Mo1191 A Pilot Study of Optimal Screening for Latent Tuberculosis in Patients With Inflammatory...
Transcript of Mo1191 A Pilot Study of Optimal Screening for Latent Tuberculosis in Patients With Inflammatory...
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Co-Administration of 5-Aminosalicylic Acid to 6-Mercaptopurine Reduces InVitro HepatoxicityMark M. Broekman, Hennie M. Roelofs, Frank Hoentjen, Wilbert H. Peters, GeertWanten, Dirk J. De Jong
Introduction: Thiopurines are widely used for the treatment of inflammatory bowel disease,but are associated with hepatotoxicity. 5-Aminosalicylic acid (5-ASA) preparations, caninfluence thiopurine metabolism by inhibiting thiopurine methyl transferase (TPMT) andsubsequently reducing the formation of 6-methylmercaptopurine (6-MMP) metabolites. Thisis of particular interest as 6-MMP metabolites are associated with the development ofhepatotoxicity, but it is unknown whether co-administration of 5-ASA with thiopurinesreduces hepatotoxicity. Our aim is to clarify whether 5-ASA co-administration has thepotential to decrease in vitro thiopurine-induced hepatotoxicity. Methods: Three humanhepatoma cell lines (Huh7, HepG2 and HepaRG) were cultured in William's E mediumcontaining 2% dimethyl sulfoxide. Azathioprine (AZA), 6-mercaptopurine (6-MP) or tiogua-nine (TG) was added in a concentration range from 3.9 to 4000 μM. In separate co-administration experiments, a fixed non toxic dose of 200 μM 5-ASA was used in combinationwith 3.9 to 4000 μM of thiopurines. Water-soluble tetrazolium salt-1 (WST-1) cytotoxicityassays were conducted after 24, 48 and 72 hours of incubation. Culture medium plusexamined drugs were refreshed every 24 hours. Cell survival curves and half maximalinhibitory concentrations (IC50 were obtained from three independent experiments con-ducted in triplicate. Results: Co-administration of 5-ASA resulted in significant changes ofthe IC50 in 7 out of 27 (26%) experiments; in 5 out of 27 (19%) a decreased and in 2 outof 27 (7%) an increased cytotoxicity was seen. In HepaRG cells incubated with 6-MP and5-ASA, the IC50 increased from 679 (95%CI 502 - 920 μM) to 5704 μM (95% CI 2174 -14962 μM) and from 412 μM (95% CI 321 - 530 μM) to 918 μM (95% CI 753 - 1118μM) compared to HepaRG cells incubated only with 6-MP for 48 and 72 hours, respectively.In HepaRG cells and HepG2 cells, IC50 was approximately 60 μM lower (more hepatotoxic)when incubated for 72 hours with the combination of AZA + 5-ASA in comparison to AZAalone. In Huh7 cells, the IC50 was 80 μM higher after 72 hours incubation with AZA + 5-ASA compared to AZA alone. Concentration based, TG was the most toxic thiopurine withan IC50 value of 18 μM after 72 hours incubation in HepaRG cells, compared to AZA (266μM) and 6-MP (412 μM). Conclusion: Addition of a fixed, non toxic dose of 5-ASA to 6-MP resulted in a decreased in vitro toxicity in hepatoma cells.
Mo1191
A Pilot Study of Optimal Screening for Latent Tuberculosis in Patients WithInflammatory Bowel DiseaseTalal Al-Taweel, Madhukar Pai, Matthew Strohl, Talat Bessissow, Alain Bitton, Ernest G.Seidman, Waqqas Afif
Introduction: Reactivation of latent tuberculosis infection (LTBI) in patients with inflamma-tory bowel disease (IBD), secondary to treatment with anti-tumour necrosis factor (TNF)-α agents, can lead to serious and life-threatening illness. No gold standard exists for thedetection of LTBI and there is conflicting evidence within the IBD literature regarding thebest screening strategy for it. The aims of our study were to assess whether the addition ofan interferon-gamma release assay (IGRA) to a tuberculin skin test (TST) would improvethe detection of LTBI, evaluate the concordance of the TST and IGRA and assess theimpact of various demographic, diagnostic and treatment factors on the each test. Methods:Consecutive IBD patients being considered for anti-TNF-α treatment underwent testing witha TST, IGRA (QuantiFERON Gold In-Tube) and chest radiography (CXR). All patientscompleted a self-administered questionnaire. The association of both tests with demographicfactors, LTBI risk factors (including CXR), Bacillus Calmette-Guérin (BCG) vaccination andimmunosuppressive therapy (steroids, thiopurines or methotrexate) were evaluated usingFisher's exact test, and agreement between TST and IGRA was evaluated using the kappastatistic. Results: