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Background: Real-world data on long-term outcomes of vedolizumab (VDZ) are scarce. Objective: To assess long-term outcomes (up to 3 years) of VDZ in treating inflammatory bowel disease (IBD). Design: A nationwide, prospective multicentre extension of a Swedish observational study on VDZ assessing Effectiveness And Healthcare resource utilization in patients with IBD (SVEAH). Methods: After re-consent, data of patients with Crohn's disease (CD) (n = 68) and ulcerative colitis (UC) (n = 46) treated with VDZ were prospectively recorded using an electronic case report form integrated with the Swedish IBD Register (SWIBREG). The primary outcome was clinical remission (defined as Harvey–Bradshaw Index ⩽4 in CD and partial Mayo score ⩽2 in UC) at 104 and 156 weeks in patients with a response and/or remission 12 weeks after starting VDZ. Secondary outcomes included health-related quality of life (HRQoL) and biochemical outcomes. Results: VDZ continuation rates were high at weeks 104 and 156, 88% and 84%, respectively, for CD and 87% and 78%, respectively, for UC. Of the 53 CD patients with a response/remission at 12 weeks, 40 (75%) patients were in remission at 104 weeks and 42 (79%) patients at 156 weeks. For UC, these numbers were 25/31 (81%) and 22/31 (71%), respectively. Improvements were seen in the Short Health Scale (p < 0.01 for each dimension; CD, n = 51; UC, n = 33) and the EuroQol 5-Dimensions, 5-levels index value (p < 0.01; CD, n = 39; UC, n = 30). Median plasma-C-reactive protein concentrations (mg/L) decreased from 5 at baseline to 4 in CD (p = 0.01, n = 53) and from 5 to 4 in UC (p = 0.03, n = 34) at 156 weeks. Correspondingly, median faecal-calprotectin (µg/g) decreased from 641 to 114 in CD patients (p < 0.01, n = 26) and from 387 to 37 in UC patients (p = 0.02, n = 17). Conclusion: VDZ demonstrated high continuation rates and was associated with improvements in clinical outcomes, HRQoL measures and inflammatory markers at 2 and 3 years after treatment initiation in this prospective national SVEAH extension study. Registration: ENCePP registration number: EUPAS22735. [ABSTRACT FROM AUTHOR]

Clinical trials demonstrated that golimumab is effective in anti-TNF naïve patients with ulcerative colitis. We aimed to assess the clinical effectiveness of golimumab in a real-world setting. This was a prospective cohort study, conducted at 16 Swedish hospitals. Data were collected using an electronic case report form. Patients with active ulcerative colitis, defined as Mayo endoscopic subscore ≥2 were eligible for inclusion. The primary outcomes were clinical effectiveness at 12 weeks and 52 weeks, i.e. response (defined as a decrease in Mayo score by ≥3 points or 30% from baseline) and remission (defined as a Mayo score of ≤2 with no individual subscores >1). Fifty patients were included. At study entry, 70% were previously exposed to anti-TNF, 16% to vedolizumab, and 96% to immunomodulators. The 12 and 52-week drug continuation rates were 37/50 (74%) and 23/50 (46%), respectively. The 12-week response rate was 14/50 (28%), the remission rate, 8/50 (16%) and the corresponding figures at week 52 were 13/50 (26%) and 10/50 (20%). Among patients who continued golimumab, the median Mayo score decreased from 7 (6–9) at baseline to 1 (0–5) at 52 weeks (p <.01) and the faecal calprotectin decreased from 862 (335–1759) µg/g to 90 (34–169) µg/g (p <.01). Clinical response at week 12 was highly predictive of clinical remission at week 52 (adjusted OR: 73.1; 95% CI: 4.5‒1188.9). The majority of golimumab treated patients represented a treatment refractory patient-group. Despite this, our results confirm that golimumab is an effective therapy in ulcerative colitis. [ABSTRACT FROM AUTHOR]

