Health Economic Impact of a Multicenter Quality-of-Care Initiative for Reducing Unplanned Healthcare Utilization Among Patients With Inflammatory Bowel Disease.

INTRODUCTION: A multicenter adult inflammatory bowel disease learning health system (IBD Qorus) implemented clinical care process changes for reducing unplanned emergency department visits and hospitalizations using a Breakthrough Series Collaborative approach. METHODS: Using Markov decision models, we determined the health economic impact of participating in the Collaborative from the third-party payer perspective. RESULTS: Across all 23 sites, participation in the Collaborative was associated with lower annual costs by an average of $2,528 ± $233 per patient when compared with the baseline period. DISCUSSION: Implementing clinical care process changes using a Collaborative approach was associated with overall cost savings. Future work should examine which specific interventions are most effective and whether such cost savings are sustainable.

Levels of Vitamin D Are Low After Crohn's Disease Is Established But Not Before.

BACKGROUND & AIMS: Low serum levels of vitamin D have been associated with Crohn's disease (CD). However, it is unclear whether low vitamin D levels cause CD or CD reduces serum vitamin D. METHODS: United States military personnel with CD (n = 240) and randomly selected individuals without CD (controls, n = 240) were matched by age, sex, race, military branch, and geography. We measured 25-hydroxyvitamin D in sera 8-3 years (pre-2) and 3 years to 3 months before diagnosis (pre-1) and 3 months before through 21 months after diagnosis (pre-0). We genotyped VDR and GC vitamin D related polymorphisms. We used conditional logistic regression, including adjustments for smoking, season, enlistment status, and deployment, to estimate relative odds of CD according to vitamin D levels and interactions between genetic factors and levels of vitamin D. RESULTS: Levels of vitamin D before diagnosis were not associated with CD in pre-2 (P trend = .65) or pre-1 samples (P trend = .84). However, we found an inverse correlation between CD and highest tertile of vitamin D level in post-diagnosis samples (P trend = .01; odds ratio, 0.51; 95% CI, 0.30-0.86). Interactions were not detected between vitamin D levels and VDR or GC polymorphisms. We observed an association between VDR Taq1 polymorphism and CD (independent of vitamin D) (P = .02). CONCLUSIONS: In serum samples from military personnel with CD and matched controls, we found no evidence for an association between CD and vitamin D levels up to 8 years before diagnosis. However, we observed an inverse-association between post-diagnosis vitamin D levels and CD. These findings suggest that low vitamin D does not contribute to development of CD-instead, CD leads to low vitamin D.

Serum kidney injury molecule 1 and ß2-microglobulin perform as well as larger biomarker panels for prediction of rapid decline in renal function in type 2 diabetes.

AIMS/HYPOTHESIS: As part of the Surrogate Markers for Micro- and Macrovascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) programme we previously reported that large panels of biomarkers derived from three analytical platforms maximised prediction of progression of renal decline in type 2 diabetes. Here, we hypothesised that smaller (n ≤ 5), platform-specific combinations of biomarkers selected from these larger panels might achieve similar prediction performance when tested in three additional type 2 diabetes cohorts. METHODS: We used 657 serum samples, held under differing storage conditions, from the Scania Diabetes Registry (SDR) and Genetics of Diabetes Audit and Research Tayside (GoDARTS), and a further 183 nested case-control sample set from the Collaborative Atorvastatin in Diabetes Study (CARDS). We analysed 42 biomarkers measured on the SDR and GoDARTS samples by a variety of methods including standard ELISA, multiplexed ELISA (Luminex) and mass spectrometry. The subset of 21 Luminex biomarkers was also measured on the CARDS samples. We used the event definition of loss of >20% of baseline eGFR during follow-up from a baseline eGFR of 30-75 ml min-1 [1.73 m]-2. A total of 403 individuals experienced an event during a median follow-up of 7 years. We used discrete-time logistic regression models with tenfold cross-validation to assess association of biomarker panels with loss of kidney function. RESULTS: Twelve biomarkers showed significant association with eGFR decline adjusted for covariates in one or more of the sample sets when evaluated singly. Kidney injury molecule 1 (KIM-1) and ß2-microglobulin (B2M) showed the most consistent effects, with standardised odds ratios for progression of at least 1.4 (p < 0.0003) in all cohorts. A combination of B2M and KIM-1 added to clinical covariates, including baseline eGFR and albuminuria, modestly improved prediction, increasing the area under the curve in the SDR, Go-DARTS and CARDS by 0.079, 0.073 and 0.239, respectively. Neither the inclusion of additional Luminex biomarkers on top of B2M and KIM-1 nor a sparse mass spectrometry panel, nor the larger multiplatform panels previously identified, consistently improved prediction further across all validation sets. CONCLUSIONS/INTERPRETATION: Serum KIM-1 and B2M independently improve prediction of renal decline from an eGFR of 30-75 ml min-1 [1.73 m]-2 in type 2 diabetes beyond clinical factors and prior eGFR and are robust to varying sample storage conditions. Larger panels of biomarkers did not improve prediction beyond these two biomarkers.

