What are the rules when treatment with 6-MP/AZA is started?

Abstract

The most important rule is assurance that the patient realizes that Crohn’s disease (CD) is a lifetime pathological process and that the gastroenterologist has explained the specific indications for using 6-mercaptopurine/azathioprine (6-MP/AZA) for their particular case, that 6-MP/AZA may result in a prolonged and possibly permanent remission, and that the risks of adverse reactions in using the drug, although infrequent, are mostly reversible and understood. While ulcerative colitis (UC) is theoretically curable by colectomy, 6-MP/AZA are effective just as much as in CD and the possibility of postoperative complications such as pouchitis, risk of mucosal cancer, impotence, or permanent ileostomy warrant a fair trial of immunosuppressives. Since the metabolism of the drug varies, the initial dose is low (I start at 50 mg/d) but an increase may be anticipated pending inadequate response, and stopped or decreased pending a fall in the white blood cell count (WBC) or platelets or development of abnormal liver function tests. The patient must be compliant with having blood drawn for complete blood count (CBC) weekly usually for the first 3 weeks and subsequently no matter how much the interval is increased. This is managed in my own center by request that reports be faxed by the laboratory and then the patients call for directions on the dose and the interval. Compliance is better achieved by monitoring the results of the blood work, and the phone call from the patient to receive directions, than by the results of serological tests that also require the patients’ cooperation and motivation but a longer lag period. While measurement of the enzyme thiopurine methyltransferase (TPMT) is of value, its measurement is rarely essential since its complete absence (potentially leading to bone marrow depression) occurs in only 1 out of 300 patients. Meanwhile, the CBC is monitored very carefully in all. Most patients are still on steroids at the time when 6-MP/AZA are introduced, which serves to increase the WBC, and the use of granulocyte stimulating factor offers further protection, although rarely needed. Whenever fever occurs, regardless of cause, 6-MP/AZA should be temporarily stopped and the CBC measured. Since early on it has been my own conviction that the initial dose of 6-MP/AZA should not be based on the patient’s weight; both experience and the pursuit of measuring levels of serological metabolites have supported these early observations. While the standard of dose introduction at 1.5 mg/kg for 6-MP and 2.5 mg/kg of AZA date back to the early placebo-controlled crossover trial conducted via the private offices of Korelitz and Present, and the National Cooperative Crohn’s Disease Study conducted at 14 centers, it soon became clear that efficacy in some patients tolerating only one-half a tablet of 6-MP every 2–3 weeks fared equally well as another patient requiring 5–6 tablets daily. This is best explained serologically by the preferential shunting via a metabolic pathway to the effective moiety 6TG rather than 6MMP, which is far less if at all effective and proportionally leads to hepatic toxicity. Therefore, in those cases when efficacy is clinically not achieved, measurement of 6TG and 6PPT may lead to increasing the dose of 6-MP/6TG much sooner. Until now this goal has been accomplished without serological measurements by reintroducing steroids (or raising the dose back to original levels), always accompanied by raising the dose of 6-MP/AZA by 25–50 mg/day at the same time. The reintroduction or raising the dose of steroids should be brief, not permitting either steroid-dependence or steroidresistance to occur. Despite the fact that 6-MP/AZA has proven to be the most effective drug for maintenance in moderate to severe UC and CD to date, its disadvantage has been the delayed time to effectiveness (3–12 months), requiring corticosteroids or infliximab to buy time until doses are raised and efficacy becomes evident. What then can be done to try to enable 6-MP/AZA to work faster? Administering the drug intravenously has not yet been shown to accomplish this purpose. There is some evidence that the use of 5-aminosalicylic acid (5-ASA) products will speed up the action of 6-MP/AZA, presumably by switching more of its metabolites to 6TG, but practically speaking almost all patients started on immunosuppressives are already taking 5-ASA products without any evident clinical counterpart. There is currently some hope that continuous use of Allopurinol, which until now has been recognized as risking severe leukopenia in those who require the drug along with the 6-MP/AZA will From the Lenox Hill Hospital, New York University School of Medicine, New York, USA. Copyright © 2008 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20705 Published online in Wiley InterScience (www.interscience.wiley.com).