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Background Infliximab and adalimumab concentrations are associated with important outcomes in inflammatory bowel disease (IBD). Antibodies to infliximab (ATI) and adalimumab (ATA) are associated with reduced drug concentrations and worse outcomes. Because the efficacy of dose escalation to overcome antibodies is unclear, we assessed the impact of this strategy to overcome immunogenicity in IBD. Methods Infliximab and adalimumab dosing, drug, and antibody concentrations were extracted from a database of patients with IBD having specimens collected for therapeutic drug monitoring. The primary outcome compared proportions with either infliximab ≥5 μg/mL or adalimumab ≥7.5 μg/mL and undetectable antibodies between dose-escalated and non-escalated patients. Area under the receiver operating characteristic curve analyses determined antibody concentrations below which dose escalation was associated with the primary outcome. Results The study included 63,176 patients treated with infliximab and 46,429 patients treated with adalimumab. We detected ATI and ATA in 23.6% (n = 14,900) of patients treated with infliximab and 19.6% (n = 9101) of patients treated with adalimumab. In patients with ATI, infliximab dose escalation (n = 453) yielded higher proportions achieving the primary outcome (47.5% vs 30.9%; P < 0.001), greater drug concentration increases (5.9 μg/mL vs 0.2 μg/mL; P < 0.001), and ATI reductions (4.3 U/mL vs 1.9 U/mL; P = 0.002) compared to no escalation (n = 204). An ATI threshold of 8.55 U/mL was associated with achieving the primary outcome with dose escalation (area under the curve = 0.66). For patients with ATI ≤8.55 U/mL (n = 274), higher proportions (59.1% vs 29.6%; P < 0.001) achieved the primary outcome compared with those with ATI >8.55 U/mL (n = 179). No patients treated with adalimumab achieved the primary outcome (0/390), regardless of dose escalation (n = 87). Conclusion Dose escalation increased drug concentrations and eliminated antibodies with infliximab but not adalimumab. Initial ATI ≤8.55 U/mL was associated with increased efficacy of dose escalation using this assay.

The aim was to compare outcomes in adult patients with inflammatory bowel disease (IBD) who switched to infliximab-dyyb with those who remained on reference product (RP) infliximab in the United States (US) in a retrospective, propensity score-matched, non-inferiority cohort trial.This study was a retrospective, non-inferiority study conducted within a US integrated healthcare system and included adult patients with a confirmed diagnosis of Crohn's disease or ulcerative colitis. A 1:1 propensity score matching was utilized to match patients who switched to infliximab-dyyb during the period April 2016-March 2018 to patients who remained on RP infliximab. The non-inferiority margin was set at + 10% of the upper limit. The primary outcome was a composite measure of disease worsening requiring acute care after the index date of switching to infliximab-dyyb or continuing RP infliximab. Disease worsening requiring acute care was defined as any IBD-related emergency room visit, hospitalization, or surgery. The secondary outcome was the composite measure of disease worsening requiring acute care or treatment failure. A switch to another biologic or tofacitinib was a proxy for treatment failure. All patients were followed for up to 9 months.After propensity score matching, the matched cohort included 1409 patients in the infliximab-dyyb group and 1409 patients in the RP infliximab group. The overall mean age (± standard deviation) was 47.7 ± 17.0 years, 50.9% of patients were of male gender, and 51.8% of patients had Crohn's disease, while the remainder of the cohort had ulcerative colitis. There were 144 patients (10.2%) in the infliximab-dyyb group and 245 patients (17.4%) in the RP infliximab group who experienced disease worsening requiring acute care (P 0.01 for non-inferiority). There were 347 patients (24.6%) in the infliximab-dyyb group who experienced disease worsening requiring acute care or treatment failure compared to 375 patients (26.6%) who remained on RP infliximab (P 0.01 for non-inferiority).There was no increased risk of (1) disease worsening requiring acute care or (2) disease worsening requiring acute care or treatment failure in patients with IBD who switched from RP infliximab to infliximab-dyyb when compared to patients who remained on RP infliximab in this US population. Infliximab-dyyb is an option for patients with IBD who need to use RP infliximab.

