Ulcerative Colitis: Rachmilewitz D

Lee J, Rachmilewitz D, Raz E. · Department of Medicine, University of California-San Diego, La Jolla, CA 92093-0663, USA. · Ann N Y Acad Sci. · Pubmed #17057215 No free full text.

Abstract: The commensal microflora of the intestinal tract confer multiple health benefits to the host, including amelioration of inflammatory bowel disease (IBD). Yet, the exact mechanisms by which it ameliorates experimental colitis in animals and human IBD are largely unknown. We tested whether the attenuation of experimental colitis by probiotic bacteria is mediated by toll-like receptor (TLR) signaling. The severity of colitis was attenuated by delivery of nonviable, gamma-irradiated, or by viable probiotics, but not by heat-killed probiotics, in wild-type mice in mice deficient in TLR2 or TLR4. In contrast we did not observe any inhibition of experimental colitis by probiotics, in mice deficient in MyD88 or TLR9. Furthermore, administration of probiotic DNA ameliorated the severity of experimental colitis, whereas methylated probiotic DNA, calf thymus DNA, and Dnase-treated probiotics had no effect. In subsequent studies, we identified that TLR9-induced type 1 IFN mediates the anti-inflammatory effects in experimental colitis. The addition of neutralization antibodies to type 1 IFN abolished the anti-inflammatory effects, whereas the administration of recombinant IFN-beta mimicked the anti-inflammatory effects induced by TLR9 agonists.Taken together, these results indicate that the protective effects of probiotics are mainly mediated by their own DNA rather than by their metabolites or their ability to colonize the colon. These findings underscore the diverse effects of indigenous microbial TLR ligands in intestinal homeostasis and intestinal inflammation and suggest that strategies, that modulate type 1 IFN may be of therapeutic value for intestinal inflammatory conditions.

Dotan I, Rachmilewitz D. · IBD Service, Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel. · Curr Opin Gastroenterol. · Pubmed #15930982 No free full text.

Abstract: PURPOSE OF REVIEW: Probiotics are live, nonpathogenic bacteria that confer health benefits beyond their nutritional value. In inflammatory bowel disease, where changes in bacterial flora have been demonstrated, there is an increasing interest in modulating the flora with probiotic strains. The beneficial effect of probiotics is demonstrated mainly in pouchitis and ulcerative colitis; however, their mechanisms of action are not well defined. The purpose of this review is to discuss the latest findings related to their mechanism of action. RECENT FINDINGS: A decrease in the secretion of pro-inflammatory cytokines, IFN-gamma, TNF-alpha and IL-12, and interference with bacterial adherence to the epithelium has been demonstrated. At the molecular level, an anti-inflammatory effect associated with NF-kappaB inhibition, heat-shock protein induction and proteasome inhibition has been suggested, although NF-kappaB induction has also been demonstrated. Unexpectedly, the beneficial effects described were achieved not only by live bacteria but also by gamma-irradiated nonviable bacteria, bacterial DNA components and probiotic-cultured media. SUMMARY: Understanding the mechanisms responsible for the beneficial effect of probiotics in inflammatory bowel disease and experimental colitis may help understand the role of bacteria in disease pathogenesis. The findings that live probiotics may not be mandatory to be beneficial, and that therapeutic effects may be obtained by systemic, rather than oral administration could have a major impact on the practical use and manufacturing of probiotics.

Pena-Rossi C, Schreiber S, Golubovic G, Mertz-Nielsen A, Panes J, Rachmilewitz D, Shieh MJ, Simanenkov VI, Stanton D, Graffner H. · New Therapies, Merck Serono International S.A., Geneva, Switzerland. · Aliment Pharmacol Ther. · Pubmed #19145731 No free full text.

Abstract: BACKGROUND: Ulcerative colitis (UC) pathophysiology is characterized by an imbalance between pro- and anti-inflammatory cytokines. Interferon (IFN)-beta-1a has potent immunoregulatory properties, including stimulation of host defence mechanisms and thus represents a potential treatment. AIM: To extend pilot data and identify a suitable dose of IFN-beta-1a to achieve endoscopically confirmed remission (ECR) in patients with moderately active UC and to evaluate safety. METHODS: In this multicentre, double-blind, placebo-controlled trial, adults with moderately active UC were randomized to IFN-beta-1a 44 or 66 microg, or placebo, subcutaneously three times weekly for 8 weeks, with a 4-week follow-up. RESULTS: Endoscopically-confirmed remission was observed in 23.4% [95% confidence interval (CI): 13.8-35.7] of placebo patients, 29.2% (95% CI: 18.6-41.8) of the IFN-beta-la 44 microg group and 20.0% (950% CI: 11.1-31.8) of the 66 microg group (P = 0.45). Improvements with IFN-beta-1a 44 microg were greater than with placebo for most secondary efficacy outcomes, although significance was not achieved. Placebo response rates were higher than expected from previous trials. Adverse events were similar to the known safety profile of IFN treatment. CONCLUSIONS: Interferon-beta-1a was generally well tolerated at the doses tested, but a significant therapeutic benefit in patients with UC was not observed.

