Calvo, Pl

Canaparo, Roberto

Castagno, F

Crocella, L

D&apos

Daperno, M

Pera, A

Rocca, R.

Serpe, Loredana

Sostegni, R

Vemetto, A

Zara, Gian Paolo

English

Institutional Research Information System University of Turin

AGAAbstractsAbbreviations. 95%CI: 95% confidence interval; n: number; NA: not applicable; Hgb: haemo-globin; RBC: red blood cell; +: active treatment; -: no treatmentS1229Genotype and Phenotype Analysis of Thiopurine-Methyl-Transferase (TPMT)in a Northern Italian PopulationMarco Daperno, Roberto Canaparo, Raffaello Sostegni, Annalisa Vernetto, Loredana Serpe,Pier L. Calvo, Sergio D'Antico, Lucia Crocellà, Franco Castagno, Angelo Pera, Gian PaoloZara, Rodolfo RoccaBackground. Immunomodulators, mainly thiopurines, are increasingly prescribed in inflam-matory bowel disease (IBD). Thiopurine-methyl-transferase (TPMT) genotype and phenotypeis expected to exhert notable effects on availability and toxicity of these drugs. Aims. Toanalyse TPMT genotype and phenotype in a Northern Italian population of healthy controlsand IBD patients. Patients & methods. All consecutive IBD out-patients (n=169) and 533healthy controls (HC) were recruited. A blood sample was drawn, DNA was extracted anderytrocytes were separated. Major TPMT genetic variants (TPMT*2, *3A, *3B, *3C) wereanalysed by means of PCR techniques, while intra-erythrocyte TMPT activity was analysedusing a standardised high pressure liquid chromatography (HPLC) technique. Clinical datawere recorded. Results. Regarding TPMT genotype, TPMT was mutated in 8/169 (4.7%;95%CI 1.5-8%) IBD cases (7 heterozigous for *3A and 1 for *3C) and in 34/533 (6.4%;95%CI 4-8%) HC (28 heterozigous for *3A, 3 for *3B and 3 for *3C); the difference wasnot statistically significant (p=0.549). Hardy Weinberg distribution was respected, no mutanthomozygous was observed among cases or controls. No significant differences were notedin subgroup analysis. As for TPMT activity, the distribution of TPMT activity was sharplydifferent in IBD cases, with distribution not-normal (p<0.001) and significantly lower thanamong HC (however not-normally distributed, p=0.014). TPMT activity figures are reportedin Table. No significant TPMT phenotype difference was noted according to IBD subgroupsbased on TPMT genotype or on clinical characteristic. We found only that IBD patients onsystemic steroids (n=16) had higher median TPMT activity (46.54 nmol/h/g Hgb) comparedto those not on steroid treatment (n=153, 26.98 nmol/h/g Hgb), p=0.0023. Discussion.This is the first report on TPMT genotypic and phenotypic characteristics in a NorthernItalian population. No difference was observed for TPMT genotype comparing cases andcontrols, however allelic frequency was lower than expected and no homozygous mutantsubject was observed. TPMT activity was lower in IBD patients compared to healthy controls.Larger groups of patients are under investigation in order to confirm observations.Abbreviations. IQR: interquartile range; p: p-value; HC: healthy controlsS1230Which 5-ASA? Variation in Colonic Mucosal Concentration of DifferentPharmaceutical mesalamine FormulationsRenata D'Incà, Martina Paccagnella, Romilda Cardin, Sandra Voltan, Vincenzo Baldo,Giacomo C. SturnioloAim: 5-Aminosalicylic acid (5-ASA or mesalamine) represents the mainstay treatment ofinflammatory bowel disease (IBD): different pharmaceutical formulations have beendeveloped in order to obtain absorption at the site of the disease. Our aim was to evaluatethe mucosal concentration of each formulation. Patients and methods: 130 consecutive IBDpatients receiving oral 5-ASA either pH-dependent release formulations (2.4 g/day) (73patients), time-dependent release formulations (3 g/day) (11 patients) or pro-drugs (3 g/day) (18 patients), were included in the study. 