Background Real-world assessments of biosimilars are needed to understand their effectiveness and safety in practice settings that may differ from those seen in clinical trials or healthcare systems in different countries. To assess the effectiveness and safety of a biosimilar (infliximab-dyyb) and its reference product (infliximab) in patients with inflammatory bowel disease (IBD) in the United States. Methods We conducted a retrospective cohort study of biologic-naive patients with IBD who started treatment with infliximab-dyyb or infliximab. The study included 3206 patients identified through electronic health records in a US integrated healthcare delivery system. The effectiveness outcome was a composite of IBD-related surgery, IBD-related emergency room visit, and IBD-related hospitalization within 12 months of initiation. Safety outcomes included incidence of any or serious infection, cancer, acute liver dysfunction, and tuberculosis. We used a non-inferiority test with an upper-limit margin of 10% to analyze effectiveness. Doubly robust methods incorporating Cox proportional hazard regression with standardized inverse probability of treatment weighting were used to analyze both effectiveness and safety outcomes. Results The composite effectiveness outcome occurred in 107 of 870 patients (12.3%) in the infliximab-dyyb and 379 of 2336 patients (16.2%) in the infliximab groups. Infliximab-dyyb was non-inferior (P < .01) and was not different (hazard ratio [HR] 0.81; confidence interval [CI] 0.65–1.01; P = .06) to infliximab. Safety outcomes were not different between infliximab-dyyb and infliximab for any infections (HR 1.01; CI 0.86–1.17; P = .95), serious infections (HR 0.83; CI 0.54–1.26; P = .38), cancers (HR 0.83; CI 0.44–1.54; P = .55), and tuberculosis (HR 0.59; CI 0.10–3.55; P = .57). Conclusions Initiation of infliximab-dyyb was non-inferior to infliximab among biologic-naive patients with IBD in an US integrated healthcare delivery system.

Purpose The aim was to compare outcomes in adult patients with inflammatory bowel disease (IBD) who switched to infliximab-dyyb with those who remained on reference product (RP) infliximab in the United States (US) in a retrospective, propensity score-matched, non-inferiority cohort trial. Methods This study was a retrospective, non-inferiority study conducted within a US integrated healthcare system and included adult patients with a confirmed diagnosis of Crohn’s disease or ulcerative colitis. A 1:1 propensity score matching was utilized to match patients who switched to infliximab-dyyb during the period April 2016–March 2018 to patients who remained on RP infliximab. The non-inferiority margin was set at + 10% of the upper limit. The primary outcome was a composite measure of disease worsening requiring acute care after the index date of switching to infliximab-dyyb or continuing RP infliximab. Disease worsening requiring acute care was defined as any IBD-related emergency room visit, hospitalization, or surgery. The secondary outcome was the composite measure of disease worsening requiring acute care or treatment failure. A switch to another biologic or tofacitinib was a proxy for treatment failure. All patients were followed for up to 9 months. Results After propensity score matching, the matched cohort included 1409 patients in the infliximab-dyyb group and 1409 patients in the RP infliximab group. The overall mean age (± standard deviation) was 47.7 ± 17.0 years, 50.9% of patients were of male gender, and 51.8% of patients had Crohn’s disease, while the remainder of the cohort had ulcerative colitis. There were 144 patients (10.2%) in the infliximab-dyyb group and 245 patients (17.4%) in the RP infliximab group who experienced disease worsening requiring acute care (P

The ever-growing prevalence of Type-2 diabetes in the world has an urgent need for multiple orally effective agents that can regulate glucose homeostasis. G-Protein coupled receptor 119 (GPR 119) agonists have demonstrated the glucose-dependent insulin secretion and showed beneficial effects on glycemic control in humans and/or relevant animal models. Herein, we describe our efforts towards identification of a potent and oral GPR 119 agonist 13c (ZY-G19), which showed in vitro potency in the cell-based assay and in vivo efficacy without exerting any significant signs of toxicity in relevant animal models.

