C-reactive protein and enhancement of tissue damage: a potential therapeutic target.

Human C-reactive protein (CRP), the classical acute phase reactant, is a member of the pentraxin family of calcium dependent ligand binding proteins. When ligand bound, particularly to phosphocholine residues found in cell membranes, bacterial cell walls and lipoprotein particles, CRP activates the complement cascade through engagement of Clq. Prior studies have suggested an important role for CRP both epidemiologically and biologically in atherothrombosis and its consequences. In the largest study to date of the epidemiological association between CRP and future cardiac events in healthy individuals, we demonstrate in contrast to previous studies, that the additive value of this inflammatory marker is less than previously thought. Further study of the biology of this ancient molecule in a number of animal models of disease has failed to confirm a protective role for CRP in endotoxaemia, and despite evidence of upregulated production in a transgenic mouse strain prone to atherosclerosis, we have demonstrated no apparent effect of human CRP on atherogenesis. Finally we have clearly and robustly shown that decamerisation of pentameric CRP by a novel low molecular weight palindromic inhibitor effectively prevents the ligand binding properties of this protein. This has established a platform for pharmacological inhibition of CRP in myocardial infarction and stroke where the complement activation initiated by CRP binding to necrotic cells has been suggested to be pro-inflammatory and deleterious

Number needed to treat with ursodeoxycholic acid therapy to prevent liver transplantation or death in primary biliary cholangitis

Objective: The clinical benefit of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) has never been reported in absolute measures. The aim of this study was to assess the number needed to treat (NNT) with UDCA to prevent liver transplantation (LT) or death among patients with PBC. Methods: The NNT was calculated based on the untreated LT-free survival and HR of UDCA with respect to LT or death as derived from inverse probability of treatment weighting-adjusted Cox proportional hazard analyses within the Global PBC Study Group database. Results: We included 3902 patients with a median follow-up of 7.8 (4.1-12.1) years. The overall HR of UDCA was 0.46 (95% CI 0.40 to 0.52) and the 5-year LT-free survival without UDCA was 81% (95% CI 79 to 82). The NNT to prevent one LT or death within 5 years (NNT5y) was 11 (95% CI 9 to 13). Although the HR of UDCA was similar for patients with and without cirrhosis (0.33 vs 0.31), the NNT5y was 4 (95% CI 3 to 5) and 20 (95% CI 14 to 34), respectively. Among patients with low alkaline phosphatase (ALP) (≤2× the upper limit of normal (ULN)), intermediate ALP (2-4× ULN) and high ALP (>4× ULN), the NNT5y to prevent one LT or death was 26 (95% CI 15 to 70), 11 (95% CI 8 to 17) and 5 (95% CI 4 to 8), respectively. Conclusion: The absolute clinical efficacy of UDCA with respect to LT or death varied with baseline prognostic characteristics, but was high throughout. These findings strongly emphasise the incentive to promptly initiate UDCA treatment in all patients with PBC and may improve patient compliance

Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis:an international follow-up study

Noninvasive surrogate end points of long-term outcomes of patients with primary biliary cirrhosis (PBC) are needed to monitor disease progression and evaluate potential treatments. We performed a meta-analysis of individual patient data from cohort studies to evaluate whether patients' levels of alkaline phosphatase and bilirubin correlate with their outcomes and can be used as surrogate end points. We performed a meta-analysis of data from 4845 patients included in 15 North American and European long-term follow-up cohort studies. Levels of alkaline phosphatase and bilirubin were analyzed in different settings and subpopulations at different time points relative to the clinical end point (liver transplantation or death). Of the 4845 patients, 1118 reached a clinical end point. The median follow-up period was 7.3 years; 77% survived for 10 years after study enrollment. Levels of alkaline phosphatase and bilirubin measured at study enrollment (baseline) and each year for 5 years were strongly associated with clinical outcomes (lower levels were associated with longer transplant-free survival). At 1 year after study enrollment, levels of alkaline phosphatase that were 2.0 times the upper limit of normal (ULN) best predicted patient outcome (C statistic, 0.71) but not significantly better than other thresholds. Of patients with alkaline phosphatase levels ≤ 2.0 times the ULN, 84% survived for 10 years compared with 62% of those with levels >2.0 times the ULN (P 1.0 times the ULN (P < .0001). Combining levels of alkaline phosphatase and bilirubin increased the ability to predict patient survival times. We confirmed the predictive value of alkaline phosphatase and bilirubin levels in multiple subgroups, such as patients who had not received treatment with ursodeoxycholic acid, and at different time points after study enrollment. Levels of alkaline phosphatase and bilirubin can predict outcomes (liver transplantation or death) of patients with PBC and might be used as surrogate end points in therapy trial