28 patients received both oral and topical(2-4 g/day enema) of pH-dependent release formulation. Two endoscopic biopsies weretaken from the sigmoid colon in each patient undergoing colonoscopy for surveillanceor symptom reexacerbation. Mesalamine concentration (ng/mg) was measured in tissuehomogenates by high-pressure liquid chromatographywith electrochemical detection. Endos-copic and histological disease activity were recorded as remission or active disease. The T-test and Mann-Whitney's test were used for statistical analysis. Results: pH-dependent releaseformulations achieved higher mucosal concentrations than prodrugs (51.75±48.88 vs33.35±24.12,p=0.01) and time-dependent release formulations (38.24±18.37,p=0.04). Fur-thermore, 28% of the patients under treatment with pH-dependent release formulations hadmucosal 5-ASA concentrations above 70 ng/mg of tissue which was the highest concentrationachieved with other formulations. Endoscopic remission was associated with significantlyhigher mucosal 5-ASA concentrations than active disease in patients receiving pH-dependentT : 11501$$CH204-02-08 16:47:06 Page 206Layout: 11501B : eA-206AGA Abstractsrelease formulations (60.14±55.11 vs 35.66±28.44,p=0.02). The same was true for histolog-ical assessment (67.53±56.11 vs 35.53±33.80,p<0.001). We found significantly highermucosal 5ASA concentrations in patients treated both orally and topically than those receivingonly oral treatment of pH-dependent release formulation (72.33±59.46 vs 51.75±48.88,p=0.03). Conclusions: Patients with IBD show significant variability in sigmoid mucosal 5-ASA concentration depending on the type of formulation, the highest concentration beingobtained with pH-dependent release formulations. Endoscopic and histological activity areinversely related to mucosal concentration of 5-ASA. Higher 5ASA dosages could be thereforejustified during active disease in order to obtain better clinical results.S1231Predictors for Failing Thiopurine Therapy in IBD Patients; Treated At AnAcademic or General District HospitalBindia Jharap, M. Seinen, Ronald K. Linskens, Jan Kees Kneppelhout, Chris J. Mulder,Nanne de Boer, Ad A. van BodegravenBackground: Several studies demonstrated that part of the IBD-patients using the immunemodulating drugs azathioprine (AZA) and 6-mercaptopurine (6-MP) fail to benefit fromthiopurines. Two 8-year interception cohorts of IBD patients with previous or present useof thiopurines from an academic and general district hospital were assessed to determinepossible predictors for failure of thiopurine therapy. Methods: The data in this retrospectivestudy are based on two 8-years hospital-based interception cohorts of previous or presentthiopurine using IBD patients, treated at an academic and general district hospital. Thiopur-ines were prescribed according to the step-up approach as recommended in current IBDguidelines (ECCO) and were supervised by one gastroenterologist per hospital. Patients weredefined as failing thiopurine therapy in case of discontinuation of AZA or 6-MP due toadverse events, refractoriness, both or non-compliance. Patients who continued thiopurinesdue to remission of IBD were defined as non-failures. Results: At the academic hospital 281/781 (36%) IBD patients were eligible for this study. Of these patients, 157 (56%) failedthiopurine therapy after a median duration of 6 months (range 0-174 months) due to adverseevents (73%), refractoriness (25%) and non-compliance (2%). At the non-academic hospital,72 out of 416 (17%) IBD patients were included. Fifty percent failed therapy after a medianduration of 1 month (range 0-64), due to adverse events (75%), refractoriness (22%) andnon-compliance (3%). No significant difference in gender, age, IBD subtype, and localizationwere found between the failure and non-failure group at both hospitals. Metabolite levelswere only available in patients treated in the academic hospital. In the failures, a significanthigher 6-MMP level of 5190 pmol/10e8RBC was found compared to 1240 pmol/10e8RBCin the non-failures. (P= 0.000) Another associated factor for failure of therapy