Algorithms for the diagnosis, management, and follow-up have been proposed for patients hospitalized for inflammatory bowel disease (IBD) colitis flare. The degree to which providers adhere to these algorithms is unknown. This study evaluated the quality of care in IBD patients hospitalized for disease-associated exacerbations and factors correlated with higher degrees of care. Retrospective chart review of 34 patients during 60 admissions to the medicine service for IBD colitis exacerbation between 2005 and 2012 at the Veterans Affairs San Diego Medical Center. Examined factors included laboratory testing, timing of consultation and intravenous steroids, abdominal imaging, endoscopic examination, venous thromboembolism (VTE) prophylaxis, narcotic use, Clostridium difficile and cytomegalovirus testing, symptomatology at discharge, timing of follow-up, and rates of readmission and mortality. Quality of care varied among the factors studied, ranging from 30.5 % for pharmacologic VTE prophylaxis to 84.7 % for gastroenterology consultation within 24 h. Of 60 admissions, 22 % were not tested for C. difficile. Fifteen percent of patients were discharged before meeting commonly used discharge criteria. Eighty percent were seen in clinic at any time post-discharge; 6.7 % were readmitted; 10 % were lost to follow-up; 1.7 % opted for outside follow-up; and 1.7 % expired. The quality of care for patients admitted with IBD colitis flares is variable. These data outline opportunities for improvement, particularly in regard to pain management, VTE prophylaxis, and follow-up. Further studies are needed to test intervention strategies for practice improvement.

International audience; BACKGROUND & AIMS: Mucosal healing has been proposed as a goal for treatment because it is associated with improved clinical outcomes of patients with Crohn's disease (CD). However, little is known about the feasibility or probability of achieving mucosal healing in clinical practice. We evaluated the feasibility of treating patients to achieve mucosal healing based on endoscopic evaluation (treating to target). METHODS: We reviewed the endoscopic outcomes of 67 patients with CD who had lesions detected by endoscopy. Patients underwent 2 to 4 subsequent endoscopic evaluations at the University of California San Diego and were followed up from 2011 through 2012; data were collected on therapies and patient management. The cumulative incidences of mucosal healing and endoscopic improvement were estimated using the Kaplan-Meier method. Factors independently associated with mucosal healing were identified using a Cox proportional hazards model. RESULTS: After a median follow-up period of 62 weeks, 34 patients (50.7%) had mucosal healing and 41 patients (61.1%) had endoscopic improvement. The cumulative probabilities of mucosal healing were 12.7% and 45.0% at 24 and 52 weeks of treatment, respectively. Factors associated with mucosal healing were as follows: fewer than 26 weeks between endoscopic procedures (hazard ratio, 2.35; 95% confidence interval, 1.15-4.97; P = .035) and adjustment to medical therapy when mucosal healing was not observed (hazard ratio, 4.28; 95% confidence interval, 1.9-11.5; P = .0003). CONCLUSIONS: In an endoscopic study of patients with CD, we found that assessment of endoscopic disease activity and adjustments to medical therapy (treat to target) increase the likelihood of mucosal healing.

A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as PPAR-pan agonists. Incorporation of structurally constrained oxime-ether based linker in the chemotype of a potent PPARδ selective agonist GW-501516 was adapted as designing strategy. In vitro, selected test compounds 12a, 12c, 17a and 18a showed PPAR-pan agonists activities and among these four compounds tested, 12a emerged as highly potent and efficacious compound, while 17a exhibited moderate and balanced PPAR-pan agonistic activity. In vivo, selected test compounds 12a and 17a exhibited significant anti-hyperglycemic and anti-hyperlipidemic activities in relevant animal models. These results support our hypothesis that the introduction of structurally constrained oxime-ether linker between lipophilic tail and acidic head plays an important role in modulating subtype selectivity and subsequently led to the discovery of potent PPAR-pan agonists.

