Alessandro Sartini

Cytokine Networks in Ulcerative Colitis

Ulcerative colitis (UC) is a relapsing inflammatory bowel disease whose pathogenesis has yet to be defined completely. A genetic predisposition is needed to develop the colitis, but environmental factors are necessary to trigger an exaggerated and aberrant immune response, which stands at the basis of the mucosal healing. Cytokines, small cell-signaling protein molecules secreted by various types of cells including immune and glia cells, are the main mediators of the mucosal healing in IBD; ulcerative colitis is characterized by a Th2 atypical immune response, since, beside the classical proinflammatory cytokines, such as IL-1, IL-6, and TNF-α, in the pathogenesis of UC, we find a complex network in which the Th2 cytokines, IL-10 and IL-13, play a key role, but little IL-4 was found. Our aim was to review the literature to point out the state of the art in terms of cytokines because the knowledge of cytokine network in UC could lead to the discovery of new therapeutical targets.

Curcuma longa extract exerts a myorelaxant effect on the ileum and colon in a mouse experimental colitis model, independent of the anti-inflammatory effect.

Background Curcuma has long been used as an anti-inflammatory agent in inflammatory bowel disease. Since gastrointestinal motility is impaired in inflammatory states, the aim of this work was to evaluate if Curcuma Longa had any effect on intestinal motility. Methods The biological activity of Curcuma extract was evaluated against Carbachol induced contraction in isolated mice intestine. Acute and chronic colitis were induced in Balb/c mice by Dextran Sulphate Sodium administration (5% and 2.5% respectively) and either Curcuma extract (200 mg/kg/day) or placebo was thereafter administered for 7 and 21 days respectively. Spontaneous contractions and the response to Carbachol and Atropine of ileum and colon were studied after colitis induction and Curcuma administration. Results Curcuma extract reduced the spontaneous contractions in the ileum and colon; the maximal response to Carbachol was inhibited in a non-competitive and reversible manner. Similar results were obtained in ileum and colon from Curcuma fed mice. DSS administration decreased the motility, mainly in the colon and Curcuma almost restored both the spontaneous contractions and the response to Carbachol after 14 days assumption, compared to standard diet, but a prolonged assumption of Curcuma decreased the spontaneous and Carbachol-induced contractions. Conclusions Curcuma extract has a direct and indirect myorelaxant effect on mouse ileum and colon, independent of the anti-inflammatory effect. The indirect effect is reversible and non-competitive with the cholinergic agent. These results suggest the use of curcuma extract as a spasmolytic agent.

Low molecular weight heparin does not increase bleeding and mortality post-endoscopic variceal band ligation in cirrhotic patients

Anticoagulants are commonly indicated in cirrhotic patients due to high rate of (pro)thrombotic conditions. Low molecular weight heparin (LMWH) is safe in patients with esophageal varices. However, the safety of LMWH is unknown in patients undergoing prophylactic endoscopic variceal ligation (EVL). To define the 4‐week risk of bleeding and death after prophylactic EVL in cirrhotic patients continuously treated with LMWH.

Non-alcoholic fatty liver disease phenotypes in patients with inflammatory bowel disease

