Luisa Spina

Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis.

IL-33 is a novel member of the IL-1 family and ligand for the IL-1 receptor-related protein, ST2. Recent evidence suggests that the IL-33/ST2 axis plays a critical role in several autoimmune and inflammatory disorders; however, its role in inflammatory bowel disease (IBD) has not been clearly defined. We characterized IL-33 and ST2 expression and modulation after conventional anti-TNF therapy in Crohn’s disease and ulcerative colitis (UC) patients and investigated the role of IL-33 in SAMP1/YitFc (SAMP) mice, a mixed Th1/Th2 model of IBD. Our results showed a specific increase of mucosal IL-33 in active UC, localized primarily to intestinal epithelial cells (IEC) and colonic inflammatory infiltrates. Importantly, increased expression of full-length IL-33, representing the most bioactive form, was detected in UC epithelium, whereas elevated levels of cleaved IL-33 were present in IBD serum. ST2 isoforms were differentially modulated in UC epithelium, and sST2, a soluble decoy receptor with anti-inflammatory properties, was also elevated in IBD serum. Infliximab (anti-TNF) treatment of UC decreased circulating IL-33 and increased sST2, whereas stimulation of HT-29 IEC confirmed IL-33 and sST2 regulation by TNF. Similarly, IL-33 significantly increased and correlated with disease severity, and potently induced IL-5, IL-6, and IL-17 from mucosal immune cells in SAMP mice. Taken together, the IL-33/ST2 system plays an important role in IBD and experimental colitis, is modulated by anti-TNF therapy, and may represent a specific biomarker for active UC.

Low vitamin B6 plasma levels, a risk factor for thrombosis, in inflammatory bowel disease: Role of inflammation and correlation with acute phase reactants

OBJECTIVES:Individuals with inflammatory bowel disease (IBD) are at increased risk for thrombosis and vitamin deficiencies. Low plasma levels of vitamin B6 are an independent risk factor for thrombosis and may cause hyperhomocysteinemia, another recognized risk factor for thrombosis. The aim of this study was to evaluate vitamin B6 plasma levels in IBD patients.METHODS:We studied 61 IBD patients: 32 with Crohn’s disease and 29 with ulcerative colitis. For each patient, three sex- and age-matched healthy control subjects were studied.RESULTS:Median vitamin B6 levels were significantly lower in IBD patients (22.0 pmol/L, range 3.6–231.0) than in controls (31.1 pmol/L, 3.7–363.4; p < 0.01). In all, 13.1% IBD patients and 5.5% controls had plasma vitamin B6 levels lower than the 5th percentile of distribution in normal controls (p < 0.05). Low vitamin B6 levels were significantly more frequent in patients with active disease than in patients with quiescent disease (seven of 26, 26.9%, vs one of 35, 2.9%; p < 0.001). Moreover, patients with active disease had significantly lower median vitamin B6 levels (13.4 pmol/L, range 3.6–124.0) than patients in a quiescent phase (27.0 pmol/L, 7.8–231.0; p < 0.001). Low vitamin B6 levels were significantly correlated with serum concentrations of C-reactive protein (r = −0.36, 95% CI = −0.59 to −0.09, p < 0.01) and α1-acid-glycoprotein (r = −0.37, 95% CI = −0.59 to −0.10, p < 0.01). Hyperhomocysteinemia was more frequent in patients with low vitamin B6 levels (three of eight, 37.5%) than in patients with normal levels (nine of 53, 17.0%; p = 0.18). There was no statistically significant correlation between vitamin B6 and homocysteine plasma levels (r = −0.13, 95% CI = −0.37 to +0.14, p = 0.33).CONCLUSIONS:Low vitamin B6 plasma levels, an independent risk factor for thrombosis, are frequent in patients with IBD, especially those with active disease.

Thrombosis in inflammatory bowel diseases : Role of inherited thrombophilia

BACKGROUND:Inflammatory bowel diseases (IBD) are characterized by an increased risk for venous and arterial thrombosis. Although the pathogenetic mechanisms of this predisposition are unclear, a possible role of inherited risk factors for thrombosis in determining this predisposition has been suggested.AIM:To evaluate the role of factor V Leiden (G1691A) and G20210A prothrombin gene mutations in determining the occurrence of thrombosis in IBD patients.PATIENTS AND METHODS: Forty-seven IBD patients (30 ulcerative colitis and 17 Crohns disease) with a positive history for thrombosis (9 at arterial sites and 38 at venous sites) were enrolled in the study. For each patient, two non-IBD subjects matched for sex and age, type, and site of thrombosis were used as controls. Peripheral blood DNA specimens were amplified by PCR using appropriate primers and analyzed by restriction analysis on agarose gel electrophoresis. Statistical analysis was performed by means of Fishers exact test.RESULTS:The total number of subjects with one or both mutations was significantly lower in IBD patients with thrombosis than in control subjects (12.8%vs 29.8%, respectively; p= 0.035, OR = 0.34, 95% CI 0.13–0.90). The total frequency of the mutated alleles was also significantly lower in IBD than in controls (7.4%vs 16.5%, respectively; p= 0.041, OR = 0.40, 95% CI 0.17–0.96). Prothrombotic mutations were particularly unfrequent in IBD patients with active disease at the time of thrombosis compared with patients with quiescent disease (8.0%vs 36.4%, respectively; p= 0.057, OR = 0.15, 95% CI 0.02–1.01).CONCLUSIONS:The major inherited risk factors for thrombosis are significantly less frequent in thrombotic IBD patients than in thrombotic non-IBD subjects, suggesting that acquired risk factors play the most relevant role in determining thromboembolic events observed in IBD patients, particularly during active phases of the disease.

