Kim L. Isaacs

Cytokine messenger RNA profiles in inflammatory bowel disease mucosa detected by polymerase chain reaction amplification

Immunoregulatory properties of cytokines may mediate disordered inflammatory events in ulcerative colitis (UC) and Crohns disease (CD). In the present study, profiles of cytokines produced by activated macrophages were studied in colonic tissue from 43 patients with and without inflammatory bowel disease (IBD). Cytokine messenger RNA (mRNA) extracted from mucosal biopsy specimens was studied using polymerase chain reaction assay techniques. A greater percentage of active UC samples had detectable levels of mRNA for interleukins (IL) 1, 6, and 8 and gro than samples in inactive UC and noninflammatory controls. These cytokines were comparable in active UC and inflammatory controls. Expression of gro mRNA in active UC tissue was significantly higher than in active CD. Tumor necrosis factor was detected in only 7 of 43 samples with no difference between groups. Active and inactive CD did not differ in percentage of cytokine mRNA expression. IL-1 receptor antagonist (IL-1ra) was detected in more inflammatory controls than in CD and was expressed in fewer IBD patients than IL-1. Expression of proinflammatory cytokines in grossly inactive CD and possible defective production of IL-1ra may explain disease reactivation and chronicity.

Tacrolimus for the treatment of fistulas in patients with Crohn's disease: a randomized, placebo-controlled trial.

BACKGROUND & AIMS This study determined the effectiveness of tacrolimus for the treatment of Crohns disease fistulas. METHODS The study was a randomized, double-blind, placebo-controlled, multicenter clinical trial. Forty-eight patients with Crohns disease and draining perianal or enterocutaneous fistulas were randomized to treatment with oral tacrolimus 0.2 mg. kg(-1). day(-1) or placebo for 10 weeks. The primary outcome measure was fistula improvement as defined by closure of >/=50% of particular fistulas that were draining at baseline and maintenance of that closure for at least 4 weeks. A secondary outcome measure was fistula remission as defined by closure of all fistulas and maintenance of that closure for at least 4 weeks. RESULTS Forty-three percent of tacrolimus-treated patients had fistula improvement compared with 8% of placebo-treated patients (P = 0.004). Ten percent of tacrolimus-treated patients had fistula remission compared with 8% of placebo-treated patients (P = 0.86). Adverse events significantly associated with tacrolimus, including headache, increased serum creatinine level, insomnia, leg cramps, paresthesias, and tremor, were managed with dose reduction. CONCLUSIONS Oral tacrolimus 0.2 mg. kg(-1). day(-1) is effective for fistula improvement, but not fistula remission, in patients with perianal Crohns disease. Adverse events associated with tacrolimus can be managed by dose reduction. Lower doses of tacrolimus should be evaluated.

Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease ☆ ☆☆ ★

BACKGROUND & AIMS Azathioprine is effective for Crohns disease but acts slowly. A loading dose may decrease the time to response. METHODS A placebo-controlled study was conducted in patients with active Crohns disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohns Disease Activity Index of </=150 points. Erythrocyte concentrations of the azathioprine active metabolite, 6-thioguanine nucleotide, were measured. RESULTS At week 8, 13 patients (25%) were in complete remission in the azathioprine-loaded group compared with 11 patients (24%) in the placebo group. The frequency of complete remission did not increase after 8 weeks in either group. Both groups achieved steady state of 6-thioguanine nucleotide by week 2, and no differences were found in mean concentrations between the groups. There were no significant differences in the frequency of adverse events between the groups. CONCLUSIONS A loading dose does not decrease the time to response in patients with steroid-treated Crohns disease beginning azathioprine therapy. Steady state of erythrocyte 6-thioguanine nucleotide and complete response occurred earlier than previously reported.

Crohn’s Disease: Pilot study comparing MRI of the abdomen with clinical evaluation

Fourteen patients underwent magnetic resonance imaging (MRI) examination (16 studies) and clinical evaluation concurrently. MRI studies included gadolinium enhancement and TI-weighted fat-suppressed spin echo. Separate investigators determined the severity of disease on MR images and on clinical evaluation in a blinded fashion. MRI studies were evaluated for percentage of mural contrast enhancement, wall thickness, and length of diseased bowel. An MR product was generated using these parameters. Clinical evaluation used the Crohns Disease Activity Index (CDAI) and modified Index of the International Organization for the Study of Inflammatory Bowel Disease (IOIBD). Linear correlation was found between the MR product and clinical indexes of disease activity. The correlation between MR product and the modified IOIBD index was statistically significant (R(2) = 0.633, p = 0.0012). The correlation of MR product and CDAI was less close (R(2) = 0.274, p = 0.0373). Among individual MR parameters, length of diseased bowel showed the greatest correlation with CDAI (R(2) = 0.537, p = 0.012). Percentage contrast enhancement and bowel wall thickness showed significant correlation to the modified IOIBD index (R(2) = 0.739, p = 0.021) but not to the CDAI (R(2) = 0.004, p = 0.825). The results of this study show that the product of mural contrast enhancement, wall thickness, and length of diseased bowel correlated with clinical indexes of disease activity in Crohns disease. Our findings suggest that MRI may be useful in evaluating the severity of Crohns disease and may provide information complementary to clinical evaluation.

