Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

A Large-Scale Genetic Analysis Reveals a Strong Contribution of the HLA Class II Region to Giant Cell Arteritis Susceptibility

We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10−40, OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1∗04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10−43) and HLA-DQα1 47 (p = 4.02 × 10−46), 56, and 76 (both p = 1.84 × 10−45) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10−6, OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10−6, OR = 1.20), and REL (rs115674477, p = 1.10 × 10−5, OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function

Feasibility of a Noninvasive Operability Assessment in Chronic Thromboembolic Pulmonary Hypertension under Real-World Practice

This study aimed to evaluate the feasibility of a noninvasive operability assessment of chronic thromboembolic pulmonary hypertension (CTEPH) based on multidetector computed tomographic angiography (MCTA). Up to 176 patients were evaluated from January 2016 to April 2018. Throughout the first phase, the initial surgical decision was made based on MCTA with further analysis of pulmonary angiography (PA) in order to evaluate in which cases the initial decision was not modified by PA. During the second phase, PA was limited to patients judged inoperable based on MCTA or those whose assessment was not possible. Patients deemed operable (50%) based on MCTA along the first phase had been adequately classified, as PA did not modify the initial decision in all but one patient. Comparable results were obtained throughout the implementation phase. Regarding operated patients, the decision of operability was based solely on MCTA in 94% of those with level I disease, in 75% with level II, and 54% with level III. This approach enabled shorter periods of time to complete surgical assessment and the avoidance of PA-related morbidity. Baseline parameters, postoperative measures, and survival rates at 1 year after surgery were comparable in both phases. Noninvasive operability assessment is feasible in a subset of CTEPH patients and optimizes surgical candidacy evaluation

Baseline characteristics of patients with early arthritis.

<p>DAS28-ESR, 28-joint Disease Activity Score; HAQ, Health Assessment Questionnaire; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; ACPA, anti-citrullinated peptide antibodies; RF, rheumatoid factor; NS, non-significant.</p

Effect of the presence of the shared epitope and the minor rs7574865 allele in <i>STAT4</i> or rs2476601 in <i>PTPN22</i> on disease activity (DAS28) and disability (HAQ) in patients with early arthritis.

<p>DAS28, 28-joint Disease Activity Score; HAQ, Health Assessment Questionnaire; Coeff., coefficient; Ref., reference; RA, rheumatoid arthritis; UA, undifferentiated arthritis; ACPA, anti-citrullinated peptide antibodies; NI, not included; NS, non-significant.</p

Patients with early arthritis who were homozygous for the minor rs7574865 allele of <i>STAT4</i> exhibited stronger disease activity during the follow-up.

<p>The data are categorized according to the rs7574865 genotype of <i>STAT4</i> (upper panel), the rs2476601 genotype of <i>PTPN22</i> (middle panel), and the number of copies of the shared epitope (SE; lower panel). Data represent the interquartile range (p75, upper edge of the box; p25, lower edge; p50, midline), p95 (line above the box) and p5 (line below the box) of the DAS28 adjusted for gender and age (aDAS28). Dots represent outliers.</p

Effect of the rs7574865 and rs2476601 polymorphisms in <i>STAT4</i> and <i>PTPN22</i> on the level of disease activity in patients with early arthritis.

<p>A) STAT4 genotypes: GG, white bars; GT, gray bars; TT, black bars. B) PTPN22 genotypes: CC, white bars; CT, gray bars; TT, black bars. Data represent the proportion of visits in which remission, or low, moderate or high disease activity was recorded in the patients of each genotype. This figure illustrates the findings presented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0043661#pone-0043661-t003" target="_blank">Table 3</a>, in which the statistical significance of the differences in disease activity associated with the genotype of each polymorphism is shown.</p

Evidence for PTPN22 R620W Polymorphism As the Sole Common Risk Variant for Rheumatoid Arthritis in the 1p13.2 Region

Item does not contain fulltextOBJECTIVE: The PTPN22 rs2476601 genetic variant has been associated with rheumatoid arthritis (RA) and other autoimmune diseases. Some reports suggest that this single-nucleotide polymorphism (SNP) may not be the only causal variant in the region of PTPN22. Our aim was to identify new independent RA-associated common gene variants in the PTPN22 region. METHODS: We analyzed Wellcome Trust Case-Control Consortium genome-wide association study data for associations in the 397.2 kb PTPN22 region and selected 9 associated SNP (with p < 5 x 10(-3)) for replication and dependence analysis. The replication cohorts comprised 2857 patients with RA and 2994 controls from Spain, Netherlands, and Norway. RESULTS: We found that 6 of the 9 selected SNP were associated in the Spanish cohort. Of these, 4 were also associated in the Dutch and Norwegian cohorts, and all 6 were associated with RA in the combined analysis. Conditional analyses showed that none of these associations was independent of rs2476601. CONCLUSION: The SNP rs2476601 located in the PTPN22 gene is the sole common genetic variant associated with RA in the 1p13.2 region, suggesting that neighbor genes of PTPN22 do not have a major influence in RA

Association of STAT4 with rheumatoid arthritis:a replication study in three European populations

Objective. This study was undertaken to investigate the previously reported association of the STAT4 polymorphism rs7574865 with rheumatoid arthritis (RA) in 3 different European populations from Spain, Sweden, and The Netherlands, comprising a total of 2,072 patients and 2,474 controls. Methods. Three different cohorts were included in the study: 923 RA patients and 1,296 healthy controls from Spain, 273 RA patients and 285 healthy controls from. Sweden, and 876 RA patients and 893 healthy controls from The Netherlands. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for the STAT4 single-nucleotide polymorphism rs7574865 using a TaqMan 5'-allele discrimination assay. The chi-square test was performed to compare allele and genotype distributions. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Results. We observed a significantly increased frequency of the minor T allele in RA patients compared with healthy controls in the Spanish population (24.8% versus 20.8%; P = 0.001, OR 1.26 [95% CI 1.09-1.45]). This association was confirmed in both the Swedish population (P = 0.03, OR 1.35 [95% CI 1.03-1.77]) and the Dutch population (P = 0.03, OR 1.45 [95% CI 1.21-1.73]). The overall P value for all 3 populations was 9.79 x 10(-6) (OR 1.25 [95% CI 1.13-1.37]). No association between rs7574865 and the presence of rheumatoid factor or anti-cyclic citrullinated peptide autoantibodies was observed. A meta-analysis of all published STAT4 associations revealed an OR of 1.25 (95% CI 1.19-1.33) (P = 1 x 10(-5)). Conclusion. Our findings indicate an association between the STAT4 polymorphism rs7574865 and RA in 3 different populations, from Spain, Sweden, and The Netherlands, thereby confirming previous data