Fabiana Castiglione

Mongersen, an Oral SMAD7 Antisense Oligonucleotide, and Crohn’s Disease

BACKGROUND Crohns disease-related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor β1 (TGF-β1) due to high levels of SMAD7, an inhibitor of TGF-β1 signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, mongersen, targets ileal and colonic SMAD7. METHODS In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of mongersen for the treatment of persons with active Crohns disease. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohns Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28. RESULTS The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (P<0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (P=0.04, P<0.001, and P<0.001, respectively). Most adverse events were related to complications and symptoms of Crohns disease. CONCLUSIONS We found that study participants with Crohns disease who received mongersen had significantly higher rates of remission and clinical response than those who received placebo. (Funded by Giuliani; EudraCT number, 2011-002640-27.).

Advanced Age Is an Independent Risk Factor for Severe Infections and Mortality in Patients Given Anti–Tumor Necrosis Factor Therapy for Inflammatory Bowel Disease

BACKGROUND & AIMS Few data are available on effects of biologic therapies in patients more than 65 years old with inflammatory bowel disease (IBD). We evaluated the risk and benefits of therapy with tumor necrosis factor (TNF) inhibitors in these patients. METHODS We collected data from patients with IBD treated with infliximab (n = 2475) and adalimumab (n = 604) from 2000 to 2009 at 16 tertiary centers. Ninety-five patients (3%) were more than 65 years old (52 men; 37 with ulcerative colitis and 58 with Crohns disease; 78 treated with infliximab and 17 with adalimumab). The control group comprised 190 patients 65 years old or younger who were treated with both biologics and 190 patients older than 65 years who were treated with other drugs. The primary end points were severe infection, cancer, or death. RESULTS Among patients more than 65 years old who received infliximab and adalimumab, 11% developed severe infections, 3% developed neoplasms, and 10% died. No variable was associated with severe infection or death. Among control patients more than 65 years old, 0.5% developed severe infections, 2% developed cancer, and 2% died. Among control patients less than 65 years old, 2.6% developed severe infections, none developed tumors, and 1% died. CONCLUSIONS Patients older than 65 years treated with TNF inhibitors for IBD have a high rate of severe infections and mortality compared with younger patients or patients of the same age that did not receive these therapeutics. The effects of anti-TNF agents in older patients with IBD should be more thoroughly investigated, because these patients have higher mortality related to hospitalization than younger patients.

Antibiotic treatment of Crohn's disease: results of a multicentre, double blind, randomized, placebo‐controlled trial with rifaximin

Background  Clinicians often employ antibiotics in Crohns disease. Rifaximin is active against bacteria frequently found in the intestinal mucosa of Crohns disease patients.

The Italian Society of Gastroenterology (SIGE) and the Italian Group for the study of Inflammatory Bowel Disease (IG-IBD) Clinical Practice Guidelines: The use of tumor necrosis factor-alpha antagonist therapy in Inflammatory Bowel Disease

Biological therapies are an important step in the management of Inflammatory Bowel Diseases. In consideration of high cost and safety issues there is the need to have clear recommendations for their use. Despite the American Gastroenterological Association and the European Crohns and Colitis Organisation have published exhaustive Inflammatory Bowel Disease guidelines, national guidelines may be necessary as cultural values, economical and legal issues may differ between countries. For these reasons the Italian Society of Gastroenterology and the Italian Group for the study of Inflammatory Bowel Disease have decided to elaborate the Italian guidelines on the use of biologics in Inflammatory Bowel Disease. The following items have been chosen: definitions of active, inactive, steroid dependent and resistant disease; measures of activity; anti-tumor necrosis factor alpha therapy use in active steroid dependent and refractory luminal Crohns Disease, in fistulising Crohns Disease, in steroid dependent and resistant active Ulcerative Colitis; risk of cancer; risk of infections during anti-tumor necrosis factor alpha therapy; special situations. These guidelines are based on evidence from relevant medical literature and clinical experience of a national working group.

Variants of CARD15 are associated with an aggressive clinical course of Crohn's disease--an IG-IBD study.

