Ivana Bravatà

Integrins and adhesion molecules as targets to treat inflammatory bowel disease

Inflammatory bowel diseases (IBD) present a typically relapsing-remitting behavior and are characterized by a disabling and progressive course. Anti-tumor necrosis factor (TNF)-α agents have drastically changed the therapeutic management of IBD. However, a significant proportion of patients does not have a primary response, some patients lose response overtime and/or experience side effects. Recently, anti-adhesion molecules were investigated and showed efficacy with a good safety profile. Vedolizumab was recently approved for both Crohns disease (CD) and ulcerative colitis (UC) and several other molecules are under evaluation in this field. Anti-adhesion molecules could represent a potential therapeutic option for future therapy in IBD. In this review we report the efficacy and safety of major anti-adhesion drugs in active IBD patients.

Liver Function Test Abnormalities in Patients with Inflammatory Bowel Diseases: A Hospital-based Survey.

Background and Aims Inflammatory bowel diseases (IBD) are frequently associated with altered liver function tests (LFTs). The causal relationship between abnormal LFTs and IBD is unclear. The aim of our study was to evaluate the prevalence and etiology of LFTs abnormalities and their association with clinical variables in a cohort of IBD patients followed up in a single center. Materials and Methods A retrospective review was undertaken of all consecutive IBD in- and outpatients routinely followed up at a single referral center. Clinical and demographic parameters were recorded. Subjects were excluded if they had a previous diagnosis of chronic liver disease. LFT abnormality was defined as an increase in aspartate aminotransferase, (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), or total bilirubin. Results A cohort of 335 patients (179 males, mean age 46.0 ± 15.6 years) was analyzed. Abnormal LFTs were detected in 70 patients (20.9%). In most cases, the alterations were mild and spontaneously returned to normal values in about 60% of patients. Patients with abnormal LFTs were less frequently on treatment with aminosalicylates (22.8 vs. 36.6%, P = 0.04). The most frequent cause for transient abnormal LFTs was drug-induced cholestasis (34.1%), whereas fatty liver was the most frequent cause of persistent liver damage (65.4%). A cholestatic pattern was found in 60.0% of patients and was mainly related to older age, longer duration of disease, and hypertension. Conclusions The prevalence of LFT abnormalities is relatively high in IBD patients, but the development of severe liver injury is exceptional. Moreover, most alterations of LFTs are mild and spontaneously return to normal values. Drug-induced hepatotoxicity and fatty liver are the most relevant causes of abnormal LFTs in patients with IBD.

Increased expression of markers of early atherosclerosis in patients with inflammatory bowel disease

BACKGROUND & AIMS Recent studies documented an increased cardiovascular risk in patients with inflammatory bowel disease (IBD). Our study aimed at investigating the prevalence of intima-media thickness (IMT) of the carotid arteries and the arterial stiffness indices as markers of early atherosclerosis in young IBD patients. METHODS We recruited 68 consecutive IBD patients, and 38 matched healthy controls less than 45years old (median age 31.6±8.1years). Clinical and demographic features, cardiovascular risk factors, history of cardiovascular events, concomitant therapies were registered on a dedicate database. Carotid IMT was evaluated by using high resolution B-mode ultrasonography. Arterial stiffness was assessed by measurement of carotid-femoral Pulse Wave Velocity (PWV) and Augmentation Index (AIx). RESULTS Total cholesterol (P<0.013) and LDL-cholesterol (P<0.019) levels were significantly lower in IBD patients compared to controls. Carotid IMT was higher in IBD than in controls (P<0.047), but there was no statistically significant difference among Crohns Disease (CD) and Ulcerative Colitis (UC) patients. Moreover, PWV and AIx were significantly higher in patients as compared to controls (P<0.006 and P<0.004 respectively). No medication seemed to affect vascular measurements, though stiffness parameters were significantly higher in patients treated with 5-ASA (11.9 (9.7) vs 18.2 (10.2), P<0.021), suggesting a lack of efficacy of 5-ASA in protecting IBD patients from early atherogenesis. CONCLUSIONS Young IBD patients show an increase in subclinical markers of atherosclerosis. Future studies need to address whether these markers result in an increased risk of cardiovascular events in these patient.

