The role of recombinant erythropoietin in the management of patients with inflammatory bowel disease (IBD)

small bowel disease, the mean affected length was 21.3 _+17.1 cm bctore surgery and 25.6 _+19.5 cm on the resectmn specimen (ns). The estimated change in small bowel aflected length was + 4.3 cms (95% C.I.: -1.9cm-+ 10 5cm). Two patients had the same length presurgery' as the)' had resected at surgery', 4 had less resected at surgery and 8 had more resected at surgery dran estimated prior to surgeD'. Among the 6 patients having colonic involvement 2 patients had the same number of aftected segments pre-surgery as they had resected at surgery, 2 had less resected segments and 2 had more resected segments Among the 10 patients who had no abscess/llstula preoperatively, 2 had an abscess/fistula at surgery. Among the 5 patients who had an abscess/fistula before surgeD', 1 had no abscess/fistula at surgeD'. Conclusion : In this series, preoperative infliximab does not appear to be associated with clinical benefit in patients operated on for CD

T1391

Steroids Versus lnfliximab: Efficacy and Swiftness of Induction to Remission Mark R. Fleisher, Steven D. Rnbin, Andrew E. Levine, Alexander W. R. Bums Purpose: The treatment algorithm for IBD is quickly evolving. Clinicians have long realized the dauntingly deleterious side effects of steroids. However, this class of drugs is held in high esteem secondary to the seemingly unsurpassed swiftness of action in those patients with active IBD. The advent of usage of inflLximah leads to many questions. One is to compare onset and profundity of efl~.cacyto steroids. Methods: In our practices, 120 Cmhn's disease patients were treated and monitored Patients were categorized as follows: those who had never received steroids previously (STEROID NAIVE) and those who had received steroids in the past (STEROID VETERANS). Despite mesalamine and antibiotic therapy, these patients had recalcitrant moderate disease activity. GROUP 1 received prednisone: 40 mg PO qD for 4 weeks and tapered 5 mg every two weeks. GROUP 2 received infliximab: 5 mg/kg at 0/2/6 weeks and q8 weeks thereafter. Their progress was monitored over a two year period. Results: The tbllowing results (clinical responders) were noted at week 7: a)GROUP1 prednisone: 95% steroid naive, 55% steroid veterans b)GROUP2 infliximab: 80% steroid naive, 65% steroid veterans Able to maintain clinical response at week 52: a)GROUP1 prednisone: t5% steroid naive, 5% steroid veterans b)GROUP2 infliximab: 75% steroid naive, 55% steroid veterans Able to maintain clinical response by week 104: a)GROUP1 prednisone: 10% steroid naive, 0% steroid veterans b)GROUP2 inflLximab:70% steroid naive, 45% steroid veterans Conclusion: Our findings support earlier and continuaI application of infliximab in patients with active Cmhn's disease. Large, muhieenter trois are needed to compare steroid and biologic therapy It may be possible to save steroids as a final salvage-type therapy and not as an initial intervention.

