Siro Bagnoli

Divergent patterns of total and cancer mortality in ulcerative colitis and Crohn’s disease patients: the Florence IBD study 1978–2001

Background and aims: Two divergent patterns of mortality for smoking related diseases in ulcerative colitis and Crohn’s disease patients were suggested in a previous population based study in Florence, Italy. Long term follow up (median 15 years) was completed to re-evaluate mortality in this Mediterranean cohort. Patients and methods: Overall, 920 patients with inflammatory bowel disease were followed until December 2001 or death, with seven patients (0.8%) lost to follow up. A total of 14 040 person years were available for analysis; 118 deaths were observed (81/689 in ulcerative colitis and 37/231 in Crohn’s disease). Expected deaths were estimated using age, sex, and calendar specific national and local mortality rates; standardised mortality ratios (SMR) and 95% confidence interval (CI) were calculated. Results: Among Crohn’s disease patients, mortality was strongly increased for gastrointestinal diseases (SMR 4.49 (95% CI 1.80–9.25)), all cancers (SMR 2.10 (95% CI 1.22–3.36)), and lung cancer (SMR 4.00 (95% CI 1.60–8.24)), leading to a significant 50% excess total mortality. Ulcerative colitis patients showed a significantly reduced total mortality because of lower cardiovascular (SMR 0.67 (95% CI 0.45–0.95)) and lung cancer (SMR 0.32 (95% CI 0.07–0.95)) mortality. No significant excess for colorectal cancer mortality was evident in this extended follow up. Conclusions: These clearly divergent patterns of mortality correlate with documented differences in smoking habits between Crohn’s disease and ulcerative colitis patients. Family doctors and gastroenterologists should consider stopping cigarette smoking a specific priority for Crohn’s disease patients; the latter should be offered free participation in structured programmes for smoking cessation, with the aim of reducing smoking related excess mortality. Overall, no evidence of an increased mortality for large bowel cancer emerged in this series.

The Vitamin D analogue TX 527 blocks NF-κB activation in peripheral blood mononuclear cells of patients with Crohn's disease

Crohns disease (CD) is an inflammatory disease characterized by the activation of the immune system in the gut. Since tumor necrosis factor (TNF-alpha) plays an important role in the initiation and perpetuation of intestinal inflammation in CD, we investigated whether TX 527 [19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3)], a Vitamin D analogue, could affect peripheral blood mononuclear cells (PBMC) proliferation and exert an immunosuppressive effect on TNF-alpha production in CD patients, and whether this immunosuppressive action could be mediated by NF-kappaB down-regulation. TX 527 significantly decreased cell proliferation and TNF-alpha levels. On activation, NF-kappaB, rapidly released from its cytoplasmatic inhibitor (IKB-alpha), transmigrates into the nucleus and binds to DNA response elements in gene promoter regions. The activation of NF-kappaB, stimulated by TNF-alpha, and its nuclear translocation together with the degradation of IKB-alpha were blocked by TX 527. At the same time, NF-kappaB protein levels present in cytoplasmic extracts decreased in the presence of TNF-alpha and increased when PBMC were incubated with TX 527. The results of our studies indicate that TX 527 inhibits TNF-alpha mediated effects on PBMC and the activation of NF-kappaB and that its action is mediated by Vitamin D receptor (VDR), which is activated when the cells are stimulated with TX 527.

Treatment of perianal fistulas in Crohn's disease by local injection of antibody to TNF-α accounts for a favourable clinical response in selected cases: A pilot study

Objective. Intravenously administered infliximab, a monoclonal antibody directed against tumor necrosis factor-α, has been proven to be efficacious in the treatment of fistulas in patients with Crohns disease. It has recently been suggested that local injections of infliximab might be beneficial as well. The aim of this study was to assess whether infliximab could play an effective role in the local treatment of perianal fistulas in Crohns disease. Material and methods. Local infliximab injections were administered to 11 patients suffering from Crohns disease complicated by perianal disease. Eligible subjects included Crohns disease patients with single or multiple draining fistulas, regardless of status of luminal disease at baseline. Patients, however, were excluded from the study if they had perianal or rectal complications, such as abscesses or proctitis or if they had previously been treated with infliximab. Twenty-milligram doses of infliximab were injected along the fistula tract and around both orifices at baseline and then every 4 weeks for up to 16 weeks or until complete cessation of drainage. No further doses were administered to patients who did not respond after three injections. Efficacy was measured in terms of response (a reduction in fistula drainage of 50% or more) and remission (complete cessation of fistula drainage for at least 4 weeks). Time to loss of response and health-related quality of life were also evaluated. Results. Overall, 8/11 patients (72.7%) responded to the therapy and 4/11 (36.4%) reached remission, whereas 3/11 patients (27.2%) showed no response. Response or remission was very much dependent on the location of the fistulas, and time to loss of response was generally longer for patients who reached remission compared to patients in response. Changes in health-related quality of life, as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ), also reflected response or remission, with more marked improvements associated with remission. After a mean 10.5 months’ follow-up (range 7–18 months), 6/11 patients (54.5%) are in response and 4/11 patients (36.4%) are in remission. No adverse events have been observed in this cohort of patients. Conclusions. Local injections of infliximab along the fistula tract seem to be an effective and safe treatment of perianal fistulas in Crohns disease. However, further controlled clinical investigations are warranted.

