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Volume 3, Supplement 1, 2003

Volume 3, Supplement 1, 2003

Table of Contents

Pharmacogenetics- The Horizon
Pharmacogenetics is a growing discipline with great potential for improving human health care. This article provides a broad overview of the field to set the stage for discussions elsewhere in this publication of pharmacogenetic applications for treatment of inflammatory bowel disease. Pharmacogenetics is defined and positioned appropriately in the large picture of drug response and failure. A vision for pharmacogenetic applications and optimal pharmacogenetic candidates is discussed. Two examples of compounds that have failed at least partly because of pharmacogenetic considerations are discussed. Finally, some predictions are presented regarding large-scale clinical applications and current hindrances to those applications. [Rev Gastroenterol Disord. 2003;3(suppl 1):S3–S8]
Clinical Applications of Advances in the Genetics of IBD
Our rapidly expanding understanding of the genetics of inflammatory bowel disease (IBD) has led to important clinical applications. It is becoming apparent that genes help determine the clinical phenotype, intestinal and extraintestinal complications, response to treatment, and drug toxicities in these disorders. For example, NOD2/CARD15 mutations are associated with ileal Crohn’s disease, possibly with a fibrosing/obstructing phenotype, but do not influence responses to infliximab treatment. Similarly, certain human leukocyte antigen (HLA) haplotypes are associated with aggressive, extensive ulcerative colitis and strongly influence extraintestinal manifestations of IBD, including uveitis and various forms of arthritis. Expression of the glucocorticoid receptor  determines the clinical response to corticosteroids, whereas genetically regulated levels of enzymes metabolizing 6-mercaptopurine/azathioprine may determine clinical responses and toxicities to these important immunosuppressive agents. Once we have a more sophisticated understanding of the mechanisms of genetic defects in IBD, it may be feasible to restore physiologic function to prevent the onset of disease in susceptible individuals. However, because we do not have the ability to prevent disease at the present time, it is premature to screen offspring and first-degree relatives of IBD patients for the NOD2/CARD15 genotype. One can anticipate that it will become feasible to prospectively determine a patient’s genotype and to individualize a drug regimen, leading to highly effective, safe treatments for IBD patients on a rational, rather than empiric, basis. [Rev Gastroenterol Disord. 2003;3(suppl 1):S9–S17]
Significant Role of Genetics in IBD: The NOD2 Gene
Inflammatory bowel disease (IBD) clusters within families, suggesting a genetic component to disease pathogenesis. Studies have identified a gene on chromosome 16cen that confers susceptibility to Crohn’s disease. The affected gene codes for the NOD2/CARD15 protein, which is involved in the immune system’s response to bacterial infection. Multiple mutations have been identified, three of which have been shown to be independently associated with Crohn’s disease—arg702trp, gly908arg, and leu1007fsinsC. Taken together, these three variants confer a 15%-20% attributable population risk among cases of familial Crohn’s disease, with decreased contribution among the more common sporadic cases of the disease. The presence of an NOD2 risk allele has been shown to be associated with ilial disease as well as an earlier age of disease onset. Further studies are needed to clarify the relationship between IBD genotype and disease behavior. [Rev Gastroenterol Disord. 2003:3(suppl 1):S18-S22]
Therapeutic Efficacy and Safety of 6-Mercaptopurine and Azathioprine in Patients with Crohn's Disease
The purine analogues 6-mercaptopurine (6-MP) and azathioprine have been found to be safe and efficacious in both inducing remission of Crohn’s disease in adults and maintaining remission in adults and children. In addition, steroid-sparing effects are demonstrable in trials of both adults and children with Crohn’s disease. Anecdotal reports of adults and very limited data from children also suggest that azathioprine and 6-MP might help prevent postoperative recurrence of Crohn’s disease. Regarding safety, adults and children reported similar rates of adverse effects from the use of these agents: reported adverse effects in adults included significant infection (7.4%), pancreatitis (3.3%), neoplasm (3.1%), bone marrow suppression (2.0%), allergy (2.0%), and drug-induced hepatitis (0.3%). Most studies also suggest there is little, if any, probability that immunomodulatory therapy might increase the risk of malignancy in patients with Crohn’s disease. Data are too limited to guide clinical decisions on how long immunomodulatory therapy should be continued, whether it is safe to take azathioprine and 6-MP during pregnancy, and whether men can take these agents at the time of conception. Although 6-MP and azathioprine have been used safely for over 30 years, the recent commercial availability of thiopurine methyltransferase (TPMT) genotype/phenotype testing and 6-MP metabolite testing offers the promise of limiting potential toxicity even more. As a result, these agents will continue to play a central therapeutic role for all clinicians caring for children or adults with Crohn’s disease. [Rev Gastroenterol Disord. 2003;3(suppl 1):S23-S29]
Clinical Use and Practical Application of TPMT Enzyme and 6-Mercaptopurine Metabolite Monitoring in IBD
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 druginduced toxicity. [Rev Gastroenterol Disord. 2003;3(suppl 1):S30–S38]