Can Conventional and Diffusion-Weighted MR Enterography Biomarkers Differentiate Inflammatory from Fibrotic Strictures in Crohn's Disease?

Background and Objectives: To retrospectively assess the value of magnetic resonance enterography (MRE) parameters derived from conventional and diffusion weighted imaging (DWI) sequences to differentiate fibrotic strictures from inflammatory ones in adult patients with Crohn's disease (CD), using surgical specimens as the histopathological reference standard. Material and Methods: Twenty-three patients with CD who had undergone surgical resection of ileal strictures with full-thickness histopathologic analysis within 3 months from preoperative MRE were included. Two radiologists blinded to histopathology in consensus evaluated the following biomarkers on MRE images matched to resected pathological specimens: T1 ratio, T2 ratio, enhancement pattern, mural thickness, pre-stenotic luminal diameter, and apparent diffusion coefficient (ADC). A blinded pathologist graded stricture histological specimens with acute inflammation score (AIS) and fibrosis score (FS). MRE measurements were correlated with the reference standard. Results: Inflammation and fibrosis coexisted in 78.3% of patients. T2 ratio was reduced in patients with severe fibrosis (p = 0.01). Pre-stenotic bowel dilatation positively correlated with FS (p = 0.002). The ADC value negatively correlated with FS (p < 0.001) and was different between FS grades (p < 0.05). The area under the receiver operating characteristic curve for discriminating between none and mild/moderate-severe bowel wall fibrosis was 0.75 for pre-stenotic bowel dilatation (sensitivity 100%, specificity 44.4%) and 0.97 for ADC (sensitivity 80%, specificity 100%). Conclusions: Inflammation and fibrosis often coexist in CD bowel strictures needing surgery. The combination of parameters derived from conventional MR sequences (T2 ratio, pre-stenotic dilatation) and from DWI (ADC) may provide a contribution to detect and grade bowel fibrosis in adult CD patients.

Gastrointestinal complications after kidney transplantation.

Gastrointestinal complications are common after renal transplantation, and they have a wide clinical spectrum, varying from diarrhoea to post-transplant inflammatory bowel disease (IBD). Chronic immunosuppression may increase the risk of post-transplant infection and medication-related injury and may also be responsible for IBD in kidney transplant re-cipients despite immunosuppression. Differentiating the various forms of post-transplant colitis is challenging, since most have similar clinical and histological features. Drug-related colitis are the most frequently encountered colitis after kidney transplantation, particularly those related to the chronic use of mycophenolate mofetil, while de novo IBDs are quite rare. This review will explore colitis after kidney transplantation, with a particular focus on different clinical and histological features, attempting to clearly identify the right treatment, thereby improving the final outcome of patients.

Anxiety, depression, chronic inflammation and aortic stiffness in Crohn's disease: the brain--gut--vascular axis.

BACKGROUND: Patients with Crohn's disease have an increased aortic stiffness, a known cardiovascular risk factor. Anxiety, a key factor of the brain--gut axis in patients with Crohn's disease, is implicated in the pathogenesis and progression of the disease, and is linked with aortic stiffening in other clinical settings. OBJECTIVES: Considering that depression is frequently linked to anxiety in Crohn's disease, we performed a mediation analysis to reveal the potential link between anxiety, depression and aortic stiffness in these patients. METHODS: Multicentre observational cross-sectional study of 86 consecutive patients with Crohn's disease and 86 matched control individuals. The connections between anxiety, depression, disease duration, aortic pulse wave velocity (aPWV), brachial and central SBP were tested using partial least squares structural equations modelling. RESULTS: In patients with Crohn's disease, anxiety (path coefficient: 0.220, P = 0.01) and disease duration (path coefficient: 0.270, P = 0.02) were associated with aPWV that in turn was associated with brachial SBP (path coefficient: 0.184, P = 0.03). These associations were even stronger in patients with active disease. The connection between anxiety and aPWV was in part mediated by central SBP (indirect effect: 0.090, P = 0.01; indirect-to-total effect ratio: 41%) as well as, in a pilot substudy, by sympathetic hyperactivity. Anxiety and depression were highly correlated in patients with Crohn's disease. Consequently, results were confirmed when anxiety was substituted by depression. CONCLUSION: The connections of anxiety, depression and chronic inflammation with aPWV and SBP could suggest the first evidence of a brain--gut--vascular axis and new potential targets for therapy in patients with Crohn's disease.

Persistence on Anti-Tumour Necrosis Factor Therapy in Older Patients with Inflammatory Bowel Disease Compared with Younger Patients: Data from the Sicilian Network for Inflammatory Bowel Diseases (SN-IBD).