Alzheimer’s Disease: Role of Size and Location of White Matter Changes in Determining Cognitive Deficits

This study investigated the contribution that white matter changes (WMCs) make to clinical and cognitive features in Alzheimer’s disease (AD), independently ofpossible confounders such as cortical atrophy and the apolipoprotein E genotype as well as their relationship to vascular risk factors. We semiquantitatively assessed the degree and location of WMCs (global, periventricular and deep white matter), lacunes and global atrophy on brain MRI scans of 86 AD cases, extensively evaluated from a clinical and neuropsychological point of view. Multivariate logistic and linear regression analysis showed that age was the only significant predictor of all WMC measures and revealed a significant association of periventricular WMCs with performance on executive function tasks as well as of deep WMCs with history of mood depression. Our results underline the significance of WMC location over size in the occurrence of specific cognitive deficits in AD.

Ultrasound discloses entheseal involvement in inactive and low active inflammatory bowel disease without clinical signs and symptoms of spondyloarthropathy

OBJECTIVE To investigate the presence of lower limb entheseal abnormalities in IBD patients without clinical signs and symptoms of SpA and their correlation with IBD clinical variables. METHODS A total of 81 IBD patients [55 Crohns disease (CD) and 26 ulcerative colitis (UC), 43 females and 38 males, mean age 41.3 (12.4) years, BMI 24 (2)] with low active (12) and inactive (67) disease were consecutively studied with US (LOGIQ5 General Electric 10-MHz linear array transducer) of lower limb entheses and compared with 40 healthy controls matched for sex, age and BMI. Quadriceps, patellar, Achilleon and plantar fascia entheses were scored according to the 0-36 Glasgow Ultrasound Enthesitis Scoring System (GUESS) and power Doppler (PD). Correlations of GUESS and PD with IBD features [duration, type (CD/UC) and activity (disease activity index for CD/Truelove score for UC)] were investigated. The intra- and inter-reader agreements for US were estimated in all images detected in patients and controls. RESULTS Of the 81 patients, 71 (92.6%) presented almost one tendon alteration with mean GUESS 5.1 (3.5): 81.5% thickness (higher than controls P < 0.05), 67.9% enthesophytosis, 27.1% bursitis and 16.1% erosions. PD was positive in 13/81 (16%) patients. In controls, US showed only enthesophytes (5%) and no PD. GUESS and PD were independent of duration, activity or type (CD/UC) of IBD. The intra- and inter-reader agreements were high (>0.9 intra-class correlation variability). CONCLUSIONS US entheseal abnormalities are present in IBD patients without clinical signs and symptoms of SpA. US enthesopathy is independent of activity, duration and type of gut disease.

Vitamin D Derivatives Induce Apoptosis and Downregulate ICAM-1 Levels in Peripheral Blood Mononuclear Cells of Inflammatory Bowel Disease Patients

Background: Lymphocytes are crucial in the pathogenesis of inflammatory bowel disease (IBD) and are an important target for drug development. Our aim was to verify whether 2 vitamin D derivatives, 1,25‐dihydroxyvitamin D3 [1,25(OH)2D3] and EB 1089, could induce cell apoptosis and affect cell–cell interaction by regulating adhesion molecule levels. Methods: Peripheral blood mononuclear cell (PBMC) proliferation was studied by [3H]thymidine incorporation and apoptosis was determined using an enzyme‐linked immunosorbent assay (ELISA) kit. (Poly(ADP‐ribose)polymerase (PARP) cleavage, caspase‐3, and ICAM‐1 protein levels were determined by Western blot analysis. Results: Our results indicate that 1,25(OH)2D3 or EB 1089 or anti‐TNF‐&agr; (infliximab) induce apoptosis in PBMC obtained from healthy subjects. In IBD patients apoptosis is induced by vitamin D derivatives and by anti‐TNF‐&agr; only in CD patients. Caspase‐3 activation and PARP cleavage are registered when PBMC were treated with vitamin D derivatives. ICAM‐1 levels remarkably increase when PBMC was incubated with lipopolysaccharide (LPS) or TNF‐&agr;. The treatment with the vitamin D derivatives, alone or in combination with LPS or TNF‐&agr;, significantly decreases ICAM‐1 levels both in healthy subjects and IBD patients. In HUVEC cocultured with PBMC, previously incubated with LPS or TNF‐&agr; associated with 1,25(OH)2D3, ICAM‐1 levels decrease both in healthy subjects and IBD patients. Conclusions: 1,25(OH)2D3 and EB 1089 inhibit PBMC proliferation, induce apoptosis in PBMC of healthy subjects and IBD patients, and affect ICAM‐1 expression on PBMC and on HUVEC cocultured with PBMC, suggesting that the ICAM‐1 downregulation could provide a new target for controlling the recruitment of leukocytes at the sites of inflammation in IBD.