Background: Prospectively and systematically collected real-world data on vedolizumab are scarce. We aimed to assess the long-term clinical effectiveness of vedolizumab in inflammatory bowel disease (IBD). Methods: This study was a prospective, observational, multicentre study. Overall, 286 patients with active IBD were included (Crohn's disease, n = 169; ulcerative colitis, n = 117). The primary outcomes were clinical response at week 12 and clinical remission at week 52, based on the Harvey Bradshaw Index and the partial Mayo Clinic score. Secondary outcomes included clinical remission at week 12, clinical response at week 52, corticosteroid-free clinical remission at week 52, changes in biochemical measures, and health-related quality of life (HRQoL). Results: At baseline, 88% of the patients were exposed to anti-TNF and 41% of the patients with Crohn's disease had undergone ⩾1 surgical resection. At week 12, clinical response was 27% and remission 47% in Crohn's disease; corresponding figures in ulcerative colitis were 52% and 34%. Clinical response, remission and corticosteroid-free remission at week 52 were 22%, 41% and 40% in Crohn's disease and 49%, 47% and 46% in ulcerative colitis, respectively. A statistically significant decrease in median faecal-calprotectin and C-reactive protein was observed at 12 and 52 weeks in patients with Crohn's disease and ulcerative colitis. The HRQoL measures Short Health Scale and EuroQol 5-Dimensions improved in both Crohn's disease and ulcerative colitis patients (p < 0.001). Clinical disease activity at baseline was inversely associated with clinical remission at week 52. Conclusion: Vedolizumab proved effective for the treatment of refractory IBD in clinical practice. [ABSTRACT FROM AUTHOR]

Objective: Randomized controlled trials have shown the effectiveness of Adalimumab in ulcerative colitis. However, real-life data is scarce. We aimed to assess the effectiveness and predictive factors of effectiveness in a large Swedish cohort. Methods: Retrospective capture of data from local registries at five Swedish IBD centers. Clinical response and remission rates were assessed at three months after starting adalimumab treatment and patients were followed until colectomy or need for another biological. Bio-naive patients were compared to bio experienced patients. Factors associated with short term responses were assessed using logistic regression model. Failure on drug was assessed using a Cox proportional hazards regression model. Results: 118 patients (59 males, 59 females) with median age 34.4 years (IQR 27.0–51.4) were included. Median disease duration was 4.3 years (IQR 2.0–9.0) and follow-up 1.27 years (IQR 0.33–4.1). A clinical corticosteroid-free remission was achieved by 38/118 (32.2%) and response by 91/118 (77%) after three months. CRP >3 mg/l at baseline was predictive of short-term failure to reach corticosteroid-free remission. Factors associated with survival on the drug were male gender, CRP <3 mg/l and absence of primary sclerosing cholangitis. Patients >42 years of age at diagnosis were more likely to respond to adalimumab and remain on treatment compared to patients <20 years. Conclusions: An elevated CRP-level, primary sclerosing cholangitis and female gender were predictors of treatment failure. In contrast older age at diagnosis was a predictor of short-term clinical response and drug survival. Prior infliximab failure, regardless of cause, did not influence the outcome of adalimumab treatment. [ABSTRACT FROM AUTHOR]

Objectives To examine the cost-effectiveness of continued treatment for patients with moderate-severe Crohn's disease in clinical remission, with a combination of anti-tumour necrosis factor alpha [anti-TNFα] [infliximab] and immunomodulator therapy compared with two different withdrawal strategies: [1] withdrawal of the anti-TNFα therapy; and [2] withdrawal of the immunomodulator therapy, respectively. Methods A decision-tree model was constructed mimicking three treatment arms: [1] continued combination therapy with infliximab and immunomodulator; [2] withdrawal of infliximab; or [3] withdrawal of the immunomodulator. Relapses in each arm are managed with treatment intensification and re-institution of the de-escalated drug according to a prespecified algorithm. State-dependent relapse risks, remission probabilities, and quality of life weights were collected from previous published studies. Results Combination therapy was less costly and more efficient than the withdrawal of the immunomodulator, and more costly and more efficient than withdrawal of infliximab. Whether or not combination therapy is cost-effective, compared with the alternatives, depends primarily on current pharmaceutical prices and the willingness-to-pay per additional quality-adjusted life-year [QALY]. Conclusions Combination therapy using a combination of anti-TNFα [infliximab] and an immunomodulator is cost-effective in the treatment of Crohn's disease compared with treatment cycles in which the immunomodulator is withdrawn. Combination treatment is cost-effective compared with treatment cycles in which infliximab is withdrawn, at prices of infliximab below€192/100 mg, given a willingness-to-pay threshold at€49 020 [Sweden] per additional QALY. [ABSTRACT FROM AUTHOR]