Farup PG, Hinterleitner TA, Lukás M, Hébuterne X, Rachmilewitz D, Campieri M, Meier R, Keller R, Rathbone B, Oddsson E. · Gjøvik County Hospital, Gjøvik, Norway. · Inflamm Bowel Dis. · Pubmed #11515850 No free full text.

Abstract: BACKGROUND: High doses of mesalazine usually result in an inconvenient dosage schedule and reduced compliance. The goal of this trial was to compare the effects of mesalazine 4 g daily given as prolonged-release granules in packets of 1 g with that of prolonged-release tablets of 0.5 g. METHODS: Two hundred twenty-seven patients with mild-to-moderate ulcerative colitis were randomized to treatment with two packets twice daily (Gr-b.i.d.), 1 packet four times daily (Gr-q.i.d.) or 2 tablets four times daily (Ta-q.i.d.) for 8 weeks. A disease activity index (ulcerative colitis disease activity index: UC-DAI) was calculated, and the granules were defined as noninferior to the tablets if the lower limit of the 95% CI for the differences was more than -1 UC-DAI score unit. RESULTS: Noninferiority of the granules compared with the tablets was demonstrated. The mean improvement in the UC-DAI in the treatment groups Gr-b.i.d., Gr-q.i.d., and Ta-q.i.d. were 3.2, 2.9, and 2.4, respectively; the proportion of complete responders in the three groups 39%, 37%, and 31%, respectively. There were no differences in side effects. CONCLUSION: Mesalazine 4 g daily given as prolonged-release granules twice and four times daily is at least as effective as prolonged-release tablets four times daily in patients with mild to moderate ulcerative colitis. The patients preferred the twice daily dosing.

Rachmilewitz D, Karmeli F, Shteingart S, Lee J, Takabayashi K, Raz E. · Department of Medicine, Shaare Zedek Medical Center, Jerusalem, Israel. · Inflamm Bowel Dis. · Pubmed #16670522 links to  free full text

Abstract: BACKGROUND: We previously showed that Toll-like receptor-9 (TLR-9) ligands ameliorate experimental colitis. In this study, we evaluated the effect of TLR-9 ligands on the generation of proinflammatory cytokines by human colonic mucosa. MATERIALS AND METHODS: Colonoscopic biopsies were obtained from patients with active ulcerative colitis (UC) and from normal subjects. The tissue was organ cultured for 24 hours in the presence or absence of different types of immunostimulatory (ISS) (CpG)-oligonucleotides (ODNs). Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in the medium were determined by enzyme-linked immunosorbent assay. RESULTS: In active UC, hTNF-alpha and hIL-lbeta generation by inflamed colonic mucosa is 7- and 3-fold higher, respectively, than their generation by normal mucosa. Class B CpG ODNs inhibited colonic TNF-alpha and IL-1beta generation by 50%, whereas class A or C ODNs had a partial or no effect, respectively. A novel class of ODNs that is based on multiple TCG repeats was as effective as class B ODNs. This inhibition resulted from the transcriptional suppression of IL-1beta that occurred within the first 2 hours after ISS-ODN incubation. The addition of chloroquine abolished the inhibitory effects of ISS-ODNs on colonic TNF-alpha and IL-1beta generation. CONCLUSIONS: Only certain classes of ISS-ODNs inhibit the enhanced TNF-alpha and IL-1beta generated ex vivo by inflamed colonic mucosa of patients with UC. The effect of ISS-ODNs is mediated by triggering of TLR-9. These results suggest a potential therapeutic value for ISS-ODNs in UC.

Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Present D, Sands BE, Colombel JF. · University Hospital Gasthuisberg, Leuven, Belgium. · N Engl J Med. · Pubmed #16339095 links to  free full text

Abstract: BACKGROUND: Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor alpha, is an established treatment for Crohn's disease but not ulcerative colitis. METHODS: Two randomized, double-blind, placebo-controlled studies--the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively)--evaluated the efficacy of infliximab for induction and maintenance therapy in adults with ulcerative colitis. In each study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2). Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2. RESULTS: In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P<0.001 for both comparisons with placebo). A response was defined as a decrease in the Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute rectal-bleeding subscore of 0 or 1. In ACT 2, 64 percent of patients who received 5 mg of infliximab and 69 percent of those who received 10 mg had a clinical response at week 8, as compared with 29 percent of those who received placebo (P<0.001 for both comparisons with placebo). In both studies, patients who received infliximab were more likely to have a clinical response at week 30 (P< or =0.002 for all comparisons). In ACT 1, more patients who received 5 mg or 10 mg of infliximab had a clinical response at week 54 (45 percent and 44 percent, respectively) than did those who received placebo (20 percent, P<0.001 for both comparisons). CONCLUSIONS: Patients with moderate-to-severe active ulcerative colitis treated with infliximab at weeks 0, 2, and 6 and every eight weeks thereafter were more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo. (ClinicalTrials.gov numbers, NCT00036439 and NCT00096655.)

Orr-Urtreger A, Kedmi M, Rosner S, Karmeli F, Rachmilewitz D. · The Genetics Institute, Tel-Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel. · Neuroreport. · Pubmed #15973160 No free full text.

Abstract: Substantial evidence suggests a negative association between cigarette smoking and the incidence and severity of ulcerative colitis, a common human inflammatory bowel disease. Nicotine has been implicated in this association. The detection of nicotinic acetylcholine receptors in colonic epithelium, the primary tissue affected in ulcerative colitis, suggests a role for these receptors in the beneficial effect of nicotine on colonic inflammation. Using an animal model, we demonstrate for the first time that alpha5 nicotinic acetylcholine receptor knockout mice have significantly more severe experimental colitis than wild-type controls and that nicotine significantly ameliorates its course when compared with wild-type controls. These findings suggest that alpha5-containing nicotinic acetylcholine receptors participate in the modulation of colitis in mice, but other nicotinic acetylcholine receptor subunits also mediate the antiinflammatory effects of nicotine.

Dotan I, Hershkoviz R, Karmeli F, Brazowski E, Peled Y, Rachmilewitz D, Halpern Z. · Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. · Aliment Pharmacol Ther. · Pubmed #11564011 links to  free full text

Abstract: BACKGROUND AND AIMS: The anticoagulants, unfractionated heparin and low-molecular-weight heparin, demonstrated anti-inflammatory effects in animal models and in humans. Because of its dual effects, high-dose heparin was proposed as a therapeutic modality for ulcerative colitis. We investigated whether a low dose of low-molecular-weight heparin-enoxaparin (Clexane, Rhône-Poulenc Rorer, France)-ameliorates the inflammatory response in two models of experimental colitis. METHODS: Colitis was induced in rats by intrarectal administration of dinitrobenzene sulphonic acid. Enoxaparin (40, 80 and 200 microg/kg) or unfractionated heparin (100, 200 and 400 U/kg) were administered subcutaneously immediately after the induction of damage. Enoxaparin, 80 microg/kg, was also administered after induction of colitis by intrarectal administration of iodoacetamide. Rats were sacrificed 1, 3 or 7 days after induction of injury. Colonic damage was assessed macroscopically and histologically. Mucosal prostaglandin E2 generation, myeloperoxidase and nitric oxide synthase activities and tumour necrosis factor-alpha levels in blood were determined. RESULTS: Enoxaparin and heparin significantly ameliorated the severity of dinitrobenzene sulphonic acid- and iodoacetamide-induced colitis as demonstrated by a decrease in mucosal lesion area, colonic weight and mucosal myeloperoxidase and nitric oxide synthase activities. The dose-response curve had a bell-shaped configuration: enoxaparin, 80 microg/kg, and unfractionated heparin, 200 U/kg, were the optimal doses. CONCLUSIONS: Low-dose enoxaparin and unfractionated heparin ameliorate the severity of experimental colitis. This effect is related to their anti-inflammatory rather than anticoagulant properties.

Eliakim R, Karmeli F, Cohen P, Heyman SN, Rachmilewitz D. · Department of Medicine, Hadassah University Hospital on Mount Scopus, Jerusalem, Israel. · Int J Colorectal Dis. · Pubmed #11317692 No free full text.

