mercaptopurine metabolite. Like xanthine oxidase, TPMT might be present in the intestinal mucosa and might also contribute to the presystemic catabolism of 6-MP. The hypoxanthine phosphoribosyltransferase enzyme is paramount to the initiation of the anabolic transformation of 6-MP to its active metabolites. The intracellular activation of 6-MP yields the first active intermediate metabolite, thioinosine monophosphate (TiMP), which is then rapidly converted to the thioguanine nucleotides (6-TGN). The cytotoxic and immunosuppressive effects of thiopurines were, until recently, presumed to be primarily mediated via the incorporation of 6-TGN into cellular nucleic acids, ultimately resulting in inhibition of lymphocyte proliferation. Recent advances in the understanding of the mechanism of action of thiopurines, however, suggest that the 6-thioguanine triphosphate (6-thio-GTP) nucleotide might play an important role in the process of signaling lymphocyte apoptosis by inhibiting Rac1 activation in T cells.3Tiede I. Fritz G. Strand S. Poppe D. Dvorsky R. Strand D. Lehr H.A. Wirtz S. Becker C. Atreya R. Mudter J. Hildner K. Bartsch B. Holtmann M. Blumberg R. Walczak H. Iven H. Galle P.R. Ahmadian M.R. Neurath M.F. 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 As illustrated in Figure 1, 6-thio-GTP is likely the final nucleotide in the activation pathway of thiopurines. Further research is needed to examine the potential therapeutic role of 6-thio-GTP in patients with IBD and perhaps other autoimmune disorders. The major competing enzymatic process that competes with the intracellular activation pathway is the thiol methylation of TiMP by TPMT. Although these methylated metabolites (Me-TiMP or 6-MMPR) have been shown in vitro to inhibit de novo purine synthesis, in vivo evidence is lacking as to their role in the mechanism of action of thiopurines.4Lennard L. The clinical pharmacology of 6-mercaptopurine.Eur J Clin Pharmacol. 1992; 43: 329-339Crossref PubMed Scopus (536) Google Scholar It has been demonstrated that not all individuals methylate thiopurines equally, and that the genetic variability in TPMT enzyme activity is responsible for the majority of the individual differences observed in both the efficacy and toxicity of thiopurines. Population-based studies have demonstrated that TPMT activity is inherited as an autosomal codominant trait.5Weinshilboum R.M. Sladek S.L. Mercaptopurine pharmacogenetics monogenic inheritance of erythrocyte thiopurine methyltransferase activity.Am J Hum Genet. 1980; 32: 651-662PubMed Google Scholar The frequency distribution of the TPMT polymorphisms reveals that 1 in 300 (0.3%) individuals have low to absent enzyme activity (homozygous TPMTL), 11% have intermediate (heterozygous TPMTH/TPMTL), and 89% have normal to high levels of activity (homozygous/wild-type TPMTH). Although a number of variant TPMT alleles have been described, TPMT*3A, a double mutant (A719G and G460A), is the most frequently occurring mutant allele and predominates in whites. Each mutant, however, TPMT*3B (G460A) and TPMT*3C (A710G), can occur independently. Although mutant allele frequencies might be similar among different ethnicities, the prevalent mutant alleles do differ, such that TPMT*3C is most common among African Americans.6Hon Y.Y. Fessing M.Y. Pui C.H. Relling M.V. Krynetski E.Y. Evans W.E. Polymorphism of the thiopurine S-methyltransferase gene in African-Americans.Hum Mol Genet. 1999; 8: 371-376Crossref PubMed Scopus (257) Google Scholar TPMT*3C is also the prevalent mutant allele among the Chinese population; however, the frequency of mutant alleles appears lower than among whites.7Lee F.J. Kalow W. Thiopurine S methyltransferase activity in a Chinese population.Clin Pharmacol Ther. 1993; 54: 28-33Crossref PubMed Scopus (43) Google Scholar The degree of reduction in TPMT activity and immunoreactive protein varies on the basis of the mutant allele present in an individual.8Tai H.L. Krynetski E.Y. Yates C.R. Loennechen T. Fessing M.Y. Krynetskaia N.F. Evans W.E. Thiopurine S-methyltransferase deficiency two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians.Am J Hum Genet. 