Golimumab improves health-related quality of life of patients with moderate-to-severe ulcerative colitis: Results of the go-care study.

BACKGROUND: In recent years, improvement of Health-Related Quality of Life (HRQoL) in Ulcerative colitis (UC) has become a relevant measure for treatment efficacy. METHODS: We report results from a multicenter prospective study in Italy investigating HRQoL in adult patients with UC treated with golimumab (GLM). Patients who had shown clinical response after a 6-week induction phase (w0), were followed for an additional 48 weeks (w48) (total 54-week treatment). RESULTS: Of the 159 patients enrolled 90 completed the study. Compared to values at the beginning of treatment (n = 137), significant improvements were observed for mean total Inflammatory Bowel Disease Questionnaire (IBDQ) scores at w0 (168.5) and w48 (181.7). Patients with baseline PMS above the median tended to have greater improvements in IBDQ at w0 (OR 2.037, p = 0.033) and w48 (OR 3.292, p = 0.027). Compared to beginning of GLM treatment, the mean Full Mayo Score (FMS) decreased by 5.9 points at w48, while mean Partial Mayo Score (PMS) decreased by 3.9 points at w0 and by 4.9 points at w48. CONCLUSIONS: GLM improved HRQoL, disease activity and inflammatory biomarkers in UC patients with moderate-to-severely active disease. The greater the burden of disease activity at baseline, the greater the improvement of HRQoL after 24 and 48 weeks of treatment.

Antibodies to tissue-type plasminogen activator (t-PA) in patients with inflammatory bowel disease: high prevalence, interactions with functional domains of t-PA and possible implications in thrombosis.

BACKGROUND: Patients with inflammatory bowel disease (IBD) have an increased prevalence of thromboembolic events. The pathogenetic mechanisms of these events include reduced fibrinolysis, which may be caused by antibodies to tissue-type plasminogen activator (t-PA). OBJECTIVES: To evaluate anti-t-PA antibodies in patients with IBD, considering clinical, biochemical and functional characteristics. PATIENTS AND METHODS: We immunoenzymatically measured anti-t-PA antibodies in plasma from 97 consecutive IBD patients and 97 age- and sex-matched healthy controls. We also assessed the antibody interactions with different epitopes of t-PA, the antibody inhibition on t-PA activity and the correlations with clinical features and other serum antibodies. RESULTS: IBD patients had higher median anti-t-PA antibody levels (5.4 U mL(-1) vs. 4.0 U mL(-1); P < 0.0001): 18 patients were above the 95th percentile of the controls (OR 5.3; 95% CI 1.7-16.3; P < 0.003), and the six with a history of thrombosis tended to have high levels (6.9 U mL(-1)). Anti-t-PA antibody levels did not correlate with IBD type, activity, location or treatment, or with age, sex, acute-phase reactants or other antibodies. The anti-t-PA antibodies were frequently IgG1 and bound t-PA in fluid phase; they recognized the catalytic domain in 10 patients and the kringle-2 domain in six. The IgG fraction from the three patients with the highest anti-t-PA levels slightly reduced t-PA activity in vitro. CONCLUSIONS: The prevalence of anti-t-PA antibodies is high in IBD patients. By binding the catalytic or kringle-2 domains of t-PA, these antibodies could lead to hypofibrinolysis and contribute to the prothrombotic state of IBD.

Variants of OCTN1-2 cation transporter genes are associated with both Crohn's disease and ulcerative colitis.

