Sa1228 Genotype Analysis of Thiopurine-Methyl-Transferase (TPMT) in Brazilian Patients With Inflammatory Bowel Disease: Correlation With Availability and Toxicity

Regarding TPMT genotype, we observed TPMT polymorphisms in 37/256 patients (8 heterozygous for *2, 11 heterozygous for *3A and 18 heterozygous for *3C). No homozygotic polymorphisms were found. A positive correlation was found between the elevation of pancreatic enzymes and either TPMT*2 (CC: 21.5%; p=0.002), or TPMT*3C (CC: 17.6%; p=0.014). Conclusions: Two genetic variants of TPMT gene (*2 and *3C) are associated with azathioprine toxicity in IBD patients from a south-eastern Brazilian population. Genetic testing may help in the selection of the most appropriate medication prior to treatment initiation. Sa1229 Infliximab as Second Anti-TNF Agent in Crohn's Disease: Durability and Tolerance of Therapy Jason E. Gonzaga, Yelena Zadvornova, Daniel J. Stein, Lilani P. Perera, Amar S. Naik, Nanda Venu Background: Infliximab was the first anti-tumor necrosis factor (anti-TNF) approved for treatment of Crohn's disease. With the availability of the subcutaneous anti-TNF agents, the first choice for anti-TNF therapy often varies. Due to patient preference and ease of administration, the subcutaneous agents are often initially chosen for Crohn's disease therapy. The tolerability and clinical benefit of adalimumab (ADA) in patients with loss of response or intolerance to infliximab (IFX) is known. There is lack of data on the tolerance and clinical benefit of IFX for salvage therapy in patients with loss of response or intolerance to ADA. The purpose of this study was to investigate the durability, safety and tolerance of IFX as a second anti-TNF agent in patients with loss of response or intolerance to ADA. Methods: This was a retrospective study at a tertiary IBD referral center. We identified patients with Crohn's disease who had received either IFX after failure of ADA (IFX Salvage Group) or ADA after failure of IFX (ADA Salvage Group). A total of 66 patients were identified for the study, IFX Salvage group =22 and ADA Salvage group= 44. Outcomes measured included SIBDQ scores before switching agents, SIBDQ scores 6 months after switching agents, complication rates, and durability of the agents. Results: 22 patients received IFX as salvage agent; 44 patients received ADA as salvage agent. The two groups were similar in age, gender, ethnicity, immunomodulator use and disease duration. There were no significant differences in SIBDQ scores between the IFX Salvage vs. ADA Salvage groups before the switch (46.67 vs. 45.42 p=0.6) and in the SIBDQ scores 6 months after the switch (49.89 vs. 47.73 p=0.4). No significant difference was seen in mean duration of therapy before switching agents IFX Salvage 15.1 months vs. ADA Salvage 17.7 months (p= 0.4). No significant difference was observed in the percentage of patients that remained on therapy after 6 months of switching; IFX Salvage vs. ADA Salvage (77.3% vs. 90.9% p= 0.128). There were no statistical significant differences between the two groups in CRP/ ESR, hospitalizations, and surgeries. The mean duration of therapy after the switch in IFX Salvage group was 15.96 months vs. ADA Salvage group was 31.1 months (p=0.0006). Conclusions: Infliximab is a viable salvage anti-TNF agent. It is comparable as a second anti-TNF agent to adalimumab in the short term. However, the long-term durability of IFX salvage therapy appears to be shorter than ADA salvage therapy in our study.