Abstract: Smoking has a dichotomous effect on inflammatory bowel disease, ameliorating disease activity in ulcerative colitis but having a deleterious effect on Crohn's disease. This effect is thought to be due to nicotine. We investigated the effect of chronic nicotine administration on the small and large bowel in iodoacetamide-induced jejunitis and colitis. Jejunitis was induced in Sprague-Dawley rats by intrajejunal administration of 0.1 ml 2% iodoacetamide and colitis by intrarectal administration of 0.1 ml 3% iodoacetamide. Nicotine was dissolved in drinking water (12.5 or 250 micrograms/ml), rats drinking ad libitum. Nicotine administration started 10 days prior to damage induction and throughout the experiment and had no effect on weight gain or daily food intake of rats. Rats were killed 5 days after iodoacetamide-induced colitis and 7 days after induction of jejunitis. The jejunum and colon were resected, rinsed, weighed, damage assessed macroscopically and microscopically and tissue processed for myeloperoxidase and nitric oxide synthase (NOS) activities and prostaglandin E2 (PGE2) generation. Effects of nicotine on gut microcirculation were also assessed. Nicotine by itself caused no damage to the colon. Nicotine had a dichotomous effect on jejunitis and colitis. At a dose of 12.5 micrograms/ml nicotine improved the macroscopic damage of colitis from 252 +/- 66 to 70 +/- 31 mm2, and segmental weight also declined significantly in the colon (from 1.7 +/- 0.2 to 1.2 +/- 0.1 g/10 cm). In contrast, the same dose of nicotine had a deleterious effect on iodoacetamide-induced jejunitis, increasing the macroscopic damage from 368 +/- 38 to 460 +/- 97 mm2 in rats treated with injury escalating to 970 +/- 147 in rats treated with 250 micrograms/ml nicotine. Nicotine treatment also significantly increased jejunal segmental weight. By itself nicotine did not change NOS activity or PGE2 generation compared to control rats, but it enhanced microcirculation in the colon, whereas in the jejunum nicotine decreased PGE2 generation and increased NOS activity but not jejunal microcirculation. Nicotine has opposite effects on iodoacetamide-induced colitis and jejunitis, which may be partly explained by decreased PGE2 generation and increased NOS activity in the jejunum and an increase in the colonic microcirculation.

Dresner-Pollak R, Karmeli F, Eliakim R, Ackerman Z, Rachmilewitz D. · Department of Medicine, Hadassah University Hospital on Mount Scopus, Hebrew University Hadassah Medical School, Jerusalem, Israel. · Am J Gastroenterol. · Pubmed #10710060 No free full text.

Abstract: OBJECTIVE: Reduced bone mineral density (BMD) is common in patients with inflammatory bowel disease (IBD), but the factors associated with its longitudinal rate of change have not been established. We prospectively assessed the rate of change in BMD, and its association with biochemical markers of bone turnover. METHODS: Twenty-two patients with Crohn's disease and 14 ulcerative colitis patients age 37.1 +/- 11.6 yr were followed for 2 yr. Lumbar spine (L2-L4) and femoral neck BMD were measured by dual x-ray absorptiometry at baseline and 24 months. Bone-specific alkaline phosphatase, osteocalcin, urinary N-telopeptide crosslinked type 1 collagen (NTx), parathyroid hormone, and 25-hydroxyvitamin-D were determined at baseline. RESULTS: At baseline, 59% of Crohn's patients and 43% of ulcerative colitis patients were osteoporotic, with spine or femoral neck BMD T-score < -2.5. Spine BMD, and spine and femoral neck T-scores were lower and disease duration was longer in nine patients with ileal resection compared with nonoperated patients (0.84 +/- 0.15 g/cm2 vs 0.96 +/- 0.11 g/cm2, -3.0 +/- 1.5 vs -1.7 +/- 1.3, -3.2 +/- 1.5 vs -2.2 +/- 1.0, respectively; all p < 0.05). At 24 months, 13/36 (36%) and 14/36 (39%) patients experienced spinal and femoral neck bone loss, respectively, with mean annual percent BMD changes of -2.0% and -1.5%, respectively. NTx, a bone resorption marker, inversely correlated with spinal BMD rate of change (r = -0.4, p < 0.05). Using quartiles analysis, patients with the highest NTx (Q4) experienced the greatest decrease in spine BMD compared with patients with the lowest NTx (Q1). CONCLUSIONS: Spine and femoral neck bone loss continues over time in more than one-third of IBD patients. Increased NTx level predicts spinal bone loss in IBD patients.