BACKGROUND:Three major variants of the CARD15 gene confer susceptibility to Crohns disease (CD). Whether or not these variants correlate with specific clinical features of the disease is under evaluation.AIM:We investigated the possible association of CARD15 variants with specific clinical characteristics, including the occurrence of anti-Saccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies (ANCA), in a large cohort of inflammatory bowel disease (IBD) patients and their unaffected relatives.METHODS:Three hundred and sixteen CD patients (156 with positive family history), 408 ulcerative colitis (UC) patients (206 with positive family history), 588 unaffected relatives, and 205 unrelated healthy controls (HC) were studied. Single nucleotide polymorphisms (SNPs) R702W, G908R, and L1007finsC of the CARD15 gene were investigated and correlated to age at diagnosis, gender, family history, localization, extraintestinal manifestations, previous resective surgery, stenosing/fistulizing pattern, ANCA, and ASCA.RESULTS:Compared to HC, the frequencies of all three variants in CD were significantly increased: 8.7%versus 4.1% for R702W (p < 0.006), 7.3%versus 2.7% for G908R (p < 0.002), 9.3%versus 0.7% for L1007finsC (p < 0.00001). At least one risk allele was found in 38.2% (p < 0.0001, compared to HC), 13.7% (NS), and 15.1% of CD, UC, and HC, respectively. The L1007finsC risk allele was also significantly increased in unaffected relatives of familial (9.5%; p < 0.00001), and sporadic CD (9%; p < 0.00001), compared to HC (0.7%). Sixteen healthy relatives, carriers of two risk alleles, were asymptomatic after 5–8 yr of follow-up. CD carriers of at least one variant were younger (p= 0.03), more likely to have ileal localization (p= 0.0001), stenosing pattern (p= 0.01), previous resective surgery (p= 0.0001), and presence of ASCA (p= 0.0001). No difference in SNPs frequency between familial and sporadic cases of CD was found.CONCLUSIONS:In our population, both familial and sporadic CD patients carrying at least one major variant of CARD15 had an aggressive clinical course.

Two mesalazine regimens in the prevention of the post-operative recurrence of Crohn's disease: a pragmatic, double-blind, randomized controlled trial

Background : The role of mesalazine in preventing the clinical recurrence of Crohns disease after surgery has been shown in a meta‐analysis of all published studies. No clear relationship, however, has been shown between dosage and response.

Hepatitis B and C Virus Infection in Crohn's Disease

Patients with Crohns disease (CD) are at higher risk of hepatitis C (HCV) and B virus (HBV) infection, because of surgical and/or endoscopic procedures. However, the prevalence of HCV and HBV infection in CD is unknown. This issue may be relevant because of the growing use of immunomodulatory drugs in CD. The purpose of this study was to assess, in a multicenter study, the prevalence and risk factors of HCV and HBV infection in CD. The effect of immunomodulatory drugs for CD on the clinical course of hepatitis virus infections and of interferon-&agr; (IFN-&agr;) on the course of CD was examined in a small number of patients. Sera from 332 patients with CD and 374 control subjects (C) were tested for the following: hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), HBcAb, HBeAg, HBeAb, anti-HCV, and HCV-RNA. An additional 162 patients with ulcerative colitis (UC) were tested as a disease control group. Risk factors were assessed by multivariate statistical analysis. Infection by either HCV or HBV was detected in 24.7% of patients with CD. In the age groups younger than 50 years, HCV prevalence was higher in CD than in C (p = 0.01). HCV infection in CD was associated with surgery (OR 1.71; 95% CI 1.00–2.93; p = 0.04), blood transfusions (OR 3.39; 95% CI 1.04–11.04; p = 0.04), and age (OR 2.3; 95% CI 1.61–3.56; p < 0.001). The event CD-related surgery appeared to be the main risk factor for HCV infection in CD. HCV prevalence was higher in CD (7.4%) than in UC (0.6%) (p = 0.001). HBcAb positivity was higher in CD (10.9%) and UC (11.5%) than in C (5.1%) (CD vs. C: p = 0.016; UC vs. C: p = 0.02), associated with age (OR 2.08; 95% CI 1.37–3.17; p = 0.001) and female gender (OR 2.68; 95% CI 1.37–3.17; p = 0.001) in CD and to UC duration (OR 1.20; 95% CI 1.06–1.36; p = 0.002). Immunomodulatory drugs did not influence the course of HBV or HCV infection in seven patients with CD, and IFN-&agr; for chronic hepatitis C did not affect CD activity in six patients with CD. It is concluded that HBV prevalence is higher in CD than in C at all ages, whereas HCV prevalence is increased in young patients with CD, because of a greater need for surgery. The higher HCV (but not HBV) prevalence in CD than in UC suggests that the host immune response may influence the risk of HCV infection. Although a relatively high proportion of patients with CD showed HBV and/or HCV infections, this should not influence treatment strategies for CD.