Objectives:Clinical trials have demonstrated the efficacy of vedolizumab in inflammatory bowel disease (IBD). However, these findings may not reflect the clinical practice. Therefore, we aimed to describe a vedolizumab-treated patient population and assess long-term effectiveness. Materials and methods:Patients initiating vedolizumab between 1 June 2014 and 30 May 2015 were identified through the Swedish National Quality Registry for IBD. Prospectively collected data on treatment and disease activity were extracted. Clinical remission was defined as Patient Harvey Bradshaw index <5 in Crohn’s disease (CD) and Patient Simple Clinical Colitis Activity index <3 in ulcerative colitis (UC). Results:Two-hundred forty-six patients (147 CD, 92 UC and 7 IBD-Unclassified) were included. On study entry, 86% had failed TNF-antagonist and 48% of the CD patients had undergone ≥1 surgical resection. After a median follow-up of 17 (IQR: 14–20) months, 142 (58%) patients remained on vedolizumab. In total, 54% of the CD- and 64% of the UC patients were in clinical remission at the end of follow-up, with the clinical activity decreasing (p < .0001 in both groups). Faecal-calprotectin decreased in CD (p < .0001) and in UC (p = .001), whereas CRP decreased in CD (p = .002) but not in UC (p = .11). Previous anti-TNF exposure (adjusted HR: 4.03; 95% CI: 0.96–16.75) and elevated CRP at baseline (adjusted HR: 2.22; 95% CI: 1.10–4.35) seemed to be associated with discontinuation because of lack of response. Female sex was associated with termination because of intolerance (adjusted HR: 2.75; 95% CI: 1.16–6.48). Conclusion:Vedolizumab-treated patients represent a treatment-refractory group. A long-term effect can be achieved, even beyond 1 year of treatment. [ABSTRACT FROM AUTHOR]

Background: Alkaline sphingomyelinase (NPP7) is an ecto-enzyme expressed in intestinal mucosa, which hydrolyses sphingomyelin (SM) to ceramide and inactivates platelet activating factor. It is also expressed in human liver and released in the bile. The enzyme may have anti-tumour and anti-inflammatory effects in colon and its levels are decreased in patients with colon cancer and ulcerative colitis. Active NPP7 is translated from a transcript of 1.4 kb, whereas an inactive form from a 1.2 kb mRNA was found in colon and liver cancer cell lines. While the roles of NPP7 in colon cancer have been intensively studied, less is known about the function and implications of NPP7 in the bile. The present study examines the changes of NPP7 in bile of patients with various hepatobiliary diseases. Methods: Bile samples were obtained at endoscopic retrograde cholangiopancreatography (ERCP) in 59 patients with gallstone, other benign disease, tumour, and primary sclerosing cholangitis (PSC). The NPP7 activity was determined. The appearance of the 1.4 and 1.2 kb products in the bile was examined by Western blot. The results were correlated to the diseases and also plasma bilirubin and alkaline phosphatase. Results: NPP7 activity in the tumour group was significantly lower than in the gallstone group (p < 0.05). The activity in the tumour plus PSC group was also lower than in gallstone plus other benign disease group (p < 0.05). Within the tumour group NPP7 activity was lowest in cholangiocarcinoma patients, being only 19% of that in gallstone patients. Bilirubin correlated inversely to NPP7 and was higher in the tumour than in the gallstone group. Western blot identified both the 1.4 kb and the 1.2 kb products in most bile samples. The density ratio for the 1.4/1.2 kb products correlated to NPP7 activity significantly. Two patients (one PSC and one cholangiocarcinoma) lacking NPP7 activity had only the 1.2 kb form in bile. Conclusion: NPP7 activity and the ratio of 1.4/1.2 kb products in bile are significantly decreased in malignancy, particularly in cholangiocarcinoma. The implications of the finding in diagnosis of cholangiocarcinoma and 1.2 kb product in hepatobiliary diseases require further investigation. [ABSTRACT FROM AUTHOR]

Background & Aims: Despite treatment with corticosteroids, severe to moderately severe attacks of ulcerative colitis have a high colectomy rate. We intended to find a rescue therapy other than cyclosporin A, which imposes a high risk of side effects and cyclosporine-related mortality. Methods: This was a randomized double-blind trial of infliximab or placebo in severe to moderately severe ulcerative colitis not responding to conventional treatment. Patients were randomized to infliximab/placebo either on day 4 after the initiation of corticosteroid treatment if they fulfilled the index criteria for fulminant ulcerative colitis on day 3 or on day 6–8 if they fulfilled index criteria on day 5–7 for a severe or moderately severe acute attack of ulcerative colitis. Results were analyzed according to the intention-to-treat principle. The primary end point was colectomy or death 3 months after randomization. Secondary end points were clinical and endoscopic remission at that time in patients who did not undergo operation. Results: Forty-five patients were included (24 infliximab and 21 placebo). No patient died. Seven patients in the infliximab group and 14 in the placebo group had a colectomy (P = .017; odds ratio, 4.9; 95% confidence interval, 1.4–17) within 3 months after randomization. No serious side effects occurred. Three patients in the placebo group required operation for septic complications. Conclusions: Infliximab 4–5 mg/kg is an effective and safe rescue therapy in patients experiencing an acute severe or moderately severe attack of ulcerative colitis not responding to conventional treatment. [Copyright &y& Elsevier]

