Sustained Clinical Efficacy and Mucosal Healing of Thiopurine Maintenance Treatment in Ulcerative Colitis: A Real-Life Study

Background and Aims. Thiopurines are commonly used for treating ulcerative colitis (UC), despite the fact that controlled evidence supporting their efficacy is limited. The aim of this study was to evaluate the long-term outcome of thiopurines as maintenance therapy in a large cohort of UC patients. Methods. All UC patients receiving thiopurine monotherapy at three tertiary IBD centers from 1995 to 2015 were identified. The primary endpoint was steroid-free clinical remission. Secondary endpoints were mucosal healing (MH), defined as Mayo endoscopic subscore 0, long-term safety, and predictors of sustained clinical remission. Results. We identified 192 patients, contributing a total of 747 person-years of follow-up (median follow-up 36 months, range 1–210 months). Steroid dependency was the most common indication for thiopurine treatment (58%). Steroid-free remission occurred in 45.3% of patients; 36.3% stopped thiopurines because of treatment failure and 18.2% for adverse events or intolerance. The cumulative probability of maintaining steroid-free remission while on thiopurine treatment was 87%, 76%, 67.6%, and 53.4% at 12, 24, 36, and 60 months, respectively. MH occurred in 57.9% of patients after a median of 18 months (range 5–96). No independent predictors of sustained clinical remission could be identified. Conclusions. Thiopurines represent an effective and safe long-term maintenance therapy for UC patients

Corticosteroids modulate the secretory processes of the rat intrahepatic biliary epithelium

Background & Aims: We investigated the expression of glucocorticoid receptors (GcRs) in the intrahepatic biliary epithelium and the role of corticosteroids in the regulation of cholangiocyte secretion. Methods: GcR was studied by immunohistochemistry, reverse-transcription polymerase chain reaction, and Western blots. The effects of dexamethasone and budesonide on billary bicarbonate excretion and H+/HCO3- transport processes were investigated in bile fistula rats, isolated intrahepatic bile duct units (IBDUs), and purified cholangiocytes. Results: GcRs were expressed by rat cholangiocytes. Although acute administration of corticosteroids showed no effect, treatment for 2 days with dexamethasone or budesonide increased (P < 0.05) biliary bicarbonate concentration and secretion, which were blocked by the specific GcR antagonist, RU-486. IBDUs isolated from rats treated with dexamethasone or budesonide showed an increased (P < 0.05) activity of the Na+/H+ exchanger (NHE1 isoform) and Cl-/HCO3- exchanger (AE2 member), which was blocked by RU-486. Protein expression of NHE1 and AE2 and messenger RNA for NH1 but not AE2 were increased (P < 0.05) in isolated cholangiocytes by dexamethasone treatment. Conclusions: The intrahepatic biliary epithelium expresses GcR and responds to corticosteroids by increasing bicarbonate excretion in bile. This is caused by corticosteroid-induced enhanced activities and protein expression of transport processes driving bicarbonate excretion in the biliary epithelium

The function of alkaline phosphatase in the liver: Regulation of intrahepatic biliary epithelium secretory activities in the rat

We studied the effects of alkaline phosphatase (AP) on the secretory processes of the rat intrahepatic biliary epithelium as well as the role of the intrahepatic biliary epithelium in the uptake and biliary secretion of exogenous AP. The effects of acute and chronic administration of AP on bile secretory parameters were investigated in vivo in normal and bile duct ligated (BDL) rats and in vitro in isolated rat bile duct units (IBDU), In vivo, acute AP administration decreased bile now and biliary bicarbonate excretion and abolished secretin choleresis in BDL rats but not in normal rats. On the contrary, the AP inhibitor, levamisole, increased in BDL rat bile flow and biliary bicarbonate excretion. In vitro, basal and secretin-stimulated Cl(-)/HCO(3)(-) exchanger activity in IBDU was immediately inhibited by AP intraluminal microinjection (apical exposure) but only after a prolonged exposure to the basolateral pole. Levamisole increased the Cl(-)/HCO(3)(-) exchanger activity of IBDU, A significant basolateral uptake of AP occurs in IBDU with a progressive transport to the apical domain. AP chronic treatment increased AP and gamma-glutamyltranspeptidase (gamma-GT) activities in the intrahepatic bile ducts and hepatocyte canalicular pole, promoted enlargement of bile canaliculi, and decreased bile flow and biliary bicarbonate excretion. In conclusion, the intrahepatic biliary epithelium plays a role in the uptake and biliary secretion of serum AP. AP inhibits the secretory processes of the intrahepatic biliary epithelium and induces features of intrahepatic cholestasis after chronic administration. These findings indicate that AP plays an active role in down-regulating the secretory activities of the intrahepatic biliary epithelium

Effectiveness of ustekinumab in patients with refractory Crohn's disease: a multicentre real-life study in Italy

Background: The effectiveness of ustekinumab in patients with refractory Crohn’s disease (CD) has been investigated in several real-world studies. However, very few data concerning the real-life experience in Italy have been reported. Therefore, this study assessed the effectiveness of ustekinumab in a large cohort of Italian patients with refractory CD. Methods: All patients who had started on ustekinumab after failure of or intolerance to antitumour necrosis factor-a (TNF-a) treatment at five tertiary centres between November 2018 and February 2020 were retrospectively enrolled. The coprimary outcome was corticosteroid-free clinical remission, defined as a Harvey–Bradshaw Index (HBI) score of !4, at weeks 26 and 52. The secondary outcomes were changes in the HBI and C-reactive protein (CRP) values at weeks 8, 26, and 52 from baseline and the normalization of CRP in patients with initially abnormal values. Results: Totally, 140 patients who had previously received at least one anti-TNF- agent were enrolled; 40.0% received two anti-TNF- agents and 20.0% received vedolizumab. At baseline, 108 patients (77.1%) had HBI scores of &gt;4; of these, 56.5% and 58.3% achieved corticosteroidfree clinical remission at weeks 26 and 52, respectively. Significant decreases in HBI and CRP values were observed at weeks 8, 26, and 52 in the entire study cohort (all p &lt; 0.0001). The CRP values were normalized in 34.9%, 37.8%, and 49.3% of the patients by weeks 8, 26, and 52, respectively. The baseline HBI score of "8 was a negative predictor of corticosteroid-free clinical remission at week 52 (odds ratio: 0.21, 95% confidence interval: 0.08–0.56, p # 0.002). The probability of remaining on ustekinumab after 52 weeks was 92.1%. Eleven (7.9%) patients discontinued ustekinumab (three for adverse events). Conclusion: Our study findings confirm the effectiveness and safety of ustekinumab in patients with CD after failure of or intolerance to anti-TNF-a therapy