BACKGROUND AND OBJECTIVE: Older people with inflammatory bowel disease (IBD) appear to have a lower response to anti-tumour necrosis factor (TNF) therapy, with more frequent complications than younger patients. The objective of this study was to assess persistence on therapy and the safety of anti-TNF therapy in older patients (aged ≥ 60 years). METHODS: We retrospectively reviewed the database of the Sicilian Network for Inflammatory Bowel Diseases (SN-IBD), extracting data regarding IBD patients aged ≥ 60 years and controls < 60 years of age at their first course of anti-TNF treatment. Data concerning persistence on therapy over the first year of treatment (primary objective) together with data on reasons for treatment withdrawal, concomitant diseases and treatments were collected. RESULTS: We identified 114 anti-TNF-naϊve patients aged ≥ 60 years (median age 64 years, range 60-80 years; 47 males) compared with 330 younger controls aged < 60 years (median age 39 years, range 18-59 years; 57 males). Older patients with Crohn's disease (n = 73) showed a significantly lower persistence with every kind of anti-TNF therapy (whether analysed together [p < 0.001] or separately for intravenous and subcutaneous [SC] therapy) than younger controls, whereas older patients with ulcerative colitis (n = 41) showed a lower persistence when combining all kinds of anti-TNF treatment (p = 0.004) and for SC therapy. Secondary failures, infections, and neoplasias, but not primary failure, occurred more frequently in older IBD patients than in younger controls. CONCLUSION: Despite a comparable number of primary failures, older IBD patients treated for the first time with anti-TNF agents showed lower treatment persistence due to higher rates of secondary failure, adverse events, infections, and tumours than younger patients in the first year of follow-up. The reasons for this difference still remain unclear.

Real-Life Effectiveness and Safety of Golimumab and Its Predictors of Response in Patients with Ulcerative Colitis.

BACKGROUND: Golimumab is a new anti-TNF-alpha monoclonal antibody for patients with ulcerative colitis. AIMS: To assess the short- and long-term effectiveness and safety of golimumab in daily clinical practice and to identify predictors of response. METHODS: Consecutive patients treated with golimumab in 22 Italian centers were enrolled. Clinical, laboratory, and endoscopic data were prospectively collected before and during treatment. A subgroup of patients completed a questionnaire to assess personal satisfaction with a golimumab autoinjector system. RESULTS: A total of 196 patients were included. After 3 months, 130 patients were responders (66.3%) and showed significant reductions in mean partial, total, and endoscopic Mayo scores and in mean ESR, C-reactive protein, and fecal calprotectin levels (p < 0.001). Multivariate analysis revealed that a higher total Mayo score (p < 0.001, OR 1.5, 95% CI 1.2-1.8) and naïve status to anti-TNF-alpha (p = 0.015, OR 3.0, 95% CI 1.2-7.5) were predictive of a favorable response. Seventy-seven (39.3%) of the 130 responders maintained a response at month 12 of therapy. There were 17 adverse events, 28 patients needed hospitalization, and 15 patients underwent surgery. Self-administration of the drug was appreciated by most patients. CONCLUSIONS: The efficacy and safety of golimumab in daily clinical practice were confirmed for the short- and long-term treatment of patients with active ulcerative colitis. Patients naïve to the anti-TNF-alpha monoclonal antibody and those with a higher total Mayo score were more likely to respond to golimumab.

Late-onset Crohn's disease: a comparison of disease behaviour and therapy with younger adult patients: the Italian Group for the Study of Inflammatory Bowel Disease 'AGED' study.

BACKGROUND: Disease phenotype and outcome of late-onset Crohn's disease are still poorly defined. METHODS: In this Italian nationwide multicentre retrospective study, patients diagnosed ≥65 years (late-onset) were compared with young adult-onset with 16-39 years and adult-onset Crohn's disease 40-64 years. Data were collected for 3 years following diagnosis. RESULTS: A total of 631 patients (late-onset 153, adult-onset 161, young adult-onset 317) were included. Colonic disease was more frequent in late-onset (P < 0005), stenosing behaviour was more frequent than in adult-onset (P < 0003), but fistulising disease was uncommon. Surgery rates were not different between the three age groups. Systemic steroids were prescribed more frequently in young adult-onset in the first year, but low bioavailability steroids were used more frequently in late-onset in the first 2 years after diagnosis (P < 0.036, P < 0.041, respectively). The use of immunomodulators and anti-TNF's even in patients with more complicated disease, that is, B2 or B3 behaviour (Montreal classification), remained significantly inferior (P < 0.0001) in late-onset compared to young adult-onset. Age at diagnosis, Charlson comorbidity index, and steroid used in the first year were negatively associated with the use of immunomodulators and biologics. Comorbidities, related medications and hospitalizations were more frequent in late-onset. Polypharmacy was present in 56% of elderly Crohn's disease patients. CONCLUSION: Thirty-two percent of late-onset Crohn's disease presented with complicated disease behaviour. Despite a comparable use of steroids and surgery, immunomodulators and biologics were used in a small number of patients.