T1389 Safety and Efficacy of 6-Thioguanine (6-TG) in Patients with Ulcerative and Indeterminate Colitis Intolerant or Resistant to Azathioprine and/or 6Mercaptopurine (Aza/6-MP) Alexander Teml, Marielnise Harrer, bfatthias Schwab, Clemens Dejaco, Martina Mand, Harald Vogelsang, Walter Reinisch 6-TG has been introduced for treatment of patients with Crohn's disease intolerant or resistant to Aza/6-MP. We conducted an open-label, prospective stud)* for 26 weeks to investigate the satety and efficacy of 6-TG in patients with ulcerative colitis (UC) and indeterminate colitis (IC). 14 patients with UC and 6 patients with IC were included. 8/20 (40%) were intokrant, and 12~0 (60%) resistant to Aza/6-MP. 12/20 (60%) patients had active disease and 8/20 (40%) inactive steroid-dependent dksease at inclusion. Acute flare was treated with steroids at 1 mg/kg followed by a weekly tapering. 6-TG was started in a daily dose of 20 mg and after week 2 elevated to 40 rag. (1) Clinical remission was defined as colitis actMty index (CAI) < 4 and complete steroid withdrawal at week 14 maintained until week 26, (2) partial response as CAI -< 6 withont an increase of -> 2 compared to baseline and a steroid tapering of at least 50% at week 14, and (3) all other patients as nonresponders Adverse events (AE) and significant laboratory changes were recorded. 18/20 (90%) patients completed the study, 2/20 (10%) had to be withdrawn due to AE (headache, thrombocy~openia). Clinical rermssion was achieved in 6,'20 (30%), partial response in 6/ 20 (30%) and 6/20 (30%) were classified as non-respouders. Median CAI decreased fl'om study initiation (6, interquartile range 1QR 5 to 9) to week 14 (median change -3, IQR -7 to 0; p
T1392 An Open Label Comparison of Asacol and Colazal in a Selected Group of Patients with Ulcerative Colitis Devang G. Patel, Kiron M, Das Background: Colazal (Balsalazide) is the most recent oral 5-ASA medication for ulcerative colitis (UC) where the 5-ASA moiety is coupled by an aso-bond with 4-aminonbensoylbeta-alanine. Similar to Sulfasalazine, Balsa]azide is acted upon by colonic bacteria, liberating the free 5-ASA in the colon. Colazal was given without aW other change of medications to patients who either could not tolerate Asacol due to side effects or had a sub-optimal therapeutic response to AsacoL Methods: Between April 2001 to September 2002, 28 patients with symptomatic UC were changed from Asacol (2.4-4.8g/day) to Colazal (4,5-6.75g/day, equivalent to 16-2.4g/day of active 5-ASA). Of the 28 patients, 18 had disease limited to the left colon, the other I0 had pancolitis. Four of the 28 patients were changed due to side effects from Asaco|. The remaining 24 patients were changed to Colazal due to persistence of symptoms despite Asacol therapy. The primary endpoint used was decrease in number of bowel movements of >50% from baseline (on Asacol). When available, endoscopic changes were also studied. Results: Of the 28 patients, 16 had a greater than 50% decrease in the number of bowel movements per day, within four weeks of beginning Colazal (57%). The four patients who could not tolerate Asacol (due to headache, nanaea/vomiting 6~ bloating), were able to tolerate Colaza|, Of the 28 patients who were changed to Colaza], eight patients had a repeat colonoscopy (median time to colonoscopy of 6.5 months). Two of the eight (25%) patients had normal endoscopic findings on colonoscopy. The other six (75%) had essentially no change in the endoscopic severity compared to previous endoscopy Four of those six, however, did have s3~ptomatic improvement, as stated above. Conclusion: About half of the patients who were changed from Asacol to Colazal at a comparable 5-ASA dosage showed significant symptomatic improvemem, with a quarter showing endoscopic improvement. Four patients who had side effects with Asacol tolerated Colaza[ well. Cohzal appears to be an ef|ective alternative oral 5-ASAmedication in patients who are unresponsive or cannot tolerate Asacol due to side effects. The efficacy was particularly seen in patients with left-sided colitis, and the beneficial effect may be related to higher deliver), of 5-ASA to the left colon from Colazal. A double-blinded study to compare the two products is needed