Assessment of Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Plasma Levels in Inflammatory Bowel Diseases

OBJECTIVES:Hypofibrinolysis has been proposed as a possible mechanism underlying the known risk of thrombosis observed in patients with inflammatory bowel diseases (IBD). Thrombin-activatable fibrinolysis inhibitor (TAFI) is a recently described inhibitor of fibrinolysis. Increased TAFI plasma levels are associated with a risk for venous thrombosis. The objective was to evaluate TAFI plasma levels and their possible correlations with clinical features and acute-phase reactants in IBD patients.METHODS:Eighty-one IBD patients (47 Crohns disease and 34 ulcerative colitis) and 81 sex- and age-matched healthy controls were enrolled in the study; moreover, we studied 30 inflammatory controls (13 Reiters syndrome, 4 Behçets syndrome, and 13 patients with newly diagnosed celiac disease). TAFI plasma levels were assessed by means of a commercially available ELISA kit. Erythrocytes sedimentation rate, C-reactive protein, and α1-acid glycoprotein were measured as acute-phase reactants. Statistical analysis was performed by means of nonparametric tests and Fishers exact test and χ2 test for independence.RESULTS:Median TAFI plasma levels were significantly higher in IBD patients (116.0%, range: 39.0–232.0%) and in inflammatory controls (176.0%, 50.0–435.0%) than in healthy controls (99.0%, 40.0–170.0%) (p≤ 0.05 and p≤ 0.001, respectively). TAFI plasma levels higher than the 95th percentile of control values were significantly more frequent in IBD patients (19.7%) and in inflammatory controls (53.3%) than in healthy controls (4.9%) (p≤ 0.008 and p≤ 0.0001, respectively) and more frequent in clinically active IBD than in clinically quiescent IBD (31.4% vs 10.9%, p≤ 0.03). Finally, in IBD, significant correlations were observed between TAFI plasma levels and erythrocytes sedimentation rate (p≤ 0.02), C-reactive protein (p≤ 0.001), and α1-acid glycoprotein (p≤ 0.05).CONCLUSIONS:TAFI plasma levels are increased in IBD patients and correlate with acute-phase reactants. Increased TAFI plasma levels might contribute to the prothrombotic state observed in IBD through the induction of hypofibrinolysis.

Oral, colonic-release low-molecular-weight heparin : an initial open study of Parnaparin-MMX for the treatment of mild-to-moderate left-sided ulcerative colitis

Background  Efficacy of heparin and low‐molecular‐weight heparins (LMWHs) in inflammatory bowel disease (IBD) treatment has been suggested. The multimatrix oral formulation MMX releases active drugs in the colon, avoiding systemic absorption. Parnaparin sodium is the LMWH chosen to be carried in the MMX formulation.

The use of thiopurines for the treatment of inflammatory bowel diseases in clinical practice.

BACKGROUND Thiopurines are the most commonly used immunomodulatory drugs in inflammatory bowel diseases. AIM To evaluate the use, the therapeutic and safety profiles of thiopurines in a large sample of IBD patients. METHODS We reviewed 3641 case histories of IBD patients. Thiopurines were prescribed in 582 patients (16.0%); the analysis was performed on the 553 (267 ulcerative colitis, 286 Crohns disease) with exhaustive clinical data. RESULTS The main indications for treatment were steroid-dependence (328/553, 59.3%) and steroid-resistance (113/553, 20.7%). Thiopurines were started when CD were younger than UC patients (p<0.001) but earlier from diagnosis in UC than in CD patients (p=0.003). Efficacy was defined as optimal (258/553, 46.6%), partial (108/553, 19.5%), absent (85/553, 15.4%) and not assessable (102/553, 18.4%). Efficacy was independent of disease type, location/extension or duration and age at starting. Side effects were observed in 151/553 (27.3%) patients, leading to drug discontinuation in 101 (18.3%). 15 out of the 130 (11.5%) patients who took thiopurines for more than 4 years relapsed, more frequently in CD than in UC (OR=3.67 95% C.I. 0.98-13.69; p=0.053). CONCLUSIONS Thiopurines confirm their clinical usefulness and acceptable safety profile in managing complicated IBD patients. The majority of patients treated for longer than 4 years maintain response. No clinical and demographic predictive factors for efficacy and side effects were identified.

