April 1995 Immunology, Microbiology, and Inflammatory Disorders A827

• OPAL BUDESONIDE AS MAINTENANO"E TREATMENT FOR CROHN'S DISERSE. G.R. Oreenberq, B.G. Feagan, F. Martin, L.R. Sutherland, AB.R. Thomson, C.N. Williams, L-G. Nilsson, T. Persson and The Canadian Inflammatory Bowel Disease Study Group. Dept. of Medicine, University of Toronto, Toronto, Canada.

_P.=_~__k,~-o~: Corticosteroids are effective treatment for active Crohn's disease but chronic administration to prevent relapse may cause serious side effects. Budesonide is a cort/costeroid with high topical anti-inflammatory activity and low systemic activity due to rapid hepatic metabolism. We investigated the efficacy and safety of an oral controlled ileal-release preparation of budesonide for maintenance of remission in patients with Crohn's disease involving the ileum or ileum and proximal colon. Methods: In a double-blind, multi-centre trial, 105 patients were randomly assigned to receive placebo or budesonide at doses of 3 or 6 mg dally for one year. The primary outcome measure was relapse of Crohn's disease as defined by a CDAI score above 150 and an increment of 60 points, or withdrawal due to disease deterioration that required other treatment. Results. Patients receiving 6 mg of budesonide had a median time to relapse or discontinuation of therapy of 178 days compared with 124 days in those receiving 3 rag of budesonide and 39 days in those receiving placebo (P=0.026). At one year, the rate of relapse in the group receiving 6 mg of budesonide (61%) was similar to the rates in the 3 rng (70%) and the placebo groups (67%) (P=0.75). Basal plasma cortisol levels were uniform in the three treatment groups throughout one year. Budesonide caused a dose-related reduction in cortiootrophin-sfimulated plasma cortisol concentrations but was not associated with clinically important corticosteroid-associated symptoms or other toxic effects. Conclusions: In a one year trial, an oral controlled-release preparation of budesonide at a daffy dose of 6 mg was well tolerated and effective in prolonging the time to relapse in patients with Crohn's disease of the ileum and proximal colon.

• CIPROFLOXACIN AND METRONIDAZOLE: COMBINATION ANTIBIOTIC THERAPY FOR ILEOCOLONIC CROHN'S DISEASE, S.L. Greenblcom, A.H. Steinhart, G.R. Greenberg, Department of Medicine, Mt. Sinai Hospital, University of Toronto, Toronto, Canada. Backoround: Recent experimental evidence underscores the importance of intestinal bacteria in contributing to the inflammatory process observed in Crohn's disease. Uncontrolled studies suggest that in pedanal Crehn's disease the addition of ciprefioxacin, to metronidazole may be more effective than metronidazole therapy alone. The purpose of this study was to determine whether the combination of ciprefloxacin and metronidazole was effective in achieving symptomatic remission in patients with active Crohn's disease involving the ileum or colon. Methods: This study was a retrospective analysis of 72 patients (27 with ileal disease, 22 with ileocolonic disease and 23 with colonic disease), who were treated with ciprofioxacin 500 mg BID and metronidazole 250 mg TID. A clinical remission was defined as a Harvey-Bradshaw index score of 3 or less; a reduction of 3 points or greater indicated a clinical response. Results: The mean duration of treatment was 10 wks (range:l-132 wks). Overall, 55 patients (76%) improved (clinical response), and 49 patients (68%) achieved a clinical remission. Twenty-nine patients were concurrently receiving prednisone (mean dose 15mg/d;range: 5-30 mg/d). Of the non-steroid treated group, 29 of the 43 patients (67%) had a clinical response, while 26 of the 29 patients (90%) concurrently treated with steroids responded. Patients with colonic disease with or without ileal involvement showed greater improvement (38•45 or 84%) when compared to those with ileal disease alone (17127 or 64 %). Patients without resections were more likely to respond (38•44 or 86%) than those with previous resections (17/28 or 61%). Seven of 10 patients showed regression of an inflammatory mass. The 65 patients that responded to treatment had a mean follow-up of 8 months (range: 1-33 months). Twenty-six patients achieved a sustained remission off treatment, and 12 patients remained well on continuous long term treatment (> 2 wks). Three patients relapsed on therapy, and 14 patients had recurrences after stopping treatment. Five patients discontinued treatment because of adverse effects. ~;onc.Jusion: This retrospective analysis suggests that ciproficxacin in combination with metronidazole is well tolerated and may play a beneficial role in achieving symptomatic remission for patients with active Crohn's disease. A prospective randomised trial is required to provide more precise data regarding the benefits of this treatment.

