3160

Thiopurine MethyI-Trancferase Activity Influences Clinical Response to Asathioprine Therapy in Patients with IBD Carmen Cuffari, Asim Maqbool, Lawrence Jones, Theodore M. Bayless, Johns Hopkins Univ, Baltimore, MD

Background: Genetic polymorphisms in Thiopurine methyl-transferese (TPMT) enzyme activity are well known to influence clinical responsiveness to anti-metabolite therapy in patients with leukemia (J Clin Onco11989;7:1816). Patients with high TPMT activity shunt azathioprine(AZA)- metabolism away from the production of its active 6-thioguanine (6-TG) metabolitas, and remain refractory to standard doses of therapy. We hypothesize that inherent differences in TPMT phenotype present in the general population may influence clinical responsiveness to AZA therapy in patients with IBD. Methods: Thirty-one consecutive patients with IBD (Crohn's Disease,22;UC,9) on long-term AZA therapy (>4months) had TPMT activity measured as per Weinshilboum et al (Clin Chem Acta 1978;85:323). E~hrocyta 6-TG metabolita levels were measured by HPLC (342nm) and were correlated with clinical response as defined by either symptomatic improvement, fistula closure, or the ability to wean off of corticostaruid therapy. Patients were divided into 4 groups based on TPMT activity and erythrocyte 6-TG levels. Group 1A: TPMT -< 16.0, 6-TG > 250; Group 1B: TPMT -< 16.0, 6-TG < 250; Group 2A: TPMT > 16.0, 6-TG < 250; Group 2£: TPt~T > 16.0, ~-TG >250. ~esoits: See Table 1. Group 1 had significantly higher erythrocyte 6-TG levels [248(70-440)] compared to Group 21121(51-674)] despite similar AZA dosing (p<O.O5).Group 1 also achieved an improved clinical response. Conclusions: TPMT phenotype influences clinical responsiveness in patients on AZA therapy. Future prospective controlled trials are in progress to determine whether TPMT phenotype testing performed prior to commencing AZA therapy would be helpful.

Clinical response correlated to TPMT phenotype and erythrocyte 6-TG levels

Group I (TPMT < 16.0) Group 2 ( TPMT >16.0) a. 6-TG (>250) b, 6-TG1<250 ) s. 6-TG (<250) b. 6-TG~>250)

Number 9 9 10 3 6-TG levels ~ 2951 181" (170-248) 108 *r (51- 300" (278-674) (257440) 185) AZA dose p 1.6_-+0.1 1.1_+0.1" 1.4~0.2" 2.0~0.2' Clin. response 6/9 7/9 4/10 3/3

median values (range) in picomoles/8xl 0 s RBCs. p mg/kg/day; * p<O.O5;Tp<O.O05.

3161

Is Preoperative Azathioprine (AZA), 6-Mercaptopurine (6-MP) or Codicosteroids (CS) Use for Elective Bowel Surgery Associated with Postoperative infectious Complications? Fatan Aberra, James D. Lewis, Gary R. Lichtenstein, Univ of Pennsylvania, Philadelphia, PA

BACKGROUND: AZA/6-MP are effective for induction and maintenance of remission in IBD and are often used alone or in combination with CS. No published studies have criticatly analyzed the risk of postoperative infection in IBD patients maintained on AZA/6MP alone or in combination with CS prior to surgery. AIMS: We hypothesize an increased risk for postoperative infection in IBD patients on AZA/6-MP plus CS or CS alone preoperatively. METHODS: We performed a retrospective study of IBD patients admitted to our hospitals from 1994-1999. We searched our database for patients with a primary or secondary diagnosis (ICD-9 code) for IBD, UC or CD along with a procedure code for bowel surgery. Emergent surgeries and patients who stopped A7_N6MP > 1 week prior to surgery were excluded. Infectious complications were defined as major (e.g. wound infections, sepsis, pneumonia, peritonitis, abdominal abscess, and wound dehiscence) or minor (e,g. urinary tract infection and fever > 101.5°F without an identifiable source) using previously published criteda (Surgery. 1995; 118(4):748-755) and were recorded until time of discharge. RESULTS: 145 patients were included in the study. Preoperative therapy included CS alone in 57 (30-UC:27-CD), CS in combination with either AZA/6-MP in 28 (12-UC:16-CD), A7_.A/6-MP without CS in 12 (2- UC:IO-CD), and neither CS or AZA/6-MP in 48 (20-UC:28-CD). 15 of the 57 patients (26.3%) on CS alone had infectious complications; 11 major and 4 minor. Among the 28 patients on AZA/6-MP and CS, 9 (32.1%) had infectious complications; 3 major and 6 minor. 3 of 48 patients (6.3%) not taking either AZA/6-MP or CS had complications; 2-mejor and 1-minor. Among the 12 patients on AZA/6-MP not taking CS, 2 patients (16.6%) bad infectious complications: 1-major, 1-minor. The risk of postoperative infectious complications was greater among patients on CS alone or in combination with A7_A/6-MP prior to surgery than in those not receiving CS (RR = 3.39, 95% CI 1.37 to 8.38). However, the risk of postoperative infection was not significantly increased in patients receiving CS with AZA/6-MP compared to those receiving CS alone (RR = 1.22, 95% CI 0.61 to 2.44). CONCLUSION: Our data suggest an association in IBD patients between CS use preoperatively (whether alone or in combination with AZA/6-MP) and postoperative infectious complications. The addition of AZA/6-MP does not appear to further increase the risk of postoperative infection with CS.