BACKGROUND: Two variants in the organic cation transporter gene cluster have been recently reported to confer susceptibility to Crohn's disease (CD). AIM: To investigate these variants in CD and ulcerative colitis (UC), and their interaction with CARD15 gene and correlation to clinical subphenotypes. METHODS: Case-control association analysis was performed in 899 patients (444 CD and 455 UC) and 611 controls. The organic cation transporter gene cluster single nucleotide polymorphisms G207G-->C and 1672C-->T, the IGR2198a_1 single nucleotide polymorphism in the IBD5 locus, and the R702W, G908R and L1007finsC variants of CARD15 gene were genotyped by ABI-7700, restriction fragment length polymorphic analysis and multiplex pyrosequencing, respectively. RESULTS: The 1672TT and -207CC genotype frequencies were increased in both CD (OR = 1.5, P = 0.011; OR = 1.6, P = 0.002), and UC (OR = 1.5, P = 0.017; OR = 1.4, P = 0.033), respectively. Compared with controls, the TC haplotype frequency was increased in both CD (36% vs. 44%, P < or = 0.01) and UC (36% vs. 45%, P < or = 0.01). The frequency of the TC haplotype was 43% in CARD15-positive and 44% in CARD15-negative CD, respectively. Similar results were found in UC. In CD a significant association of the TC haplotype was found with presence of perianal fistulae (P = 0.007) and steno-fistulizing behaviour (P = 0.037). In UC, the TC haplotype was more frequent in patients with more extensive disease (P = 0.015), and those on immunosuppressives (P = 0.004). CONCLUSIONS: Organic cation transporter gene cluster variants may confer susceptibility to both CD and UC, and the TC haplotype may influence some clinical features of IBD, but does not interact with CARD15 variants.

Multidrug resistance 1 gene polymorphisms are not associated with inflammatory bowel disease and response to therapy in Italian patients.

BACKGROUND: Host genetic factors may be important in determining not only disease susceptibility, but also disease behaviour and response to therapy in inflammatory bowel disease. Two polymorphisms (C3435T and G2677T/A) of the multidrug resistance 1 gene have been correlated with the altered P-glycoprotein expression and function in humans, and associated with predisposition to ulcerative colitis and Crohn's disease. AIM: To investigate the contribution of these polymorphisms to disease susceptibility and response to medical therapy. METHODS: A total of 946 inflammatory bowel disease patients (478 Crohn's disease, 272 males, mean age 43 +/- 14 years and 468 ulcerative colitis, 290 males, mean age 48 +/- 15 years) and 450 healthy controls were genotyped for the single nucleotide polymorphisms C3435T and G2677T/A. Patients were also classified on the basis of response to medical therapy (mesalazine, steroids, immunosuppressives and infliximab). RESULTS: Both single nucleotide polymorphisms were in Hardy-Weinberg equilibrium and significant linkage disequilibrium. No significant difference in the allele, genotype, and haplotype frequencies was found in both Crohn's disease and ulcerative colitis patients compared with the controls. No correlation with clinical features was found, except for a reduced frequency of extra-intestinal manifestations in Crohn's disease patients with the G2677T genotype (40%) compared with GG2677 and 2677TT genotypes (54% and 58%, respectively) (P = <0.02). No significant difference was also found after stratifying the patients on the basis of their response to medical therapy. CONCLUSION: The investigated polymorphisms of the multidrug resistance 1 gene have no significant role in disease susceptibility and response to medical therapy in our Italian population of inflammatory bowel disease patients.

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 Crohn's disease. The relative role of CARD15 genotype and smoking in Crohn's disease progression is also debated. AIM: To investigate the association between CARD15 variants and history of resective surgery in patients with Crohn's ileal disease, taking into account smoking as a possible confounding factor. METHODS: We originally assessed CARD15 genotype in 239 north Italian Crohn's disease patients (mean follow-up: 10.1 +/- 8.1 years). We then focused on 193 patients with proven ileal involvement, 70 of whom (36.3%) carried CARD15-mutated alleles (G908R, R702W, L1007fs). RESULTS: Carriage of CARD15 variants was positively associated with family history and ileal-only disease and negatively associated with uncomplicated behaviour at maximal follow-up (P < 0.05). Ileal resection was the only variable independently associated with CARD15 variants at multivariate analysis (OR 3.8; 95% CI 1.6-9.2; P = 0.003). Kaplan-Meier analysis showed that ileal resection was favoured both by CARD15 variant-carriage (P = 0.01) and by smoking (P = 0.05), but smoking did not affect progression to surgery in variant carriers (P = 0.31). Thirteen of 14 (93%) patients being resection-free at 15-year follow-up, had CARD15 wild-type genotype (P = 0.01), whereas only seven (50%) had never smoked (P = 1.0). CONCLUSIONS: In summary, CARD15 variant-associated Crohn's ileitis is virtually committed to stricturing and/or penetrating disease and, eventually, to resective surgery. Smoking accelerates progression to surgery in patients with wild-type CARD15 genotype, but it seems to exert no additional effect in CARD15-variant carriers.