1996; 58: 694-702PubMed Google Scholar TPMT*3B mutation alone is associated with a 9-fold reduction in catalytic activity, whereas the TPMT*3C leads to a 1.4-fold reduction. The presence of both mutations (TPMT*3A), however, is associated with a complete loss of enzyme activity. Similarly, the less common mutant TPMT*2 leads to complete loss of activity. Four other rare TPMT alleles have since been described.9Otterness D.M. Szumlanski C.L. Wood T.C. Weinshilboum R.M. Human thiopurine methyltransferase pharmacogenetics kindred with a terminal exon splice junction mutation that results in loss of activity.J Clin Invest. 1998; 101: 1036-1044Crossref PubMed Scopus (122) Google Scholar TPMT methylation competes with the activation pathway and influences the relative proportion of intracellular active 6-TGN produced by a given individual. This inverse relationship between TPMT and 6-TGN has important implications in both the efficacy and toxicity of thiopurines. Patients with intermediate or absent TPMT activity can produce significantly higher concentrations of 6-TGN. The negative correlation between TPMT and 6-TGN was first reported in the treatment of childhood leukemia10Lennard L. Van Loon J.A. Weinshilboum R.M. Pharmacogenetics of acute azathioprine toxicity relationship to thiopurine methyltransferase genetic polymorphism.Clin Pharmacol Ther. 1989; 46: 149-154Crossref PubMed Google Scholar and has since been confirmed among pediatric IBD patients.11Dubinsky M.C. Lamothe S. Yang H.Y. Targan S.R. Sinnett D. Theoret Y. Seidman E.G. 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 The most noteworthy of the safety implications is that TPMT deficiency is associated with major elevations in 6-TGN levels, and patients experience profound, potentially life-threatening myelosuppression when treated with standard or even low dose therapy.12Lennard L. Lilleyman J.S. Variable 6-mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia.J Clin Oncol. 1989; 7: 1816-1823Crossref PubMed Scopus (227) Google Scholar, 13Lennard L. Van Loon J.A. Weinshilboum R.M. Pharmacogenetics of acute azathioprine toxicity purine methyltransferase genetic polymorphism.Clin Pharmacol Ther. 1989; 46: 149-154Crossref PubMed Scopus (520) Google Scholar Concomitant medications might also influence TPMT enzyme activity and can affect the safety and efficacy of thiopurines. It has been demonstrated among IBD patients that mesalamine-containing compounds cause in vitro inhibition of recombinant human TPMT.14Szumlanski C.L. Weinshilboum R.M. Sulphasalazine inhibition of thiopurine methyltransferase possible mechanism for interaction with 6-mercaptopurine and azathioprine.Br J Clin Pharmacol. 1995; 39: 456-459Crossref PubMed Scopus (212) Google Scholar The clinical correlate of this interaction has been reported with both 6-MP and olsalazine.15Lewis L.D. Benin A. Szumlanski C.L. Otterness D.M. Lennard L. Weinshilboum R.M. Nierenberg D.W. Olsalazine and 6-mercaptopurine-related bone marrow suppression a possible drug-drug interaction.Clin Pharmacol Ther. 1997; 62: 464-475Crossref PubMed Scopus (156) Google Scholar Caution should be taken when co-administering mesalamines and thiopurines, because TPMT inhibition might increase the risk of developing myelosuppression. This effect might also vary depending on the mesalamine an individual is receiving, such that mesalamine might have the greatest effect on the metabolism of thiopurines.16Lowry P.W. Franklin C.L. Weaver A.L. Szumlanski C.L. Mays D.C. Loftus E.V. Tremaine W.J. Lipsky J.J. Weinshilboum R.M. Sandborn W.J. Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide.Gut. 2001; 49: 656-664Crossref PubMed Scopus (196) Google Scholar A recent study suggested that, although an interaction between AZA and mesalamines does exist, an alternate mechanism to TPMT inhibition might be responsible for the change in thiopurine pharmacokinetics.17Dewitt O. Vanheuverzwyn R. Desager J.P. Horsmans Y. Interaction between azathioprine and aminosalicylates an in vivo study in patients with Crohn’s disease.Aliment Pharmacol Ther. 2002; 16: 79-85Crossref Scopus (109) Google Scholar After mesalamine withdrawal the mean 6-TGN levels significantly decreased without significant changes in TPMT activity or blood counts. This effect might be additive in patients already genetically determined to produce lower levels of the TPMT enzyme, such that diligent blood count monitoring is necessary. An understanding of the role of TPMT in the overall metabolism of thiopurines and its mechanisms of action is critical to optimizing and individualizing IBD therapy. The role of TPMT in optimizing thiopurine therapy will be discussed further. The efficacy of AZA and 6-MP for both the induction and maintenance of a disease-free remission in CD has been evaluated in a number of controlled clinical trials. The study reported by Present et al.18Present D.H. Korelitz B.I. Wisch N. Glass J.L. Sachar D.B. Pasternack B.S. Treatment of Crohn’s disease with 6-mercaptopurine a long-term, randomized, double blind study.N Engl J Med. 1980; 302: 981-987Crossref PubMed Scopus (976) Google Scholar in 1980 was really the first to demonstrate, in a convincing manner, the efficacy of 6-MP in the induction of remission in CD. By using a dose of 1.5 mg · kg−1 · day−1, 67% of patients responded to therapy as compared to only 8% of patients who received placebo. To date, not all controlled trials report such a positive clinical response to thiopurines in the induction of disease remission in CD, as illustrated in Table 1. 18Present D.H. Korelitz B.I. Wisch N. Glass J.L. Sachar D.B. Pasternack B.S. Treatment of Crohn’s disease with 6-mercaptopurine a long-term, randomized, double blind study.N Engl J Med. 1980; 302: 981-987Crossref PubMed Scopus (976) Google Scholar, 19Rhodes J. Bainton D. Beck P. Campbell H. Controlled trial of azathioprine in Crohn’s disease.Lancet. 1971; 2: 1273-1276Abstract PubMed Scopus (158) Google Scholar, 20Willoughby J.M.T. Kumar P.J. Beckett J. Dawson A.M. Controlled trial of azathioprine in Crohn’s disease.Lancet. 1971; 731: 944-947Abstract Scopus (249) Google Scholar, 21Summers R.W. Switz D.M. Sessions Jr, J.T. Becktel J.M. Best W.R. Kern Jr, F. Singleton J.W. National Cooperative Crohn’s Disease Study results of drug treatment.Gastroenterology. 1979; 77: 847-869PubMed Scopus (1068) Google Scholar, 22Candy S. Wright J. Gerber M. Adams G. Gerig M. Goodman R. A controlled double blind study of azathioprine in the management of Crohn’s disease.Gut. 1995; 37: 674-678Crossref PubMed Scopus (540) Google Scholar, 23Ewe K. Press A.G. Singe C.C. Stufler M. Ueberschaer B. Hommel G. Meyer zum Buschenfelde K.H. Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn’s disease.Gastroenterology. 1993; 105: 367-372Abstract PubMed Google Scholar, 24Klein M. Binder H.J. Mitchell M. Aaronson R. Spiro H. Treatment of Crohn’s disease with azathioprine a controlled evaluation.Gastroenterology. 1974; 66: 916-922Abstract Full Text PDF PubMed Scopus (139) Google Scholar Despite the conflicting reports, the meta-analysis performed by Pearson et al.25Pearson D.C. May G.R. Fick G.H. Sutherland L.R. Azathioprine and 6-mercaptopurine in Crohn’s disease a meta-analysis.Ann Intern Med. 1995; 123: 132-142Crossref PubMed Scopus (925) Google Scholar reported an odds ratio of 3.09 (confidence interval [CI], 2.45–3.91), favoring therapy over placebo. The Cochrane analysis published by Sandborn et al.,26Sandborn W. Sutherland L. Pearson D. May G. Modigliani R. Prantera C. Azathioprine or 6-mercaptopurine or inducing remission of Crohn’s disease.Cochrane Database Syst Rev. 2000; 3Google Scholar most recently updated in 2003, reports an overall response rate of 54% (CI, 47%–61%) for treatment as compared to 33% (CI, 27%–40%) for placebo for active CD. The number needed to treat 1 patient to respond was 5, and the pooled odds ratio for response was 2.36 (CI, 1.57–3.53).Table 1Induction of Remission: Crohn’s DiseaseStudy (reference)Total no. of patientsEfficacy (%), drugEfficacy (%), placeboP valueThiopurine & starting dose (mg · kg−1 · day−1)Treatment duration (mo)PresentaFistula response assessed.bSteroid-sparing effect assessed.