Gabriele Bianchi Porro

Mucosal Healing Predicts Late Outcomes After the First Course of Corticosteroids for Newly Diagnosed Ulcerative Colitis

BACKGROUND & AIMSnIt is uncertain whether mucosal healing after the first course of corticosteroids therapy predicts outcome in patients with ulcerative colitis (UC). We evaluated whether early clinical and endoscopic responses to this therapy are associated with late outcomes in UC.nnnMETHODSnPatients with newly diagnosed UC who were prescribed corticosteroid therapy (n = 157) were followed up for 5 years. They were evaluated using clinical (Powel-Tuck [PT]) and endoscopic (Baron) indexes after 3 and 6 months, then every 6 months. Outcomes at month 3 (early response) were used to identify patients with complete (group A: PT, 0-1; Baron, 0), partial (group B: PT, 0-1; Baron, 1-3), or no response (group C: persistence of clinical and endoscopic activity). The association between early and late outcomes was assessed.nnnRESULTSnAfter 5 years, there were significant differences between complete and partial responders in the rates of hospitalization (25% in group A vs 48.7% in group B; P = .0152; odds ratio [OR], 2.85; 95% confidence interval [CI], 1.21-6.72), immunosuppression therapy (5% in group A vs 25.6% in group B; P = .0030; OR, 6.55; 95% CI, 1.67-25.67), colectomy (3.3% in group A vs 18.0% in group B; P = .0265; OR, 6.34; 95% CI, 1.24-32.37), and their combination (26.7% in group A vs 48.7% in group B; P = .0249; OR, 2.61; 95% CI, 1.12-6.11). After multivariate analysis, lack of mucosal healing was the only factor associated with negative outcomes at 5 years (immunosuppressors: hazard risk [HR], 10.581; 95% CI, 2.193-51.039; P = .0033; hospitalization: HR, 3.634; 95% CI, 1.556-8.485; P = .0029; colectomy: HR, 8.397; 95% CI, 1.278-55.186; P = .0268).nnnCONCLUSIONSnNo mucosal healing after corticosteroid therapy is associated with a more aggressive disease course.

Prevalence and pathogenesis of anemia in inflammatory bowel disease. Influence of anti-tumor necrosis factor-α treatment

Background Anemia is a common complication of inflammatory bowel disease, but its epidemiology may be changing due to earlier diagnosis and improved treatments. We investigated the prevalence and pathogenesis of anemia in patients with inflammatory bowel disease. Design and Methods In a cross-sectional study 263 out-patients with inflammatory bowel disease (165 with Crohn’s disease, 98 with ulcerative colitis) were investigated. The influence of time from diagnosis, disease activity, inflammation and the status of iron and hematinic vitamins on the level of hemoglobin and prevalence of anemia were evaluated. In a second group of 27 patients with Crohn’s disease, undergoing anti-tumor necrosis factor-α treatment with infliximab because of refractory or fistulizing disease, we determined the effects of infliximab on disease activity, hemoglobin, serum erythropoietin levels, iron status and inflammation. Results In all, 104 of the 263 patients with inflammatory bowel disease were anemic. Age, gender and azathioprine treatment had no influence on anemia. The prevalence of anemia was highest at diagnosis (65%), decreased during the first 4 years after disease onset, and was stable thereafter. Active disease was associated with higher rates of anemia. At diagnosis most anemic patients had anemia of chronic disease; during follow-up iron deficiency and multifactorial forms of anemia became more prevalent. Eighteen of 27 patients undergoing treatment with infliximab were anemic; most of them had anemia of chronic disease. Infliximab reduced disease activity and improved anemia in 12 patients. This was mediated by an increased production of erythropoietin for the degree of anemia. In vitro infliximab increased the growth of erythroid progenitors from the peripheral blood of patients with active disease. Conclusions Anemia is a common problem in out-patients with inflammatory bowel disease; the prevalence and severity of anemia are related to the activity of the bowel disorder. The pathogenesis of anemia changes during the course of the disease, with anemia of chronic disease having a major role at diagnosis and iron deficiency and multifactorial forms of anemia during follow-up. In patients requiring anti-tumor necrosis factor-α treatment, response to therapy improves erythropoiesis.

