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.

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.

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.

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.

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.

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.

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.

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.

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.

Prediction of cardiovascular events in patients with ankylosing spondylitis and psoriatic arthritis: role of lipoproteins in a high-risk population.

OBJECTIVE: To evaluate lipids and apolipoproteins as predictors of cardiovascular mortality and morbidity (CVD) in patients with spondyloarthritis (SpA). METHODS: In the pooled cohort of participants in the IDEAL, TNT, and CARDS trials, 50 had ankylosing spondylitis (AS), 36 had psoriatic arthritis (PsA), and 21,641 did not have AS or PsA (non-SpA). We compared lipid levels at baseline between AS or PsA and non-SpA, and hazard ratios (HR) for CVD were calculated in a Cox proportional hazard model. RESULTS: Atherogenic lipids were lower in samples from AS, but not in PsA, compared to non-SpA. The HR for 1 SD increase in baseline lipids for future CVD was for total cholesterol 1.39 (95% CI 0.82, 2.36) in AS, 1.01 (95% CI 0.44, 2.31) in PsA, and 1.10 (95% CI 1.07, 1.14) in non-SpA. Both high-density lipoprotein (HDL) and apolipoprotein (ApoA-1) were significantly associated with CVD in AS (HR 3.67, 95% CI 1.47, 9.06, and HR 1.89, 95% CI 1.02, 3.54, respectively), in contrast to PsA (HDL: HR 1.03, 95% CI 0.49, 2.15; ApoA-1: HR 0.79, 95% CI 0.34, 1.89) and non-SpA (HDL: HR 0.86, 95% CI 0.84, 0.89; ApoA-1: HR 0.88, 95% CI 0.85, 0.91). CONCLUSION: HDL and ApoA-1 were surprisingly associated with increased risk of future CVD in patients with AS, whereas these lipids were protective in non-SpA.

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.

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.

'A lipaemic mystery': a patient with hypertriglyceridaemic pancreatitis and cerebral infarction.

Hypertriglyceridaemia (HTG) causes up to 10% of all cases of acute pancreatitis (AP). It is the third most common cause after gallstones and alcohol. Despite this frequency, there are no clear guidelines for its specific management, mainly due to the paucity of evidence. The authors present a case and discussion of hypertriglyceridaemic pancreatitis (HTGP) complicated by an acute cerebral infarct. The patient's subsequent death secondary to cerebral infarction opens the discussion as to whether HTG should be more urgently treated.

Pitavastatin - results from phase III & IV.

The pitavastatin Phase III and IV studies assessed the efficacy and safety of standard dose pitavastatin vs. comparable doses of alternative statins in a broad range of patients with hypercholesterolaemia. Phase III studies conducted in Europe included five 12-week, randomised, double-blind trials evaluating the non-inferiority of pitavastatin 1-4mg vs. atorvastatin 10-20mg, simvastatin 20-40 mg and/or pravastatin 10-40mg in patients with primary hypercholesterolaemia and combined dyslipidaemia, including patients with high cardiovascular risk, type II diabetes, and age ≥65 years. The primary endpoint was the adjusted mean percent change from baseline in low-density lipoprotein-cholesterol (LDL-C); secondary endpoints included changes from baseline in lipid and lipoprotein profiles, LDL-C-target attainment rates and safety parameters. For each study, treatment was continued in open-label, long-term extension studies. Phase IV Japanese studies included CHIBA - a 12-week, open-label active control, non-inferiority investigator-led trial comparing the efficacy and safety of pitavastatin 2mg and atorvastatin 10 mg in patients with hypercholesterolaemia; PIAT - a 52-week open-label, investigator-led, randomised, parallel-group study comparing the efficacy and tolerability of pitavastatin 2mg and atorvastatin 10 mg in patients with hypercholesterolaemia and glucose intolerance; and LIVES - a 2-year prospective post-marketing surveillance of pitavastatin in 20,279 patients with hypercholesterolaemia. The primary endpoint for the first two studies was the percent change from baseline in non-high-density lipoprotein-C (non-HDL-C) and HDL-C, respectively; secondary endpoints included % changes from baseline in other lipid/lipoprotein parameters, safety and tolerability. Overall, Phase III and IV studies demonstrate that pitavastatin 1-4mg is well tolerated, improves atherogenic lipid profile and increases LDL-C target attainment rates with a similar or greater efficacy to comparable doses of atorvastatin, simvastatin and pravastatin in most patient groups. In each of these studies, improvements in lipid profile were sustained or improved during the long term suggesting benefits for continued treatment with pitavastatin.

Is the current therapeutic armamentarium in diabetes enough to control the epidemic and its consequences? What are the current shortcomings?

The prevalence of diabetes is expected to rise together with an increase in morbidity and a reduction in life expectancy. A leading cause of death is cardiovascular disease, and hypertension and diabetes are additive risk factors for this complication. Selected treatment options should neither increase cardiovascular risk in patients with diabetes, nor increase risk of hyperglycaemia in patients with hypertension. The efficacy of present antihyperglycaemic agents is limited and new therapies, such as incretin-targeted agents, are under development. Even though most patients do not achieve glycated haemoglobin targets, trial data show that such interventions reduce the incidence of macrovascular events; however, intensive lowering may be detrimental in patients with existing cardiovascular disease. Currently available oral drugs do not address the key driver of type 2 diabetes--loss of functional beta-cell mass. In the future, new oral treatments must improve this, whilst providing durable blood glucose control and long-term tolerability.