The mechanism underlying ethanol-induced apoptosis in liver cells is not clear. Sphingomyelin (SM) metabolism is a novel signal transduction pathway that has an impact on apoptosis in many cell types. We investigated whether the SM pathway is involved in ethanol-induced apoptosis in the liver. Hep G2 cells were treated with ethanol followed by assaying apoptosis, sphingomyelinase (SMase) activity, caspase-3 activity, and the changes of SM content in the cells. We found that ethanol dose-dependently increased apoptosis and the effect was accompanied by increases of caspase-3 activity and neutral SMase activity. At concentrations of 80 and 160 mM, ethanol significantly increased caspase-3 activity by 120% and neutral SMase activity by 24%. The activity of acid SMase was only slightly increased without statistical significance. C2-ceramide, the exogenous SM metabolite, mimicked the effects of ethanol on apoptosis and caspase-3 activation. When the SM content was determined 24 h after treatment with ethanol, its level was 15% lower than that of controls. The results indicate that metabolism of SM triggered by neutral SMase participates in ethanol-induced apoptosis in Hep G2 cells and activation of caspase-3 is involved in the apoptotic pathway. [ABSTRACT FROM PUBLISHER]

Background: As the patents of originator biologics are expiring, biosimilar versions are becoming available for the treatment of inflammatory bowel disease (IBD). However, published switch studies of the first infliximab biosimilar, CT-P13, have delivered ambiguous results that could be interpreted as showing a trend towards inferior effectiveness in Crohn's disease (CD) compared with ulcerative colitis (UC). The aim of this study was to investigate the effectiveness and safety of switching IBD patients from treatment with Remicade to CT-P13. Methods: In this prospective observational cohort study, all adult IBD patients on Remicade treatment, at four hospitals, were switched to CT-P13. The primary endpoint was change in clinical disease activity at 2, 6, and 12 months after the switch. Secondary endpoints were subgroup analyses of patients with and without concomitant immunomodulators; changes in biomarkers, quality of life, drug trough levels and anti-drug antibodies (ADAbs); and adverse events. Results: A total of 313 IBD patients were switched (195 CD; 118 UC). There were no significant changes in clinical disease activity, quality of life, biomarkers (except a small but significant increase in albumin in CD) including F-calprotectin, drug trough levels, or proportion of patients in remission. Disease worsening rates were 14.0% for CD and 13.8% for UC; and 2.7% developed ADAbs and 2.2% developed serious adverse events. Conclusions: This is the largest study of switched IBD patients published to date, and it demonstrates that switching from Remicade to CT-P13 may be done with preserved therapeutic effectiveness and safety in both CD and UC. [ABSTRACT FROM AUTHOR]

Background: Alkaline sphingomyelinase (NPP7) is an ecto-enzyme expressed in intestinal mucosa, which hydrolyses sphingomyelin (SM) to ceramide and inactivates platelet activating factor. It is also expressed in human liver and released in the bile. The enzyme may have anti-tumour and anti-inflammatory effects in colon and its levels are decreased in patients with colon cancer and ulcerative colitis. Active NPP7 is translated from a transcript of 1.4 kb, whereas an inactive form from a 1.2 kb mRNA was found in colon and liver cancer cell lines. While the roles of NPP7 in colon cancer have been intensively studied, less is known about the function and implications of NPP7 in the bile. The present study examines the changes of NPP7 in bile of patients with various hepatobiliary diseases.Methods: Bile samples were obtained at endoscopic retrograde cholangiopancreatography (ERCP) in 59 patients with gallstone, other benign disease, tumour, and primary sclerosing cholangitis (PSC). The NPP7 activity was determined. The appearance of the 1.4 and 1.2 kb products in the bile was examined by Western blot. The results were correlated to the diseases and also plasma bilirubin and alkaline phosphatase.Results: NPP7 activity in the tumour group was significantly lower than in the gallstone group (p < 0.05). The activity in the tumour plus PSC group was also lower than in gallstone plus other benign disease group (p < 0.05). Within the tumour group NPP7 activity was lowest in cholangiocarcinoma patients, being only 19% of that in gallstone patients. Bilirubin correlated inversely to NPP7 and was higher in the tumour than in the gallstone group. Western blot identified both the 1.4 kb and the 1.2 kb products in most bile samples. The density ratio for the 1.4/1.2 kb products correlated to NPP7 activity significantly. Two patients (one PSC and one cholangiocarcinoma) lacking NPP7 activity had only the 1.2 kb form in bile.Conclusion: NPP7 activity and the ratio of 1.4/1.2 kb products in bile are significantly decreased in malignancy, particularly in cholangiocarcinoma. The implications of the finding in diagnosis of cholangiocarcinoma and 1.2 kb product in hepatobiliary diseases require further investigation. [ABSTRACT FROM AUTHOR]

