Gaetano Inserra

Increased arterial stiffness in inflammatory bowel diseases is dependent upon inflammation and reduced by immunomodulatory drugs

BACKGROUND Inflammatory bowel diseases (IBD) are associated with an increased cardiovascular risk that is not fully explained by traditional cardiovascular risk factors but may be due to inflammation and mediated by an increased arterial stiffness. AIMS Study 1, to investigate the relationship between inflammation and arterial stiffening; Study 2, to look whether aortic stiffening is reduced by immunomodulatory therapy in IBD. METHODS Study 1 (Cross-sectional study): pulse wave velocity (PWV) was measured in 74 IBD subjects (40 ulcerative colitis and 34 Crohns disease) and 80 matched controls. Study 2 (Longitudinal study): the effect of therapy on PWV was measured at baseline and 3.4 ± 0.5 years later in 14 IBD subjects treated only with salicylates, 11 subjects treated with steroids and azathioprine, 7 subjects treated with anti TNF-alpha and 30 matched controls. RESULTS Study 1: All parameters were comparable between subjects with ulcerative colitis and Crohns disease. Compared to controls, subjects with ulcerative colitis and those with Crohns disease have both higher carotid-femoral PWV (7.0 ± 1.1, 7.8 ± 1.7 and 8.0 ± 1.6 m/s, respectively; P < 0.001) and carotid-radial PWV (7.2 ± 0.9, 8.8 ± 1.4 and 8.8 ± 1.3 m/s, respectively; P < 0.001). In fully adjusted models carotid-femoral PWV was positively associated with disease duration whereas carotid-radial PWV was associated with C-reactive protein and history of relapse. Study 2: in fully adjusted model carotid-femoral PWV increased significantly at follow-up in IBD subjects treated with salicylates but not in those treated with steroids and azathioprine or anti TNF-alpha. CONCLUSION Increased arterial stiffness in IBD is dependent upon inflammation and reduced by immunomodulatory drugs.

Arterial structure and function in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is the result of a combination of environmental, genetic and immunologic factors that trigger an uncontrolled immune response within the intestine, which results in inflammation among genetically predisposed individuals. Several studies have reported that the prevalence of classic cardiovascular risk factors is lower among subjects with IBD than in the general population, including obesity, dyslipidaemia, diabetes and hypertension. Therefore, given the risk profile of IBD subjects, the expected cardiovascular morbidity and mortality should be lower in these patients than in the general population. However, this is not the case because the standardized mortality ratio is not reduced and the risk of coronary heart disease is increased in patients with IBD. It is reasonable to hypothesize that other factors not considered in the classical stratification of cardiovascular risk may be involved in these subjects. Therefore, IBD may be a useful model with which to evaluate the effects of chronic low-grade inflammation in the development of cardiovascular diseases. Arterial stiffness is both a marker of subclinical target organ damage and a cardiovascular risk factor. In diseases characterized by chronic systemic inflammation, there is evidence that the inflammation affects arterial properties and induces both endothelial dysfunction and arterial stiffening. It has been reported that decreasing inflammation via anti tumor necrosis factor alpha therapy decreases arterial stiffness and restores endothelial function in patients with chronic inflammatory disorders. Consistent with these results, several recent studies have been conducted to determine whether arterial properties are altered among patients with IBD. In this review, we discuss the evidence pertaining to arterial structure and function and present the available data regarding arterial stiffness and endothelial function in patients with IBD.