High prevalence of hyperchomocysteinemia in patients with inflammatory bowel disease: a pathogenic link with thromboembolic complications?

BACKGROUND AND AIMS: Why patients with inflammatory bowel disease are at increased risk for thrombosis is unknown. Since they may have impaired absorption of vitamins that regulate the metabolism of homocysteine, we tested the hypothesis that they have hyperhomocysteinemia, an established risk factor for arterial and venous thrombosis. METHODS: The concentrations of total homocysteine (tHcy), folate and cobalamin were measured in blood samples from 61 consecutive patients with inflammatory bowel disease and 183 age- and sex-matched healthy controls. RESULTS: The mean (+/- S.D.) concentration of plasma tHcy was higher in patients (12.2 +/- 7.7 micromol/l) than in controls (10.5 +/- 4.6, p = 0.045). Eight patients (13%) had concentrations of tHcy higher than the 95th percentile of distribution among controls, as compared with 9 healthy controls (5%, p = 0.04). The prevalence of folate deficiency was higher in patients (15%) than in controls (5%, p = 0.02). Oral administration of folate, cobalamin and pyridoxine to 15 patients for 30 days decreased their mean tHcy levels from 20.3 +/- 9.9 to 9.5 +/- 3.4 (p <0.001). CONCLUSIONS: In patients with inflammatory bowel disease there is an increased prevalence of hyperhomocysteinemia, which can be corrected by the administration of folate, cobalamin and pyridoxine. The high prevalence of hyperhomocysteinemia may account for the thrombotic risk of IBD patients; whether or not its correction will decrease the thrombotic risk should be tested in properly designed clinical trials.

Review article: diagnosis, monitoring and treatment of distal colitis.

The diagnostic work-up of ulcerative colitis at presentation is based on the collection of clinical, microbiological, radiological, endoscopic and histologic data. Serological markers are characterized by too low a sensitivity to be commonly utilized in clinical practice. Although endoscopic and histologic features are characterized by very high sensitivity and specificity for the diagnosis of ulcerative colitis, negative stool cultures and parasites are mandatory to exclude an infectious aetiology at presentation. The treatment of choice of an acute flare-up of distal ulcerative colitis is represented by oral or topical mesalazine, or a combination of both, whereas the use of topical or systemic steroids should be restricted to patients who prove to be refractory to first-line treatments. Preliminary data suggest that the achievement of endoscopic and histologic remission after an acute flare of the disease might be associated with a prolonged remission.

Diagnostic role and clinical correlates of anti-Saccharomyces cerevisiae antibodies (ASCA) and anti-neutrophil cytoplasmic antibodies (p-ANCA) in Italian patients with inflammatory bowel diseases.

BACKGROUND: Anti-Saccharomyces cerevisiae antibodies (ASCA) and perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) are serological markers associated, respectively, with Crohn's disease and ulcerative colitis, whose clinical significance and possible diagnostic role are still poorly defined. AIMS: (a) To evaluate the sensitivity, specificity and predictive values of isolated and combined ASCA and p-ANCA assays in a large cohort of Italian patients with inflammatory bowel disease (IBD) and (b) to assess whether their presence is associated with particular clinical features of the disease. PATIENTS AND METHODS: Hundred and forty-six IBD patients (93 with Crohn's disease and 53 with ulcerative colitis) and 54 control patients were enrolled in the study. ASCA (IgA and IgG) and p-ANCA were determined by means of enzyme-linked immunosorbent assay and indirect immunofluorescence, respectively. RESULTS: The specificities were excellent for both tests (ASCA in Crohn's disease, 98.1% both for IgA and IgG, and p-ANCA in ulcerative colitis, 92.5%); however, the sensitivities of both tests were low (59.1% for ASCA IgA, 44.1% for ASCA IgG, 39.6% for p-ANCA). ASCA specificity and positive predictive value reached 100% when positivity for both IgA and IgG was present. No significant association was found between the presence of a specific serological marker and patients' clinical features. CONCLUSIONS: This study confirms the low prevalence of p-ANCA observed in ulcerative colitis patients from the Mediterranean area. The low sensitivity of ASCA and p-ANCA, despite their rather high specificity, renders them of little value in the screening of the general population, where the prevalence of IBD is low. However, in our series, a double positivity for ASCA IgA and IgG identifies with certainty the presence of Crohn's disease.