Ninety-one consecutive IBD patients (73 Crohn's disease, 17 ulcerativecolitis and 1 indeterminate colitis) underwent testing with both TST and IGRA. Three patients(3.3%) had indeterminate IGRA results and were excluded from the analysis. Fourteen (17%)patients had a history of BCG vaccination. Twenty-two patients (25%) had at least one riskfactor for LTBI, including two patients (2%) with an abnormal CXR. Sixty patients (69%)were taking immunosuppressive therapy at time of inclusion. Five patients were TST positiveand 5 patients (6%) were IGRA positive. Concordance between TST and IGRA was 90.1%(but κ = 0.15), with only 1 patient being positive for both tests. If positivity by either TSTor IGRA was used to define LTBI, the prevalence was 10.2% (95% CI, 3.9-16.6%). Neithertest was affected by age, gender or BCG vaccination status. In bivariate analysis, the presenceof risk factors for LTBI was found to positively influence TST results (OR 10.6, 1.6-72.4), butnot the IGRA (OR 0.97, 0.1-6.6). IGRA was negatively influenced by any immunosuppressivetherapy (OR 0.13, 0.02-0.89), but not TST. Three of the 4 patients who were IGRA positivebut TST negative were treated or advised to begin treatment for LTBI by a respirologist.Conclusion: There is poor agreement between the TST and the IGRA test. The addition ofIGRA testing to the standard practice of TST and CXR increased the number of casespresumed to have LTBI and influences management. The IGRA was negatively associatedwith any immunosuppressive therapy. Given these findings, dual testing with TST and IGRAshould be considered in IBD patients.
Mo1192
Psoriasis Phenotype in Inflammatory Bowel Disease: A Case-ControlProspective StudyElisabetta Lolli, Rosita Saraceno, Alessandra Ventura, Giovanna Condino, Sara Onali,Patrizio Scarozza, Alessandra Capanna, Marta Ascolani, Carmelina Petruzziello, EmmaCalabrese, Sergio Chimenti, Francesco Pallone, Livia Biancone
Background. Psoriasis has been associated with Inflammatory Bowel Disease (IBD). However,whetherIBD is associated with specific phenotypes of psoriasis is unknown. Method. In acase-control prospective study, we aimed to assess psoriasis phenotype in IBD patients (pts),
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when compared with non-IBD control pts (non-IBD C). From January 2011 to November2013, dermatological assessment was performed in 251 IBD pts under follow up. Dermatolog-ical assessment was focused in detecting the presence of psoriasis (present/absent) andin defining characteristics of psoriasis (localization, phenotype) including severity (mild/moderate/severe). In order to define psoriasis phenotype, each IBD pt with psoriasis wasmatched for gender, ethnicity and age (±5 years) with one non-IBD pt with psoriasis, referringto the same University/Hospital. Data were expressed as median and range and differencesbetween groups assessed by the T test. Results. Dermatological assessment was performedin 251 IBD pts (115 F, age 46 yrs, range 16-85; IBD duration 9 yrs, range 1-46): 93 UC(42 M, age50, range 22-85; UC duration 7 yrs, range 1-41; UC extent: proctitis 33, left 13,extensive 42, ileal pouch 3, ileostomy 1, ileo-rectal anastomosis 1) and 158 CD (91 M, age43, range 16-80; CD duration 10 yrs, range 1-46; CD colitis 13, ileo-colitis 32, ileitis 51,neo-terminal ileum 56, ileostomy 2, distal ileum + jejunum 4). Non-IBD C included 62 pts(35 M, age 47, range 18-75). Among the 251 IBD pts, psoriasis was detected in 62 (25%;36 CD, 26 UC). In the IBD group, the median age and IBD duration were comparable inpts with or without psoriasis (age 50 range 23-72 vs 47 range 16-85; IBD duration 9.5 yrs,range 1-46 vs 9 yrs range 1-41; p= ns for both). Mild plaque type psoriasis was detectedin a higher proportion of IBD pts (52/62; 84%) than non-IBD C (33/62; 53%; p<0.001).Scalp psoriasis and sebopsoriasis were the more common psoriasis phenotype in IBD (21/62; 84%), followed by palmo-plantar psoriasis (9/62; 14%) and by inverse psoriasis (8/62;13%). Psoriatic arthritis was detected in 10/62 (16%) non-IBD-C and in 6/62(10%) IBD pts(p=n.s.). In 6/62 (10%) IBD pts, psoriasis developed after anti-TNFs (palmo-palmar 4,sebopsoriasis 1, inverse psoriasis 1). Conclusions. Results from a cohort of IBD pts matchedwith non-IBD control pts suggest that specific phenotypes of psoriasis may be associatedwith IBD.