Sa1227 Should Screening for Latent Tuberculosis Infection Be Repeated After Travel to Tuberculosis Endemic Areas in Patients Treated With TNF-Alpha Inhibitor Therapy? Regina Hofland, Marc Verhagen, Regina Huisman, Ailko Bossink Rationale: Treatment with prophylactic therapy in case of latent tuberculosis infection (LTBI) is necessary before TNF-alpha-inhibitor treatment. Data concerning the development of active tuberculosis infection during TNF-alpha-inhibitor treatment are rare. The aim of this study is to evaluate the safety of TNF-alpha-inhibitor treatment after screening for and treatment of LTBI. Methods: A prospective, single-center study was conducted. Adult patients with immune mediated disorders from gastro-enterology, dermatology and rheumatology outpatients department, planned for TNF-alpha-inhibitor treatment, were included from 2007 until 2011. Screening for LTBI included Tuberculin Skin Test (TST), defined positive above five millimeters skin reaction, and an Interferon Gamma Release Assay (IGRA): ELISpot. Prophylactic therapy according to the Dutch guidelines was given to BCG-vaccinated persons with positive IGRA. Non-BCG-vaccinated persons received prophylactic therapy when at least one test was positive. All patients were observed during and after TNF-alpha-inhibitor treatment for development of active tuberculosis infection. Results: A total of 195 subjects were included; 109 subjects were female. The majority (164 persons) was not BCG-vaccinated. Twenty-eight persons were born in a tuberculosis-endemic country, 77 others were at risk for LTBI, because of traveling to those countries, history of tuberculosis infection, or exposure to someone with tuberculosis. Fourteen persons, all diagnosed with LTBI, received prophylactic therapy before TNF-alpha-inhibitor treatment. During the TNF-alphainhibitor treatment, two persons developed active tuberculosis infection. To one of them, a 48-years old woman, no prophylactic therapy was prescribed, because of a negative TST and an indeterminate IGRA. Few months after TNF-alpha-inhibitor treatment, she traveled to a tuberculosis-endemic country. In the weeks after return, she developed tuberculosis meningitis and died. Second, a 41-years old male person developed active extrapulmonal tuberculosis during TNF-alpha-inhibitor treatment. Again, no prophylactic therapy was given, because of a negative TST and IGRA. He also recently traveled to a tuberculosisendemic country. A primary tuberculosis infection is likely in these two cases. Conclusion: TNF-alpha-inhibitor treatment is safe after screening for and treatment of LTBI. However, traveling to tuberculosis-endemic countries during TNF-alpha-inhibitor treatment should be strongly discouraged. We recommend screening for LTBI after travelling to tuberculosisendemic areas.

Sa1230 Frequency and Type of Side Effects of Immunomodulating Medication in the Swiss Inflammatory Bowel Disease Cohort Sébastien Godat, Nicolas Fournier, Valérie Pittet, Ekaterina Safroneeva, Darius Moradpour, Alain Schoepfer Background: Medical treatment of inflammatory bowel disease (IBD) is becoming more and more complex, as several classes of immuno-modulating drugs (IMD) are often used simultaneously. Thus, the probability of adverse effects is greatly increased. Most studies reporting on adverse effects focus on single therapy, and studies providing a global survey of side effects for multiple treatments are lacking. Aim: To assess the type and frequency of adverse events in IBD patients treated with single and multiple IMD therapy. Methods: Analysis of data from the Swiss IBD Cohort Study (SIBDCS) that collects data on a large sample of IBD patients from hospitals and private practices across Switzerland. The following IMD categories were analyzed: 5-ASA, azathioprine (Aza), 6-mercaptopurine (6-MP), methotrexate (MTX), anti-TNF (infliximab, adalimumab, certolizumab-pegol), cyclosporine, tacrolimus, and steroids. The following side effects were assessed: hepatitis, pancreatitis, leucopenia, thrombopenia, nephritis, allergic reaction, pneumonitis, infections (including tuberculosis), osteoporosis, abdominal pain/diarrhea (unrelated to IBD activity), cataract, diabetes, exanthema, hirsutism, lupus-like syndrome, myalgias, depression/psychosis, tumor development. Results: A total of 1,961 patients were analyzed (977 [50%] female, mean age 42.1 ± 14.4 years): 1,119 with Crohn's disease (CD), 800 with ulcerative colitis (UC), and 42 with indeterminate colitis (IC). Three-hundred eighteen (16.2%) patients were not treated with any of the above-mentioned medications, while 650 (33.2%), 569 (29%) and 424 (21.6%) patients had one-, two-, and three- or more- IMD therapy, respectively. Of the 1,643 patients treated with IMD, 535 (32.6%) patients reported at least one side effect. We found a significant correlation between the number of drugs used by a patient and the frequency of side effects (17.4% side effects for one drug, 29% for 2 drugs, and 60.6% for three or more drugs, p < 0.001). The frequency of side effects for the different IMD classes were as follows: 5-ASA (n = 980 treated patients) 10.8%, Aza/6-MP (n = 636) 51.9% (pancreatitis in 57 = 9%, hepatitis in 17 = 2.7% of treated patients), MTX (n = 146) 42.5% (hepatitis in 4 = 2.7% of treated patients), anti-TNF (n = 255) 23.1%, cyclosporine (n = 49) 10.2%, tacrolimus (n = 5) 20%, steroids (systemic or topical, n = 1,150) 9.6%. Conclusion: IBD treatment is associated with a significant number of side effects. A direct correlation between the number of IMD used simultaneously and the frequency of side effects was observed. The results of this study indicate that treating physicians should be vigilant for the occurrence of side effects in IBD patients under single and/or multiple drug therapy.