• TOTAL ENTERAL IMMUNOMODULATORY NUTRITION (TEIN) TREATMENT FOR SEVERE ACTIVE ULCERATIVE COLITIS. S.L. Greenbloom, B, Wendland, A.H. Steinhart, R.S. McLeod, Z. Cohen,

G.R. Greenberg. Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Canada.

Back,qmund: In acute ulcerative colitis total enteral nutrition has not been shown to be efficacious as a primary therapeutic modality. Recent formulation of new immunomodulatory enteral preparations prompted a preliminary evaluation of one such diet (Impact~) containing 14 g of arginine, 1,7 g of omega-3 fatty acids, and 1.25 g of RNA nucleotides per 1000 mL for patients with severe active ulcerative colitis in whom colectomy was a therapeutic option. Methods: Fifteen patients with severe active ulcerative colitis with a mean clinical activity score (NEJM 1994;330:16) of 13 were started on TEIN. Eleven of the 15 patients had been unresponsive to a minimum of 7 days of high dose corticosteroid therapy. Enteral feeding was provided as a continuous infusion at a rate of 75 to 125 mL/hour via a nasal-duodenal feeding tube placed at the ligament of Trietz. Results: Fourteen patients had pancolitis and one patient had left-sided colitis. Thirteen of the 15 patients received concurrent intravenous corticosteroids. After two weeks of TEIN, 13 patients achieved clinical remission (mean clinical activity score=l), were able to resume a standard oral diet and were discharged from hospital on tapering doses of prednisone; two patients required colectomy. No complications or feed intolerances were observed. Nine patients remain in remission on maintenance prednisone (10-15 mg daily) and/or 5-ASA with a mean follow-up of eight months (range: 1-12 months). Four patients have relapsed; one patient responded to prednisone and 3 patients came to colectomy. Conclusion: In the setting of severe active ulcerative colitis total enteral immunomodulatory nutrition may have beneficial effects independent of those of corticosteroids. The favorable risk-benefit ratio of this intervention warrants its consideration as a component of the therapeutic armementadum for hospitalized patients with severe active ulcerative colitis before the addition of more aggressive immunosuppressive therapy.

LOCAL EXPRESSION AND PRODUCTION OF MONOCYTE- ATTRACTING CHEMOKINES IN INFLAMMATORY BOWEL DISEASE. M.C. Grimm, P. Pavli*, W.B. Doe. Division of Clinical Sciences, John Curtin School of Medical Research, Australian National University and *Gastroenterology Dept, Woden Valley Hospital, Canberra, ACT, Australia

Recruitment of blood monocytes appears to be important to the pathogenesis of the chronic inflammatory lesion of IBD. Chemokines comprise a large family of chemotacfic peptides which includes monocyte-specific attractants, of which monocyte ehemoattractant protein-1 has been shown previously by us to be produced in IBD-affected mucosa. The purpose of this study was to determine whether other potent monocyte-attracting chemokines are implicated in blood monocyte recruitment in IBD. Formalin- fixed tissue from 4 uninflamed cancer-beating colons ("normal"), 4 ulcerative colitis resections and 5 Crohn's disease resections was subjected to in situ hybridisation using sense and antisense ribo- probes for ~-interferon-indudble protein(IP)-10, Regulated on Ac- tivation, Normal TExpressed and Secreted (RANTES), macrophage inflammatory protein(MIP)-la and MIP-I~. Normal and inflamed tissues also were examined by immunohistochemistry using a rabbit polyclonal antibody directed against MIP-la. Normal tissue demonstrated minimal detectable mRNA for IP-10, MIP-lc~ or -1[~ but some lamina proptia lymphocytes expressed RANTES mRNA. Macrophages, lymphocytes and endothelial cells in lamina proptia, submucosa and muscularis of all IBD-affected tissues strongly ex- pressed IP-10, RANTES and MIP-la; little MIP-I[~ mRNA expres- sion was observed. Mononuclear cells in loosely-formed Crohn's disease granulomata expressed MIP-la, IP-10 and RANTES mRNA. MIP-lc~ protein was detected immunolfistochemically in the same distribution as mRNA, witli mouonuclear and endothelial cells staining positively in inflamed IBD tissue. These studies implicate monocyte- and T lymphocyte-attracting chemokines in the patho- genesis of chronic IBD and suggest their involvement in Crohn's disease granuloma formation. Elucidation of such differential chemokine production in IBD eventually may provide novel thera- peutic options to block leucocyte recruitment.