AG

AA

bst

ract

s

*IBD Not Otherwise SpecifiedTable 2: Odds of pancreatitis from adding a TNF-α inhibitor to other IBD therapies

*OR not calculated due to small sample size

Mo1199

Characteristics and Outcome of Psoriasiform Skin Lesions Caused by Anti-TNF Agents Used for the Treatment of Inflammatory Bowel DiseaseAkash Gadani, Lauren George, Guruprasad D. Jambaulikar, Raymond Cross, Leyla J.Ghazi

Background: Tumor Necrosis Factor (TNF) antagonists used for the treatment of Inflamma-tory Bowel Disease (IBD) have been associated with the development of de novo psoriasiformlesions. We assessed the clinical characteristics, risk factors, and outcomes of patients withanti-TNF-induced psoriasiform lesions. Methods: Patients with Crohn's disease (CD) andulcerative colitis (UC) receiving treatment with anti-TNF therapy (infliximab, adalimumab,or certolizumab pegol) at a tertiary referral center were identified using an IBD database.Charts were reviewed to include those patients with psoriasiform lesions after initiation ofanti-TNF therapy. Demographics, clinical variables, and outcome of treatment were obtainedfor each patient. We used univariate analysis to describe the study sample. Results: Fivehundred twenty-one patients with IBD undergoing treatment with anti-TNF therapy wereidentified; of these, 18 had psoriasiform lesions (16 CD and 2 UC). Ten patients werereceiving treatment with infliximab, 5 with adalimumab, and 3 with certolizumab pegol.Lesions developed a mean of 58 weeks (range 4-240 weeks) after starting anti-TNF therapy.The majority of patients were female and Caucasian (78 and 61%, respectively). Two patientshad history of atopy and none had prior diagnosis of psoriasis. Fourteen patients (78%)were current or former smokers. Eight patients were receiving concomitant immunosuppres-sants and 2 patients were receiving steroids. Location of psoriasiform lesions were palmo-plantar (53%), trunk (47%), and scalp (53%), with 88% reporting involvement of ≥ 2locations. Ninety-three percent (13/14) of patients with validated disease scores had mildto quiescent disease. Treatment of psoriasiform lesions was instituted with topical therapyin 8 patients and systemic therapy (plus or minus phototherapy) in 5 patients. Nine patients

S-584AGA Abstracts

(50%) discontinued anti-TNF therapy secondary to the skin lesions; of those, 3 were re-treated with another anti-TNF agent and all had recurrence of psoriasiform lesions. Conclu-sions: Anti-TNF-induced psoriasiform lesions developed in 3.5% of our IBD population ata tertiary referral center. Similar to prior published studies, most patients were female, hadinvolvement of the palmo-plantar and scalp regions, and did not have severe IBD activity.Skin lesions led to discontinuation of anti-TNF therapy in 50% of patients; recurrent lesionsdeveloped in the small group re-treated with another anti-TNF agent, suggesting a classeffect. Providers caring for IBD should advise patients of the potential for anti-TNF-inducedpsoriasiform lesions, promptly refer to dermatology when the lesions occur, and institute achange to an alternative agent if conventional methods fail to control the lesions. Furtherresearch is needed to determine which patients are at greatest risk to develop psoriasi-form lesions.

Mo1200

Effect of Pegylated Murinized Rabbit Anti-Mouse TNF on Incisional Muscleand Skin After Laparotomy in Experimental Crohn's DiseaseLaura J. Reingold, Laure Rittie, Joshua N. Hurlburt, Phyllissa Schmiedlin-Ren, Paul M.Prax, Scott R. Owens, Ellen Zimmermann