(18Present D.H. Korelitz B.I. Wisch N. Glass J.L. Sachar D.B. Pasternack B.S. Treatment of Crohn’s disease with 6-mercaptopurine a long-term, randomized, double blind study.N Engl J Med. 1980; 302: 981-987Crossref PubMed Scopus (976) Google Scholar)727214<0.016-MP 1.512RhodesaFistula response assessed. (19Rhodes J. Bainton D. Beck P. Campbell H. Controlled trial of azathioprine in Crohn’s disease.Lancet. 1971; 2: 1273-1276Abstract PubMed Scopus (158) Google Scholar)1600NSAZA 4.0 × 10 days, then 2.02Group 1: WilloughbyaFistula response assessed.bSteroid-sparing effect assessed. (20Willoughby J.M.T. Kumar P.J. Beckett J. Dawson A.M. Controlled trial of azathioprine in Crohn’s disease.Lancet. 1971; 731: 944-947Abstract Scopus (249) Google Scholar)1210017<0.01AZA 4.0 × 10 days, then 2.06Part 1, phase 1: Summers (21Summers R.W. Switz D.M. Sessions Jr, J.T. Becktel J.M. Best W.R. Kern Jr, F. Singleton J.W. National Cooperative Crohn’s Disease Study results of drug treatment.Gastroenterology. 1979; 77: 847-869PubMed Scopus (1068) Google Scholar)1363626NSAZA 2.54Part 1: CandybSteroid-sparing effect assessed. (22Candy S. Wright J. Gerber M. Adams G. Gerig M. Goodman R. A controlled double blind study of azathioprine in the management of Crohn’s disease.Gut. 1995; 37: 674-678Crossref PubMed Scopus (540) Google Scholar)637363NSAZA 2.53EwebSteroid-sparing effect assessed. (23Ewe K. Press A.G. Singe C.C. Stufler M. Ueberschaer B. Hommel G. Meyer zum Buschenfelde K.H. Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn’s disease.Gastroenterology. 1993; 105: 367-372Abstract PubMed Google Scholar)4276380.03AZA 2.54KleinaFistula response assessed.bSteroid-sparing effect assessed. (24Klein M. Binder H.J. Mitchell M. Aaronson R. Spiro H. Treatment of Crohn’s disease with azathioprine a controlled evaluation.Gastroenterology. 1974; 66: 916-922Abstract Full Text PDF PubMed Scopus (139) Google Scholar)264646NSAZA 3.04NS, not significant.a Fistula response assessed.b Steroid-sparing effect assessed. Open table in a new tab NS, not significant. The notion of the delayed onset of action of 6-MP really stems from the study by Present et al.,18Present D.H. Korelitz B.I. Wisch N. Glass J.L. Sachar D.B. Pasternack B.S. Treatment of Crohn’s disease with 6-mercaptopurine a long-term, randomized, double blind study.N Engl J Med. 1980; 302: 981-987Crossref PubMed Scopus (976) Google Scholar which reported that the mean time to response was 3.1 months, with 89% of responders doing so within 4 months of initiating therapy. However, it should be noted that the first clinical evaluation in this study was not performed until the 12-week mark; thus it is likely that a certain proportion of patients were actually responding before then. Both the Pearson analysis and the Cochrane analysis demonstrated that the odds ratio of response increased significantly when patients were treated for at least 17 weeks.25Pearson D.C. May G.R. Fick G.H. Sutherland L.R. Azathioprine and 6-mercaptopurine in Crohn’s disease a meta-analysis.Ann Intern Med. 1995; 123: 132-142Crossref PubMed Scopus (925) Google Scholar, 26Sandborn W. Sutherland L. Pearson D. May G. Modigliani R. Prantera C. Azathioprine or 6-mercaptopurine or inducing remission of Crohn’s disease.Cochrane Database Syst Rev. 2000; 3Google Scholar What makes the results of these clinical trials difficult to interpret and perhaps inconclusive as to the role of AZA/6-MP as induction therapies is the lack of uniformity in the use of corticosteroids as well as the chosen end points and outcome measures. The delayed onset of action of thiopurines might preclude their use in the induction of a timely remission, in particular in the face of moderate to severely active disease. More rapidly acting induction therapies such as corticosteroids and/or infliximab for