Repifermin (keratinocyte growth factor-2) for the treatment of active ulcerative colitis: A randomized, double-blind, placebo-controlled, dose-escalation trial

Background: Repifermin (keratinocyte growth factor‐2) has been shown to reduce inflammation in animal models of colitis.

Pneumatosis intestinalis : Two case reports and a retrospective review of the literature from 1985 to 1995

SummaryPneumatosis intestinalis (PI) is characterized by subserosal or submucosal gas-filled cysts of the gastrointestinal tract. The course may be benign or may lead to the need for urgent surgery. Knowledge of the differential diagnosis, course, and treatment modalities are key in providing optimal care to patients who present with this entity. In this article, two cases of “benign” pneumatosis seen at our institution over a one-month period are presented, along with a retrospective review of the English literature from January 1985 to March 1995. Incidence, symptoms, gross and microscopic appearance, radiographic appearance, etiology, differential diagnosis and therapy are reviewed.

Role of probiotic therapy in IBD

There is mounting evidence that probiotic therapy may alter disease expression in both animal models of IBD and in patients with IBD. The effects appear to be modest at best and may reflect the choice of probiotic organism, the variability in concentrations of organisms administered, and the variability of the diseases being treated. This review examines the data of all fully published articles currently available for the role of probiotics in the treatment of IBD.

State of the Art: Ibd Therapy and Clinical Trials in Ibd

&NA; Inflammatory bowel diseases (IBD) encompass Crohns disease and ulcerative colitis, which are diseases characterized by chronic intestinal inflammation. IBD is believed to result from predisposing genetic and environmental factors (specific antigens and pathogen‐associated molecular patterns) acting on the immunoregulatory system and causing inflammation of the gastrointestinal mucosa. IBD may be the result of an imbalance of effector (proinflammatory) and regulatory T‐cell responses. Three scenarios indicative of the outcome of this balance exist in animal models: balanced effector and regulatory T cells resulting in a normal controlled inflammation; overactive effector T cells resulting in inflammation and disease; and an absence of regulatory T cells resulting in uncontrolled inflammation and severe, aggressive disease. The number of products under study for the treatment of IBD has increased from 3 products and 1 target in 1993 to more than 30 products and more than 10 targets in 2005. The number of products under development and continued investigations into the pathogenesis of IBD emphasize the need to expand clinical research efforts in IBD.

Rifaximin for the treatment of active pouchitis: A randomized, double-blind, placebo-controlled pilot study

Background: The efficacy of the nonabsorbable antibiotic rifaximin in patients with active acute or chronic pouchitis is unknown. Methods: We performed a placebo‐controlled pilot trial to evaluate the efficacy and safety of rifaximin in patients with active pouchitis. Eighteen patients with active pouchitis were randomized to receive oral rifaximin 400 mg or placebo 3 times daily for 4 weeks. Active pouchitis was defined as a total Pouchitis Disease Activity Index (PDAI) score = 7 points. Clinical remission was defined as a PDAI score <7 points and a decrease in the baseline PDAI score = 3 points. The primary analysis was clinical remission at week 4. Results: Eight patients were randomized to rifaximin and 10 patients were randomized to placebo. One patient in the placebo group did not have a post‐baseline efficacy evaluation and was excluded from the efficacy analysis. Two of 8 patients (25%) treated with rifaximin were in clinical remission at week 4 compared to 0 of 9 patients (0%) treated with placebo (P = 0.2059). None of 8 patients in the rifaximin group withdrew from the trial prior to week 4. Two of 9 patients in the placebo group withdrew prior to week 4 due to lack of efficacy and were categorized as treatment failures. Conclusions: Clinical remission occurred more frequently in patients treated with rifaximin 400 mg 3 times daily but the difference was not significant in this pilot study. A larger trial would be required to determine if rifaximin is effective for the treatment of active pouchitis. Rifaximin was well tolerated. (Inflamm Bowel Dis 2007)

Conjugated linoleic acid modulates immune responses in patients with mild to moderately active Crohn's disease

BACKGROUND & AIMS Conjugated linoleic acid (CLA) has demonstrated efficacy as an immune modulator and anti-inflammatory compound in mouse and pig models of colitis. We investigated the immunoregulatory efficacy of CLA in patients with mild to moderate Crohns disease (CD). METHODS Thirteen patients with mild to moderately active CD were enrolled in an open-label study of CLA (6 g/d orally) for 12 weeks. Peripheral blood was collected at baseline, 6 and 12 weeks after treatment initiation for isolation of peripheral blood mononuclear cells for functional analyses of lymphoproliferation and cytokine production. Disease activity was calculated using the CD activity index (CDAI) and quality of life was assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS CLA significantly suppressed the ability of peripheral blood CD4+ and CD8+ T cell subsets to produce IFN-γ, TNF-α and IL-17 and lymphoproliferation at week 12. There was a statistically significant drop in CDAI from 245 to 187 (P = 0.013) and increase in IBDQ from 141 to 165 (P = 0.017) on week 12. CONCLUSION Oral CLA administration was well tolerated and suppressed the ability of peripheral blood T cells to produce pro-inflammatory cytokines, decreased disease activity and increased the quality of life of patients with CD.