Interleukin-10 promoter polymorphisms influence susceptibility to ulcerative colitis in a gender-specific manner

Objective. Pathological evidence supports a potential role of the pro- and anti-inflammatory cytokine network in the pathogenesis of inflammatory bowel disease (IBD). Moreover, associated studies suggest a possible involvement of cytokine-related genes in IBD susceptibility. In this study, we evaluated the effect of the anti-inflammatory interleukin-10 (IL10) gene on ulcerative colitis (UC). Material and methods. Two functional single nucleotide polymorphisms (−1082 G/A, −819 T/C) in the IL10 promoter in 203 Italian sporadic UC patients and 391 controls were determined using high-resolution melting analysis. Results. The frequency of the −1082A allele was significantly higher in the UC patients than in controls (p=0.00003); −1082 genotype frequencies were also significantly different between UC patients and controls (p=0.0001). Allele and genotype frequencies of −819 T/C were not significantly associated with UC. Furthermore, the frequencies of haplotypes −1082A/−819C and −1082A/−819T, which have been reported to have a lower promoter activity, were significantly higher in UC patients than in controls (p=0.0004). After gender stratification, we found a significant difference in the −1082A allele (p=0.00004) and genotype (p=0.0002) frequencies only between female UC patients and controls; the same result was obtained for the −1082A/−819C and −1082A/−819T haplotypes (p=0.0006). Conclusions. A gender effect is observed, with women of AG/AA IL10 genotypes and AC/AT haplotypes having a higher risk of developing UC at a younger age. This finding could be related to the previously documented lower IL10 production associated with the −1082A allele and to the IL10 down-regulating effect of estrogens.

PPARγ in Inflammatory Bowel Disease

Peroxisome proliferator-activated receptor gamma (PPARγ) is member of a family of nuclear receptors that interacts with nuclear proteins acting as coactivators and corepressors. The colon is a major tissue which expresses PPARγ in epithelial cells and, to a lesser degree, in macrophages and lymphocytes and plays a role in the regulation of intestinal inflammation. Indeed, both natural and synthetic PPARγ ligands have beneficial effects in different models of experimental colitis, with possible implication in the therapy of inflammatory bowel disease (IBD). This paper will specifically focus on potential role of PPARγ in the predisposition and physiopathology of IBD and will analyze its possible role in medical therapy.

Susceptibility to Refractory Ulcerative Colitis Is Associated with Polymorphism in the hMLH1 Mismatch Repair Gene

The hMLH1 gene lies in the linkage susceptibility region to inflammatory bowel disease (IBD) on 3p21. A single nucleotide polymorphism, 655A>G, in exon 8 of the gene causes an I219V change in the MLH1 protein. To test whether hMLH1 may confer susceptibility to ulcerative colitis (UC), we investigated an association between the 655A>G polymorphism and the disease. DNA-based technologies were used to analyze the 655A>G polymorphism in 201 UC patients and 126 healthy ethnically matched controls. The comparison of the allelic frequencies of the 655A>G polymorphism in UC patients and healthy controls did not show significant differences. However, genotype frequencies at the hMLH1 655 position were found to be significantly different when patients with and without refractory UC were compared. This was mainly attributable to a higher level of homozygosity for the G allele in refractory UC patients. Almost 5 times as many (4.9 times) refractory UC patients carried the GG genotype compared with nonrefractory patients (P < 0.0001). The present study provides evidence that the hMLH1 gene is involved in genetic susceptibility to refractory UC. If confirmed by other studies, the GG genotype at position 655 of the hMLH1 gene may represent a useful predictive factor for the clinical management of UC patients.

Brain metabolic differences between sporadic and familial Alzheimer’s disease

This FDG-PET study with SPM99 compared 46 patients with sporadic Alzheimer disease (SAD) to 40 patients with familial AD (FAD) and to 35 matched controls. AD groups had equivalent metabolic (METglu) reductions in several cortical and limbic areas with respect to the controls. Patients with FAD showed decreased METglu in the posterior cingulate, parahippocampal, and occipital cortex as compared to the patients with SAD (p < 0.001). Genetic factors lead to phenotypic differences in AD.