Biologic targeting in the treatment of inflammatory bowel diseases

The etiology of inflammatory bowel disease (IBD) has not yet been clarified and immunosuppressive agents which nonspecifically reduce inflammation and immunity have been used in the conventional therapies for IBD. Evidence indicates that a dysregulation of mucosal immunity in the gut of IBD causes an overproduction of inflammatory cytokines and trafficking of effector leukocytes into the bowel, thus leading to an uncontrolled intestinal inflammation. Under normal situations, the intestinal mucosa is in a state of “controlled” inflammation regulated by a delicate balance of proinflammatory (tumor necrosis factor [TNF-α], interferon-gamma [IFN-γ], interleukin-1 [IL-1], IL-6, IL-12 and anti-inflammatory cytokines IL-4, IL-10, IL-11). The mucosal immune system is the central effector of intestinal inflammation and injury, with cytokines playing a central role in modulating inflammation. Cytokines may therefore be a logical target for inflammatory bowel disease therapy using specific cytokine inhibitors. Biotechnology agents targeted against TNF, leukocyte adhesion, Th1 polarization, T cell activation, nuclear factor-kappaB (NF-κB), and other miscellaneous therapies are being evaluated as potential therapies for the treatment of inflammatory bowel disease. In this context, infliximab and adalimumab are currently the only biologic agents approved in Europe for the treatment of inflammatory Crohn’s disease. Other anti-TNF biologic agents have emerged, including CDP571, certolizumab pegol, etanercept, onercept. However, ongoing research continues to generate new biologic agents targeted at specific pathogenic mechanism involved in the inflammatory process. Lymphocyte-endothelial interactions mediated by adhesion molecules are important in leukocyte migration and recruitment to sites of inflammation, and selective blockade of these adhesion molecules is a novel and promising strategy to treat Crohn’s disease. Therapeutics agents to inhibit leukocyte trafficking include natalizumab (approved for use in Crohn’s disease in USA), MLN-02, and ISIS 2302. Other agents being investigated for the treatment of Crohn’s disease include inhibitors of T cell activation, proinflammatory cytokine receptors, Th1 polarization, growth hormone, and growth factors. Agents being investigated for treatment of ulcerative colitis include many of those mentioned above. Controlled clinical trials are currently being conducted, exploring the safety and efficacy of old and new biologic agents, and the search certainly will open new and exciting perspective on the development of therapies for inflammatory bowel disease. A review is made of the main areas of research exploring the mechanisms associated with the pathogenesis of IBD, providing advances in the agents currently in use, and identifying a host of new therapeutic biologic targets.

Vitamin D and Inflammatory Bowel Disease

Crohns disease (CD) and ulcerative colitis (UC) are the main forms of inflammatory bowel disease (IBD), chronic relapsing-remitting inflammatory conditions of uncertain origin affecting the gastrointestinal tract. Much effort has recently been made both in defining the mechanisms underlying the development of IBD, and in broadening the spectrum of effective treatment. Substantial progress has been made in characterising immune-cell populations and inflammatory mediators in IBD. 1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the bioactive form of Vitamin D(3), besides having well-known control findings of calcium and phosphorus metabolism, bone formation and mineralization, also has a role in the maintenance of immune- omeostasis. The immune-regulatory role of vitamin D affects both the innate and adaptive immune system contributing to the immune-tolerance of self-structures. Impaired vitamin D supply/regulation, amongst other factors, leads to the development of autoimmune processes in animal models of various autoimmune diseases, including IBD. The administration of vitamin D in these animals leads to improvement of immune-mediated symptoms. Future studies now need to focus on the potential of vitamin D and its derivatives as therapeutic adjuncts in the treatment of IBD.