Perioperative anti-TNF may affect wound healing and infection rates in patients with Crohn'sdisease (CD). We have previously shown that anti-TNF affects collagen and key cytokinesin wound and gut. Our aim was to determine the timing of anti-TNF effects on woundhealing and tissue factors. Methods: Peptidoglycan-polysaccharide (PGPS) or human serumalbumin (HSA, control) was injected into the bowel wall of Lewis rats at laparotomy. PGPSand HSA-injected rats were given pegylated murinized rabbit anti-mouse TNF or vehicle sq3 times a week beginning d1 post-op. Animals were sacrificed on d7, d14 and d21 (n=12each time point). Gut and incisions were collected and analyzed. Results: In cecal tissue,procollagen I & III mRNAs, profibrotic factors IGF-I and TGFβ mRNAs, and proinflammatorycytokines TNFα, IL-1β, IL-6 mRNAs were increased in PGPS/veh compared to HSA/veh asearly as d7. Interestingly, collagen increased during the 21 day course whereas the highestlevels of TNFα, IL-1β and IL-6 were seen at d7. Treatment with anti-TNF decreased thecollagen mRNAs most significantly at d21 (collagen I 9.6±0.2 vs. 2.3±1.3, p=0.003; collagenIII 7.9±1.2 vs. 2.4±0.7, p=0.009). IGF-I and TGFβ1 mRNAs were decreased in PGPS/aTNFgroup as early as d7; these factors were also decreased in HSA/aTNF group compared toHSA/veh. Gut TNFα and IL-1β were decreased at d7 in PGPS/aTNF vs. PGPS/veh; mRNAswere unchanged in the HSA groups. Incisional muscle and skin were separately analyzedat d7 and d21. Laparotomy resulted in a 6-10 fold increase in incisional muscle collagenmRNAs at d7; there was no difference between PGPS vs. HSA groups at d7. HSA/veh hadhigher muscle collagen III than HSA/aTNF (21.2±1.6 vs. 11.6±1.7, p=0.02). Muscle collagenmRNA was increased in the PGPS/veh rats at d21 with a trend toward normalization in thePGPS/aTNF group. Incisional levels of PDGF-A and VEGF mRNAs were decreased at d7 inPGPS and HSA groups. Skin VEGF and bFGF mRNAs were decreased in the PGPS/aTNFgroup vs. PGPS/veh (p<0.01 for both). There was a trend toward increased histologicinflammatory score in the PGPS group with normalization with aTNF treatment that didnot reach significance. Second Harmonic Generation imaging demonstrated reduced maturecollagen content in skin scars of PGPS/aTNF vs. PGPS/veh animals at d21. Conclusion: Asin patients with CD, there were early changes in gut mRNAs for proinflammatory andprofibrotic factors with peak changes in inflammatory factors early in the course and fibrosisfactors late in the course of experimental CD. Incisions were associated with changes inskin and muscle mRNAs and were similar in all groups. Anti-TNF treatment changedexpression of skin collagen and key factors in both CD and control groups. Changes in keygrowth factor expression could affect wound healing and wound integrity in patients with CD.

Mo1201

Colon Cancer in IBD Patients Treated or Untreated With Anti-TNFs: ARetrospetive Matched-Pair Study in a 13 Years Follow UpMarta Ascolani, Giovanna Condino, Carmelina Petruzziello, Sara Onali, Elisabetta Lolli,Alessandra Ruffa, Emma Calabrese, Francesco Pallone, Livia Biancone

BACKGROUND AND AIM: Blocking TNFalpha showed efficacy in colitis-associated coloncancer in murine models. Chronic inflammation in Inflammatory Bowel Disease (IBD) colitishas been associated with colon cancer. In a monocentric retrospective matched-pair studyin a cohort of IBD patients (pts) in follow up, we compared the frequency of colon cancerin pts treated or untreated with anti-TNFs. The role played by clinical characteristics of IBD indetermining the frequency of colon cancer was also evaluated. MATERIAL AND METHODS:Clinical records of all IBD pts in follow up from 2000 to 2013 developing cancer of thelower GI tract (IBD-K)(small intestine, appendix, colon or anal canal) were reviewed. EachIBD-K pt was retrospectively matched with 2 IBD pts with no cancer (IBD-C), for IBD type(MDC/RCU), gender, age(±5yrs). Anti-TNFs (Infliximab or Adalimumab≥1 dose) and IMM(≥6mos) use was reported. Statistical analysis: data expressed as median (range); Student'sT test, Chi squared test. RESULTS: During the study period, 2387 IBD pts were in followup: 384(16%) received anti-TNFs. From 2000 to 2013, 15 IBD pts (9CD,6UC) developedcancer of the lower GI tract (0.62%), including 12 colon cancers (6UC,6CD),1 ileal adenocar-cinoma (1CD),1 carcinoid of the appendix (1CD),1 anal canal squamous carcinoma(1CD).Among the 15 IBD-K (7M), median age at diagnosis of cancer was 51(28-73) yrs, IBDduration 19yrs (1-47). CD involved the ileum (I) in 4 pts, colon (C) in 2 pts and ileum-colon (IC) in 3 pts; UC was distal in 3, left in 1 and total in 2 pts. Among the 15 IBD-Kpts, 3 (20%) received anti-TNFs and/or IMM (all 3 both). These 3 pts developed cancer (2colon,1 carcinoid): 2CD (2F,age 40 and 54yrs, CD duration 28 and 26 yrs; fistulizing I-C)and 1 UC (1F, age30, duration 19yrs; pancolitis). Among the 384/2387 (16%) IBD ptstreated with anti-TNFs, colon cancer developed in 3 (0.78%) (IMM in 3).Among the 2003/2387 pts never treated with anti- TNFs during the follow-up, 12 (0.6%) developed cancerof the lower GI tract, 10 (0.5%) colon cancer (p=ns vs pts treated with anti-TNFs). IBD-Cincluded 30 pts (18CD,12UC;14 M/16 F, age 54,range 37-75; CD of the I(n=13), C(n=2),I-C(n=3); UC distal (n=11),left-sided (n=1), total (n=0). Anti-TNFs were used by a comparablenumber of IBD patients developing or not cancer (IBD-C n= 6/30; 20% vs IBD-K n=3/15;20%). In IBD-C, IMM use was reported in 10 (33%) (combined with anti-TNFs in 2;6.7%).