Val34Leu factor XIII polymorphism in Italian patients with inflammatory bowel disease.

BACKGROUND: Coagulation Factor XIII is implicated in fibrin stabilization and wound healing. Plasma levels of Factor XIII are reduced in inflammatory bowel disease patients; recently, a valine 34 to leucine polymorphism of the Factor XIII-A subunit gene with a defined protective effect against thrombosis and as yet undetermined effect on wound healing has been described. AIM: To evaluate Val34Leu Factor XIII polymorphism distribution and to find possible correlations with clinical features in Italian inflammatory bowel disease patients. STUDY POPULATION: A total of 152 inflammatory bowel disease patients, 90 with ulcerative colitis and 62 with Crohn's disease and 130 healthy volunteers were studied. METHODS: Val34Leu polymorphism was detected by RFLP with BsaH I. Statistical analysis was performed by means of Fisher exact test. RESULTS: In inflammatory bowel disease, 57.2% of patients showed the wild type status, 37.5% were heterozygous and 5.3% were homozygous for the 34Leu allele; the frequency of the mutated allele was 24.0%. In controls, 66.1% of subjects showed the wild type status, 28.5% were heterozygous and 5.4% were homozygous for the 34Leu allele; the frequency of the mutated allele was 19.7%. There was no difference in genotype distribution and prevalence of the mutated allele between inflammatory bowel disease patients and controls. CONCLUSIONS: The present data do not show any differences in Val34Leu Factor XIII polymorphism distribution between inflammatory bowel disease patients and controls. The prothrombotic state described in inflammatory bowel disease patients does not depend on an altered distribution of Val34Leu Factor XIII polymorphism.

Exploring the relationships between inflammatory response and coagulation cascade in inflammatory bowel disease.

BACKGROUND: The inflammatory network and the coagulation cascade are strictly correlated biological systems. Inflammatory Bowel Diseases (IBD) are characterised by a prothrombotic state, a hypercoagulability state and an increased prevalence of thromboembolic events. METHODS: We reviewed the IBD literature in which the relationships between inflammation and coagulation were evaluated. RESULTS: Several risk factors and mechanisms have been suggested to be implicated in determining the increased risk for thrombosis of IBD. Even if IBD may be per se a prothrombotic condition, systemic inflammation and vitamin deficiencies appear to play a relevant role in determining such a risk. CONCLUSIONS: A good and continuous control of the intestinal disease and vitamin supplementation are strongly recommended in order to correct some of the risk factors for thrombosis in IBD patients.

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. AIM: To assess the safety of three different oral dosages (70, 140 and 210 mg once daily) of Parnaparin-MMX (CB-01-05) in left-sided ulcerative colitis (UC). METHODS: Left-sided UC patients, with a mild-to-moderate relapse were enrolled. All patients received Parnaparin-MMX for 8 weeks. Clinical Activity Index (CAI), Disease Activity Index (DAI), Endoscopic Activity Index and IBD-QoL were assessed throughout the study. A strict clinical and laboratory follow-up, including assessment of anti-factor Xa activity, was performed. Clinical remission was defined as CAI <4. RESULTS: Ten UC patients were enrolled. One patient retired for clinical deterioration. No relevant side effects, including either interference with haemostasis parameters or increased bleeding, were observed. At the end of the treatment, seven patients (70%) were in clinical remission, only one achieving endoscopic healing. Mean final CAI, DAI and IBD-QoL scores were significantly improved from baseline. CONCLUSIONS: Parnaparin-MMX appears to be a safe treatment option in mild-to-moderate UC. Controlled studies are warranted.

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 Crohn's 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.

Serum von Willebrand factor levels in patients with inflammatory bowel disease are related to systemic inflammation.