T1390

"Retrospective Review of the Role of Intravenous Iron Replacement Therapy in Treatment of Anemia in Patients with Inflammatory Bowel Disease" Barbara Rosado, Vandana Nehra, William Sandbom Anamm often complicates inflammatory, bowel disease (IBD). Aim: To evaluate the tolerability and benefit of intravenous iron dextran supplementation m a referral center cohort of IBD patients presenting with severe, refractory' iron deficiency anemia. A secondary aim was to detemame if the use of 1BD- related immunnsuppressor therapy protects against adverse reactiorts trom iron therapy. Methods: A retrospective chart review stud), of 52 consecutive IBD patients with severe anemia (Hb< = 10.5 g/dl) Who were ueated with intravenous iron dextran at the Mayu Cltmc, Rochester MN from January l, 1996 to December 3I, 2001 was conducted. 38 IBD patients (73% with Crohn's and 23% with CUC) patients were included in the study.14 patients were excluded due to anemia from other causes (8), red blood cell transthsions within 4 weeks of iron infusion (3), tbUow up hemoglobin level not available after iron infusion (3) A mean dose of 916 mg (range 25rag- 4000mg) of iron daxtran was administered over 4-5 hours preceded by a test dose of 25 rag. Treatment response to inuavenous iron dextran was defined as complete if Hb increased more than 2 g/dl; partial if Hb increased ] g/dl or failure to response if no increase or drop in the Hb was observed at 4 8, 12 weeks after infusion treatment. Results: Twenty-five of 29 patients (83%) responded to iron dextran therapy within 12 weeks of therapy- 15 of those 29 (39%) had a complete response with an increase in the hemoglobin concentration of morn than 2gra/dl.'['he mean difference ot Hb concentration before and after iron dextran intusion was 17 at 4 weeks, 2.3 at 8 weeks, and 2.6 at 12 weeks. Ttm administration of iron dextran was discominued prior to completion in W38 patients (24%) due to severe infusion reaction. ]he pre-treatment use of immunosuppressor therapy for IBD was riot associated with a lower mcideme of adverse reactions. (P = 0,452). Conclusions: Most patients with severe, refractor 3, iron deficiency IBD- associated anemia respond to intravenous iron therapy. However, its use was associated with a relatively high incidence of adverse reactions to the infusion therapy. ]'he use of immunosuppressor therapy for the treatment of IBD patients does not appear to protect against adverse reactions from iron dextran therapy-. This stud)' suggests that intravenous iron therapy is eftective but iron tbrmulations with a safer profile shoukt be identified fbr the treatment of IBD- related anemia.

AGA Abstracts

TI393

The Role of Recombinant Erythropoietin in the Management of Patients with Inflammatory Bowel Disease (IBD) George Kokozidis, Panagiotis Xiarchos, Kalliopi Kinigopoulou, O, Chatzizisi, Theofams Marls, John Georgoulis, George g~riazis, George Kitis Background. Some patients with IBD have anemia of chronic disease, which affects quality of life. It was suggested that it is related to the increased levels of promflammatorycytokines (IL-6, IL-8,IL-Ib,TNF-a and TGF-B) and the decreased levels of anti-inflammatory cytokines (IL-IO) . Recombinant human erythropoietin in combination with iron has sho,sm to be effective in the anemia of IBD. Objectives. 1.To evaluate the efficacy of recombinant human erythropoietm (r-HuEPO) in combination wath oral iron in patients with IBD and anemia of chronic disease. 2.T0 investigate the relationship between anemia and IL-6, IL-8, IL-10 and TNF-a. 3.To assess the changes in the quality of life of these patients before and after treatment. Patients and methods. Eighteen patients with 1BD (14 with Cmhn's disease and 4 with ulcerative colitis) and chronic anemia (Hb<- 10g/dl) were treated with subcutaneous r-HuEPO (IO.O00IU three times pet" week) and oral iron 100rag per day tor four weeks Response was defined as an increase in hemoglobin levels >-12g/dl. Pretreatment and post treatment determinations of 1L-6, II_-8, IL-10, TNF-a were performed with Quantitive Sandwich Enzymedmmunoassay Technic and of the R&D Systems, Mmeapohs, USA (Qnantikine). Erythropoietm was measured before and after treatment with EL1SAmethod. The quality of life was evaluated with the FACT-An scale. The statistical analysis was performed with Linear Regression Analysis, Student's t, and Mann Whitney methods. Results. The mean serum tmmoglobin concentration increased from 9,4 _+0,8 to 12,2 + 1,5g/ dl, (p
A-524