CONCLUSIONS : In a retrospective matched-pair study, a comparable low frequency ofcolon cancer was observed in IBD patients treated or untreated with anti-TNFs.

Mo1202

Characterization of Anti-Tumor Necrosis Factor Agent-Induced Lupus inPatients With Inflammatory Bowel DiseaseTravis B. Murdoch, Laura Stinton, Remo Panaccione, Gilaad Kaplan, Subrata Ghosh, CarlA. Anderson, Bertus Eksteen

Background: The advent of biologic agents that bind to tumor necrosis factor (TNF) hasrevolutionized therapy of inflammatory bowel disease (IBD). However, these agents carry aunique set of adverse effects, including development of a lupus-like syndrome termed anti-TNF induced lupus (ATIL). This adverse effect often leads to cessation of the anti-TNFagent. The clinical manifestations and criteria for ATIL are incompletely defined in patientswith IBD. We explored aspects of ATIL in a series of IBD patients. Methods: Patients fromthe University of Calgary IBD clinic in whom ATIL was diagnosed by the treating physicianwere included (N=10). Ethics approval was obtained from the Conjoint Health ResearchEthics Board at the University of Calgary. Charts were reviewed for pertinent clinical data.Blood was drawn and sent for serology including anti-nuclear antibody (ANA) and extractablenuclear antigens (ENA), by the Mitogen Advanced Diagnostics Laboratory (mitogen.ca,Calgary, AB). DNA was sent to the Sanger Institute (Cambridge, UK) for whole-exomesequencing (analysis pending). Results: The cohort consisted of largely females (8/10) withCrohn's disease (CD) (7/10). In CD patients, disease location was mainly ileocolonic (6/7),while all UC patients had left-sided disease (3/3). Median age at diagnosis was 39 (range19-62). Seven patients developed ATIL on infliximab, and 3 on adalibumab. Reportedmanifestations included rash (70%), and arthritis (50%) or arthralgias (40%). Antinuclearantibody (ANA) was positive in 9 patients. The most common pattern was speckled (7/9)and homogenous (5/9), with a median titer of 1:320. No patients were ENA positive. Allpatients had thiopurine exposure, and 50% had a previous adverse reaction to thiopurines(2 hepatotoxicity, 2 leukopenia, and 1 pancreatitis). Of patients who developed ATIL onadalibumab, 2/3 had a history of infusion reaction to infliximab. Six patients who developedATIL on infliximab subsequently received adalibumab, 3/6 developing recurrent ATIL symp-toms. Conclusions: In the present study we sought to characterize ATIL in a series of IBDpatients. There was a predominance of ileocolonic CD patients treated with infliximab; thismay purely reflect historical predominance of infliximab use. However, a putative mechanismof ATIL is via anti-cellular immunity against cells expressing membrane-bound anti-TNF,and it is possible that the chimeric infliximab induces more avid epitope spreading, andthus predisposes to ATIL. There was a high prevalence of previous adverse reaction tothiopurines, suggesting a possible association with development of ATIL. Introduction ofanother anti-TNF agent was possible in some without recurrent ATIL. Understanding charac-teristics of ATIL may help in early recognition and development of predictive markers ofthis important adverse effect.

