TNF promoter hypomethylation is associated with mucosal inflammation in IBD and anti-TNF response.

Background and aims: Inflammatory Bowel Diseases (IBD) are chronic inflammatory conditions influenced heavily by environmental factors. DNA methylation is a form of epigenetic regulation linking environmental stimuli to gene expression changes and inflammation. Here, we investigated how DNA methylation of the TNF promoter differs between inflamed and uninflamed mucosa of IBD patients, including anti-TNF responders and non-responders. Methods: We obtained mucosal biopsies from 200 participants (133 IBD and 67 controls) and analyzed TNF promoter methylation using bisulfite sequencing, comparing inflamed with uninflamed segments, in addition to paired inflamed/uninflamed samples from individual patients. We conducted similar analyses on purified intestinal epithelial cells from bowel resections. We also compared TNF methylation levels of inflamed and uninflamed mucosa from a separate cohort of 15 anti-TNF responders and 17 non-responders. Finally, we sequenced DNA methyltransferase genes to identify rare variants in IBD patients and functionally tested them using rescue experiments in a zebrafish genetic model of DNA methylation deficiency. Results: TNF promoter methylation levels were decreased in inflamed mucosa of IBD patients and correlated with disease severity. Isolated IECs from inflamed tissue showed proportional decreases in TNF methylation. Anti-TNF non-responders showed lower levels of TNF methylation than responders in uninflamed mucosa. Our sequencing analysis revealed two missense variants in DNMT1, one of which had reduced function in vivo. Conclusions: Our study reveals an association of TNF promoter hypomethylation with mucosal inflammation, suggesting that IBD patients may be particularly sensitive to inflammatory environmental insults affecting DNA methylation. Together, our analyses indicate that TNF promoter methylation analysis may aid in the characterization of IBD status and evaluation of anti-TNF therapy response.

Improved Hemoglobin Response with Ferric Carboxymaltose in Patients with Gastrointestinal-Related Iron-Deficiency Anemia Versus Oral Iron.

AIMS: To compare the efficacy and safety of intravenous (IV) ferric carboxymaltose (FCM) versus oral iron and other IV iron therapies in patients with iron-deficiency anemia (IDA) resulting from gastrointestinal (GI) disorders. METHODS: A pooled analysis of four prospective, randomized, active-controlled trials in patients with IDA was performed. Efficacy measures included change from baseline in hemoglobin (Hb), ferritin, and transferrin saturation (TSAT) and correlations of baseline Hb, ferritin, and TSAT to change in Hb. The incidence and type of adverse events were evaluated. RESULTS: A total of 191 patients were evaluated. The mean change in Hb from baseline to the maximum value was 0.8 g/dL with oral iron (P = 0.001 vs. FCM), 2.2 g/dL with FCM, 2.0 g/dL with any IV iron (P = 0.391 vs. FCM), and 1.9 g/dL with iron sucrose (P = 0.329 vs. FCM). Patients treated with FCM and iron sucrose had larger increases in Hb. This effect may have been attributed to a lower baseline Hb level. Drug-related adverse events occurred in 11.9, 12, 26.2, and 25% and serious adverse events (SAEs) occurred in 6.9, 4, 9.8, and 12.5% of patients in the FCM, oral iron, other IV iron therapies, and iron sucrose groups, respectively. No SAEs were considered treatment related in the FCM group, compared with two treatment-related SAEs in two patients (6.3%) in the iron sucrose group. CONCLUSIONS: FCM is an effective therapy in patients with IDA who have GI disorders and has a safety profile comparable to that of other IV iron agents.

Ascertainment, classification, and impact of neoplasm detection during prolonged treatment with dual antiplatelet therapy with prasugrel vs. clopidogrel following acute coronary syndrome.