Increased cardiovascular risk in subjects with a low prevalence of classic cardiovascular risk factors: The inflammatory bowel disease paradox.

lupus erythematosus are characterized by various clusters of these non-traditional cardiovascular risk factors. Apparently, the positive relationship between the burden of the classic cardiovascular risk factors and the risk to develop cardiovascular events has not been confirmed among patients with IBD. Several studies have described a lower prevalence of classic cardiovascular risk factors among patients with IBD compared with the general population, including lower body mass indices and lipid levels [8–11] ,a s well as lower prevalence of diabetes, obesity, and hypertension [11]. Therefore, we would anticipate a decrease in cardiovascular morbidity and mortality in patients with IBD compared with the general population. Surprisingly, it has been reported that in IBD, the standardized mortality ratio is not decreased [12]; Rungoe et al. [7] in this issue of Trends in Cardiovascular Medicine conclude that most studies are indicative of a modestly increased relative risk of coronary artery disease among patients with both ulcerative colitis and Crohns disease; the risk appears to be higher in women. The majority of studies regarding the risk of cardiovascular disease in the setting of IBD did not stratify based on IBD subtypes (ulcerative colitis or Crohns disease). The few that did separately analyze the risk in the setting of ulcerative colitis and Crohns disease determined that the risk was similar between the two groups of patients. Taken together, these results suggest that as an alternative to the traditional cardiovascular risk factors, other factors may be associated with the cardiovascular risk of patients with IBD. Chronic inflammation has recently been linked to an increased risk of cardiovascular disease. In contrast with other chronic

Disease patterns in late-onset ulcerative colitis: Results from the IG-IBD “AGED study”

BACKGROUND Late-onset UC represents an important issue for the near future, but its outcomes and relative therapeutic strategies are yet poorly studied. AIM To better define the natural history of late-onset ulcerative colitis. METHODS In a multicenter retrospective study, we investigated the disease presentation and course in the first 3 years in 1091 UC patients divided into 3 age-groups: diagnosis ≥65years, 40-64 years, and <40years. Disease patterns, medical and surgical therapies, and risk factors for disease outcomes were analyzed. RESULTS Chronic active or relapsing disease accounts for 44% of patients with late-onset UC. Across all age-groups, these disease patterns require 3-6 times more steroids than remitting disease, but immunomodulators and, to a lesser extent, biologics are less frequently prescribed in the elderly. Advanced age, concomitant diseases and related therapies were found to be inversely associated with the use of immunomodulators or biologics, but not with surgery. CONCLUSIONS The conclusion that late-onset UC follows a mild course may apply only to a subset of patients. an important percentage of elderly patients present with more aggressive disease. Since steroid use and surgery rates did not differ in this subgroup, lower use of immunosuppressive therapy and biologics may reflect concerns in prescribing these therapies in the elderly.

Arterial stiffness in inflammatory bowel disease: a systematic review and meta-analysis.

Background: Arterial stiffness is increased with chronic inflammatory disorders. The reduction of inflammation by immunomodulatory therapy is associated with a restoration of arterial function. The aims of the study were to perform a meta-analysis to determine whether arterial stiffness is increased in patients with inflammatory bowel disease (IBD) and a meta-regression analysis to correlate arterial stiffness with anti-TNF&agr; therapy. Methods: Systematic review registration number: CRD42015017364. A systematic literature search for arterial stiffness in IBD was performed using PubMed, Scopus, and Google Scholar databases (last accessed on 23 September 2015). The search terms were ‘arterial stiffness,’ ‘vascular stiffness,’ or ‘pulse wave velocity’ in combination with ‘inflammatory bowel disease,’ ‘inflammatory bowel diseases,’ ‘Crohns disease,’ or ‘ulcerative colitis.’ Inclusion criteria included peer-reviewed publications reporting original data, a minimum of 20 study participants tested, and pulse wave velocity (PWV) measured via validated devices. Publications with titles or abstracts appearing to meet the inclusion criteria were selected and reviewed by two authors according to PRISMA 2009 guidelines. Results: Carotid–femoral PWV (cf-PWV) was measured in nine cross-sectional studies (234 patients with Crohns disease, 342 with ulcerative colitis, and 435 control study participants). Compared with control patients, cf-PWV was significantly increased in patients with Crohns disease [mean difference 1.34 z-score; 95% confidence interval (CI) 0.71–1.97 z-score; P < 0.0001] and ulcerative colitis (mean difference 1.08 z-score; 95% CI 0.55–1.61 z-score; P < 0.0001). In a meta-regression analysis, cf-PWV was reduced in IBD patients treated with anti-TNF&agr; therapy (&bgr; −2.6 m/s; 95% CI −4.9 to −0.2 m/s; P = 0.03). Conclusion: cf-PWV is increased in both ulcerative colitis and Crohns disease patients.

