Side effects of azathioprine treatment given for inflammatory bowel disease-a 30 year audit

April 2000

AGAA787

4201

4203

SIDE EFFECTS OF AZATHIOPRINE TREATMENT GIVEN FOR INFLAMMATORY BOWEL DISEASE· A 30 YEAR AUDIT. Alan G. Fraser, Derek P. Jewell, Dept of Gastroenterology, Oxford, United Kingdom. Background: The use of azathioprine for inflammatory bowel disease is limited by short and long-term toxicity. Limited data from large clinic populations is available. Methods: The clinical records of patients attending the Oxford inflammatory bowel disease at the John Radcliffe Hospital, Oxford, from 1968-1999 were reviewed. Results: The notes of 2205 patients were reviewed; 621 patients were treated with azathioprine (270 Crohn's disease and 351 ulcerative colitis). The mean duration of the initial course of treatment was 634 days; total usage over the review was 1350 patient-years. Dose range was 0.6 to 2.9mglkg; 25th centile 1.4; 75th centile 1.9 mglkg). 175 patients (28%) had significant side-effects which led to stopping medication in 152 patients (85%). The most common side-effect was nausea and vomiting (68 patients); this did not appear to be doserelated. Other side-effects were influenzal symptoms 22 patients, headache 7, diarrhoea 11, skin rash 11, abnormal liver enzymes (15 raised alk phos +1- GGT) 17 and other 4. The onset of liver enzyme elevation was between 2-6 months after starting treatment; all changes were reversible. Six patients had acute abdominal pain but only two had a raised amylase. Leucopenia (WBC < 3.0 or neutrophils < 2.0) was seen in 29 patients (4.6%). Medication was stopped in 21 patients, observation only for 4 and dose reduction for 4. Two patients had significant pancytopenia. The onset of leucopenia was < 3 months for 5 patients (17%), 3-6 months 7 (24%), 6-24 months II and> 24 months for 6 patients (range 47 - 1514 days). Only 4 patients had significant sepsis (requiring hospital admission and iv antibiotics) related to leucopenia; there was no mortality. 517 patients had stopped treatment at time of review. The reasons for stopping were sideeffects 152 patients (28%), planned after defined duration (usually 2 years) 203 (37%), treatment ineffective or patient required surgery 113 (21%), stopped because of patient request 67 (12%), and 7 wished to conceive (I %). Conclusion: Azathioprine is well tolerated and caused no mortality over a 30 year period and 1350 patient years. Side-effects were the main reason for stopping medication in the first 6 months. The risk of leucopenia and serious sepsis can be managed with careful clinic follow-up. Leucopenia occured in the first 6 months for 41% of patients.

GASTROINTESTINAL SIDE EFFECTS OF AZATHIOPRINE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE ARE NOT RELATED TO THIOPURINE METHYLTRANSFERASE POLYMORPIDSM. Bernd A. Kaskas, Elke SchSffeler, Thomas Lang, Ulrich Zanger, Claudia Marx, Christine Fischer, Michel Eichelbaum, Michael Gregor, Matthias Schwab, Univ Hosp, Dept of Internal Medicine I, Tuebingen, Germany; Dr Margarete-Fischer-Bosch-Institute of Clin Pharmacology, Stuttgart, Germany. Azathioprine (AZA) is used as an immunosuppressive drug in patients with steroid resistent inflammatory bowel disease (IBD). Approximately, 15% of these patients develop severe adverse reactions (e.g. pancytopenia, pancreatitis) often resulting in drug withdrawal. AZA is inactivated by thiopurine methyltransferase (TPMT). 89-94% of the population have high, 6-11% have intermediate, and 0.3% have very low TPMT activity. Recent identification of the molecular basis for low TPMT activity enabled rapid assessment of AZA metabolism by PCR methods. The aim of this retrospective study was to detect an association between severe adverse reactions to AZA and the individual pheno-/genotype ofTPMTin patients with IBD. Methods: 72 patients with Crohn's disease (CD, mean age 40.7:!:11, male 32) and 16 with ulcerative colitis (UC, 40.7:!: II, m 12) who had taken or are taking AZA, were phenotyped for TPMT activity quantitated by HPLC with fluorescence detection in erythrocytes and were genotyped for TPMT*2, *3A,*3B,*3C and *3D using allele-specific PCR and PCR-RFLP. Anamnestic and clinical data were also recorded. Results: 11 patients with CD and 2 with UC had serious side effects under AZA (partly more than one per patient) which led to drug withdrawal: pancytopenia (n== I), leucopenia (n==2), anemia (n==4), elevated cholestasis enzymes (n==2), pancreatitis (n==3) and nausea (n==3). Whereas pancytopenia was associated with TPMT-deficiency (TPMT <2units,*3A1*3A) only 1 patient with leucopenia/anemia showed intermediate activity and was heterozygous (*1/ *3A). All patients with gastrointestinal side effects had normal TPMT activity. In patients with CD, TPMT activity of 5 non-responders compared with 56 responders did not differ significantly (44.8:!:14.7 vs 45.6:!:12.4). Genotyping revealed wild-type TPMT in all non-responders. Conclusion: With the exception of pancytopenia which occured in the patient homozygous for TPMT deficiency, 70% of hematological and all gastrointestinal side effects are not related to TPMT polymorphism. Nevertheless, we recommend TPMT pheno-/genotyping prior to the initiation of AZA in order to avoid severe drug toxicity (pancytopenia). Supported by the Robert-Bosch-Stiftung, Stuttgart and by BMBF (FKZ OIGG9846)