BACKGROUND: Increased levels of circulating von Willebrand factor (vWF) have been found in patients with inflammatory bowel disease (IBD); this increase may reflect either endothelial damage or systemic inflammation. Our aim was to evaluate serum vWF levels in patients with IBD and their correlation with clinical and biochemical disease activity. METHODS: We evaluated serum vWF levels in 32 patients with ulcerative colitis (UC) (10 active with increased acute-phase reactants (APR), 6 active with normal APR, 16 in remission), 27 with Crohn disease (CD) (10 active, 12 quiescent, and 5 quiescent with increased APR), and 31 healthy controls. RESULTS: Mean levels of vWF were 100.1 (standard deviation (s), 51.4) in IBD and 89.9 (s, 36.9) in controls (P = 0.33). Only five (8.47%) patients (three with active UC, one with active CD, and one with inactive CD but increased APR) showed circulating vWF levels higher than the upper limit of normal (150), compared with 1 (3.2%) of controls (P = 0.32). Among CD patients vWF levels were 80.0+/-25.4 in patients with quiescent disease and normal APR, 123.3+/-63.4 in patients with active disease (P = 0.04 versus inactive with normal APR), and 135.8+/-90.0 in patients with quiescent disease and increased APR (P = 0.059 versus inactive with normal APR). Among UC patients vWF levels were 82.7+/-35.6 in patients with quiescent disease and normal APR and 125.1+/-54.2 in those with active disease and increased APR (P = 0.002). Overall, mean vWF levels were significantly higher in patients with increased APR than in patients with normal APR (P = 0.0005) and controls (P = 0.009). CONCLUSIONS: Our data show slight but significant increases in serum vWF levels in patients with IBD, which are correlated with signs of systemic inflammation.

Reduced free protein S levels in patients with inflammatory bowel disease: prevalence, clinical relevance, and role of anti-protein S antibodies.

We evaluated free plasma levels of protein S, a natural anticoagulant factor, the prevalence of anti-protein S antibodies, a possible cause of protein S deficiency, and their correlation with anti-phospholipid antibodies in 53 patients with inflammatory bowel disease (IBD) and 53 age- and sex-matched controls. Mean free plasma protein S levels (+/- SD) were significantly lower in IBD patients (0.98+/-0.32 IU/ml) than in controls (1.06+/-0.28 IU/ml) (P < 0.05); only one patient showed protein S deficiency. Specific antibodies to protein S were found in four IBD patients (7.5%) and in one control (1.9%) (P = NS). Five IBD patients (9.4%) and none of the controls showed anti-phospholipid antibodies (P < 0.06). No correlation was found between free protein S levels and anti-protein S antibodies or between anti-protein S and anti-phospholipid antibodies. In conclusion, free plasma protein S levels are slightly but significantly decreased in IBD patients. The prevalence of anti-protein S and antiphospholipid antibodies is increased in IBD patients. Anti-protein S antibodies do not appear to determine low protein S levels or to overlap with or belong to anti-phospholipid antibodies.

Inflammatory bowel diseases are not associated with major hereditary conditions predisposing to thrombosis.

Patients with inflammatory bowel diseases (IBD) are at increased risk for thromboembolic complications. Our aim was to evaluate whether the increased risk for thrombosis in IBD could be due to a genetic association of IBD with hereditary prothrombotic conditions. In all, 102 IBD patients (51 with ulcerative colitis and 51 with Crohn's disease) with no history of thrombosis and 204 matched normal subjects were enrolled. DNA specimens were evaluated by PCR and restriction fragment length polymorphism for factor V Leiden, methylene tetrahydrofolate reductase (MTHFR) and prothrombin gene mutations. In IBD patients and matched controls the observed allele frequencies were similar, being 1.5% and 1.2% for factor V Leiden gene mutation, 1.1% and 0.7% for prothrombin gene mutation, and 45.1% and 47.4% for MTHFR gene mutation, respectively. These rates also were not significantly different when patients were analyzed according to age and sex distribution, diagnosis, and extension and clinical type of disease. In conclusion, our study shows no association between IBD and the most frequent hereditary prothrombotic conditions. Other factors should be evaluated in order to understand the mechanisms underlying the thrombotic risk of IBD.