Contribution of IBD5 Locus to Clinical Features of IBD Patients

AIM:The aim of this study was to investigate the influence of the IBD5 locus on clinical features of inflammatory bowel disease (IBD) patients, and its possible interaction with the CARD15 gene.PATIENTS AND METHODS:A cohort of 1,199 IBD patients (570 with CD and 629 with ulcerative colitis [UC]), and 357 healthy subjects were investigated. Information on clinical features was fully available for 855 IBD patients. Two SNPs in the IBD5 locus (IGR2198a_1 and IGR2096a_1) and the three major variants of CARD15 gene were genotyped in patients and controls.RESULTS:Homozygous carriers of risk alleles were significantly more frequent in CD (22.6% for IGR2198a_1, OR = 1.6, p= 0.015; 21.9% for IGR2096a_1, OR = 1.6, p= 0.012) compared to controls (16.8% and 15.7%, respectively). The homozygote frequency was also increased in UC patients, but not significantly. No significant gene-gene interaction was detected between IBD5 and CARD15. A univariate analysis detected association between IBD5 and steno/fistulizing behavior in CD patients (OR = 1.9; p= 0.004), and presence of more extensive colitis in UC patients (OR = 1.7; p= 0.01). Results from multiple logistic regression, after correction for covariates, showed that the influence of IBD5 on clinical outcome of CD was completely masked by that of CARD15, while the influence on more extensive colitis in UC patients was confirmed.CONCLUSIONS:Our study shows that presence of the IBD5 risk alleles, particularly in the homozygous state, is associated with IBD and especially with CD, without a significant epistasis with CARD15. The contribution of CARD15 risk alleles to CD clinical features is prominent on that of IBD5.

Carriage of CARD15 variants and smoking as risk factors for resective surgery in patients with Crohn's ileal disease

Background:  It is controversial whether CARD15 variants are truly associated with a more severe form of Crohns disease. The relative role of CARD15 genotype and smoking in Crohns disease progression is also debated.

Neurological disorders and inflammatory bowel diseases

Extraintestinal manifestations occur in about one-third of patients living with inflammatory bowel disease (IBD) and may precede the onset of gastrointestinal symptoms by many years. Neurologic disorders associated with IBD are not frequent, being reported in 3% of patients, but they often represent an important cause of morbidity and a relevant diagnostic issue. In addition, the increasing use of immunosuppressant and biological therapies for IBD may also play a pivotal role in the development of neurological disorders of different type and pathogenesis. Hence, we provide a complete and profound review of the main features of neurological complications associated with IBD, with particular reference to those related to drugs and with a specific focus on their clinical presentation and possible pathophysiological mechanisms.

Microscopic Colitis and Colorectal Neoplastic Lesion Rate in Chronic Nonbloody Diarrhea: A Prospective, Multicenter Study

Background:Lymphocytic and collagenous colitis are emerging as common findings in subjects undergoing colonoscopy for chronic non-bloody diarrhea (CNBD). Data concerning microscopic colitis (MC) are still limited and affected by controversial epidemiological evidences. Recent converging lines of evidence suggest that MC correlates a lower risk of colorectal neoplasia. Accordingly, we prospectively assessed MC prevalence in a multicenter cohort of subjects submitted to colonoscopy for CNBD, thereby defining whether MC influences the risk of colorectal neoplasia. Methods:Consecutive patients with CNBD of unknown origin underwent pan-colonoscopy with multiple biopsies. The prevalence of neoplastic patients in MC was compared with that observed in negative CNBD subjects. Results:Among 8006 colonoscopy, 305 subjects were enrolled for CNBD. Patients with CNBD were more likely to be women than men (odds ratio = 1.5; P = 0.001). Histopathology detected high prevalence of MC (16%) with a clear predominance of collagenous colitis (70%). A striking age-dependent rise in MC-associated risk was observed, depicting outstanding differences among varying age groups, as in the number needed to screen 1 new case. Gender distribution was balanced within MC patients (Female/Male = 1.5/1), especially among lymphocytic colitis (Female/Male = 1.2/1). MC patients were negatively associated with the risk of neoplastic polyps compared with negative CNBD subjects (odds ratio = 0.22; P = 0.035). Conclusions:MC is the first cause of CNBD in subjects submitted to colonoscopy. Multiple biopsies are strongly recommended, even in the case of uneventful endoscopic inspection, especially for age ≥40 years. MC has a reduced risk of colorectal neoplasia, suggesting that this model of chronic inflammation plays a protective effect against colorectal carcinogenesis.