AIMS: Studies have suggested increased cancer incidence associated with long-term dual antiplatelet therapy (DAPT) for acute coronary syndrome (ACS). We evaluated cancer incidence and treatment-related differences in an analysis of DAPT for ACS. METHODS AND RESULTS: The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial enrolled 9326 participants with ACS, who received aspirin plus clopidogrel or prasugrel. Median treatment exposure was 15 months. Cancer history and screening procedures were collected. Suspected non-benign neoplasm events were reported and adjudicated. The primary outcome was detection of new, non-benign neoplasm. Factors associated with neoplasm events, the relationship of these events to cardiovascular and bleeding endpoints, and treatment-related differences in neoplasm detection were studied. Among 9240 participants who received ≥1 dose of study drug, 1.8% had a confirmed neoplasm event. The efficacy composite of cardiovascular death, myocardial infarction, or stroke occurred more frequently among those with a neoplasm event vs. those without (18.2 vs. 13.5%) as did Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding (11.2 vs. 1.5%). Screening rates were substantially higher in North America and Western Europe/Scandinavia vs. other regions. Factors most strongly associated with detection of neoplasm events were older age, region, male sex, and current/recent smoking. Among the pre-specified population without a history of neoplasm or previous curative treatment for neoplasm (n = 9105), the incidence of neoplasm events was similar with prasugrel vs. clopidogrel (1.8 vs. 1.7%; HR = 1.04; 95% CI 0.77-1.42; P = 0.79). CONCLUSIONS: Neoplasm events were infrequent during long-term DAPT after ACS, were associated with differential cancer-screening practices across regions, and the frequency of neoplasm detection was similar with prasugrel vs. clopidogrel. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00699998.

A multicenter, randomized, active-controlled study to investigate the efficacy and safety of intravenous ferric carboxymaltose in patients with iron deficiency anemia.

BACKGROUND: Many patients receiving oral iron for iron deficiency anemia (IDA) cannot tolerate or fail to respond to therapy, and existing intravenous (IV) iron formulations often require repeated administrations. Ferric carboxymaltose (FCM), a nondextran IV formulation, permits larger single doses. STUDY DESIGN AND METHODS: We evaluated FCM versus oral iron in IDA patients. After 14 days of oral iron, 507 participants responding inadequately to oral iron (hemoglobin [Hb] increase <1 g/dL; Cohort 1) were assigned to Group A (two doses of FCM, 750 mg, 1 week apart) or Group B (oral iron, 325 mg, 3 × day for 14 additional days). Also, 504 subjects not appropriate for oral iron (Cohort 2) were assigned to Group C (FCM as above) or Group D (standard-of-care IV iron). The primary efficacy endpoint was change to highest observed Hb from baseline to Day 35. The composite safety endpoint included all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, unstable angina, heart failure, arrhythmias, and hyper- or hypotensive events. RESULTS: Mean (± standard deviation [SD]) Hb increase was significantly greater in Group A-FCM than Group B-oral iron: 1.57 (±1.19) g/dL versus 0.80 (±0.80) g/dL (p = 0.001). Post hoc comparison of Group C-FCM and Group D-IV standard of care also demonstrated significant mean (±SD) increase in Hb from baseline to highest value by Day 35 in Group C versus Group D: 2.90 (±1.64) g/dL versus 2.16 (±1.25) g/dL (p = 0.001). Safety endpoints occurred in 17 of 499 (3.4%) participants receiving FCM versus 16 of 498 (3.2%) in comparator groups. CONCLUSION: Two 750-mg FCM infusions are safe and superior to oral iron in increasing Hb levels in IDA patients with inadequate oral iron response.

Ferric carboxymaltose in patients with iron-deficiency anemia and impaired renal function: the REPAIR-IDA trial.