2 7 -+ 2,7g/dl) There" was a positive correlation between s#rum hemoglobin and erythropoietin before treatment (r=0,720p<0,O01) and alier treatment (r=O,314,p=O,015) Mean e~/lhmpoietin concentration showed mild decrease (NS), The mean levels of proinflammatory cytokines 1I_-6, IL-8 and "INFa were slightly decreased post treatment (NS) The post treatment mean levels of IL-10 increased from 22,14 + 45,9 to 30,2 +_71,9 pg/ml (p<0,O01) The quality of life s
intravenous inflaston. Current doses of mesalamine (0 75g, rectally), sulhsalazine (lg t.id) and'or mesalamine (0.Sg t.id) were maintained, and prednisohme was tapered and stopped. Patients were assessed by tire Di~ase Activity Index, colonoscopically and histologically before and after tfiis therapy Results: Nine of the 11 patients responded to the therapy and achieved clinical and endoscopical remissions after an aw.rage of 6 weeks Two patients ,,;'ere withdrawn because of the worsening conditions and required colectomy Nine patients who completed the trial showed a significant change m the median Disease Activity index score fi'om 8 (range; 4-9) to 1 (range; 0-3) (p< 0 0 1 ) in the median colonoseopic score from 3 (range; 2-4) to 1 (range; 0-4) (p< 0.05), and in the median histological score fiom 2 (range; 1-3) to i (range; 1-2) (p< 0 0 5 ) There was no significant change in a partial thromboplastin time of these palients during this trial No serious complications were associated with this use of heparin Seven ot the nine patmnts are still in clinical remission after a median follow-up period of 4 months Conclusions: Low-dose heparin combined with 5-aminosaficylic acids proved to be a safe and usetul adjuvant therapy tbr treating patients "~vith active ulcerative cnfitis retkactory to steroid therapy A controlled study is necessary to confirm our results

T1394 Thalidomide Therapy for Pediatric Patients with Refractory Crohn's Disease Not Responding to Infliximab i%neet Gnpta, Haikaeli Andrew Barbara S Knsehner Background: Ihalidomide, a drag ruth anti-tumor necrosis tactm~alpha activity has been successfully used to treat patients with refractory Crohn's Disease (CD) including those initially responding to inlhximab Aim: To evaluate effectiveness of thalidomide as rescue therapy tor children with refi'actm'y CD who failed to respond to infliximab Methods: A computerized database at University of Chicago Children's Hospital was used to ldentit}~ children with CD who tailed infl/ximab treatment and subsequently received thalidomide rescue therapy. Six patients (4 males, mean age 16 }*ears, range 9-19 years) were given daily dose of thalidomide in an own-labeled method All had evidence of ileocofitis. Three patients also had tlstulizing Cf) (1 fleocolonie, 1 colocutaneous, and 1 rectovaginal) One patient lu~d severe gm,s~h failtu~, and one had chronic mufiifocal osteranyelitis and anemia These patients had previously tailed immunosnppressant therapy (6MP, methotrexate or tacroliruns) Pediatric Crohn's Disease Activity Index (PCDAi) and steroid dose were calculated /mfhre and afler 2 months of thalidomide treatment Resuhs were: compared using paired Student's t- test Resahs: The palients lvceived a mean of 2 3 infliximab intusions (range 14) without irnpmvement in their symptoms. They were subsequently treated wTth thalidomide (mean dose 50 rag, range 25q00 rag) for an average duration of 14 months (range 1-24 nmnths) During treatment with thalidomide, PCDAI score improved significantly (P<0 01; "Fable) Average dose of prednisone decreased fror~ 15.5 to 8 5 mg (P<0.05; Table) Of the three patients with fistulae, 2 had complete fistula closure on thalidomide and one patient had ileocecal resection betore starting thalidomide. No side etfecta usually associated ,with thalidomide (like dm*`vsiness rash or peripheral neuropathy) w'ere reported Conclusions: Pha/idomide is a safe arid effective rescue therapy for rehactory CD in children railing inflixia~ab