BackgroundThe ability to measure the expression of proinflammatory cytokines from intestinal biopsies in patients with Crohn's disease in an accurate and reproducible way is critical for proof-of-concept and mechanism-of-action trials; however, the number of biopsies from a segment of the ileum or colon required to yield reproducible results has not been rigorously evaluated. We examined intestinal biopsies from patients with Crohn's disease to validate methods for detecting changes in inflammatory gene expression.MethodsTo evaluate the reproducibility of gene expression measurements, intestinal biopsies were obtained from designated segments from 6 healthy controls, 6 patients with active Crohn's disease, and 6 patients with inactive Crohn's disease. Disease activity was based on the simple endoscopic score for Crohn's disease. Expression of 7 proinflammatory genes was measured from each biopsy using quantitative polymerase chain reaction. Using a linear mixed effects model, the power to detect transcriptional changes corresponding to active and inactive Crohn's disease was calculated.ResultsTotal simple endoscopic score for Crohn's disease score corresponds with expression of most inflammatory biomarkers. For most genes, 2 to 5 biopsies are needed to reduce sampling error to

This study examined gastrointestinal hormone and peptide responses when glucose was ingested after prolonged exercise. Six endurance-trained male athletes ran on a treadmill for 2 h at 60% V̇o2 max. Immediately after the run, the athletes consumed 75 g of glucose in 250 ml of water (ExGLU) or flavored water as a placebo control (ExPL). On a separate visit, the athletes rested for 2 h and then consumed glucose (ConGLU). During the first 60 min of recovery from exercise alone (ExPL), plasma vasoactive intestinal peptide (VIP), gastrin, and glucagon-like peptide-1 (GLP-1) all increased significantly, whereas glucose, insulin, and gastric inhibitory polypeptide (GIP) were unchanged from the immediate postexercise value. When glucose was ingested after exercise (ExGLU), glucose, insulin, VIP, gastrin, GLP-1, and GIP were all increased ( P < 0.01). However, when glucose was ingested after resting for 2 h (ConGLU), VIP levels were unaffected, although glucose, insulin, gastrin, GLP-1, and GIP levels increased ( P < 0.05). The plasma glucose response was greater ( P < 0.03) and the plasma insulin response lower ( P < 0.004) during ExGLU compared with ConGLU. There was a significantly higher ( P < 0.01) VIP response during the initial period of recovery in ExGLU than there was with both ExPL and ConGLU. Plasma VIP showed a modest negative correlation with circulating glucose ( r = −0.35, P < 0.03) and insulin ( r = −0.37, P < 0.03) during the ExGLU recovery period. In summary, when glucose is ingested after prolonged exercise, there is mild insulin resistance and a corresponding rapid transitory increase in plasma VIP. These data suggest that VIP may play an important glucoregulatory role when glucose is ingested during the immediate postexercise recovery period.

Summary Background Accurate and reproducible measurement of expression of pro-inflammatory cytokines in colonic biopsies from patients with ulcerative colitis (UC) is essential for proof-of-concept and mechanism-of-action studies. Few studies have rigorously established the number of biopsies required for accurate and reproducible biomarker measurements. Aim To validate methods for measuring changes in gene expression in colonic biopsy samples. Methods Twelve colonic biopsies were obtained from each of six healthy controls, six patients with inactive UC and seven patients with active UC. Mayo endoscopic scores were used as a clinical reference standard. Quantitative PCR was used to assess mRNA expression of eight known inflammatory genes. The power to detect a reduction in gene expression in active vs. inactive UC was calculated using a linear mixed effect model. Results mRNA analysis of colonic biopsies is a sensitive and feasible approach for measuring inflammatory gene expression in colonic biopsies. Inflammatory biomarkers correlate with Mayo endoscopic subscores for each colonic region. For most genes, three rectal biopsies from two to four patients are required to detect changes in gene expression corresponding to active vs. inactive UC to achieve a power of 80% with an alpha of 0.05. Conclusion Our data suggest that systematic measurement of inflammatory biomarkers at the mRNA level can be a valuable tool for hypothesis testing, and assessment of clinical activity and response to therapy in ulcerative colitis.