Meuwissen SG, Ewe K, Gassull MA, Geboes K, Jewell D, Pallone F, Rachmilewitz D, Rask-Madsen J, Riddell BH, Sandborn BJ, Schmuck ML. · International Organization for the Study of Inflammatory Bowel Disease, Department of Gastroenterology, University Hospital, Vrije Universiteit, Amsterdam, The Netherlands. · Eur J Gastroenterol Hepatol. · Pubmed #10656204 No free full text.

Abstract: OBJECTIVE: To obtain information on the clinical experience with azathioprine (AZA), 6-mercaptopurine (6-MP), cyclosporin A (CyA) and methotrexate (MTX) in the treatment of patients with inflammatory bowel disease (IBD) by gastroenterologists and internists in different countries. DESIGN: A questionnaire designed by the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) was mailed to 300 gastroenterologists, living in North America (n = 76) and Europe (n = 224) (12 countries), to obtain information on clinical experience. PARTICIPANTS: More than half of the respondents (168/298; 56.4%) worked in university hospitals and 58/298 (19.5%) in general (non-university) hospitals. Two-thirds (65%) had more than 10 years' experience in gastroenterology. RESULTS: The respondents had personal experience with AZA (88.4%), 6-MP (33.3%), CyA (48.7%) and MTX (36.3%). AZA was prescribed more frequently in Europe (92.6%) than in North America (74.2%) (P = 0.0002), 6-MP less frequently by the European than the North American respondents (23.8 and 53.3% respectively, P = 0.0001). Two-thirds (69.7%) usually prescribed AZA together with steroids to Crohn's disease patients; 62.4% of the respondents prescribed AZA for periods longer than 24 months. For ulcerative colitis, 77.9% had experience with AZA (Europe > North America, P = 0.0001). AZA had been prescribed by 69 respondents to pregnant patients, without apparent toxicity. Acute pancreatitis had been observed after AZA by 56.7% respondents; 25 malignancies were mentioned (six lymphoma, three leukaemia, three colon cancer, four renal carcinoma, nine others). CyA had been prescribed in acute ulcerative colitis by 140/291 respondents (North America 45.1%, Europe 49.1 %); of all respondents 63.9% treated < 5 patients with CyA, 36.1% 6-20 cases. CyA results were considered good in 29.5%, acceptable but with recurrences in 58.6%, and poor in 14.3%. MTX was prescribed in North America by 47.8% of the respondents, and by 33.9% in Europe (not significant). Several significant differences were observed between the prescription behaviour of respondents working at university hospitals and non-university hospitals, in particular in relation to participation in clinical trials. CONCLUSIONS: Considerable experience exists in the use of immunosuppressive therapy in IBD; however, differential prescription behaviour exists in the choice of immunosuppressives between North America and Europe. These IOIBD study results may contribute to a better insight in the daily use of immunosuppressive agents in IBD by gastroenterologists and other specialists.

Dotan I, Chowers Y, Rachmilewitz D, Chermesh I, Lavy A, Israeli E, Karban A, Schwaber MJ, Odes S, Eliakim R. · Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. · Harefuah. · Pubmed #17183961 No free full text.

Abstract: Infliximab, the monoclonal anti-tumor necrosis factor-alpha (TNF-alpha) antibodies preparation, is efficacious in the treatment of inflammatory bowel diseases. However, the optimal therapeutic approach is still under investigation. Reports on side effects and potential complications of infliximab therapy, as well as of other anti-TNF-alpha blocking agents are accumulating. Hence, the Israeli Gastroenterological Association had initiated a conference in order to discuss the frequent clinical issues that have arisen following the use of infliximab for the treatment of inflammatory bowel diseases. The aim was to report on the published clinical experience and problems regarding several practical aspects of the use of Infliximab, to suggest guidelines that are evidence-based and to discuss them with experienced IBD-oriented gastroenterologists. The subjects that were discussed include: (1) treatment protocols; (2) maintenance therapy in Crohn's disease; (3) prevention of infections and (4) therapeutic potential in ulcerative colitis. These topics reflect everyday issues that gastroenterologists deal with while treating inflammatory bowel disease patients. The manuscript summarizes the literature and evidence that were presented in the conference, the points raised at the discussions as well as guidelines suggested by work groups that were established for each subject. These guidelines may assist and direct the gastroenterologist treating inflammatory bowel disease patients with infliximab.