Meta-analysis of genome-wide association studies of HDL cholesterol response to statins.

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation. METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10-4 from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10-8) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment. CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.

Residual macrovascular risk in 2013: what have we learned?

Cardiovascular disease poses a major challenge for the 21st century, exacerbated by the pandemics of obesity, metabolic syndrome and type 2 diabetes. While best standards of care, including high-dose statins, can ameliorate the risk of vascular complications, patients remain at high risk of cardiovascular events. The Residual Risk Reduction Initiative (R3i) has previously highlighted atherogenic dyslipidaemia, defined as the imbalance between proatherogenic triglyceride-rich apolipoprotein B-containing-lipoproteins and antiatherogenic apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL), as an important modifiable contributor to lipid-related residual cardiovascular risk, especially in insulin-resistant conditions. As part of its mission to improve awareness and clinical management of atherogenic dyslipidaemia, the R3i has identified three key priorities for action: i) to improve recognition of atherogenic dyslipidaemia in patients at high cardiometabolic risk with or without diabetes; ii) to improve implementation and adherence to guideline-based therapies; and iii) to improve therapeutic strategies for managing atherogenic dyslipidaemia. The R3i believes that monitoring of non-HDL cholesterol provides a simple, practical tool for treatment decisions regarding the management of lipid-related residual cardiovascular risk. Addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe are all options for combination with a statin to further reduce non-HDL cholesterol, although lacking in hard evidence for cardiovascular outcome benefits. Several emerging treatments may offer promise. These include the next generation peroxisome proliferator-activated receptorα agonists, cholesteryl ester transfer protein inhibitors and monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9. However, long-term outcomes and safety data are clearly needed. In conclusion, the R3i believes that ongoing trials with these novel treatments may help to define the optimal management of atherogenic dyslipidaemia to reduce the clinical and socioeconomic burden of residual cardiovascular risk.

Effect of intensive lipid-lowering therapy on cardiovascular outcome in patients with and those without inflammatory joint disease.