Non-alcoholic fatty liver disease (NAFLD) can be detected in up to 33.6% of inflammatory bowel disease (IBD) patients, often in absence of metabolic risk factors. Nevertheless, most of previous studies on such issue were conducted within the IBD population only. The primary aim of this study was to compare clinical and metabolic features of NAFLD in patients with and without IBD (w/o IBD) and to identify specific NAFLD phenotypes within the IBD population. Among 223 NAFLD patients, 78 patients with IBD were younger compared to 145 without (w/o) IBD, were less likely to have altered liver enzymes, had lower mean body weight, smaller waist circumference and lower body mass index (BMI); at the same time, MetS was more prevalent among patients w/o IBD (56.6 vs. 23.1%, p < 0.001). Within IBD population, patients with severe IBD showed more often severe steatosis (S3) at ultrasound (US) (32.1 vs. 16.6%, p = 0.01), compared to mild-to-moderate disease. Independent risk factors for S3 US steatosis in IBD patients at the multivariate logistic regression analysis were: more than 1 IBD relapse per year during disease history (OR 17.3, 95% CI 3.6–84), surgery for IBD (OR 15.1, 95% CI 3.1–73.7) and more extensive intestinal involvement (OR 19.4, 95% CI 3.4–110.9); the ongoing anti-Tumor Necrosis Factor alpha (antiTNFα) therapy was the only independent factor which protect toward the presence of altered liver enzymes (OR 0.15, 95% CI 0–0.8, p = 0.02). In conclusion, NAFLD in IBD patients is different from that in patients w/o IBD, who seem to develop different NAFLD phenotypes according to intestinal disease clinical course. More severe IBD seem to predict the presence of more severe steatosis. Therapy with antiTNFα antibodies could prevent alteration of liver enzymes in such population.

The use of obeticholic acid for the management of non-viral liver disease: current clinical practice and future perspectives

ABSTRACT Introduction: Farnesoid X nuclear receptor is involved in the regulation of lipid and glucose metabolism, though mainly in the homeostasis of bile acids. Indeed, the agonists of farnesoid X nuclear receptor represent promising drugs. Areas covered: Obeticholic acid, a novel semisynthetic analogue of the naturally occurring bile acid, has led to encouraging preliminary results in both cholestatic and metabolic liver disease. In patients with primary biliary cholangitis, obeticholic acid determines a significant biochemical improvement although the effects on liver fibrosis are lacking. Obeticholic acid has been suggested for the treatment of nonalcoholic liver disease with good laboratory results. In cirrhotic animal models, the drug seems to reduce both portal hypertension and gut bacterial translocation. Expert commentary: The use of obeticholic acid for the treatment of primary biliary cholangitis shows satisfying results. However, some open questions remain unresolved. Herein, we provide an overview of the current knowledge about the use of obeticholic acid in the field of nonviral chronic liver diseases. We tried to give a global point of view using a translational approach.

Antimicrobial stewardship in a Gastroenterology Department: Impact on antimicrobial consumption, antimicrobial resistance and clinical outcome

BACKGROUND A major cause of the increase in antimicrobial resistance is the inappropriate use of antimicrobials. AIMS To evaluate the impact on antimicrobial consumption and clinical outcome of an antimicrobial stewardship program in an Italian Gastroenterology Department. METHODS Between October 2014 and September 2015 (period B), a specialist in infectious diseases (ID) controlled all antimicrobial prescriptions and decided about the therapy in agreement with gastroenterologists. The defined daily doses of antimicrobials (DDDs), incidence of MDR-infections, mean length of stay and overall in-hospital mortality rate were compared with those of the same period in the previous 12-months (period A). RESULTS During period B, the ID specialist performed 304 consultations: antimicrobials were continued in 44.4% of the cases, discontinued in 13.8%, not recommended in 12.1%, de-escalated 9.9%, escalated in 7.9%, and started in 4.0%. Comparing the 2 periods, we observed a decreased of antibiotics consumption (from 109.81 to 78.45 DDDs/100 patient-days, p=0.0005), antifungals (from 41.28 to 24.75 DDDs/100pd, p=0.0004), carbapenems (from 15.99 to 6.80 DDDsx100pd, p=0.0032), quinolones (from 35.79 to 17.82 DDDsx100pd, p=0.0079). No differences were observed in incidence of MDR-infections, length of hospital stay (LOS), and mortality rate. CONCLUSIONS ASP program had a positive impact on reducing the consumption of antimicrobials, without an increase in LOS and mortality.