Oral contrast-enhanced sonography for the diagnosis and grading of postsurgical recurrence of Crohn's disease.

Background: Postsurgical recurrence (PSR) is very common in patients with Crohns disease (CD) and previous surgery. Endoscopy is crucial for the diagnosis of PSR, also showing high prognostic value. Bowel sonography (BS) with or without oral contrast enhancement (OCBS) is accurate for CD diagnosis but its role in PSR detection and grading is poorly investigated. The aim was to evaluate the diagnostic accuracy of BS and OCBS for PSR compared to the endoscopical Rutgeertss grading system. Methods: We prospectively performed endoscopy, BS, and OCBS in 40 CD patients with previous bowel resection to provide evidence of possible PSR. Endoscopy, BS, and OCBS were executed 1 year after surgery, with PSR diagnosis and grading made in accordance with Rutgeerts. BS and OCBS were considered suggestive for PSR in the presence of bowel wall thickness (BWT) >3 mm. OCBS was performed after ingestion of 750 mL of polyethylene glycol (PEG). Also, a receiver operating characteristic (ROC) curve was constructed in order to define the best cutoff of BWT to discriminate mild from severe PSR (grade 0–2 versus 3–4 of Rutgeerts) for both BS and OCBS. Results: In all, 22 out of the 40 CD showed an endoscopic evidence of PSR (55%). A severe PSR was present in 14 patients (64%). Sensitivity, specificity, and positive and negative predictive values were 77%, 94%, 93%, and 80% for BS, and 82%, 94%, 93%, and 84% for OCBS. On the ROC curve a BWT >5 mm showed sensitivity, specificity, and positive and negative predictive values of 93%, 96%, 88%, and 97% for the diagnosis of severe PSR at BS, while a BWT >4 mm was the best cutoff differentiating the mild from the severe CD recurrence for OCBS, with a sensitivity, specificity, and positive and negative predictive values of 86%, 96%, 97%, and 79%, respectively. Conclusions: Both BS and OCBS show good sensitivity and high specificity for the diagnosis of PSR in CD, with a BWT >5 mm for BS and BWT >4 mm for OCBS strongly indicative of severe endoscopic PSR. Accordingly, these techniques could replace endoscopy for the diagnosis and grading of PSR in many cases.

Antibiotic treatment of small bowel bacterial overgrowth in patients with Crohn's disease

Background : Small bowel bacterial overgrowth is common in Crohns disease but its treatment is not clearly defined. Metronidazole and ciprofloxacin are effective antibiotics in active Crohns disease.

Noninvasive diagnosis of small bowel Crohn's disease: direct comparison of bowel sonography and magnetic resonance enterography.

Background:The diagnosis of small bowel Crohn’s disease (CD) is performed by ileocolonoscopy, whereas the assessment of its extension can be achieved by radiologic studies or, noninvasively, by magnetic resonance (MR) enterography and bowel sonography (BS). However, few comparative studies exist directly comparing the diagnostic accuracy of BS and MRI. The aim of this study was to evaluate the diagnostic accuracy of BS and MRI for the diagnosis of small bowel CD. Methods:We prospectively performed a noninferiority diagnostic study including 234 consecutive subjects with suspected small bowel CD. All patients underwent IC (used as gold standard for diagnosis), BS, and MR enterography performed in random order by physicians who were blinded about the results. Results:The diagnosis of small bowel CD was made in 120 of 249 subjects (48%). Sensitivity, specificity, positive predictive value, and negative predictive value for CD diagnosis were 94%, 97%, 97%, and 94% for BS and 96%, 94%, 94%, and 96% for MR enterography, respectively. BS was less accurate than MR enterography in defining CD extension (r = 0.69), whereas the concordance in terms of CD location between the 2 procedures was high (k = 0.81). Also, MRI showed a fair concordance with BS about strictures (k = 0.82) and abscesses (k = 0.88), with better detection of enteroenteric fistulas (k = 0.67). Conclusions:BS and MR enterography are 2 accurate procedures for the diagnosis of small bowel CD, although MR seems to be more sensitive in defining its extension. BS could be used to select the patients for subsequent MRI examination.