OBJECTIVE: To examine the effect of intensive lipid-lowering therapy on a composite cardiovascular outcome (cardiovascular disease [CVD]), consisting of mortality and morbidity end points, in patients with inflammatory joint disease (rheumatoid arthritis [RA], ankylosing spondylitis [AS], or psoriatic arthritis [PsA]) by post hoc analysis of 2 prospective trials of statins with a secondary end point of CVD outcome (the Treating to New Targets [TNT] and Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL] studies). METHODS: Of the 18,889 patients participating in the 2 trials, 199 had RA, 46 had AS, and 35 had PsA. Lipid-lowering therapy consisted of an intensive regimen of atorvastatin 80 mg or a conventional/low-dose regimen of atorvastatin 10 mg or simvastatin 20-40 mg. The median duration of followup was nearly 5 years. Changes in lipid levels were examined by analyses of covariance. The effect on CVD was examined by Cox regression analyses, and heterogeneity tests were performed. RESULTS: Patients with RA and those with AS had lower baseline cholesterol levels than patients without inflammatory joint disease (least squares mean ± SEM 180.7 ± 2.3 mg/dl and 176.5 ± 4.7 mg/dl, respectively, versus 185.6 ± 0.2 mg/dl; P = 0.03 and P = 0.05, respectively). Statin treatment led to a comparable decrease in lipid levels and a 20% reduction in overall risk of CVD in both patients with and those without inflammatory joint disease. CONCLUSION: Our findings indicate that patients with and those without inflammatory joint disease experience comparable lipid-lowering effects and CVD risk reduction after intensive treatment with statins.

Probiotics for the treatment of inflammatory bowel disease.

Probiotics are organisms which provide a desired and beneficial effect on human health. With recent evidence implicating a disruption in the balance of the gastrointestinal microbiome and intestinal immunity as a potential trigger for inflammatory bowel disease (IBD), there has been growing interest in using probiotics as an adjunct to standard anti-inflammatory and immune suppressing therapy. Animal models describe potential and plausible mechanisms of action for probiotics to counter inflammation of colonic mucosa. Although there are insufficient data to recommend probiotics in ulcerative colitis or Crohn's disease, good evidence supports the use of specific probiotics for maintenance of remission in pouchitis. Although there are limited regulatory standards for the agents, probiotics are relatively safe with minimal reported side effects or contraindications. More rigorous studies need to be published supporting efficacy and safety of these agents before they become a mainstay of IBD medical treatment.

Clinical codes combined with procedure codes increase diagnostic accuracy of Crohn's disease in a US Military health record.

Background and aims: Previous examinations of International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes to predict accuracy of diagnosis in inflammatory bowel disease have had limited chart review to confirm diagnosis. We aimed to evaluate using the ICD-9-CM for identifying Crohn's disease (CD) in a large electronic health record (EHR) database. Methods: This is a retrospective case-control study with a 3:1 allocation of EHRs of active duty service members diagnosed with CD from 1996 to 2012. Subjects were selected by having two ICD-9-CM codes for CD during the study period. Gastroenterologists reviewed each chart and confirmed the diagnosis of CD by analysing medication history and clinical, endoscopic, histological, and radiographic exams. Results: 300 cases of CD were selected; 14 cases were discarded due to lack of data, limiting our analysis to 284 subjects. Two diagnostic codes for CD had sensitivity, specificity, and positive predictive value (PPV) of 1.0, 0.53, and 0.69, respectively, for confirmed CD. If two encounters listing CD were with a gastroenterologist, the sensitivity, specificity, and PPV was 0.76, 0.81, and 0.80, respectively. If a colonoscopy was performed within 90 days of any three encounters with a CD code, the sensitivity, specificity, and PPV was 0.51, 0.94, and 0.89, respectively. Conclusions: The poor PPV of ICD-9-CM codes in making the diagnosis of CD should be taken into consideration when interpreting results and when conducting research using such codes. Limiting these codes to those patients who have been given this diagnosis by a gastroenterologist, or to those who have had a colonoscopy near the time of diagnosis, increases the PPV.

Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study.

AIMS: To examine the changes in coronary, all-cause, and cancer mortality in patients with heterozygous familial hypercholesterolaemia (FH) before and after lipid-lowering therapy with statins. METHODS AND RESULTS: A total of 3382 patients (1650 men) aged <80 years were recruited from 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2006 for 46 580 person-years. There were 370 deaths, including 190 from coronary heart disease (CHD) and 90 from cancer. The standardized mortality ratio (compared with the population in England and Wales) was calculated before and from 1 January 1992. In patients aged 20-79 years, CHD mortality fell significantly by 37% (95% CI = 7-56) from 3.4- to 2.1-fold excess. Primary prevention resulted in a 48% reduction in CHD mortality from 2.0-fold excess to none, with a smaller reduction of nearly 25% in patients with established disease. Coronary mortality was reduced more in women than in men. In patients without known CHD at registration, all-cause mortality from 1992 was 33% (21-43), lower than in the general population, mainly due to a 37% (21-50) lower risk of fatal cancer. CONCLUSION: The results emphasize the importance of early identification of FH and treatment with statins.