Mo1203

Clinical Risk Factors for Complications After Laparoscopic Ileal-Pouch-AnalAnastomosis in Patients With Ulcerative ColitisRaquel González, Lisandro Pereyra, Mariana Omodeo, Estanislao J. Gómez, Guillermo N.Panigadi, José M. Mella, Carolina Fischer, Beatriz Vizcaíno, Adrián R. Hadad, MaximilianoBun, Alejandro Canelas, Nicolas A. Rotholtz, Daniel G. Cimmino, Silvia C. Pedreira, LuisA. Boerr

Introduction: Although most patients with ulcerative colitis (UC) are managed successfullywith medical therapy, there are a number of patients who require a surgical treatment. Therestorative proctocolectomy is the procedure of choice. In the last years the laparoscopicapproach has gain more popularity but there are few studies that examined clinical riskfactors for laparoscopic postoperative complications. Aim: To determine the prevalence andclinical risk factors for complications after laparoscopic ileal-pouch-anal anastomosis (LAP-IPAA) among patients with UC. Materials and methods: A retrospective analysis was doneusing a prospective data base. Sixty patients with UC who underwent LAP-IPAA from January2003 to June 2013 were included. Demographic, clinical and surgical characteristics datawere collected from medical records (age at diagnosis and at surgery, gender, body massindex [BMI], smoking status, extent and activity of disease, preoperative treatment, durationof disease prior to surgery, extraintestinal manifestations, indication for surgery, elective oremergent surgery, number of steps of procedure). Univariate analysis was performed toassess risk factors for postoperative complications using Fisher's Test. Risk was measuredin odds ratio (OR) and its corresponding confidence intervals 95% (CI). A p value ≤ 0.05was considered statistically significant. Results: Twenty nine patients (48%) had less thanfive years since diagnosis. The average age was 35 (16-73) years, 62% were men and 79%had BMI ≤ 25. Most patients had pancolitis (60%) and 46 (77%) had moderate or severeactivity disease. Fifteen patients (25%) had extraintestinal manifestations. Indication forsurgery was: no response to medical therapy in 77% (steroid dependent in 35% and steroidrefractory in 65%), colorectal cancer/dysplasia in 20% and refractory colonic stricture in3%. Prior to surgery, 27% received intravenous steroids, 32% oral steroids, 8% thiopurines,7% cyclosporine and 2% biologic therapy. Most of the procedures were elective (70%) andperformed in two steps (53%). The prevalence of postoperative complications was 41/60(68%) and 5 of these (12%) required reintervention (4/5 anastomosis site dehiscence and1/5 pouch fistula). BMI ≤ 25 was associated with postoperative complications within thefirst month after surgery (OR 4.08, CI 0.57-15.35, p 0.02). The use of thiopurines andcyclosporine prior to surgery was associated with fewer postoperative complications: OR0.082 (CI 0.03-0.83, p 0.016) and OR 0.109 (CI 0.00-1.18, p 0.004), respectively. Conclu-sion: The use of thiopurines and cyclosporine are associated with fewer complications afterLAP-IPAA. Patients with BMI ≤ 25 have increased risk for postoperative complications. Themajority of these are minor and occured in the early outcome.

S-585 AGA Abstracts

Mo1204

Screening for Latent Tuberculosis Is Effective but Does Not Fully ProtectAgainst Tuberculosis Reactivation During antiTNF Treatment in Areas WithHigh Background Incidence of TuberculosisZuzana Zelinkova, Maria Zakuciova, Laura Gombosova, Eduard Veseliny, Marta Horakova,Peter Lietava, Katarina Palencikova, Barbora Kadleckova, Milos Gregus, KatarinaGregusova, Igor Pav, Tibor Hlavaty, Tomas Koller, Jozef Toth, Milan Hlista, Ivan -.Bunganic, Jozef Zan, Martin Huorka