BACKGROUND: Iron-deficiency anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD) frequently requires parenteral iron replacement, but existing therapies often require multiple administrations. We evaluated the efficacy and cardiovascular safety of ferric carboxymaltose (FCM), a non-dextran parenteral iron permitting large single-dose infusions, versus iron sucrose in patients with iron-deficiency anemia and NDD-CKD. METHODS: A total of 2584 participants were randomized to two doses of FCM 750 mg in one week, or iron sucrose 200 mg administered in up to five infusions in 14 days. The primary efficacy endpoint was the mean change to highest hemoglobin from baseline to Day 56. The primary composite safety endpoint included all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, unstable angina, congestive heart failure, arrhythmias and hyper- and hypotensive events. RESULTS: The mean hemoglobin increase was 1.13 g/dL in the FCM group and 0.92 g/dL in the iron sucrose group (95% CI, 0.13-0.28). Similar results were observed across all subgroups, except Stage 2 CKD. More subjects in the FCM group achieved a hemoglobin increase of ≥ 1.0 g/dL between baseline and Day 56 (48.6 versus 41.0%; 95% CI, 3.6-11.6%). There was no significant difference between FCM and iron sucrose recipients with respect to the primary composite safety endpoint, including the major adverse cardiac events of death, myocardial infarction, or stroke. A significant difference in the number of protocol-defined, predominantly transient hypertensive episodes was observed in the FCM group. CONCLUSIONS: Two 750-mg infusions of FCM are a safe and effective alternative to multiple lower dose iron sucrose infusions in NDD-CKD patients with iron-deficiency anemia.

Randomized evaluation of efficacy and safety of ferric carboxymaltose in patients with iron deficiency anaemia and impaired renal function (REPAIR-IDA): rationale and study design.

BACKGROUND: Patients with iron deficiency anaemia (IDA) in the setting of non-dialysis-dependent chronic kidney disease (NDD-CKD) may benefit from treatment with intravenous (IV) iron. Ferric carboxymaltose (FCM) is a novel IV iron formulation designed to permit larger infusions compared to currently available IV standards such as Venofer(R) (iron sucrose). METHODS: The primary objective of REPAIR-IDA is to estimate the cardiovascular safety and efficacy of FCM (two doses at 15 mg/kg to a maximum of 750 mg per dose) compared to Venofer(R) (1000 mg administered as five infusions of 200 mg) in subjects who have IDA and NDD-CKD. REPAIR-IDA is a multi-centre, randomized, active-controlled, open-label study. Eligible patients must have haemoglobin (Hgb) < or = 11.5 g/dL and CKD defined as (1) GFR < 60 mL/min/1.73 m(2) on two occasions or (2) GFR < 90 mL/min/1.73 m(2) and either evidence of renal injury by urinalysis or elevated Framingham cardiovascular risk score. Two thousand and five hundred patients will be randomized to FCM or Venofer(R) in a 1:1 ratio. The primary efficacy endpoint is mean change in Hgb from baseline to the highest observed Hgb between baseline and Day 56. The primary safety endpoint is the proportion of subjects experiencing at least one of the following events: death due to any cause, non-fatal myocardial infarction, non-fatal stroke, unstable angina requiring hospitalization, congestive heart failure requiring hospitalization or medical intervention, arrhythmias, hypertension or hypotension during the 120 days following randomization. CONCLUSION: REPAIR-IDA will assess the efficacy and safety of two 750-mg infusions of FCM compared to an FDA-approved IV iron regimen in patients with NDD-CKD at increased risk for cardiovascular disease.

Inflammatory bowel disease following solid organ transplantation.

Inflammatory bowel disease (IBD) is a T cell driven inflammatory condition of the gut. Following solid organ transplantation (SOT), de novo IBD has been reported despite anti-T cell therapy for the prevention of organ rejection. This paradox is illustrated with a case report, highlighting the difficult diagnostic criteria, the potential role of Damage or Pathogen Associated Molecular Pattern Molecules [DAMPs and PAMPs] that drives aspects of ongoing inflammation within the transplanted organ as well as the intestine, and the therapeutic strategies applied. Recurrent IBD is more common than de novo IBD following transplantation, with cumulative risks ten years after orthotopic liver transplantation of 70% and 30%, respectively. Furthermore, the annual incidence of de novo IBD following solid organ transplantation has been estimated to be 206 cases/100,000 or ten times the expected incidence of IBD in the general population (approximately 20 cases/100,000). The association of IBD with other autoimmune conditions such as primary sclerosing cholangitis and autoimmune hepatitis, both common indications for liver transplantation, may play a contributory role, particularly in view of the observation that IBD is more common following liver transplant than other solid organ transplants. Recurrent IBD following transplant appears to run a more aggressive course than de novo IBD, with a higher proportion requiring colectomy for medically refractory disease. Risk factors that have been associated with development of post-transplant IBD include acute CMV infection and the use of tacrolimus.