Inflammation and Aortic Stiffness: An Individual Participant Data Meta‐Analysis in Patients With Inflammatory Bowel Disease

Background The recent finding that aortic pulse wave velocity (aPWV) is increased in patients with inflammatory bowel disease may explain why the cardiovascular risk is increased despite the low prevalence of traditional cardiovascular risk factors. We aimed to test whether inflammation is associated with aortic stiffening in this setting after adjustment for major confounders and to perform subgroup analyses. Methods and Results A systematic literature search for aPWV in inflammatory bowel disease was performed using PubMed, Scopus, Web of Science, and Google Scholar databases (last accessed May 7, 2017). Inclusion criterion was peer‐reviewed publications on clinical studies reporting original data. This study followed the Preferred Reporting Items for Systematic Review and Meta‐Analyses of individual participant data 2015 guidelines. Data were provided for 4 cohorts in 3 countries (151 participants with ulcerative colitis, 159 with Crohns disease, and 227 control patients). Using aPWV, cohort‐specific z scores were calculated after loge‐transform and combined in meta‐analysis to form pooled effects using a random‐effects model. Compared with controls, aPWV was increased in patients with Crohns disease (mean difference 0.78 z score; 95% confidence interval, 0.56–1.00 z score [P<0.001]) and ulcerative colitis (mean difference 0.75 z score; 95% confidence interval, 0.52–0.97 z score [P<0.001]). In an outlier‐robust multivariate linear regression model adjusted for prespecified confounders, aPWV was associated with disease duration (years, β=0.05 z score; 95% confidence interval, 0.02–0.08 z score [P<0.001]) and white blood cell count (billion cells/L, β=0.07 z score; 95% confidence interval, 0.02–0.11 z score [P=0.002]) but not with markers of acute inflammation (C‐reactive protein and erythrocyte sedimentation rate), cardiovascular risk factors, and therapy. Conclusions The increased aPWV reported in patients with inflammatory bowel disease is associated with inflammation. Clinical Trial Registration URL: http://www.crd.york.ac.uk. Unique identifier: PROSPERO 2016: CRD42016053070.

P303 Ulcerative colitis (UC) in the elderly – Moderate at onset but then a milder course? An IG-IBD study

P302 Utility of “trough levels” determination and anti-infliximab antibodies in patients with inflammatory bowel disease. Estimation of individual pharmacokinetic parameters (PK) through population pharmacokinetic model G. Juan1,2 *, A. Alvarino3,4, L. Oltra4, N. Maroto4, N. Cano2, I. Ferrer2, J. Hinojosa2,4. 1Hospital de Manises, Farmacia Hospitalaria, Valencia, Spain, 2Hospital de Manises, Digestivo, Manises, Spain, 3Hospital de Manises, LABCO, Valencia, Spain, 4Hospital de Manises, Gastroenterology, Valencia, Spain

Pulse wave velocity differs between ulcerative colitis and chronic kidney disease