in the describedcohorts was the 6-MMPR:6-TGN ratio. The failures had a median ratio of 34.73 comparedto 9.44 in the group that continued the use of AZA or 6-MP (P=0.000). There was nosignificant difference in 6-TGN levels between failures and non-failures. (P= 0.210) Conclu-sion: Analysis of two large 8-year interception cohorts demonstrated that more than half ofIBD patients discontinue thiopurine therapy, mostly due to the development of adverseevents. The drop-out rates were approximately the same for the academic and non-academichospital. Positive predictors for failing thiopurine therapy were 6-MMP levels and the ratiobetween 6-MMP and 6-TGN levels.S1232The TOUCH™ Program and Risk Management Plan for the Administration ofNatalizumab: Lessons and Updated Safety Results from the Use ofNatalizumab in Patients with Relapsing Multiple Sclerosis and Implicationsfor Potential Use in Crohn's DiseaseBruce E. Sands, Gordon Francis, Glyn Belcher, Mariska Kooijmans, Richard Kim, FrancesLynn, Carmen Bozic, William Maier, Jean-Frédéric ColombelPurpose: Natalizumab (TYSABRI®), the first alpha-4-integrin antagonist in late stage develop-ment for the treatment of Crohn's disease (CD) was shown in 3 randomized, double-blind,placebo-controlled clinical trials to be efficacious in the treatment of patients with moderatelyto severely active CD. Following the occurrence of 3 cases of progressivemultifocal leukoence-phalopathy (PML) in natalizumab-treated patients [2 in Multiple Sclerosis (MS) and 1 inCD] and a subsequent dosing suspension, a risk management plan has been developed tofurther assess natalizumab's safety. The risk management plan includes the TYSABRI Out-reach: Unified Commitment to Health (TOUCH™) Prescribing Program for both MS andCD; the TYSABRI Global Observation Program In Safety (TYGRIS) for MS, and the CD-Observational Study. This abstract will show the components of the TOUCH™ risk manage-ment program proposed to the FDA for the use of natalizumab in Crohn's disease, and willprovide updates on natalizumab utilization and safety data from the TOUCH™ PrescribingProgram and the TYGRIS study in patients receiving natalizumab for the treatment ofrelapsing forms of MS. Methods: The TOUCH™ Prescribing Program for CD will be anongoing, mandatory safety registry in the U.S. to ensure appropriate and informed use ofnatalizumab; determine the incidence of and risk factors for serious opportunistic infections(OIs), including PML; and monitor patients for signs and symptoms of PML. The CD-Observational Study will be a global observational study to investigate the long-term safetyof natalizumab use in CD. TYGRIS is a global observational study to investigate the long-term safety of natalizumab use in MS. Results: As of August 23, 2007, a total of 14,010patients receiving natalizumab for the treatment of relapsing forms of MS had been enrolledin TOUCH™. The most current exposure and safety data from patients receiving natalizumabworldwide will be presented. As of October 11, 2007, there have been no new reports ofconfirmed cases of PML. Conclusions: Cumulative data from TOUCH™ suggest a similarsafety profile to those seen in previous clinical studies of natalizumab. Data from TOUCH™and TYGRIS will expand our knowledge regarding the long-term safety and tolerability ofnatalizumab. Preliminary data from TOUCH™ and TYGRIS continue to support the favorablebenefit-risk profile of natalizumab for patients with relapsing forms of MS. These studiesare supported by Biogen Idec, Inc., Cambridge, MA, United States and Elan Pharmaceuticals,Inc., South San Francisco, CA, United States.

Genotype and phenotype analysis of thiopurine-methyl-transferase (TPMT) in a northern Italian population

https://iris.unito.it/bitstream/2318/69443/1/TPMT%20population.pdf

Genotype and phenotype analysis of thiopurine-methyl-transferase (TPMT) in a northern Italian population

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