Budesonide foam vs. hydrocortisone acetate foam in the treatment of active ulcerative proctosigmoiditis.

AbstractINTRODUCTION: Rectal administration of corticosteroids is advocated in patients with proctosigmoiditis who have failed therapy with mesalamine enema. Foam offers patients better tolerability than an enema. In this study the efficacy and adverse effects of a new budesonide foam are compared with the presently available hydrocortisone foam. nMETHODS: Two hundred fifty-one patients with proctosigmoiditis were randomly assigned to receive either budesonide foam or hydrocortisone foam for eight weeks. nRESULTS: Remission rates were comparable in the budesonide and hydrocortisone groups, 53 and 52 percent, respectively. The mean disease activity index for the two groups decreased to a similar extent, from 7.2 ± 1.9 and 7 ± 2 to 3.6 ± 3.1 and 3.9 ± 3.4 in the budesonide and hydrocortisone groups, respectively. In a subgroup of patients who had not responded to rectal administration of mesalamine, 23 of 44 (52 percent) patients who received budesonide responded favorably to the foam, as compared with 14 of 38 (37 percent) patients who received hydrocortisone (P = not significant). Low plasma cortisol occurred in 3 percent of the budesonide group and in none of the hydrocortisone patients. nCONCLUSIONS: This trial demonstrates a similar efficacy and safety of the two foams in patients with proctosigmoiditis.

Prospective Study of Long-Term Results and Prognostic Factors After Conservative Surgery for Small Bowel Crohn's Disease

BACKGROUND & AIMSnSeveral bowel-sparing techniques have been proposed for treating patients with CD, but there have been no prospective studies analyzing risk factors and long-term outcome. We prospectively evaluated safety and long-term efficacy of conservative surgery for patients with complicated CD.nnnMETHODSnFrom 1993-2007, 393 of 502 consecutive patients underwent surgery for complicated CD of the small bowel. Those with colonic involvement were excluded. The Student t test, chi(2) test, Kaplan-Meier estimates, and Cox proportional hazard model were used to analyze postoperative complications and long-term outcome.nnnRESULTSnA total of 865 jejunoileal segments underwent 318 small bowel resections and 367 strictureplasties (either classic or nonconventional). There were no deaths; the complication rate was 5.6%, and the cumulative 10-year recurrence rate was 35%. None of the prognostic factors were correlated with postoperative complications. Younger age, an upper jejunoileal location, stricturing behavior, and small-bowel wall thickening 12 months after surgery showed hazard ratios of 2.4 (95% confidence interval [CI], 1-5.4; P = .03), 2.5 (95% CI, 1.3-4.7; P = .004), 2.2 (95% CI, 1.1-4.1; P = .01), and 4.5 (95% CI, 2.3-8.6; P = .000), respectively. Immunomodulator therapy failed to reduce long-term surgical recurrence.nnnCONCLUSIONSnYoung patients with extended and stricturing disease are at high risk for disease recurrence after surgery. Bowel wall thickening was a reliable prognostic factor for these patients. Conservative surgery is safe and effective in treating patients with jejunoileal CD and should be considered as the first-line surgical treatment, preventing the risk of short bowel syndrome caused by repeated resections.

CARD15 gene variants and risk of reoperation in Crohn's disease patients.