BACKGROUND We hypothesized that a reversal of the physiological stiffness gradient, previously reported in end-stage renal disease, begins in the early stages of chronic kidney disease (CKD) and that chronic inflammation produces a different arterial phenotype in patients with ulcerative colitis (UC). OBJECTIVES To assess the extent of arterial stiffening in the central (carotid-femoral pulse wave velocity, cf.-PWV) and peripheral arteries (carotid-radial pulse wave velocity, cr-PWV) and to explore the determinants of the stiffness gradient in UC and in CKD. METHODS We enrolled 45 patients with UC, 45 patients with stage 3-4 CKD and 45 matched controls. RESULTS Despite the comparable cf.-PWV, the cr-PWV was higher in patients with UC than in those with CKD (median: 8.7 vs. 7.5m/s; p<0.001) and, consequently, the PWV ratio was lower (median: 0.97 vs. 1.12; p<0.001). In patients with CKD a stiffness mismatch was reported starting from stage 3B. The PWV ratio was associated with age and C-reactive protein (beta: 0.08 z-score, 95%CI 0.02-0.14; p=0.01) or active disease (beta: 0.43 z-score, 95%CI 0.003-0.857; p=0.048) in patients with UC and with age and glomerular filtration rate (beta: -0.56 z-score, 95%CI -1.05 to -0.07; p=0.02) in patients with CKD. CONCLUSIONS The arterial phenotype differed between UC and CKD. The reversal of the arterial stiffness gradient is evident in CKD patients starting from stage 3B but not in patients with UC and comparable cf.-PWV. In patients with UC, the stiffness of both elastic and muscular arteries is increased as a consequence of inflammation.

A propensity score-matched comparison of infliximab and adalimumab in TNF-α inhibitors naïve and non-naïve patients with Crohn’s disease: real-life data from the Sicilian Network for Inflammatory Bowel Disease (SN-IBD)

Background and Aims There is an unmet need to better understand the effectiveness of different biologics in inflammatory bowel diseases. We aimed at performing a multicentre, real-life comparison of the effectiveness of infliximab [IFX] and adalimumab [ADA] in Crohns disease [CD]. Methods Data of consecutive patients with CD treated with IFX and ADA from January 2013 to May 2017 were extracted from the cohort of the Sicilian Network for Inflammatory Bowel Disease. We used propensity score-matching accounting for the main baseline characteristics in TNF-α inhibitor-naïve and non-naïve patients. Results A total of 632 patients [735 total treatments] were included. Among naïve patients, a clinical benefit [the sum of steroid-free remission plus clinical response] was achieved in 81.8% patients treated with ADA and in 77.6% patients treated with IFX (adjusted odds ratio [OR]: 1.23, 95% CI 0.63-2-44, p = 0.547] at 12 weeks; after 1 year, a clinical benefit was achieved in 69.2% of patients treated with ADA and in 64.5% patients treated with IFX [adjusted OR: 1.10, 95% CI 0.61-1.96, p = 0.766]. Among non-naïve patients, a clinical benefit was achieved in 61.7% of patients treated with ADA and in 68.1% of patients treated with IFX [adjusted OR: 0.72, 95% CI 0.21-2.44, p = 0.600] at 12 weeks; after 1 year, a clinical benefit was achieved in 48.9% of patients treated with ADA and in 40.4% patients treated with IFX [adjusted OR: 1.23, 95% CI 0.54-2.86, p = 0.620]. Conclusions In this propensity score-matched comparison of ADA and IFX in CD, both drugs showed high rates of clinical benefit, without significant differences between them.

A real life comparison of the effectiveness of adalimumab and golimumab in moderate-to-severe ulcerative colitis, supported by propensity score analysis

BACKGROUND Adalimumab and golimumab are effective in the treatment of moderate to severe ulcerative colitis. AIMS We reported the comparative effectiveness of adalimumab and golimumab in ulcerative colitis. METHODS 118 patients treated with adalimumab and 79 treated with golimumab were included and evaluated at 8 weeks and at the end of follow up. RESULTS Overall clinical benefit was 72.6% at 8 weeks and 58.9% at the end of follow up. Patients with longer disease duration and those treated with adalimumab had a better outcome. Clinical benefit was 78.8% in adalimumab patients and 63.3% in golimumab patients (p = 0.026) after 8 weeks; it was 66.9% in adalimumab patients and 46.8% in golimumab patients (p = 0.008) at the end of follow up. These data were confirmed by propensity score analysis. A further analysis considering adalimumab optimization as treatment failure showed that the difference between adalimumab and golimumab was not significant. CONCLUSION Adalimumab and golimumab are effective in the treatment of ulcerative colitis. Adalimumab seems to be more effective than golimumab. This difference is probably affected by the impossibility of golimumab to be optimized in Italy while adalimumab is.