Extraintestinal Manifestations Are Common in Obese Patients with Crohn's Disease.

INTRODUCTION: Crohn's disease (CD) is a chronic condition associated with the risk of malabsorption. The incidence of obesity worldwide is increasing, and the effect of obesity on patients with CD is unknown. We aim to identify traits related to obesity in a cohort of patients with CD. METHODS: We conducted a retrospective study of 209 adult patients with CD. Age, Montreal disease classification, sex, race, duration of disease, erythrocyte sedimentation rate, C-reactive protein levels, physician global assessment, endoscopic appearance, histologic activity, medication use, and body mass index (BMI) were collected about each patient. RESULTS: The mean age was 43.4 ± 14.9 years; 68.9% were white, and 51.7% were male. The mean duration of disease was 11.0 ± 10.6 years. The mean BMI was 26.8 ± 5.7: underweight 7.7%; normal weight 29.3%; overweight 38.0%; and obese 25%. Patients with higher BMI were more likely to have extraintestinal manifestations (EIM) (P = 0.005) and more likely to have nonarthralgia extraintestinal manifestations (P = 0.047). There was a linear association between proximal CD and decreasing BMI (underweight 31.3%, normal weight 14.8%, overweight 15.0%, obese 7.7%; P = 0.046). There was no difference in BMI between patients with and without perianal disease (P = 0.216). CONCLUSIONS: Most patients were overweight or obese, which correlates with national population trends. Our data suggest disease location plays a role in weight modulation in patients with CD. Increased extraintestinal manifestations in patients with high BMI suggests that the chronic inflammation associated with obesity may play a role in extraintestinal inflammation.

Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.

BACKGROUND: Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes. METHODS: We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993. FINDINGS: Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups. INTERPRETATION: Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.

Advanced glycation endproducts in nondiabetic patients with obstructive sleep apnea.

SUBJECT OBJECTIVE: The formation and accumulation of advanced glycation endproducts (AGEs) has been implicated in the progression of age-related diseases such as diabetes mellitus and atherosclerosis. We hypothesize that AGE concentrations may be increased in subjects with obstructive sleep apnea (OSA), a condition associated with increased oxidative stress. METHODS: One hundred nineteen nondiabetic patients with OSA and 234 age-matched healthy controls and 134 patients with type 2 diabetes were recruited for participation in the study. Serum AGEs were assayed by competitive enzyme-linked immunosorbent assay using a polyclonal rabbit antisera raised against AGE-RNase. RESULTS: Serum AGEs were increased in OSA subjects, as compared with controls, but were less increased than the AGEs of patients with type 2 diabetes (control: 3.22 +/- 0.54 unit per mL; OSA: 3.68 +/- 0.39; diabetes mellitus: 4.11 +/- 0.99; analysis of variance p < .01). In the subjects with OSA, serum AGEs correlated with the duration of nocturnal desaturation (r = 0.21, p = .025) and plasma total 8-isoprostane concentration, a biochemical marker of oxidative stress (r = 0.22, p = .015), but not with fasting glucose level. On general linear model univariate analysis, the association between serum AGEs and 8-isoprostane was independent of age, sex, body mass index, smoking status, and glucose. CONCLUSION: Serum levels of AGEs were increased in nondiabetic subjects with OSA and were associated with the severity of OSA. Whether increased AGE formation contributes significantly to the high cardiovascular risk associated with OSA remains to be determined.