Splenic littoral cell hemangioendothelioma in a patient with Crohn's disease previously treated with immunomodulators and anti-TNF agents: a rare tumor linked to deep immunosuppression.

Splenic Littoral Cell Hemangioendothelioma in a Patient With Crohns Disease Previously Treated With Immunomodulators and Anti-TNF Agents: A Rare Tumor Linked to Deep Immunosuppression

Genetic predisposition to thrombophilia in inflammatory bowel disease.

Background Inflammatory bowel disease (IBD) is linked to a definite risk of thromboembolic events (TE), but data on the role of prothrombotic genetic mutations are conflicting. Study Fourteen genetic factors involved in TE pathogenesis were investigated in a homogeneous cohort of Sicilian patients with IBD with and without history of TE and in healthy controls. Forty IBD patients (21 CD, 19 UC) and 20 healthy individuals were enrolled. Genetic testing was based on the reverse hybridization principle by a commercial assay that analyzes 14 polymorphisms involved in thrombophilia and cholesterol metabolism. The rate of genetic polymorphisms and mutations was compared between IBD patients and healthy controls. Results No significant difference in allelic frequency was found between IBD patients and controls except AGT T/T, though a trend toward significance was found also for ACE D/D. Eight out of 9 patients with earlier history of TE had more than 1 polymorphism, compared with 12 out of 31 without TE. In patients with IBD the mutation AGT T/T was related to male sex (P<0.0259) and, marginally, to arterial hypertension (P<0.06) and diabetes (P<0.09). Conclusions Our data confirm a definite risk of TE in IBD (22.5% of our series). An increased frequency of the genotypes ACE D/D and AGT T/T, never reported so far, was found. In IBD patients TE has a multifactorial genesis with involvement of several genes as well and acquired factors. Genetic screening for prothrombotic factors could help segregate IBD patients at higher risk of TE.

Non-Organ Specific Autoantibodies (NOSA) Induced by Anti-Tumor Necrosis Factor-Alpha Agents for Inflammatory Bowel Disease (IBD) Are Not Associated With Overt Autoimmune Disease

Background: Hepatosplenic T-cell lymphoma is a feared complication of thiopurine treatment for Inflammatory Bowel Disease. While estimates of the risk of Hepatosplenic T-cell lymphoma have been stated in the past, it has not been possible to calculate an estimated incidence as no population based studies of patients with IBD on thiopurines has yet reported a case of HSTCL. Aims: Here we aim to calculate the incidence of HSTCL via a meta-analysis of three population based studies of IBD patients taking thiopurine therapy. We also aim to calculate the relative risk of HSTCL. Methods: We included three population based studies in our analysis, a study from the UK, (Armstrong 2010 Am J of Gastro), one from France (CESAME; Beaugerie 2009 Lancet), and one from Spain (Gisbert Gastro 2010). In our study data were extracted from the Spanish collaborative registry ENEIDA (of which the Gisbert study was published). We examined overall incidence, the incidence in men, those less than 36 years old, and men under 36 years old. 95% confidence intervals (CIs) were estimated by summing observed and expected cases of lymphoma. CIs assumed a Poisson distribution. To examine for heterogeneity, the deviance statistic from Poisson regression models was examined. All patient studies were in compliance with the Helsinki Protocol. Results: One case of HSTCL was present among the three studies, (in ENEIDA). The overall incidence was 1.32 cases per 100,000 person-years with a number needed to harm (NNH) of 1:75,488 patients per year. For men, the incidence was 2.69 cases per 100,000 person-years with an NNH of 1:37,208 per year, and in those under 36 years of age the incidence was 3.63 cases per 100,000 person years with an NNH of 1:27,528. In men under 36, the incidence was 7.93 cases per 100,000 person years with an NNH of 1:12,616 patients per year. Confidence intervals were very large secondary to only one patient being described and there was no significant heterogeneity (see Table 1). Conclusion: In a recent systematic review of HSTCL in IBD (Kotlyar 2010, Clin Gastroenterol Hepatol), while incidence could not be estimated, the absolute risk was estimated at being 1:44,444 overall and 1:7404 in men under 35. These estimates accord with calculated numbers needed to harm of 1:75,488 per year overall and 1:12,616 per year in men under 36. Confidence Interval for Incidence and Tests for Heterogeneity