patients with CD or perhaps cyclosporine for patients with UC would be more appropriate, given the delayed onset of action of thiopurines. Although the short-term efficacies of these induction therapies are very favorable, their long-term efficacy and safety profiles necessitate the implementation of alternate long-term maintenance therapies. Natural history studies have shown that approximately one third of patients become dependent on corticosteroids for the maintenance of an inactive disease state, and another 20% of patients are no longer responding to the anti-inflammatory properties of steroids after just 12 months of therapy.27Munkholm P. Langholz E. Davidsen M. Binder V. Frequency of glucocorticoid resistance and dependency in Crohn’s disease.Gut. 1994; 35: 360-362Crossref PubMed Scopus (645) Google Scholar To date, thiopurines remain the therapy of choice for the successful maintenance of a steroid-free quiescent disease state. The timing of the introduction of thiopurines in patients dependent on corticosteroids for disease remission might vary among clinicians. In general, it is recommended that thiopurines be added to the therapeutic regime in patients failing to wean off corticosteroids during their first attempt at tapering the dose or alternatively after a second attempt. Two different studies have reported on the efficacy of combination steroid and thiopurine therapy for both the induction and maintenance of a steroid-free remission. Given the implications of steroid dependency in children, Markowitz et al.28Markowitz J. Grancher K. Kohn N. Lesser M. Daum F. 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 Scholar conducted a pivotal study in newly diagnosed pediatric CD patients in which children were randomized to prednisone in conjunction with 6-MP (1.5 mg · kg−1 · day−1) vs. prednisone and placebo. This trial showed a relapse rate of 28% at 6 months in patients receiving placebo as compared to only 4% in 6-MP recipients. Moreover, by 18 months, only 9% of 6-MP treated patients had relapsed as compared to 47% in the placebo group after induction of remission. Significant steroid-sparing effects were also observed. Candy et al.22Candy S. Wright J. Gerber M. Adams G. Gerig M. Goodman R. A controlled double blind study of azathioprine in the management of Crohn’s disease.Gut. 1995; 37: 674-678Crossref PubMed Scopus (540) Google Scholar similarly showed that AZA offers a therapeutic advantage over placebo (47% vs. 7% remission rate at 15 months; P = 0.001) in the maintenance of remission in CD patients. Both studies showed no difference in the proportions of patients who had achieved remission at 12 weeks because corticosteroids serve as the induction therapy for both groups. These results highlight the steroid-sparing benefits of thiopurines and suggest that the short-term use of corticosteroids for the induction of remission can serve as a bridge to the more long-term maintenance of a steroid-free remission with thiopurines. The steroid-sparing benefits have been summarized in the Cochrane analysis, in which 65% (CI, 56%–74%) of patients with active disease who received AZA/6-MP reduced their steroid dose, compared to 36% (CI, 27%–45%) of those receiving placebo.18Present D.H. Korelitz B.I. Wisch N. Glass J.L. Sachar D.B. Pasternack B.S. Treatment of Crohn’s disease with 6-mercaptopurine a long-term, randomized, double blind study.N Engl J Med. 1980; 302: 981-987Crossref PubMed Scopus (976) Google Scholar, 20Willoughby J.M.T. Kumar P.J. Beckett J. Dawson A.M. Controlled trial of azathioprine in Crohn’s disease.Lancet. 1971; 731: 944-947Abstract Scopus (249) Google Scholar, 22Candy S. Wright J. Gerber M. Adams G. Gerig M. Goodman R. A controlled double blind study of azathioprine in the management of Crohn’s disease.Gut. 1995; 37: 674-678Crossref PubMed Scopus (540) Google Scholar, 23Ewe K. Press A.G. Singe C.C. Stufler M. Ueberschaer B. Hommel G. Meyer zum Buschenfelde K.H. Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn’s disease.Gastroenterology. 