The use of pholasin as a probe for the determination of plasma total antioxidant capacity.

BACKGROUND AND OBJECTIVES: Total antioxidant capacity (TAC) reflects the capacity of plasma, or other body fluid, to resist oxidation. The aim of the present study was to assess the prognostic value of Pholasin as a probe for the determination of plasma TAC. DESIGN AND METHODS: Plasma samples either oxidised using the free radical generator 2'-azobis-(2-amidinopropane) hydrochloride (AAPH) at 60 degrees C for 180 min or obtained from diabetic (type 1 and type 2) patients (n = 61 and 124, respectively) with or without polyneuropathy (PN) and/or cardiovascular autonomic neuropathy (CAN) and control subjects (n = 70) were analysed for TAC status. TAC was assessed using two versions of Analysis By Emitted Light (ABEL) tests including quenching of Pholasin chemiluminescence (QPC) with peroxynitrite (ONOO(-)-QPC) and with superoxide anion (O2(-)-QPC). RESULTS: The utilisation of AAPH to induce peroxyl radical mediated plasma oxidation produced a significant decrease in TAC as assessed by ONOO(-)-QPC and O2(-)-QPC assays in a time-dependent manner. Type 1 and type 2 diabetic patients without PN and/or CAN had lower TAC (ONOO(-)-QPC and O2(-)-QPC) than in control subjects. Further alterations in TAC were noted in the presence of PN and/or CAN. Correlations were found between TAC (ONOO(-)-QPC and O2(-)-QPC) values on duration of diabetes and neurological impairment score-lower limb (NIS-LL) in type 1 diabetic patients. CONCLUSIONS: This study has established that the ONOO(-)-QPC and O2(-)-QPC versions of the ABEL test fulfil the criteria in terms of simplicity, sensitivity and reliability for the measurement of plasma TAC. These biomarkers may prove useful in studies evaluating the impact of therapeutic drugs or antioxidant interventions aimed at delaying the onset of complications in clinical conditions associated with oxidative stress.

Nicotinic acid in the management of dyslipidaemia associated with diabetes and metabolic syndrome: a position paper developed by a European Consensus Panel.

Individuals with type 2 diabetes and metabolic syndrome are at markedly increased risk of cardiovascular morbidity and mortality. The increasing prevalence of both conditions poses a major challenge for clinicians in the 21st century. Both diabetes and metabolic syndrome are associated with a clustering of cardiovascular risk factors. In particular, dyslipidaemia characterised by low plasma levels of high-density lipoprotein cholesterol (HDL-C), elevated triglycerides and an increase in small, dense low-density lipoprotein (LDL) particles (the lipid triad), has been established as the most important modifiable risk factor for coronary heart disease (CHD). Current treatment guidelines recognise the increased CHD risk associated with diabetes and metabolic syndrome and focus on LDL-C lowering with statin treatment, in addition to dietary and lifestyle modification, as the primary lipid-modifying therapy. However, while there is no doubt that statin therapy significantly reduces CHD risk in these patients, their residual absolute risk remains higher than in individuals without diabetes or metabolic syndrome. Thus, there is a clear need to target other aspects of lipoprotein metabolism, notably low HDL-C and hypertriglyceridaemia, to further reduce CHD risk. Combining statin therapy (targeting LDL-C) with interventions that also modify low HDL-C and elevated triglycerides could be a useful strategy to optimise CHD risk reduction. Cautious combination of a fibrate or nicotinic acid with a statin is useful for the management of combined dyslipidaemia. Nicotinic acid is the more potent agent for raising HDL-C (by up to 29% at clinically recommended doses). It also substantially reduces triglycerides and LDL-C, and promotes a shift from small, dense LDL to larger, more buoyant LDL particles. Preliminary clinical data suggest that combining nicotinic acid with a statin will produce a greater reduction in cardiovascular risk in patients with diabetes and metabolic syndrome than statin monotherapy alone. Nicotinic acid is also safe for use in patients with diabetes, with no evidence of clinically relevant deterioration in glycaemic control at recommended doses (< or = 2 g/day). On review of the available evidence, this European Consensus Panel recommends the combination of nicotinic acid and a statin, together with lifestyle modification, as a useful strategy to lower CHD risk in patients with diabetes and metabolic syndrome. Prolonged-release nicotinic acid with improved tolerability compared with previous formulations may have obvious advantages for use in this setting.