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 Crohn's 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 Reiter's syndrome, 4 Behçet's 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 alpha1-acid glycoprotein were measured as acute-phase reactants. Statistical analysis was performed by means of nonparametric tests and Fisher's exact test and chi(2) 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< or = 0.05 and p< or = 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< or = 0.008 and p< or = 0.0001, respectively) and more frequent in clinically active IBD than in clinically quiescent IBD (31.4%vs 10.9%, p< or = 0.03). Finally, in IBD, significant correlations were observed between TAFI plasma levels and erythrocytes sedimentation rate (p< or = 0.02), C-reactive protein (p< or = 0.001), and alpha1-acid glycoprotein (p< or = 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.

Activated platelets are the source of elevated levels of soluble CD40 ligand in the circulation of inflammatory bowel disease patients.

BACKGROUND: The CD40/CD40L system, a key regulator and amplifier of immune reactivity, is activated in inflammatory bowel disease (IBD) mucosa. AIMS: To determine whether plasma levels of sCD40L are elevated in Crohn's disease (CD) and ulcerative colitis (UC) patients compared with normal controls, to investigate the cellular source of sCD40L, and to explore CD40L induction mechanisms. PATIENTS: CD, UC, and normal control subjects were studied. METHODS: The concentration of sCD40L in plasma and supernatants of freshly isolated platelets and autologous peripheral blood T cells (PBT) was measured by ELISA. Surface CD40L expression level was measured by flow cytometry in resting and thrombin activated platelets, and unstimulated and CD3/CD28 stimulated PBT before and after coculture with human intestinal microvascular endothelial cells (HIMEC). RESULTS: Compared with normal controls, plasma sCD40L levels were significantly higher in both CD and UC patients and proportional to the extent of mucosal inflammation. Platelets from IBD patients displayed a significantly higher surface CD40L expression than those from control subjects, and released greater amounts of sCD40L than autologous PBT. Contact with IL-1beta activated HIMEC induced significant upregulation of CD40L surface expression and release by platelets. CONCLUSIONS: Elevated levels of sCD40L in the circulation of IBD patients reflect enhanced surface expression and release of CD40L by platelets. This phenomenon translates to an increased platelet activation state apparently induced by passage through an inflamed mucosal microvascular bed, a conclusion supported by the positive correlation of plasma sCD40L levels with the extent of anatomical involvement by IBD. These results suggest that platelet-endothelial interactions critically contribute to activation of the CD40 pathway in IBD.

Segmental colitis associated with diverticula: a prospective study. Gruppo di Studio per le Malattie Infiammatorie Intestinali (GSMII).

OBJECTIVE: Little is known about the clinical features and natural history of segmental colitis associated with diverticula. Our aim was to evaluate the incidence of segmental colitis associated with diverticula in patients undergoing colonoscopy, its clinical picture, and its outcome. METHODS: This was a multicenter, prospective study. Patients with inflammatory bowel disease (IBD)-like lesions limited to colonic segments with diverticula were enrolled. Patients were treated with oral and topical 5-aminosalicylic (5-ASA) until remission was achieved; clinical and endoscopic follow-up was planned at 6 wk and 12 months. RESULTS: A total of 5457 consecutive colonoscopies were recorded at five participating institutions; 20 patients (0.36%) met the endoscopic criteria for segmental colitis associated with diverticula. All had lesions in the left colon, and one also had lesions in the right colon. In six cases, a specific diagnosis was made thereafter. The remaining 14 patients (0.25% of colonoscopies; eight men; age range, 49-80 yr) were in clinical and endoscopic remission at the first follow-up visit. At onset, 13/14 had hematochezia, seven had diarrhea, and five had abdominal pain; only one had weight loss. No subject had fever. In all but one case, blood chemistries were normal. Five patients had had similar symptoms previously. Thirteen of 14 patients were in clinical and endoscopic remission at 12 months. CONCLUSIONS: This endoscopic picture is not an exceptional finding. Hematochezia was the main clinical feature, and no relation with gender, age, or smoking habit was found. Blood chemistries were generally normal and the rectum was spared. The histological features were not diagnostic and most patients did not complain of any abdominal symptoms 12 months after enrollment.