Mo1193
Infliximab Is Not Increasing Colonic Cancer Risk in Experimental IBDFranco Scaldaferri, Loris Riccardo Lopetuso, Valentina Petito, Viviana Gerardi, ValerioCufino, Vincenzo Arena, Egidio Stigliano, Maria Elena Caristo, Andrea Poscia, FrancescoFranceschi, Giovanni Cammarota, Alfredo Papa, Alessandro Sgambato, Antonio Gasbarrini
BACKGROUND: IBD is a leading cause of colonic cancers in humans. Several animalmodel sustained this epidemiological finding, showing a crucial role for TNF-a and activeinflammation in cancer formation and progression. Infliximab (IFX) blocks TNF-a activityand is actively used in IBD, but few information exists on IFX effect on colonic cancer riskin these patients or animal models. AIM&METHODS: Aim of this study was to explore theeffect of IFX on cancer formation and progression in experimental IBD associated to coloniccancer. C57BL/6 mice were injected intraperitoneally with 7 mg/Kg of azoxymethane (AOM)and then exposed to 3 cycles of 2.5% Dextran Sodium Sulfate (DSS), given for 7 days intap water. IFX (5mg/Kg) was injected during the III day of each DSS cycle while controlmice received saline. Body weight, occult blood test and stool consistency were measuredtwice a week and used to calculate the Disease Activity Index (DAI); survival was expressedas %. Mice were sacrificed at week X and whole colon was analyzed macroscopically andmicroscopically for number of cancer. The expression of p53 was assessed by immune-hystochemistry. Cultures of murine colon cancer epithelial cells (CT26) were used to assesseffect of IFX on viability and proliferation of cancer cells by MTT test, utilizing the abilityof this cells to metabolize and reduce 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide salt, a yellow tetrazole. A scratch assay was evaluated to assess effect of IFX onCT26 motility. In both cases cells were treated for 24 hours in 24-wells with TNF-a (25ng/ml) or IFX (50μg/ml) alone or a combination of the two. RESULTS: IFX significantly reducedDAI in treated mice compared to controls, preserving body weight loss, reducing diseaseactivity and preserving colon length at sacrifice. Hystology showed a reduction of the numberof ulcers and their depth, as well as extent of inflammation. IFX treated mice showed alower macroscopic number of tumor lesions compared to controls (3.8 vs 4.4), and a lowermicroscopic count of tumors compared to controls (2.5 vs 3.5), with differences which werenot statistically significant. P53 expression on tumor lesion did not differ significantly betweenIFX treated mice and controls. In vitro, IFX did not influence CT26 proliferation at MTTtest neither motility at scratch assay, when used alone or in combination with TNF-α.CONCLUSION:IFX did not increase colonic cancer risk in AOM-DSS model of cancer onchronic colitis nor influence directly the proliferation of murine colon cancer epithelial cells(CT26). More data are necessary in order to establish the real effect of IFX on humancolonic lesions.
Mo1194
Anti-TNFα Therapies Are Safe During Pregnancy in Women WithInflammatory Bowel Disease: A Systematic Review and Meta-AnalysisNeeraj Narula, Raed Al-Dabbagh, Amit Dhillon, Bruce E. Sands, John K. Marshall
Background: The use of anti-TNFα agents is well described for inflammatory bowel disease(IBD), but their safety profile during pregnancy is yet to be fully elucidated. A systematicreview and meta-analysis were performed to identify studies that explored the safety of anti-TNFα therapy during pregnancy in patients with IBD. Method: A systematic literature searchwas conducted to identify studies that investigated the pregnancy outcomes among womenwith IBD on anti-TNFα therapy. The primary outcome was the overall rate of unfavourablepregnancy-related outcomes among women with IBD on anti-TNFα therapy. Secondaryoutcomes included rates of abortions (spontaneous or elective), preterm delivery, low birthweight, and congenital malformations. Odds ratios (OR) with 95% CI are reported. Studiesincluded met the following criteria: observational or treatment design; had subjects withIBD on anti-TNFα therapy for at least one trimester; and comparison with appropriatelymatched controls. Results: Overall, five studies with a total of 1216 participants were eligiblefor inclusion in the meta-analysis. There was no significant difference in the rates of totalunfavourable pregnancy outcomes between pregnant women with IBD who were on anti-TNFα therapy compared to controls not on anti-TNFα therapy (OR 1.12 (95% CI 0.79-1.59)). Similarly, there were no statistically significant differences in the rates of abortion(OR 1.48 (95% CI, 0.93-2.35)), preterm birth (OR 1.00 (CI 95%, 0.62-1.62)), low birthweight (OR 1.05 (CI 95%, 0.62-1.78)), or congenital malformation (OR 1.10 (CI 95%,