Sa1228 Genotype Analysis of Thiopurine-Methyl-Transferase (TPMT) in Brazilian Patients With Inflammatory Bowel Disease: Correlation With Availability and Toxicity Barbara C. Esberard, Renata S. Fróes, Davy Rapozo, Ana B. Grinman, Tatiana D. Simão, Juliana D. Santos, Luis Felipe Ribeiro-Pinto, Heitor S. Souza, Ana Teresa P. Carvalho Background and aims: Although azathioprine is commonly used for treating patients with inflammatory bowel disease (IBD), there is still concern about potential severe side effects. Determining the Thiopurine-Methyl-Transferase (TPMT) genotype is expected to identify patients' predisposition in respect of availability and toxicity prior to azathioprine administration. The prevalence of IBD is rapidly rising in Brazil, which is constituted by a heterogeneous population. We analyzed TPMT genotypes in Brazilian patients with IBD and correlated them to treatment response and drug toxicity. Patients & methods: Consecutive IBD outpatients (n= 256) were recruited (152 CD, 103 ulcerative colitis (UC), and 1 indeterminate colitis), using established diagnostic criteria. A blood sample was drawn from each patient, erythrocytes were separated and the DNA was extracted. Major TPMT genetic variants (TPMP*2, *3A, *3C) were analyzed by means of PCR techniques (specific allele PCR and RFLP PCR). Clinical data were systematically recorded and correlated with the genotype results. Detailed phenotypic information was obtained and registered in a worksheet platform to be analyzed in multivariate models adjusting for confounding factors. Results: In regard to clinical and epidemiological data of the patients, 140 were female and 116 male. Their median age was 39.8 years, and the disease onset was before 40 years-old in 60% of the patients. In CD the disease behavior was classified as nonstricturing nonpenetrating in 58 patients, penetrating in 48, and stricturing in 46. In UC, disease extent was classified as pancolitis in 46.6% of the patients. In terms of treatment, 83.7% of CD, and 45.9% of UC patients were using azathioprine. Of the patients taking azathioprine, 14 presented pancreatitis and/or elevation of pancreatic enzymes, while 6 had liver toxicity, and 2 had mielossupression/neutropenia.

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AGA Abstracts

AGA Abstracts

“safety,” “infliximab,” “adalimumab,” & “certolizumab.” Articles and abstracts published in English documenting birth outcomes after maternal drug exposure within 3 months of conception or during any trimester of pregnancy were included. Reference lists of the primary articles were hand-searched to identify additional studies. RESULTS: The initial search yielded 11,452 citations. Fifty studies met criteria for full review, including 13 case series, 36 case reports, and 2 prospective studies with control groups. The total number of patients exposed to anti-TNFs was 471 (IFX 195/ADA 259/CTZ 17). Of these, 404 exposures (85.8%) resulted in live births. Nineteen congenital abnormalities associated with live births (4.1%) were recorded (IFX 6/ADA 12/CTZ 0). No pattern of specific birth defects was identified. Seven miscarriages, 28 spontaneous abortions, and 2 stillbirths were recorded for a total of 37 (7.9%) fetal deaths. Seven (5.7%) low birth weight infants were reported. These are similar to rates in the general US population (ephtracking.cdc.gov) and in women with IBD unexposed to anti-TNFs (Dominitz J et al. AJG 2002). Thirty nine (19%) preterm or premature births were recorded. This rate is slightly higher than that of the US population but may be expected in the IBD population (Cornish et al. Gut 2007). Limitations include small samples, paucity of studies with control groups, and inability to adjust for comorbidities, concomitant medications, and disease activity. CONCLUSION: These data suggest that the rates of congenital malformations and adverse birth events are similar to those in the general population and in the pregnant IBD population. Although promising, there is insufficient evidence to prove absolute safety for use of anti-TNFs during pregnancy given the lack of controlled trials.