The activity of the human enzyme thiopurine methyltransferase (TPMT) varies greatly between individuals because of genetic polymorphism. TPMT is involved in the detoxification and activation of thiopurines such as 6-mercaptopurine, 6-thioguanine, and azathioprine. These drugs are used in the treatment of acute lymphoblastic leukemia and inflammatory bowel disease. A total of 29 sequence variants have been identified so far in the TPMT gene. However, most of these variants are rare and not fully characterized.In this study, we describe the identification and characterization of a novel TPMT sequence variant, originally found in a Swedish man of Italian origin. Sequencing of the variable number tandem repeats region of the TPMT promoter and exons III-X revealed a T-to-C transition at nucleotide 611, causing an amino acid substitution from isoleucine to threonine at amino acid 204, positioned in an α-helix, approximately 16 Å from the active site. This new variant was found in the patient and in his son. Both had intermediate enzyme activity (8.1 U/ml packed red blood cells and 8.8 U/ml packed red blood cells, respectively) and neither carried other variants in the coding region of the gene. To be able to study this variant in more detail, the TPMT∗28 variant was expressed in Escherichia coli, and an in-vitro characterization of the variant revealed that the protein was destabilized and showed a stronger tendency towards degradation at 37°C than the wild-type protein. The individuals carrying the TPMT∗28 variant had less TPMT protein and lower TPMT activity in both red and white blood cells compared with a wild-type control.We present a detailed in-vivo and in-vitro characterization of a novel TPMT sequence variant (TPMT∗28) causing decreased TPMT activity. Individuals carrying TPMT∗28 might have an increased risk for developing severe side effects if treated with conventional doses of thiopurines. [ABSTRACT FROM AUTHOR]