Does Metabolic Syndrome and Not the Inflammatory Load Predict Nonalcoholic Fatty Liver Disease Severity in Inflammatory Bowel Disease Patients

We read with great interest the paper by Carr et al. [1] on the role of metabolic syndrome (MetS) and intestinal inflammation in the severity of nonalcoholic fatty liver disease (NAFLD) in patients with inflammatory bowel disease (IBD). They intercepted IBD patients with established NAFLD by using ICD-9 codes, finding that the majority of IBD patients (77%) had NAFLD in the absence of MetS, obesity, diabetes, and/or insulin resistance, but the presence of MetS predicted NAFLD severity. This suggests that IBD patients could develop NAFLD and fibrosis not only because of metabolic risk factors. Two main issues in the paper of Carr et al. should be underlined. IBD activity and severity have been already linked to NAFLD development [2, 3]. Surrogate markers of severe disease such as active IBD (HR 1.58), disease duration (HR 1.12), and prior bowel surgery (HR 1.34) independently predicted the development of NAFLD [4]. Carr et al. assessed IBD activity at the time of NAFLD diagnosis according to clinical scores only or with an even more indirect indicator, i.e., medication in use. However, clinical scores are not the best predictors of mucosal inflammation and disease activity in IBD patients [5]. Moreover, IBD has a dynamic course with possible multiple disease flares and NAFLD and fibrosis development are strictly time-dependent events. The retrospective design of the study, indeed, did not allow to correctly describe such dynamic processes, so that author themselves recognize that it limited their ability to determine whether temporal pattern of IBD flare or the prolonged use of medications could really affect NAFLD development and severity. In our opinion, a study exploring the role of gut inflammatory load in NAFLD severity should take into account the number of ‘‘real’’ disease flares during IBD course, evaluating mucosal inflammation, rather than a single-point evaluation of disease activity scores. Even though colonoscopy cannot be repeated beyond routinely patients’ follow-up, a surrogate marker of mucosal inflammation, able to predict endoscopic, histologic, and clinical activity, such as fecal calprotectin, should be used [6]. The second issue concerns the assessment of NAFLD severity using NAFLD fibrosis score (NFS). Authors observed higher NFS values among patients with MetS; nonetheless, both groups (MetS vs nonMetsS) had values within the normal range. They also identified a trend toward higher NFS in UC and CD patients with remitting compared to active IBD, concluding that MetS, but not IBD extent and severity, is associated with NAFLD severity. However, NFS includes platelets count, a marker of inflammatory activity, which is very often elevated in IBD patients, especially in those with active disease. In NFS, the more elevated platelets count, the lower is the NAFLD score. For this reason, the predictive value of NAFLD FS among IBD population should be still validated. We think that only a prospectively designed study, possibly with a baseline histologically assessment of NAFLD and a dynamic evaluation of IBD activity (e.g., with repeat fecal calprotectin measurements), would more accurately identify the role of intestinal inflammatory load on NAFLD and fibrosis development in IBD patients. & Alessandro Sartini ale.sartini@gmail.com

BactDNA as an Independent Risk Factor for Short-Term Crohn's Disease Recurrence.