Background Mucosal healing (MH) as a treatment target for ulcerative colitis is of growing interest because it is associated with improved clinical outcomes. However, the feasibility and probability of reaching MH in clinical practice is unknown. We therefore evaluated the feasibility of "treating to target" according to endoscopic findings to reach MH. Methods All endoscopic outcomes of patients with ulcerative colitis followed in a single inflammatory bowel disease unit from 2011 to 2012 were reviewed and subsequent therapeutic management. Cumulative incidence of MH and histologic healing (HH) were estimated using a Kaplan-Meier method. Results A total of 60 patients underwent at least 2 consecutive endoscopic assessments, of whom 45 and 48 patients had endoscopic and histologic evidence of active disease, respectively. After a median follow-up of 76 weeks, 27 of 45 (60%) patients with endoscopic disease activity at baseline achieved MH and 24 (50%) of 48 patients with histologic disease activity at baseline had HH. The cumulative probabilities of MH were 26%, 52%, and 70% at 26, 52, and 76 weeks, respectively. The cumulative probabilities of HH at weeks 26, 52, and 76 from the time of initial procedure were 19%, 41%, and 57%, respectively. Any adjustment in medical therapy in case of persistent endoscopic activity was associated with both MH and HH. Conclusions Repeated assessment of endoscopic disease activity with adjustment of medical therapy to the target of MH is feasible in clinical practice in patients with ulcerative colitis, and seems to be of benefit.

Magnetic resonance enterography (MRE) is a relatively new imaging modality that has shown promise for diagnosing, staging, and monitoring Crohn's disease (CD) and its complications while avoiding exposure to ionizing radiation. In addition to clinical implications, MRE has the potential to be used as an objective measure of disease activity for clinical trials. We provide the rationale for MRE, indications for its use, and an overview of the typical procedure and common findings for institutions who want to begin or refine the use of MRE for CD.

Computed tomography (CT) and magnetic resonance (MR) enterography are now widely used to diagnose and monitor Crohn’s disease. We sought to assess the use of enterography for management of inflammatory bowel disease (IBD) in our medical center. We performed a retrospective review of all patients diagnosed with IBD who underwent MR or CT enterography from November 1, 2010 to October 25, 2012 at our institution. We assessed disease complications identified by enterography, agreement between disease activity determined by endoscopy and enterography, association between inflammatory markers and enterography-determined disease activity and recommended changes in medical and surgical management following enterography. A total of 311 enterography studies (291 MR and 20 CT enterographies) were performed on 270 patients, including 258 (83.0 %) on patients with presumed Crohn’s disease and 53 (17.0 %) with presumed ulcerative colitis. Active small bowel (SB) disease was noted in 73/311 (23.5 %) studies. Complications including strictures, perianal fistulas, abscesses and SB fistulas were noted in 108/311 (34.7 %) studies. Endoscopic and enterography defined active disease had an agreement of κ = 0.36 in the ileum (n = 179). A total of 142/311 (45.7 %) enterographies were associated with recommended medication changes within 90 days while surgery or endoscopic dilation of stricture was recommended following 41/311 (13.2 %) enterographies. Enterography resulted in a change in diagnosis from ulcerative colitis to Crohn’s in 5/311 (1.6 %) studies. Enterography reveals active disease and complications not evident on endoscopy and should be considered in the initial diagnosis, assessment of disease activity, and monitoring of therapy in patients with IBD.