Background: The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy., Methods: This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021., Findings: Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded., Interpretation: In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation., Funding: European Union's Horizon 2020., Competing Interests: Declaration of interests EL has received educational and research grants from Janssen, Pfizer, AbbVie, and Takeda, Fresenius-Kabi; speaker fees from AbbVie, Dr Falk Pharma, Ferring, Janssen, Pfizer, Celgene, Bristol Myers Squibb (BMS), Galapagos, and Takeda; advisory board fees for AbbVie, Celgene, Ferring, Janssen, BMS, Pfizer, Takeda, Gilead-Galapagos, Arena, and Elli Lilly; and consultancy fees from AbbVie. JS reports research support from European Commission Horizon 2020 programme. ND has received research grants from AbbVie, Janssen, and Takeda; speaker fees from AbbVie, Celltrion, Pfizer, Janssen, and Takeda; and advisory board fees from AbbVie, Dr Falk Pharma, and Janssen. BS has served as a consultant for AbbVie, Arena, BMS, Boehringer, CT Scout, Galapagos, Gilead, Janssen, Lilly, and PredictImmune; and has received speaker's fees from AbbVie, CED Service GmbH, Dr Falk Pharma, Ferring, Janssen, Materia Prima, Pfizer, and Lilly. GD'H reports consultancy activities for AbbVie, Agomab, Alimentiv, AstraZeneca, AM Pharma, AMT, Arena Pharmaceuticals, BMS, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Exo Biologics, Galapagos, Index Pharmaceuticals, Kaleido, Roche, Gilead, GlaxoSmithKline, Gossamerbio, Pfizer, Immunic, Johnson & Johnson, Origo, Polpharma, Procise Diagnostics, Prometheus laboratories, Prometheus Biosciences, Progenity, and Protagonist; speaker's bureau for AbbVie, Arena, Galapagos, Gilead, Pfizer, BMS, and Takeda; and fees for data monitoring board activities for Galapagos, AbbVie, Astrazeneca, and Seres Health. PB has received financial support for research from AbbVie, Amgen, Celltrion, Mylan, Pfizer and Takeda; lecture fees from AbbVie, Celltrion, Galapagos, Janssen, Lilly, Pentax, and Takeda; advisory board fees from AbbVie, Arena Pharmaceuticals, BMS, Celltrion, Dr Falk Pharma, Galapagos, Janssen, Lilly, Pentax, PSI-CRO, Roche, Takeda, and Tetrameros. LV has received fees from AbbVie, Amgen, Biogen, Mylan, Takeda, MSD, Janssen, Pfizer, Ferring, and Galapagos. PI has received honoraria for talking on behalf of AbbVie, BMS, Celgene, Celltrion, Dr Falk Pharma, Ferring, Galapagos, Gilead, MSD, Janssen, Lilly, Pfizer, Takeda, Tillotts, Sapphire Medical, Sandoz, Shire, and Warner Chilcott; and for acting in an advisory capacity to AbbVie, Arena, Boehringer-Ingelheim, BMS, Celgene, Celltrion, Connect Biopharma, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor Pharma, and Warner Chilcott. SV has received consulting or lecture fees for AbbVie, Amgen, Sandoz, Janssen, MSD, Pfizer, Celltrion, and Takeda. CAL has received grants from Genentech, AbbVie, Eli Lilly, Pfizer, Roche, UCB Biopharma, Sanofi Aventis, Biogen IDEC, Orion OYJ, and AstraZeneca; grants and personal fees from Janssen, Takeda, and Ferring; and personal fees from Dr Falk Pharma, outside the submitted work. FB has received grant or research support from AbbVie, Amgen, Janssen, and Takeda; honoraria from AbbVie, Dr Falk Pharma, Arena, Celgene, Mundipharma, Ferring, Vifor, Janssen, Merck Sharp & Dohme, Pfizer, Norgine, and Takeda. MN received board membership, consultancy, or lecture fees from AbbVie, Amgen, Arena, Biogen, CTMA, Celltrion, Ferring, Fresenius, Janssen, Mayoli-Spindler, MSD, Pfizer, Sandoz, and Takeda. MF received consulting or lecture fees for AbbVie, Amgen, Biogen, Gilead, Sandoz, Janssen, MSD, Pfizer, Ferring, Lilly, Tillots, Celltrion, Fresenius, Galapagos, and Takeda. CG received consulting or lecture fees from AbbVie, Amgen, Celltrion, Biogen, Fresenius, Gilead, Janssen, MSD, Mylan, Pfizer, Takeda, and Vifor. SB-H has received advisory board or consulting fees from AbbVie, Takeda, Janssen, Celltrion, Pfizer, GlaxoSmithKline, Ferring, Novartis, Roche, Gilead, NeoPharm, Predicta Med, Galmed, Medial Earlysign, and Eli Lilly, and research support from AbbVie, Takeda, Janssen, Celltrion, Pfizer, and Galmed. J-FC has received research grants from AbbVie, Pfizer, and Takeda; payment for lectures from AbbVie, Amgen, Pfizer, and Takeda; consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Novartis, Otsuka, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi, Takeda, TiGenix, and Vifor; and holds stock options in Intestinal Biotech Development. EH has received lecture fees from Takeda, Janssen, and BMS; and consultant or advisory board fees from AbbVie, Gilead, and Janssen. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: We investigated the effects of inducing deep remission in patients with early Crohn's disease (CD)., Methods: We collected follow-up data from 122 patients (mean age, 31.2 ± 11.3 y) with early, moderate to severe CD (median duration, 0.2 years; interquartile range, 0.1-0.5) who participated in the Effect of Tight Control Management on CD (CALM) study, at 31 sites, representing 50% of the original CALM patient population. Fifty percent of patients (n = 61) were randomly assigned to a tight control strategy (increased therapy based on fecal level of calprotectin, serum level of C-reactive protein, and symptoms), and 50% were assigned to conventional management. We categorized patients as those who were vs were not in deep remission (CD endoscopic index of severity scores below 4, with no deep ulcerations or steroid treatment, for 8 or more weeks) at the end of the follow-up period (median, 3.02 years; range, 0.05-6.26 years). The primary outcome was a composite of major adverse outcomes that indicate CD progression during the follow-up period: new internal fistulas or abscesses, strictures, perianal fistulas or abscesses, or hospitalization or surgery for CD. Kaplan-Meier and penalized Cox regression with bootstrapping were used to compare composite rates between patients who achieved or did not achieve remission at the end of the follow-up period., Results: Major adverse outcomes were reported for 34 patients (27.9%) during the follow-up period. Significantly fewer patients in deep remission at the end of the CALM study had major adverse outcomes during the follow-up period (P = .01). When we adjusted for potential confounders, deep remission (adjusted hazard ratio, 0.19; 95% confidence interval, 0.07-0.31) was significantly associated with a lower risk of major adverse outcome., Conclusions: In an analysis of follow-up data from the CALM study, we associated induction of deep remission in early, moderate to severe CD with decreased risk of disease progression over a median time of 3 years, regardless of tight control or conventional management strategy., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Intestinal alkaline sphingomyelinase (alk-SMase) generates ceramide and inactivates platelet-activating factor (PAF) and was previously suggested to have anticancer properties. The direct evidence is still lacking. We studied colonic tumorigenesis in alk-SMase knockout (KO) mice. Formation of aberrant crypt foci (ACF) was examined after azoxymethane (AOM) injection. Tumor was induced by AOM alone, a conventional AOM/dextran sulfate sodium (DSS) treatment, and an enhanced AOM/DSS method. β-Catenin was determined by immunohistochemistry, PAF levels by ELISA, and sphingomyelin metabolites by mass spectrometry. Without treatment, spontaneous tumorigenesis was not identified but the intestinal mucosa appeared thicker in KO than in wild-type (WT) littermates. AOM alone induced more ACF in KO mice but no tumors 28 weeks after injection. However, combination of AOM/DSS treatments induced colonic tumors and the incidence was significantly higher in KO than in WT mice. By the enhanced AOM/DSS method, tumor number per mouse increased 4.5 times and tumor size 1.8 times in KO compared with WT mice. Although all tumors were adenomas in WT mice, 32% were adenocarcinomas in KO mice. Compared with WT mice, cytosol expression of β-catenin was significantly increased and nuclear translocation in tumors was more pronounced in KO mice. Lipid analysis showed decreased ceramide in small intestine and increased sphingosine-1-phosphate (S1P) in both small intestine and colon in nontreated KO mice. PAF levels in feces were significantly higher in the KO mice after AOM/DSS treatment. In conclusion, lack of alk-SMase markedly increases AOM/DSS-induced colonic tumorigenesis associated with decreased ceramide and increased S1P and PAF levels., (©2014 American Association for Cancer Research.)