3162

Drug Monitoring of Azathioprine (AZA) and 6-mercaptopurine (6-MP) Among Adult Patients with Inflammatory Bowel Disease (IBD). UIf Na Hindorf, Ebbe Lyrenas, Dept of Internal Medicine, Blekinge County Hosp, Karlskrona Sweden; Ake Nilsson, Dept of Gastroenterology, Univ Hosp, Land Sweden; Kjeld Schmiegelow, Dept of Pediatric II, National Hosp, Copenhagen Denmark

Background: AZA and 6-MP has proven long-term efficacy in the treatment of IBD. A correlation between disease activity and 6-thioguanine nuclectide (TGN) levels has been noted among pediatric IBD patients. Objective: To evaluate the measurement of nucleotide metaboUte levels in relation to disease activity in adult patients with IBD. Methods: 46 patients (23 M, mean age 36 yr) currently treated with 1.61(0.57-2.72)mg AZA/kg/day (n = 45) or 1.44 mg 6-MP/

kg/day (n = 1) for a duration of 42 (6-188) mo. were included in a prospective county-based study (Blekinge County, Sweden). 34 patients had Crohn's disease (CD) and 12 had ulcerative colitis (UC). Disease activity was measured by using Crohn's disease activity index (CDAI) for CD and Simple clinical colitis activity index (SCCAI) for UC. Remission was defined as CDAI -<150 or SCCAI -<2 with no corticosteroids (CS) or a low dose (10 mg QOD). Thiopurine methyitransferase (TPMT) activity, TGN and methylated mercaptopudne metabolite (MeMP) levels were analysed at the Laboratory for Pediatric Oncology, National Hospital, Copenhagen, Denmark. A TPMT activity -> 11 U/ml RBC (red blood cells)is considered normal. A TGN value of 100 nmol/mmol Hb is equal to 200 pmol/8*lOe RBC. Results: 34 patients were in remission (24 CO, 18 UC) and 12 had active disease (10 CD, 2 UC). COAl values ranged 6- 135 in remission and 84-318 in active disease. SCCAI values was 0-1 in remission and 3-6 in active disease. Concurrent medication included CS (n=9) and 5-ASA (n =35). Among CD patients there were prior treatment with TNF-e (n=8) and surgery -> 1 occasion (n=17). TPMT deficiency (<1 U/ml Hb) was noted in 1 patient and 5 had intermediate TPMT activity (2 with active disease). 84 TGN samples in remission gave a mean of 158 nmol/mmol Hb compared to 36 samples with a mean of 113 nmol/mmol Hb in active disease (p=O.OO7, Welch unpaired t-test). 3 patients were excluded due to obvious non-complianea. Patients with active disease were treated with 1.84 mg AZk~kg/day compared to 1.52 mg/kg/day in remission (p = 0.02, Mann-Whitney test). MeMP levels did not correlate to either TPMT activity or TON levels, No difference in MeMP was noted between the two groups. Conclusion: TGN levels were significantly higher among patients in remission, although patients in active disease were treated with significantly higher AZA doses. This could be due to a difference in tbiopudne metabolism and it might be wiser to practice AZA/6-MP dosage based on TGN values rather than by bodyweight,

3163

The Clinical Utility of Measuring Levels of 6-methylmercaptopurine (6-MMP) and 6- thioguanine (6-TG) in Managing Inflammatory Bowel Disease Patients Treated with 6-mercaptopurine (6-MP) in a Clinical Practice Selling. Houssam E. Mardini, George L. Arnold, UPMC Shadyside, Pittsburgh, PA