Ulcerative colitis is a chronic inflammatory disease of the colon; as many as 25% of patients with this disease require hospitalization. The goals of hospitalization are to assess disease severity, exclude infection, administer rapidly acting and highly effective medication regimens, and determine response. During hospitalization, patients should be given venous thromboembolism prophylaxis and monitored for the development of toxic megacolon. Patients who do not respond to intravenous corticosteroids should be considered for rescue therapy with infliximab or cyclosporine. Patients who are refractory to medical therapies or who develop toxic megacolon should be evaluated promptly for colectomy. Patients who do respond to medical therapies should be discharged on an appropriate maintenance regimen when they meet discharge criteria. We review practical evidence-based management principles and propose a day-by-day algorithm for managing patients hospitalized for ulcerative colitis.

Patients with malignant biliary obstruction are commonly living longer than previously due to improved oncologic therapies, often exceeding expected times of self-expanding metal stent patency.The purpose of this study was to assess the long-term risk and impact of cholangitis in these patients.Retrospective review of electronic medical records at an academic medical center.One hundred and one patients had a self-expanding metal stent placed for malignant biliary obstruction. The median survival after SEMS was 214 days. Of these patients, 22 % developed at least one episode of cholangitis requiring inpatient admission, 20 % (9/45) of patients were hospitalized for cholangitis at 6 months, 40 % (8/20) at 1 year, and 75 % (3/4) at 2 years. All of the (8/8) patients receiving chemotherapy prior to hospitalization for cholangitis experienced delays in subsequent chemotherapy. Follow-up of 36 episodes of cholangitis revealed a 14 % 30-day mortality.Cholangitis develops commonly in long-term survivors with self-expanding metal stents for malignant biliary obstruction, and is associated with delays in chemotherapy and a 14 % 30-day mortality.

A novel series of oxime containing benzyl-1,3-dioxane- r -2-carboxylic acid derivatives ( 6a – k ) were designed as selective PPAR α agonists, through bioisosteric modification in the lipophilic tail region of PPAR α / γ dual agonist. Some of the test compounds ( 6a , 6b , 6c and 6f ) showed high selectivity towards PPAR α over PPAR γ in vitro. Further, highly potent and selective PPAR α agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPAR α binding pocket correlate its in vitro selectivity profile toward PPAR α over PPAR γ . Together, these results confirm discovery of novel series of oxime based selective PPAR α agonists for the safe and effective treatment of various metabolic disorders.

Successful Use of Infliximab in the Treatment of Corticosteroid Dependent Collagenous Colitis

end points were time to surgery and time to tx failure (defined as either need for surgery, biologic therapy stopped or switched due to lack of efficacy or adverse events).Specific MRE findings ; 1. penetrating complications e.g fistulae, 2. Small bowel stenosis (SBS) +/dilatation, 3. Small bowel wall thickening (SBWT) and 4. Relative contrast enhancement (RCE) were then correlated to primary and secondary end points. RESULTS: In total,353 patients were commenced on aTNFtx for CD(182 adalimumab and 171 infliximab).Of these 54 patients had an MRE prior to commencing aTNFtx(23 infliximab;31 adalimumab).The median time from MRE to aTNFtx was 66.2 days (+/58.4). 13/54(24.1%) had surgery within the following year due to tx failure.The proportion of patients with SBS on MRE was significantly greater in those who went on to have surgery within 1 year;10/13 (76.9%) vs 3/ 41(7.3%)respectively (chi-square p,0.001).The frequency of penetrating complications, SBWT and RCE was not significantly different in the group who required early surgery.Time to surgery was significantly shorter in patients with SBS on MRE (log rank p=0.001).34 patients were defined as tx responders vs 20 who experienced tx failure. In a multivariate analysis using cox proportional hazards model, the MRE variables independently associated with time to tx failure were SBS (p ,0.001, hazard ratio 17.9, 95% CI 4.5-71.4) and penetrating complications (p,0.027, hazard ratio 14.5 95% CI 1.4-155.3) . CONCLUSION: The presence of SBS on MRE can help predict need for early surgery and is associated with tx failure in patients who commence aTNFtx. These findings demonstrate the utility of MRE in planning tx and suggest that aTNFtx may be more effective when commenced early in disease course, prior to onset of fibrostenotic or penetrating complications.