1993; 105: 367-372Abstract PubMed Google Scholar, 24Klein M. Binder H.J. Mitchell M. Aaronson R. Spiro H. Treatment of Crohn’s disease with azathioprine a controlled evaluation.Gastroenterology. 1974; 66: 916-922Abstract Full Text PDF PubMed Scopus (139) Google Scholar The pooled odds ratio was 3.86 (CI, 2.14–6.96), and the number needed to treat to obtain a steroid-sparing effect in 1 patient was 3 patients. The steroid-sparing effects have also been analyzed in maintenance of remission studies. More specifically, in the 2 maintenance trials reporting steroid data,20Willoughby J.M.T. Kumar P.J. Beckett J. Dawson A.M. Controlled trial of azathioprine in Crohn’s disease.Lancet. 1971; 731: 944-947Abstract Scopus (249) Google Scholar, 29Rosenberg J.L. Levin B. Wall A.J. Kirsner J.B. A controlled trial of azathioprine in the management of Crohn’s disease.Dig Dis. 1975; 20: 721-726Crossref Scopus (171) Google Scholar 87% (CI, 60%–98%) receiving maintenance therapy with AZA were able to reduce steroid use compared to 53% (CI, 27%–79%) of those on placebo with an odds ratio of 5.22 (CI, 1.06–25.68).30Pearson D.C. May G.R. Fick G. Sutherland L.R. Azathioprine for maintenance of remission in Crohn’s disease.Cochrane Database Syst Rev. 2003; 3Google Scholar Table 2 summarizes all the controlled trials reported for the maintenance of remission.20Willoughby J.M.T. Kumar P.J. Beckett J. Dawson A.M. Controlled trial of azathioprine in Crohn’s disease.Lancet. 1971; 731: 944-947Abstract Scopus (249) Google Scholar, 21Summers R.W. Switz D.M. Sessions Jr, J.T. Becktel J.M. Best W.R. Kern Jr, F. Singleton J.W. National Cooperative Crohn’s Disease Study results of drug treatment.Gastroenterology. 1979; 77: 847-869PubMed Scopus (1068) Google Scholar, 22Candy S. Wright J. Gerber M. Adams G. Gerig M. Goodman R. A controlled double blind study of azathioprine in the management of Crohn’s disease.Gut. 1995; 37: 674-678Crossref PubMed Scopus (540) Google Scholar, 28Markowitz J. Grancher K. Kohn N. Lesser M. Daum F. 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 Scholar, 29Rosenberg J.L. Levin B. Wall A.J. Kirsner J.B. A controlled trial of azathioprine in the management of Crohn’s disease.Dig Dis. 1975; 20: 721-726Crossref Scopus (171) Google Scholar, 31O’Donoghue D.P. Dawson A.M. Powell-Tuck J. et al.Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn’s disease.Lancet. 1978; 2: 955-957Abstract PubMed Scopus (291) Google Scholar The Pearson meta-analysis reported an odds ratio of 2.27 (CI, 1.76–2.93) for maintenance of remission with an overall response rate of 67% (CI, 59%–75%) as compared to 53% (CI, 45%–60%) for placebo. The Cochrane analysis also reported an overall remission rate of 67% (CI, 59%–75%) for treatment compared to 52% (CI, 45%–60%) for placebo, essentially identical to the Pearson analysis. The odds ratio for response to AZA was 2.16 (CI, 1.35–3.47), and the number needed to treat to prevent 1 recurrence was 7. When the maintenance therapy data were analyzed for the effect of AZA dose (range, 1.0–2.5 mg · kg−1 · day−1), the odds ratio for response increased from 1.20 (CI, 0.60–2.41) at 1.0 mg · kg−1 · day−1 to 3.17 (CI, 1.33–7.59) at 2.0 mg · kg−1 · day−1 and 4.13 (CI, 1.59–10.71) at 2.5 mg · kg−1 · day−1, demonstrating a dose response phenomenon.Table 2Maintenance of Remission: Crohn’s DiseaseStudy (reference)Total no. of patientsEfficacy (%), drugEfficacy (%), placeboP valueThiopurine & starting dose (mg · kg−1 · day−1)Treatment duration (mo)Group 2: WilloughbyaFistula response assessed.bSteroid-sparing effect assessed. (20Willoughby J.M.T. Kumar P.J. Beckett J. Dawson A.M. Controlled trial of azathioprine in Crohn’s disease.Lancet. 1971; 731: 944-947Abstract Scopus (249) Google Scholar)128040<0.01AZA 2.06Part 1, phase 2: Summers (21Summers R.W. Switz D.M. Sessions Jr, J.T. Becktel J.M. Best W.R. Kern Jr, F. Singleton J.W. National Cooperative Crohn’s Disease Study results of drug treatment.Gastroenterology. 1979; 77: 847-869PubMed Scopus
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