OBJECTIVES:Several studies have investigated, with conflicting results, the risk factors for reoperation in Crohns disease (CD) patients. CARD15 gene variants have been identified as a major genetic risk factor for CD patients and associated with ileal disease, stenosis, and risk of surgery. However, data regarding the association between these variants and the need for reoperation are very few and conflicting. This study evaluated the risk factors of reoperation, including CARD15 gene variants.METHODS:A total of 253 consecutive CD patients, recruited in four Italian tertiary-care inflammatory bowel disease (IBD) referral centers, who had submitted to surgery for CD, were included in the study. Clinical characteristics of CD patients, time and main indications for surgery, type of operation, postoperative therapy, and time to second surgery were recorded. CARD15 gene variants were determined by DNA sequencing analysis in each center. Factors related to surgical recurrence, including CARD15 variants, were estimated by Cox proportional hazard regression.RESULTS:In all, 89 patients (35.1%) showed at least one surgical recurrence. Reoperation was significantly correlated with stenosis as indications at initial surgery only. CARD15 variants were found in 36.0% of patients, but did not correlate significantly with the demographic and clinical characteristics of the patients, rate of first surgical recurrence, and time to second operation. CARD15 variants did not significantly affect the reoperation rate, irrespective of indications for surgery.CONCLUSIONS:Reoperation for CD is correlated with stenosis at initial surgery, but not with CARD15 gene variants. This finding does not justify more aggressive prophylactic therapy on the basis of CARD15 genotype.

Review: Immunomodulators for all patients with inflammatory bowel disease?:

Recent insight into the pathogenesis of Crohn’s disease (CD) and ulcerative colitis (UC) have led to the development of new treatment options, with a progressive shift to more evidence-based strategies based on sound pathophysiological rationales. A better understanding of inflammatory bowel disease (IBD) pathophysiology has progressively resulted in a more frequent use of immunomodulators. We review the recommended or suggested use of conventional immunomodulators such as azathioprine, 6-mercaptopurine, methotrexate in the treatment of IBD. Moreover, an effort is made to explore some critical areas in which early and more diffuse use of these agents may be advocated.

Predictors of long-term outcome of functional dyspepsia and duodenal ulcer after successful Helicobacter pylori eradication--a 7-year follow-up study.

Aims To investigate the course of dyspeptic symptoms, predictors of symptom relief and use of antidyspeptic drugs in patients with duodenal ulcer disease and functional dyspepsia 6–7 years after successful Helicobacter pylori eradication. Patients and methods Patients with H. pylori-positive duodenal ulcer or functional dyspepsia, included in a prospective, randomized study from January 1996 to June 1997, and successfully treated with standard triple therapy, were eligible. After 6–7 years, case histories of 142 patients were retrieved and patients were interviewed by telephone. They were asked about the presence of dyspeptic symptoms and health care needs during the last week and over the last 6–7 years. Predictive factors of complete long-term relief of symptoms have been evaluated. Results Of the 114 eligible patients, 104 (49 with duodenal ulcer and 55 with functional dyspepsia) were included in the study. The mean duration of follow up was 6.6±0.5 years. Complete relief of dyspeptic symptoms was reported, in this period, by 49.0% of duodenal ulcer patients and 36.4% of patients with functional dyspepsia (P=0.271). Persistence of symptoms within 3 months of H. pylori eradication and female sex were predictive of persistence of symptoms in the following 6–7 years, in patients with functional dyspepsia. In turn, approximately 50% of the patients with complete symptom remission, within 6 months of H. pylori eradication, later became symptomatic. Since the end of the H. pylori eradication trial, 26.9% of patients were still using or had used antidyspeptic drugs; patients with functional dyspepsia having used them more frequently than duodenal ulcer patients (36.4 vs. 16.3%; P=0.037). Conclusion In clinical practice, long-term symptomatic benefit, in duodenal ulcer patients, after H. pylori eradication, is similar to that in patients with functional dyspepsia. Early evaluation of symptoms after successful H. pylori eradication may be predictive of outcome in dyspeptic patients. Most symptomatic patients did not seek antidyspeptic drugs. Use of antisecretory medications was, however, greater in patients with functional dyspepsia than in duodenal ulcer patients.

Ultrasound of the gastrointestinal tract

Part I: Acute Abdomen.- Part II: Chronic InflammatoryBowel Diseases.- Part III: Infections.- Part IV: Neoplasm.- Part V: Procedures and Technical Developments.- Part VI: Transperineal Ultrasound.