ple of 228 CD patients in clinical remission, bDNA was detected in 34%, regardless of therapies (mesalamine, immunosuppressants, and/or anti-TNF-α antibodies). However, as authors stated, bacterial translocation (BT) is itself a transient phenomenon, widely variable at diff erent times: therefore, a “single shot” evaluation may not refl ect a real condition. Furthermore, only 38% of patients made a baseline colonoscopy prior to inclusion in the study and almost 50% had macroscopic mucosal lesions, attesting a condition of still active CD; no mention is made about histology. Despite this, interestingly the presence of bDNA in blood did not correlate with the fi nding of mucosal lesions at the colonoscopy and it was the only independent risk factor for CD recurrence (hazard ratio 8.75) at the Cox regression analysis at 6 months. It derives that BT can occur even during clinical and endoscopic remission, and/or on course of anti-TNF-α therapy, thus revealing the persistence of altered barrier function. Circulating bDNA is known to be a marker of BT, but its relevance in the clinical practice is still debated ( 2 ); studies on cirrhotic patients have demonstrated its immunogenicity, the production of pro-infl ammatory cytokines, and the development of a systemic infl ammatory response ( 3 ), but other studies have failed to correlate markers of infl ammation to bDNA detection ( 4 ). Nevertheless, data from Gutiérrez et al. ( 1 ) are the fi rst evidence supporting the role of bDNA in the short-term prognosis of CD patients; therefore, its absence in patients in “deep remission” could represent a new “stopping rule” for biologic therapies, rather than mucosal healing only. Moreover, it might be justifi able in this population the long-term use of high dose of the minimally absorbed, non-systemic antimicrobial agent rifaximin (10–50 mg/Kg/day), which regulate barrier permeability, inhibiting intestinal infl ammation, and reducing the aerobic and anaerobic BT to the lamina propria in models of colitis ( 5 ). Further studies on the predictive value of bDNA and on the impact of antibiotics on it could help in a better understanding of pathophysiology and clinical relevance of bacterial antigens in infl ammatory bowel disease onset and recurrence; at least, it Pasalar, Maryam Mosaff a-Jahromi; critical review of manuscript and supervision: Kamran B. Lankarani. Financial support: None. Potential competing interests: None.

Is Early Endoscopy-Based Therapy the Best Strategy to Prevent All Crohn’s Disease Postoperative Recurrence?

1 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 Dear Editors: We read with great interest the article by Regueiro et al on the PREVENT study results. In this prospective, multicenter, randomized, double-blind, placebo-controlled trial, authors compared infliximab (IFX) and placebo in the prevention of postoperative Crohn’s disease (CD) recurrence, showing that IFX is able to reduce endoscopic, but not clinical postoperative recurrence of CD. Indeed, the trial was prematurely stopped at week 104 because of failure of the primary endpoint. Nevertheless, in their discussion, the authors conclude that patients at low risk for recurrence should undergone to colonoscopy at 6 months and initiate treatment in presence of recurrence, whereas high-risk patients should be treated immediately with tumor necrosis factor antagonists. The POCER study revealed that postoperative endoscopy-based treatment intensification is superior to standard drug therapy in preventing disease recurrence, but endoscopic recurrence is not always predictive of clinical recurrence. It has been known since the 1990s that endoscopic CD recurrence rate in the first year after surgery is a common occurrence, ranging from 73% to even 94%. In a randomized controlled trial, McLeod et al observed an endoscopic recurrence rate of 27.5% at 1 year, 60.8% at 2 years, and 77.3% at 3 years; despite this, only 37% of patients were symptomatic at the time of first endoscopic recurrence detection and only 37.5% of asymptomatic patients subsequently became symptomatic, in a mean time of 13 ± 8.8 months; 72% of patients with severe endoscopic lesions developed symptoms compared with 42% with minimal lesions, but became symptomatic in a longer mean time (19.1 ± 15.7 vs 18.8 ± 10.8 months). From the results of this study, it derives that the significance of minimal endoscopic recurrence lesions detected at 6 or 12 months is questionable, because many of these patients will not become symptomatic subsequently; in contrast, many patients with severe endoscopic lesions are already symptomatic at the time of lesion detection, so that they would not benefit from a prophylactic treatment. Moreover, Regueiro et al concluded that IFX is not able to prevent clinical recurrence, although it was already been demonstrated that

Complete resolution of non-necrotizing lung granuloma and pyoderma gangrenosum after restorative proctocolectomy in a woman with severe ulcerative colitis and cytomegalovirus infection.

Here, we report the unusual case of an ulcerative colitis female patient presenting together with cytomegalovirus infection, pyoderma gangrenosum and a noncaseating lung granuloma, both resistant to immunomodulatory drugs which dramatically obtained a clinical stable remission after restorative proctocolectomy.