Association between acute-phase reactants and advanced glycation end products in type 2 diabetes.

OBJECTIVE: Type 2 diabetes is associated with chronic low-grade inflammation, but the underlying mechanism(s) is not well understood. Because in vitro studies have shown that advanced glycation end products (AGEs) can trigger inflammatory responses, the present study has investigated whether serum concentration of AGEs is an important determinant of circulating levels of inflammatory markers, like C-reactive protein (CRP), in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Diabetic patients (n = 210) and healthy control subjects (n = 110) of similar BMI were recruited. Serum AGEs were assayed by competitive enzyme-linked immunosorbent assay using a polyclonal rabbit anti-sera raised against AGE-RNase. Plasma high-sensitivity CRP was measured by an immunoturbidimetric assay and interleukin (IL)-6 by enzyme-linked immunosorbent assay. RESULTS: Serum AGEs were increased in diabetic patients compared with control subjects (4.24 +/- 0.88 vs. 3.15 +/- 0.81 unit/ml, respectively, P < 0.01). Both plasma CRP (1.55 [0.81-2.95] vs. 0.88 mg/dl [0.51-1.89], respectively, P < 0.01; median [interquartile range]) and IL-6 (0.80 [0.68-0.97] vs. 0.69 pg/ml [0.48-0.84], respectively, P < 0.01) were also higher in diabetic patients than in control subjects. In the diabetic patients, log(CRP) correlated with AGEs (r = 0.22, P = 0.002) and with log(IL-6) (r = 0.29, P < 0.001). Forward stepwise linear regression analysis showed that BMI, log(IL-6), and AGEs were significant independent determinants of log(CRP) in the diabetic patients, accounting for 17, 12, and 10% of the variation in log(CRP), respectively. CONCLUSIONS: Serum concentration of AGEs is increased in patients with diabetes and is an independent determinant of plasma CRP levels. Subclinical inflammation in these patients may therefore be partly due to activation of the inflammatory response by AGEs.

Drug-induced liver injury from initial dose of infliximab.

Acute hepatotoxicity secondary to infliximab can occur with or without autoimmunity. A growing body of infliximab drug-induced liver injury cases without autoantibody formation is emerging. Nearly all other reported cases occur after at least three doses. This suggests infliximab may have a direct cytotoxic effect on the liver. We report a case of drug-induced liver injury resulting after an initial dose of infliximab.

Impact of female sex on lipid lowering, clinical outcomes, and adverse effects in atorvastatin trials.

The aim of this study was to evaluate the effect of atorvastatin on lipid lowering, cardiovascular (CV) events, and adverse events in women compared with men in 6 clinical trials. In the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial (atorvastatin 80 mg vs simvastatin 20 to 40 mg), the Treating to New Targets (TNT) trial (atorvastatin 80 vs 10 mg), the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial (atorvastatin 80 mg vs placebo), and the Collaborative Atorvastatin Diabetes Study (CARDS), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), and the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) (atorvastatin 10 mg vs placebo), lipid changes on treatment were compared between genders with studies grouped by dose. The association of on-study low-density lipoprotein (LDL) cholesterol and CV events by gender was evaluated in the combined studies and the impact of gender on adverse events in each study separately. Major CV events occurred in 3,083 of 30,000 men (10.3%) and 823 of 9,173 women (9.0%). Changes in lipids were similar in women and men. Major CV events were associated with gender-specific quintiles of on-treatment LDL cholesterol for women and men. In women, LDL cholesterol was a significant predictor of stroke, but not in men. Discontinuation rates due to adverse events were higher in women in 4 of 6 trials, but in only 1 trial was a significant treatment-gender interaction seen. Myalgia rates were slightly higher in women in both statin and placebo groups. In conclusion, the response of women to atorvastatin was similar to that of men, with slightly more discontinuations due to adverse events. Higher on-treatment LDL cholesterol was significantly associated with more CV events in both genders, but the association was stronger for stroke in women and for coronary heart disease death in men.