We previously showed that dietary sphingomyelin (SM) inhibited cholesterol absorption in animals. The key enzyme hydrolyzing SM in the gut is alkaline sphingomyelinase (alk-SMase, nucleotide pyrophosphatase/phosphodiesterase 7). Here using the fecal dual-isotope ratio method we compared cholesterol absorption in the wild-type (WT) and alk-SMase knockout (KO) mice. The animals were fed an emulsion containing [(14)C]cholesterol and [(3)H]sitosterol. The radioactivities in the lipids of the fecal samples collected 4, 8, and 24 h thereafter were determined, and the ratio of (14)C/(3)H was calculated. We found that the fecal [(14)C]cholesterol recovery in the KO mice was significantly higher than in the WT mice. A maximal 92% increase occurred 8 h after feeding. Recovery of [(3)H]sitosterol did not differ between the two groups. Accordingly, the (14)C-to-(3)H ratio of fecal lipids was 133% higher at 8 h and 75% higher at 24 h in the KO than in the WT mice. Decreased [(14)C]cholesterol was also found in the serum of the KO mice 4 h after feeding. Supplement of SM in the emulsion reduced the differences in fecal [(14)C]cholesterol recovery between the WT and KO mice because of a greater increase of [(14)C]cholesterol recovery in the WT mice. Without treatment, the KO mice had significantly higher SM levels in the intestinal content and feces, but not in the intestinal mucosa or serum. The expression of Niemann-Pick C1 like 1 protein in the small intestine was not changed. In conclusion, alk-SMase is a physiological factor promoting cholesterol absorption by reducing SM levels in the intestinal lumen., (Copyright © 2014 the American Physiological Society.)