Background.6-MP and its parent compound Azathioprine are effective agents for the treatment of inflammatory bowel diseases (IBD). Monitoring hepatic enzyme levels and leukocyte count is important for patients on these drugs. However, it only allows physicians to react to problems. Measuring metabolita levels may allow the clinician to be pro-active by adjusting the dose of the drug to optimize therapeutic response while minimizing toxicity. Aim: To evaluate the clinical value of 6-MMP and 6-TO levels in a clinical practice setting. Methods: Using out-patient clinic medical records at UPMC Shadyalde Hospital, Pittsburgh, PA we identified 26 patients (13 M and 13 F) ages 21 to 76 receiving 6 MP treatment for IBD and who had 6-MMP and 6-TG levels checked (Prometheus, Inc. assay) during their course of the treatment for different specific indications including inadequate clinical response, elevated liver enzymes, anemia and leukopenia. 6-TG level of > 230 pmol per 8x108 RBC was considered therapeutic and 6-MMP level > 5700 pmol per 8x108 RBC was considered potentially hepato- toxic. Resu/ts2O patients (77%) had persistent symptoms despite medical therapy, 2 (7.7%) bad unexplained anemia, and 4 (15.3%) had elevated LFTs. Among patients with persistent symptoms 6-TG levels were therapeutic in 13 patients (65%) and other interventions were required (steroids and/or infliximab), 1 patient (5 %) had undetectable levels of both metabolites indicating non compliance, 6 patients (30%) had sub-therapeutic 6TG level and low to normal 6MMP level. 6MP dose was increased and remission was achieved in 4 patients, while the rest required additional therapy. In the elevated liver enzymes group, 2 patients (50%) had high 6-MMP level and dose was decreased, 2 (50%) patients had low levels and were kept on the same dose. In the anemia group, 1 (50%) patient bad therapeutic range metabolite levels and it was felt that her anemia was not related to the medication. The other patient had elevated 6-TG levels and this anemia responded to 6-MP dose reduction. Conclusion.Mea- suring 6-MMP and 6-TG levels help the physician customize 6-MP dosing, identity drug-related myelotoxicity and/or liver injury, and inadequate clinical response due to non-compliance. This allows for dose adjustment leading to improved clinical outcomes.

3164

The lO-year F.xperienca with Purinethol (6MP) at The Crohn's and ColHis Center of New Jersey. Kenneth D. Glazier, Adam Palance, Louis H. Griffel, Kiron M. Das, UMDNJ-Robert Wood Johnson Medical Sch, New Brunswick, NJ

Objective: To report the 1g-year experience of a single clinician in treating patients with refractory inflammatory bowel disease (IBg) treated with 6MP and/or Imuren. Methods: The charts of 285 patients with IBD receiving 6MP were reviewed: Crohn's disease (CD)-160 and ulcerative colitis (UC)-125. Clinical response, subsequent breakthrough while on 6MP and relapse when 6MP was discontinued were assessed. Only patients who tolerated drug for at least 3 months were included in response evaluation. Patient demographics, side effects, infectious complications and malignant tumors are also reported. Results: Complete remission was achieved in 63.4%, partial remission in 13.3%, and failure to achieve remission in 23.3%. Of complete respondere, 27.3% had breakthrough while continuing 6MP. Nine percent of those that achieved a complete remission experienced a relapse of the disease when 6MP was discontinued. Response rata was similar in UC and CO as welt as between men and women. Toxicity, directly induced by 6UP included pancreatitis in 7 (2.5%) and drug hepatitis in 14 (4.9%). Six stopped 6MP due to nausea (2.1%), 8 for headaches (2.8%), 4 had fevers (1.4%), 3 had hair loss (1%), and 2 had rash (0.7%). Leukopenia of a mean 3K (sd .526) occurred in 32 patients (11.2%) at a mean dose of 1.084 mg/kg (sd .497) of 6MP. Infectious complications were seen in 9 (3.1%), including CMV pneumonia. Two cancers occurred while patients were taking 6MP: melanoma on the finger with an accummulative dose of 70,500 mg 6MP, and fatal colonic lymphome in the second patient with an accumulative dose of 120,125 mg 6MP. Four patients had safe pregnancies with mean dose of .658 mg/kg 6MP. Conclusion: 6MP is a relatively safe and effective drug in the treatment of IBD. However, patients should be monitored carefully for infrequent but possible serious side effects.

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