Oxidised lipoproteins may promote inflammation through the selective delay of engulfment but not binding of apoptotic cells by macrophages.

During normal tissue homeostasis apoptotic cells (AC) are rapidly recognised and engulfed by neighbouring cells or macrophages (Mphi), thus preventing an inflammatory response. Conversely, in chronically inflamed tissues, including the atherosclerotic artery and rheumatoid joint, removal of AC is defective despite the co-localisation of seemingly adequate numbers of Mphi. Mechanisms preventing removal of AC in vivo remain obscure, but might include oxidised low-density lipoprotein (ox-LDL), which is abundant in chronic inflammatory lesions. Although implicated in their pathogenesis, defining the role of ox-LDL on inflammatory processes has proved complicated. In fact, seemingly contradictory results have previously been described, though these may in part reflect the heterogeneous nature of ox-LDL applied in these studies. We wished to investigate the effect of physiologically representative ox-LDL on the binding and engulfment of apoptotic vascular smooth muscle cells (VSMC) and fibroblasts, as these have previously been shown to co-localise with Mphi in chronically inflamed tissues in vivo. We show that Mphi recognition of AC in vitro is not affected at physiological levels of ox-LDL. However, engulfment of intact AC is dramatically reduced/delayed. Importantly, in the absence of ox-LDL rapid phagocytosis of intact AC suppresses Mphi inflammatory cytokine release. In striking contrast, in the presence of ox-LDL, despite binding of AC to Mphi, release of IL-6 and MCP-1 is no longer suppressed. We propose that ox-LDL could maintain an inflammatory response by inhibiting the engulfment of AC, required for Mphi de-activation. This mechanism may contribute to chronic persisting inflammation in the atherosclerotic artery and rheumatoid joint.

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

Inflammatory bowel disease prevalence by age, gender, race, and geographic location in the U.S. military health care population.

BACKGROUND: There is limited data examining the prevalence of inflammatory bowel disease (IBD) in a diverse North American population. METHODS: Using International Classification of Diseases, Ninth Revision codes, patients with Crohn's disease (CD) and ulcerative colitis (UC) seen within the military health care system (Tricare) from October 1, 2008 to September 30, 2009 were identified. This database comprised all active duty military, retirees, and dependents. The overall prevalence of IBD, UC, and CD was calculated, and the prevalence by age, gender, race, and geographic location. RESULTS: A total of 35,404 cases of IBD were identified in 10.2 million military health care beneficiaries establishing a prevalence of total IBD, UC, and CD of 348, 202, and 146 per 100,000, respectively. IBD was more prevalent in females compared with males (417 versus 284 per 100,000; relative risk, 1.53; 95% confidence interval, 1.50-1.57). There was an increased prevalence of IBD with each decade of life. IBD was more common in Caucasians (324 per 100,000) compared with blacks, Asians, Hispanics, and American Indians (239, 162, 147, and 224 per 100,000, respectively; relative risk, 1.60; 95% confidence interval, 1.53-1.67). There was no difference in prevalence when comparing Northern versus Southern states (339 versus 333 per 100,000, respectively, P = 0.114). CONCLUSIONS: This large population study establishes a prevalence of IBD, UC, and CD (348, 202, and 146 per 100,000, respectively) in the military health care population. The prevalence of IBD, UC, and CD was higher in females and with increasing age, whereas IBD was most common in whites compared with other ethnicities in our patient population.