T1397 Parenteral Methotrexate Is Not Effective Treatment for Refractory Ulcerative Colitis Gerald M. Fraser, Ofer Ben-Bassat, Negba Segal, Michal Fishmau-Mor, Yaron Niv Background: Few treatment options other than surgeD" am available to patients with chronically active ulcerative colitis (UC) refiactory to treatment with corticosteroids and azathioprine/6-MP Previous studies peflbrmed to establish a treatment protocol tor methotrexate (MTX) have tailed to provide a consensus concerning dosage, route of administration or efficacy. Aim: To investigate the etfica{T of parenteral methotrexate in patients with re fi'actory UC Me~hods: Eight patients w~th moderate to severe refractory UC confirmed by sigmoidoscopy were treated with 25mg im MTX (and folic acid) tot 16 weeks. Bloodwork was performed weekly Seventy of disease was assessed by the Mayo Clinic score at the beginning and end of treatment Results: Five male and 3 temale patients, mean age 38 y, were recruited Median Mayo Clinic score at entry was 9 (range 7-11). Six patients had left-sided disuse, i pancolitis and 1 proctosigmoiditis. All patients had received corticosteroids and azathioprine/ 6-MP without achieving remission, and 2 had relapsed after cyclosponn-A treamrent 6/8 patients completed 16w of MTX treatment. One patient withdrew due to a severe exacerbation and 1 withdrew because of thi/nre to improve Two patients developed anemia and 1 patient hypertransammasemia The median Mayo Clinic score at 16 w was 8 (range 6-11). Two patients were referred for proctocolectomy at the end of the study Conclusion: Treatment with 25rag MTX im for 16 w was ineffective in this small group of patients with refractory UC

Responseto Thalidomidein Refrl~:toryCD failing lufliximab Before Thalidomide 2 Months aft.orThalidomide PCDAI (mean) 39.5 20 Prednisone(nlg) 15 8 Fistulae* 2 0 *3rd patentwith fistulahad surgicalresectionpriorto startingIhalidomir

T1398

P value <0.01 <0,05 ND

Long-term Patient-led Maintenance of Remission in Ulcerative Colitis with Balsalazide: Is it Effective and Safe? Jonathan R Green, Charles H Swan, john A Gibson, Graeme D Kerr, Edwin Swarbrick, Philip C Fhornton The use of a single 5-aminusalicylate (5-ASA), previously shown to be effective tbr acute relapse and maintenance of remission in ulcerative colitis (UC), could enhance and simplity longer-term management by aIIowmg the patient to decide their appropriate dose of (herapy. The efficacy and safety of this approach has not previouaIy been tested over a prolonged period. Balsalazide, a 5-ASA prodmg, was used to assess the strategy of patientded dosing m two groups of patients in remission from UC Fifty-two patients in long-term (stable) remission (SR) and 76 m recent remission (RR) were given guidelines about changes and limits of therapy and ,#ere followed prospectively tot 3 years. Assessments of symptoms, mucosa] inflammation, general ;veil-being and adverse events were made every 3 momhs with laboratory assessments every 6 months. Patients were very satisfied with this approach Analysis of the dosages used showed a wide range (1 5-6.0g/day) in both groups, but an average daily dose of balsalazide over 3 ),ears of 3.0g in both groups Relapse needing steroid therapy occurred in 23 SR patients (45%) at 3 ),ears (median time to relapse: 36 montfis) compared with 45 RR patients (59%) (median time to relapse: 22 months) Fewer patients experienced a relapse in each successive year in both groups, clitoral scores (well hemg, signs/symptonrs, underlying disease) for SR patients were consistent over 3 years while RR patients still in remission showed a slight improvement Both groups needed less dose increases as time progressed "lime since last relapse was significantly associated with relapse during the first year of treatment (p<0.033) flrr SR patients Laboratory a~lalyses showed no adverse medication-related haematologiea/ or bioci~emical changes and there was no mortality or significant morbidity (eg, need for colecmmy) in either patient group In conclusion, this long-term patient-led maintenance therapy with balsalazide appears to be well tolerated, safe and ef[?'ctive tot patients with UC