4202 6-MERCAPTOPURINE (6MP) METABOLITE LEVELS IN CHILDREN WITH mD: LACK OF CORRELATION OF 6-THIOGUANINE (6TG) LEVELS WITH CLINICAL RESPONSE. Puneet Gupta, Ranjana Gokhale, Barbara S. Kirschner, Univ of Chicago, Chicago, IL. The immunomodulatory and cytotoxic properties of 6-MP and azathioprine are mediated by conversion of 6MP to its thiopurine metabolites: 6-TG and 6-methylmercaptopurine (6-MMP). It is suggested that leukopenia and hepatotoxicity correlate with elevated 6TG and 6MMP levels respectively. RBC 6TG levels >23OpmoV8x108 correlate with clinical response in some studies. Aim of this study was to study the usefulness of 6MP metabolites in assessing therapeutic response and toxicity of 6MP in our pediatric population. Methods: 6MP metabolite levels from 54 children with IBD on 6MP >4 months were measured at Prometheus Labs, CA. Response to 6MP was defined as clinical remission (PCDAI 230, compared with 30% of patients in remission. Of 37 patients with 6TG levels<230, 21 (57%) were in remission vs. nine (50%) of 18 patients with 6TG levels>230. Leukopenia (WBC<4000) was observed in five (9%) patients, all had significant elevations in 6TG levels (43Ovs214; p<0.05). None of the nine patients with 6MMP >5550 (614019805), had elevated ALT. Two (4%) patients with ALT >2x N had mean 6MMP level of only 2987. In 32 patients 6MMP was undetectable. six of whom also had undetectable 6TG probably reflecting poor compliance. Thiopurine methyl-transferase (TPMT) genotyping was performed in 12 patients, eight had normal TPMT and 4 patients had intermediate TPMT. Patients with intermediate TPMT had higher 6TG levels (510 vs. 185; p230 did not correlate with higher likelihood of clinical remission. Elevated 6MMP levels did not correlate with hepatotoxicity. Group

n

Mean 6·TG

Mean6·MMP

6MP Dose (Mg/Kg)

Remission Relapse Leukopenia

30 25 5

226 208 433

2008 2325 1854

1.4

1.2 1.0

4204 HIGH DOSES OF AZATHIOPRINE BUT NOT 6·MERCAPTOPURINE INHIBIT THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES IN INFLAMMATORY BOWEL DISEASES: AN IN VITRO STUDY. Edouard Louis, Fabienne Aboul Nasr El Yafi, Jacques Belaiche, CHU of Liege, Liege, Belgium. The mechanisms of action of azathioprine (aza) and 6-mercaptopurine (6-mp) in inflammatory bowel diseases (IBD) are still not well understood. The 6-mp comes from the release of a nitro-imidazole metabolite from aza and approximately corresponds to 50% of the aza dose. Our aim was to study the effect of various pharmacological doses of aza or 6-mp on the production of pro-inflammatory cytokines by colonic mucosa in IBD. Patients and methods: 14 patients with IBD have been studied. Colonic biopsies taken from inflamed areas of the colon were cultured for 18 hours with different concentrations of aza and 6-mp (1, 10 and 100 ug/ml and 0.5,5 and 50 p.g/ml, respectively). The concentrations ofTNFa, IL-IJ3 and IL-6 were measured on the supernatants of cultures by using specific ELISA, and expressed per ml of supernatant and per mg of tissue. These concentrations were compared between controls and various doses of aza and 6-mp by using a paired t-test. Results: With aza, we observed a dose-response effect and the concentration of 100 p.g/ml induced an almost complete inhibition of the production of pro-inflammatory cytokines (in % of the control: 18.5%:!:7,p