Inflammation and Aortic Pulse Wave Velocity: A Multicenter Longitudinal Study in Patients With Inflammatory Bowel Disease.

Background Inflammatory bowel disease ( IBD ) is characterized by a low prevalence of traditional risk factors, an increased aortic pulse-wave velocity ( aPWV ), and an excess of cardiovascular events. We have previously hypothesized that the cardiovascular risk excess reported in these patients could be explained by chronic inflammation. Here, we tested the hypothesis that chronic inflammation is responsible for the increased aPWV previously reported in IBD patients and that anti-TNFa (anti-tumor necrosis factor-alpha) therapy reduce aPWV in these patients. Methods and Results This was a multicenter longitudinal study. We enrolled 334 patients: 82 patients with ulcerative colitis, 85 patients with Crohn disease, and 167 healthy control subjects matched for age, sex, and mean blood pressure, from 3 centers in Europe, and followed them for 4 years (range, 2.5-5.7 years). At baseline, IBD patients had higher aPWV than controls. IBD patients in remission and those treated with anti-TNFa during follow-up experienced an aortic destiffening, whereas aPWV increased in those with active disease and those treated with salicylates ( P=0.01). Disease duration ( P=0.02) was associated with aortic stiffening as was, in patients with ulcerative colitis, high-sensitivity C-reactive protein during follow-up ( P=0.02). All these results were confirmed after adjustment for major confounders. Finally, the duration of anti-TNFa therapy was not associated with the magnitude of the reduction in aPWV at the end of follow-up ( P=0.85). Conclusions Long-term anti-TNFa therapy reduces aPWV , an established surrogate measure of cardiovascular risk, in patients with IBD . This suggests that effective control of inflammation may reduce cardiovascular risk in these patients.

A Propensity Score-matched Comparison of Infliximab and Adalimumab in Tumour Necrosis Factor-α Inhibitor-naïve and Non-naïve Patients With Crohn's Disease: Real-Life Data From the Sicilian Network for Inflammatory Bowel Disease.

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 Crohn's 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.

Responsibility of hepatitis C virus in the development of hepatocellular carcinoma: From molecular alterations to possible solutions.

There are several causes of hepatocellular carcinoma (HCC), but certainly the hepatitis C virus (HCV) is one of the most common. The HCV is able to contribute, both directly and indirectly, to the development of HCC. Determining early HCV clearance before an advanced liver disease develops, is absolutely necessary as this prevents the initiation of the cascade of events induced by HCV that may result in the development of HCC. The early treatment of the infection and the clearance of HCV represents today, in the age of the direct antiviral agents (DAAs), an extraordinary opportunity for true prevention of the development of HCV-related HCC.

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.

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.

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 Crohn's 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 Crohn's 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, ß=0.05 z score; 95% confidence interval, 0.02-0.08 z score [P<0.001]) and white blood cell count (billion cells/L, ß=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.

Patient and physician views on the quality of care for inflammatory bowel disease after one-year follow-up: Results from SOLUTION-2, a prospective IG-IBD study.

BACKGROUND AND AIMS: Perception of quality of care is important in the management of patients with chronic diseases, particularly inflammatory bowel disease. AIMS AND METHODS: This longitudinal study aimed to investigate variations of the Quality of Care through the Patients' Eyes (QUOTE-IBD) questionnaire scores one year after the basal evaluation in the Studio Osservazionale quaLità cUre malatTIe crOniche intestiNali (SOLUTION-1) study. RESULTS: Of the cohort of 992 patients, 936 were evaluable. The QUOTE-IBD score overcame satisfactory levels of more than the 80%, overall and in all subdomains except for the "Continuity of Care" sub-dimension (mean, 8.3; standard deviation, 1.49), scored satisfactory only by 34% of the patients. No significant changes in satisfaction were recorded overall, or considering patients subgroups. Significant differences were found at the end of the follow-up between physicians' and patients' perceptions of quality of care, with the former over-rating their performance in "Continuity of Cares" and under-rating "Costs", "Competence", and "Accessibility" sub-domains of the score (p<0.05 for all). CONCLUSION: Perceived quality of care in a large cohort of Italian patients with inflammatory bowel disease remains unchanged after one-year follow-up and was not significantly affected by disease activity or therapeutic interventions. Differences between physicians' and patients' perceptions of quality of care should be taken into account.

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-TNFα 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,' 'Crohn's 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 Crohn's disease, 342 with ulcerative colitis, and 435 control study participants). Compared with control patients, cf-PWV was significantly increased in patients with Crohn's 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-TNFα therapy (ß -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 Crohn's disease patients.

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.