The polymorphic enzyme thiopurine methyltransferase (TPMT) is involved in the methylation of thiopurines. On comparing the phenotype with the genotype in Swedish patients with inflammatory bowel disease and healthy individuals, we found two discordant cases with low TPMT enzyme activity (0.3 and 0.4 U/ml packed red blood cells (pRBC). Genotyping by pyrosequencing revealed that they carried the nucleotide substitutions 460G>A and 719A>G, giving two possible genotypes (TPMT*1/*3A or TPMT*3B/*3C). DNA sequencing of exon III to X was performed in the patients and their parents. We identified an A>G transition in the start codon (exon III, 1A>G, Met>Val, TPMT*14) in one of the patients and her father (6.3 U/ml pRBC). The mother in this family carried the 460G>A and 719A>G nucleotide substitutions (TPMT*1/*3A; 5.0 U/ml pRBC). In the second family, sequencing revealed a G>A transition in the acceptor splice site in intron VII/exon VIII (IVS7 -1G>A, TPMT*15) in the patient and his mother (6.9 U/ml pRBC). His father was genotyped as TPMT*1/*3A (6.0 U/ml pRBC). Hence, we report the identification of two novel sequence variants, present in highly conserved nucleotide positions of the human TPMT gene, resulting in a loss of enzyme activity.

No surveillance is recommended after radical excision of low-risk adenomas (pedunculated adenoma irrespective of size, sessile adenoma < or = 10 mm, number < or = 2. An endoscopic check-up is recommended 3-6 months after radical excision of high-risk adenomas (sessile adenoma > 10 mm, number > or = 3), as well as after excision of a pedunculated or a sessile adenoma with an unclear resection margin. All above is irrespective of histopathological adenoma classification. An endoscopic check-up is recommended 3 months after radical excision of a highly or moderately differentiated malignant polyp with no sign of invasion into blood or lymph vessels and with a maximum invasion depth stage T1-sm1. Surgical resection is necessary if the malignant polyp is poorly differentiated, and/or invades into blood or lymph vessels, and/or is stage T1-sm3, or is excised with unclear resection margins. Treatment for stage T1-sm2 polyps may be individualized. Individuals with low-risk adenomas and a first degree relative with colorectal cancer, individuals having high-risk adenomas or malignant polyps removed, as well as individuals operated on for colorectal cancer should be subjected to colonoscopy after three years and then every fifth year when < or = 75 years of age.

Sphingomyelin (SM) metabolism in the gut may have an impact on colon cancer development. In this study, we purified alkaline sphingomyelinase (alk-SMase) from human intestinal content, and studied its location in the mucosa, expression in colon cancer, and function on colon cancer cells. The enzyme was purified by a series of chromatographies. The molecular mass of the enzyme is 60 kDa, optimal pH is 8.5, and isoelectric point is 6.6. Under optimal conditions, 1 mg of the enzyme hydrolyzed 11 mM SM per hour. The properties of the enzyme are similar to those of rat intestinal alk-SMase but not to those of bacterial neutral SMase. Immunogold electronmicroscopy identified the enzyme on the microvillar membrane in endosome-like structures and in the Golgi complexes of human enterocytes. The expression and the activity of the enzyme were decreased in parallel in human colon cancer tissues compared with the adjacent normal tissue. The enzyme inhibited DNA biosynthesis and cell proliferation dose dependently and caused a reduction of SM in HT29 cells. Intestinal alk-SMase is localized in the enterocytes, down-regulated in human colon cancer, and may have antiproliferative effects on colon cancer cells.

Background: It has recently been reported that sulindac has an apoptotic effect on KYN-2 cells, an undifferentiated hepatoma cell line. The present work investigates whether sulindac also has an apoptotic effect on well-differentiated hepatoma cells and what its potential mechanism might be., Materials and Methods: Hep G2 cells were treated with sulindac at different concentrations. Apoptosis rate, cell proliferation and 3H-thymidine incorporation were measured. The activities of caspase-3, acid and neutral sphingomyelinase and the changes of sphingomyelin content were also assayed., Results: Sulindac dose-dependently induced apoptosis in Hep G2 cells; both sulindac sulfone and sulfide had similar effects. The apoptosis was accompanied by an increase of caspase-3 activity and a decrease of cell proliferation and 3H-thymidine incorporation. No significant change could be observed for the activity of sphingomyelinase and sphingomyelin content., Conclusion: Sulindac induces apoptosis and inhibits proliferation in Hep G2 cells. The effect may be mediated by a pathway related to caspase-3 activation but independent of sphingomyelin metabolism