Bromelain treatment decreases secretion of pro-inflammatory cytokines and chemokines by colon biopsies in vitro.

Oral bromelain has been anecdotally reported to decrease inflammation in ulcerative colitis (UC). Proteolytically active bromelain is known to decrease expression of mRNAs encoding pro-inflammatory cytokines by human leukocytes in vitro. To assess the effect of bromelain on mucosal secretion of cytokines in inflammatory bowel disease (IBD), endoscopic colon biopsies from patients with UC, Crohn's disease (CD), and non-IBD controls were treated in vitro with bromelain or media, then cultured. Secretion of pro-inflammatory cytokines and chemokines was measured. Significant increases in granulocyte colony-stimulating factor (G-CSF), interferon (IFN)-gamma, interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF) were detected in the media from actively inflamed areas in UC and CD as compared with non-inflamed IBD tissue and non-IBD controls. In vitro bromelain treatment decreased secretion of G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN-gamma, CCL4/macrophage inhibitory protein (MIP)-1beta, and TNF by inflamed tissue in IBD. Bromelain may be a novel therapy for IBD.

Infliximab maintenance therapy for fistulizing Crohn's disease.

BACKGROUND: Infliximab, a monoclonal antibody against tumor necrosis factor, is an effective maintenance therapy for patients with Crohn's disease without fistulas. It is not known whether infliximab is an effective maintenance therapy for patients with fistulas. METHODS: We performed a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of infliximab maintenance therapy in 306 adult patients with Crohn's disease and one or more draining abdominal or perianal fistulas of at least three months' duration. Patients received 5 mg of infliximab per kilogram of body weight intravenously on weeks 0, 2, and 6. A total of 195 patients who had a response at weeks 10 and 14 and 87 patients who had no response were then randomly assigned to receive placebo or 5 mg of infliximab per kilogram every eight weeks and to be followed to week 54. The primary analysis was the time to the loss of response among patients who had a response at week 14 and underwent randomization. RESULTS: The time to loss of response was significantly longer for patients who received infliximab maintenance therapy than for those who received placebo maintenance (more than 40 weeks vs. 14 weeks, P<0.001). At week 54, 19 percent of patients in the placebo maintenance group had a complete absence of draining fistulas, as compared with 36 percent of patients in the infliximab maintenance group (P=0.009). CONCLUSIONS: Patients with fistulizing Crohn's disease who have a response to induction therapy with infliximab have an increased likelihood of a sustained response over a 54-week period if infliximab treatment is continued every 8 weeks.

Treatment patterns and costs associated with sessile colorectal polyps.

OBJECTIVES: Because of the paucity of existing literature on treatment and costs associated with sessile lesions, the objectives of this study were to perform a retrospective analysis on patients with sessile polyps to identify patient and polyp characteristics, to determine treatment patterns, and to estimate the cost of treating these patients. METHODS: We conducted a retrospective, observational cohort study of 280 patients who presented to a large teaching hospital between 1997 and 2000 with at least one sessile or broad-based pedunculated colorectal polyp of any size or histology, not including adenocarcinoma greater than stage T1. RESULTS: Mean polyp size was 1.3 cm, and two thirds of polyps were removed in a single procedure. The number of repeat procedures increased with polyp size (Kendall T-b = 0.47; 95% CI = 0.39-0.55). Patients with polyps > or = 2 cm were 5.88 times more likely than patients with smaller polyps to undergo a surgical procedure. Surgical procedures required 88.01 min longer than nonsurgical procedures (95% CI = 74.43-102.42). Mean total cost of treatment was $2,038 (range $153 to $14,838). Open resection ($6,165) was the most costly surgical procedure, and piecemeal polypectomy ($892) was the most costly nonsurgical therapeutic procedure. CONCLUSIONS: One third of polyps required more than one procedure. Surgical procedures accounted for the majority of resource use in this sample. Finally, patients with polyps > or = 2 cm incurred almost half the total costs while accounting for only 22% of the sample. The greatest economic gains could be made by improving efficiency of polyp removal for these patients.