C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease

BACKGROUND: C-reactive protein is an inflammatory marker believed to be of value in the prediction of coronary events. We report data from a large study of C-reactive protein and other circulating inflammatory markers, as well as updated meta-analyses, to evaluate their relevance to the prediction of coronary heart disease.&lt;br/&gt; METHODS: Measurements were made in samples obtained at base line from up to 2459 patients who had a nonfatal myocardial infarction or died of coronary heart disease during the study and from up to 3969 controls without a coronary heart disease event in the Reykjavik prospective study of 18,569 participants. Measurements were made in paired samples obtained an average of 12 years apart from 379 of these participants in order to quantify within-person fluctuations in inflammatory marker levels. &lt;br/&gt;RESULTS: The long-term stability of C-reactive protein values (within-person correlation coefficient, 0.59; 95 percent confidence interval, 0.52 to 0.66) was similar to that of both blood pressure and total serum cholesterol. After adjustment for base-line values for established risk factors, the odds ratio for coronary heart disease was 1.45 (95 percent confidence interval, 1.25 to 1.68) in a comparison of participants in the top third of the group with respect to base-line C-reactive protein values with those in the bottom third, and similar overall findings were observed in an updated meta-analysis involving a total of 7068 patients with coronary heart disease. By comparison, the odds ratios in the Reykjavik Study for coronary heart disease were somewhat weaker for the erythrocyte sedimentation rate (1.30; 95 percent confidence interval, 1.13 to 1.51) and the von Willebrand factor concentration (1.11; 95 percent confidence interval, 0.97 to 1.27) but generally stronger for established risk factors, such as an increased total cholesterol concentration (2.35; 95 percent confidence interval, 2.03 to 2.74) and cigarette smoking (1.87; 95 percent confidence interval, 1.62 to 2.16). &lt;br/&gt;CONCLUSIONS: C-reactive protein is a relatively moderate predictor of coronary heart disease. Recommendations regarding its use in predicting the likelihood of coronary heart disease may need to be reviewed

Risk of gallbladder cancer in patients with primary sclerosing cholangitis and radiographically detected gallbladder polyps

Contains fulltext : 220003.pdf (Publisher’s version ) (Closed access)BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is associated with an increased risk of gallbladder cancer (GBC). Gallbladder polyps potentially harbour malignancy and thus international guidelines recommend prophylactic cholecystectomy for gallbladder polyps of any size in patients with PSC. To best inform patient care we sought to quantify the malignant risk of gallbladder polyps in patients with PSC. METHODS: A retrospective cohort study of patients followed in secondary and tertiary care settings in two large PSC clinics in North America was performed. RESULTS: In total, 453 patients were included with a median (IQR) follow-up time of 7.7 (4.1-12) years. A gallbladder polyp was radiographically detected in 16% (n = 71) with median size (range) of 4 (2-18) mm. In this group, post-cholecystectomy histology (n = 17) reported benign or no polyp in 77% (n = 13), dysplasia in 5.9% (n = 1) and malignancy in 18% (n = 3). The GBC rate was 8.8 (95% CI 1.8-25.7) per 1000 person-years in patients with a radiographically detected gallbladder polyp. GBC was associated with polyps >10 mm, interval growth or mass-like lesions on pre-operative imaging. In patients who did not have cholecystectomy (n = 50), the polyp was only transiently seen in 80% (n = 40), remained stable or decreased in size in 10% (n = 5) and increased in size in 6% (n = 3). The majority of gallbladder polyps did not show significant growth over time (0.041 mm/year [95% CI -0.017 to 0.249]). CONCLUSIONS: Most gallbladder polyps in patients with PSC are benign. Short-term surveillance imaging may be considered prior to recommending immediate cholecystectomy in patients with PSC without high-risk imaging features

Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study

Background: The aim of this study was to evaluate the long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis using 3-year interim data from the 5-year open-label extension of the pivotal phase 3 POISE trial. Methods: In the double-blind phase of POISE, 217 patients with primary biliary cholangitis with inadequate response to or intolerance to ursodeoxycholic acid were randomised to receive placebo, obeticholic acid 5 to 10 mg, or obeticholic acid 10 mg once daily for 12 months. During the open-label extension phase, patients received variable, adjusted doses of obeticholic acid. Markers of cholestasis and liver injury, alkaline phosphatase (ALP), and total and direct bilirubin were evaluated, and safety was assessed for up to 48 months of treatment with obeticholic acid. All analyses in the open-label extension were done in the safety population, defined as any patient randomised in the double-blind phase who received at least one dose of obeticholic acid during the open-label extension. This trial is registered at ClinicalTrials.gov (NCT01473524) and with EudraCT (2011-004728-36). Findings: 193 patients were treated during the open-label extension. In this 3-year interim analysis, ALP concentrations were significantly reduced compared with baseline at 12 months (mean change 12105\ub72 U/L [SD 87\ub76]), 24 months ( 12101\ub70 U/L [98\ub75]), 36 months ( 12108\ub76 U/L [95\ub77]), and 48 months ( 1295\ub76 U/L [121\ub71]; p&lt;0\ub70001 for all yearly time points). Total bilirubin concentrations were stabilised, with significant reductions versus baseline at 12 months (mean change 120\ub79 \u3bcmol/L [SD 4\ub71]; p=0\ub70042) and 48 months ( 120\ub78 \u3bcmol/L [3\ub78]; p=0\ub7016). Stabilisation was also noted for direct bilirubin, with a significant change from baseline at 12 months (mean change 120\ub75 \u3bcmol/L [SD 3\ub70]; p=0\ub7021). However, changes in total and direct bilirubin were not significant at other time points. Obeticholic acid was generally well tolerated, with pruritus (149 [77%] patients) and fatigue (63 [33%]) being the most common adverse events. No serious adverse events were considered related to obeticholic acid. Interpretation: Interim analyses suggest long-term efficacy and safety of obeticholic acid in patients with primary biliary cholangitis who are intolerant to or inadequately responsive to ursodeoxycholic acid. Funding: Intercept Pharmaceuticals