INTRODUCTION: Screening for latent tuberculosis (LTB) prior anti-tumor necrosis factor(antiTNF) treatment is recommended but its true effectiveness in prevention of TB reactivationis unknown. AIMS&METHODS: The aim of this study was to assess the results and effective-ness of screening for LTB prior antiTNF therapy. We performed a retrospective survey ofresults of screening for LTB in all IBD patients referred for antiTNF therapy to 9 out of 12referral centres for biological therapy in Slovakia since 2003. Medical records of all patientswere reviewed and results of respective LTB screening procedures, i.e. X-ray, tuberculineskin test (TST) and interferon gamma releasing assay (IGRA), were noted. RESULTS: Intotal 945 patients were screened prior antiTNF therapy (54% males; Crohns disease/ulcerativecolitis/unclassified 601/342/2, 63.6%/36.2%/0.2%). In the screening procedure, X-ray wasperformed in 98% of patients, TST in 82% and an IGRA test in 95%. Based on the screening,LTB was found in 53 (5.6%) patients. LTB diagnosis was based on a positive IGRA testalone in 35 pts (66%), in 9 pts (17%) on a positive TST, 2 pts (4%) had findings on X-raywithout positivity of other tests. Positive findings at more than one of screenings procedurewere present only in 7 pts (13%; 3 pts positive X-ray and TST or IGRA; 4 pts with positiveTST and an IGRA). All patients with positive screening for LTB received prophylactictreatment, initiated the treatment with antiTNF after 2 to 6 months of prophylactic treatmentand had no TB reactivation during antiTNF treatment. In total, 8 (0.8%) cases of TB werediagnosed after initiation of antiTNF therapy; 5 cases within the first year of treatment (twoafter 3 months, one after 5 months and two after 9 months of antiTNF treatment), the otherthree after 3, 3 and 4 years of treatment, respectively. All but one patient were screenedfor LTB prior therapy and tested negative in the screenings procedure. All patients consideredto have TB reactivation rather than de novo infection (i.e. TB complicating antiTNF treatmentduring the first year of the treatment after testing negative in the screening) were fromregions with high background incidence of TB. CONCLUSION: Screening for latent tubercu-losis based on a combination of chest X-ray, Mantoux and an IGRA test with subsequentprophylactic treatment in patients tested positive seems to be effective in preventing TBreactivation during antiTNF treatment. This, however, does not apply for regions with highbackground incidence of tuberculosis.

Mo1205

Evaluation of Site Versus Central Assessment of Endoscopies in Crohn'sDisease: Comparison Using Data From EXTENDPaul J. Rutgeerts, Walter Reinisch, William Sandborn, Geert R. D'Haens, Jean-FredericColombel, Joel Petersson, Qian Zhou, Roopal Thakkar

Background: Interobserver variation in the endoscopic assessment of disease activity hasbeen reported for ulcerative colitis clinical trials1. We performed a post hoc analysis tocompare the agreement between site and central readings of endoscopies from the adalimu-mab Crohn's disease clinical trial EXTEND2. Methods: All randomized patients (pts) fromEXTEND who had endoscopies reviewed by one central reviewer and by site reviewers wereincluded in this analysis. Endoscopies were performed at baseline (BL), week (wk) 12, and52 and scored using SES-CD at all 19 sites and CDEIS at six sites. Agreement between siteand central reading was determined by calculating the kappa (κ) coefficient for categoricalvariables and the Pearson (r) coefficient for continuous variables. Results: Of the 129randomized pts in EXTEND, 52 pts at BL, 49 at wk 12, and 34 at wk 52 had CDEIS scoredendoscopies by both the one central reviewer and the site reviewer, whereas 129, 122, and84 pts, respectively, had SES-CD scored endoscopies by both reviewers. A high degree ofagreement on total CDEIS score or total SES-CD score occurred between central and sitereviewers at all three time points (Table). Site and central readers showed good to very goodagreement (κ [or r]=0.6-1.0) in scoring CDEIS deep ulceration and surface involved by thedisease at all three time points and in all segments, except right colon, where fair to moderateagreement was observed regardless of time point (κ [or r]=0.4-0.6). The weakest agreementbetween site and central reading was observed at BL for CDEIS ulcerated surface score andSES-CD large ulceration score compared to the agreement at wks 12 and 52 (CDEIS ulceratedsurface r=0.67, 0.88, 0.89 at BL, wk 12, wk 52; SES-CD large ulceration κ =0.04, 0.53,0.42 at BL, wk 12, wk 52, respectively). A high degree of correlation was observed betweencentral and site reading in the assessment of change in total CDEIS or SES-CD score fromBL at wks 12 and 52, with stronger agreement for reductions at wk 52. Conclusion: Overall,very good agreement between site and central reading of endoscopies occurred in EXTEND,with the weakest agreement at study BL. References: 1. Feagan, B et al. 2013. Gastroenterol.145:149-57. 2. Rutgeerts, P, et al. 2012. Gastroenterol. 142:1102-11.Correlation between site and central assessment on total CDEIS or SES-CD score at each visit

AG

AA

bst

ract

s