T1395 Antisense Inhibitor of ICAM4 Given as Enema Improves Symptomatic Pouehitis Philip B. Miner Jr., Barbara L Bane, Syed A, Sadiq, Joann D Bradley, Mark Wedel Backgronnd and Siguificance: The surgical constmcti~ra of an ileal pouch cmmected to the anal canal creating a comment ileomml anastamosis Ires revolutionized the treatment ot patients requiring a total colectomy tot ulcerative colitis or familial polyposis. Unfortunately, inflammation m the pouch ofleu causes symptoms of pain, urgency and bleeding as troublesome as Ihe ongmal disease Treatment of pouchitis is olden disappointing. ICAM-1 influences lymphocyte inaction, is pivotal m cell tralhcking, and is over expressed in pouchitis. ISIS 2302 is an antisense inhibitor of I(i?~M-1 Our aim was to determine if enema administration of ISiS 2302 would improve the symptom score, endo~opic appearance and pouch mucosal histology in patients with chronic pouchitis, Methods: 6 patients with chronic unremitting pouchRis with a Pouchitis Disease Activity Index (PDA1) of glvater than 7 were giwm 240 mg 15IS 2302 antisense enemas nightly for 6 weeks in an unblmded, open-label study. Clinical evaluation arid endoscopy were perfbrmed at baseline and at 3 and 6 weeks of treatment Histologlc a~essment ,*as done at baseline and 6 weeks. Results: Median PDAI (symptom score, endoscopy and histology) fell from a baselnie value of 115 (range 10 to 13) after 6 weeks (p=003). Benefit was seen in the Clinical PDAI (symptom score and endoscopy) with a median score of 8 5 (range 8 to I l) at baseline, 55 (range 1 to 8) at 3 weeks ( p = 0 03) and 3.0 (range 3 to 8) at 6 weeks (p=0.03) with rio change in histology'. Conclusion: Topically admmiatered antisense nihibition of ICAM- 1 holds promise for managing patients with chronic unremitting pouchitis

T1396

T1399

Low-dose Heparin in Active Ulcerative Colitis Refractory to Steroid Therapy Atsushi lkehata, Mitsunl Yamakawa, Takao Fujiwara, Masaki Kitagawa, Tatsuya Miura, Akihiko Murakami, Mitsum Ono~ Sadahide Ono

Effects of Rebamipide on Cytokine Production and Restitution by Epithelial Cells May Be Related to Its Clinical Efficacy in Ulcerative Colitis Patients Kenji Ina, Ryuu-hi Fnmta, Ynji Kuno Kazuo Nobata, Tomoyuki Tsuzuki, Takahlmi Ando, Kazuo Kusugami

Background: Untractionated heparin has ~ e n tound to be beneficial in the treatment ot severe ulcerative colitis. The effect of heparin was assumed to be due to a promotion of epithelial wound healing as ;*,'ell as its anticoagulant and anti-inflammatmT properties. However, it has been sometimes associated with serious bleeding complications by using of high dose without 5-aminosalicylic acid, Methods: We evaluated the efficacy and safety oflow-dose heparin combined with 5-amino~licylic acids in the treatment of active ulcerative colitis rekactory to steroid therapy Eleven patients whose condition had not improved after at least seven days of intravenous corticosteroid thenapy were included in an open-labelled tnal These patients received 5,000 units of unfi'actionated heparin daily by continuous

Background: Immunomodulatory treatment is accepted as corticostemid-sparing therapy t\)r ulcerative colitis (UC) patients Rebamipide, a cytoprotective agent, has been reported to attenuate the, inflammatory events in animal colitis models. There are preliminary reports suggesting the effectiveness of rebamipide enema therapy in UC patients, however, its precise mechanism remains unclear Methods: The anti-inflammatory potential of rebanrtpide *`vas examined by the cBanges in c}'tokine production by (he colon ic epithelial cell line, T84 cells, in vitro. Its modulatory ettiects on mucosal repair were tested using the wound model

A-525

AGA Abstracts