OBJECTIVE:Patients with rheumatoid arthritis (RA) have an increased risk of serious infections. Comparing infection rates across RA populations is complicated by differences in background infection risk, population composition and study methodology. We measured infection rates from five RA registries globally, with the aim to contextualise infection rates from an RA clinical trials population.METHODS:We used data from Consortium of Rheumatology Research of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (Sweden), Norfolk Arthritis Register (UK), CORRONA International (multiple countries) and Institute of Rheumatology Rheumatoid Arthritis (Japan) and an RA clinical trial programme (fostamatinib). Within each registry, we analysed a main cohort of all patients with RA from January 2000 to last available data. Infection definitions were harmonised across registries. Sensitivity analyses to address potential confounding explored subcohorts defined by disease activity, treatment change and/or prior comorbidities and restriction by calendar time or follow-up. Rates of infections were estimated and standardised to the trial population for age/sex and, in one sensitivity analysis also, for Health Assessment Questionnaire (HAQ) score.RESULTS:Overall, age/sex-standardised rates of hospitalised infection were quite consistent across registries (range 1.14-1.62 per 100 patient-years). Higher and more consistent rates across registries and with the trial programme overall were seen when adding standardisation for HAQ score (registry range 1.86-2.18, trials rate 2.92) or restricting to a treatment initiation subcohort followed for 18 months (registry range 0.99-2.84, trials rate 2.74).CONCLUSION:This prospective, coordinated analysis of RA registries provided incidence rate estimates for infection events to contextualise infection rates from an RA clinical trial programme and demonstrated relative comparability of hospitalised infection rates across registries.

Background We implemented a novel method for providing contextual adverse event rates for a randomised controlled trial (RCT) programme through coordinated analyses of five RA registries, focusing here on cardiovascular disease (CVD) and mortality.Methods Each participating registry (Consortium of Rheumatology Researchers of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (SRR) (Sweden), Norfolk Arthritis Register (NOAR) (UK), CORRONA International (East Europe, Latin America, India) and Institute of Rheumatology, Rheumatoid Arthritis (IORRA) (Japan)) defined a main cohort from January 2000 onwards. To address comparability and potential bias, we harmonised event definitions and defined several subcohorts for sensitivity analyses based on disease activity, treatment, calendar time, duration of follow-up and RCT exclusions. Rates were standardised for age, sex and, in one sensitivity analysis, also HAQ.Results The combined registry cohorts included 57251 patients with RA (234089 person-years)24.5% men, mean (SD) baseline age 58.2 (13.8) and RA duration 8.2 (11.7) years. Standardised registry mortality rates (per 100 person-years) varied from 0.42 (CORRONA) to 0.80 (NOAR), with 0.60 for RCT patients. Myocardial infarction and major adverse cardiovascular events (MACE) rates ranged from 0.09 and 0.31 (IORRA) to 0.39 and 0.77 (SRR), with RCT rates intermediate (0.18 and 0.42), respectively. Additional subcohort analyses showed small and mostly consistent changes across registries, retaining reasonable consistency in rates across the Western registries. Additional standardisation for HAQ returned higher mortality and MACE registry rates.Conclusions This coordinated approach to contextualising RA RCT safety data demonstrated reasonable differences and consistency in rates for mortality and CVD across registries, and comparable RCT rates, and may serve as a model method to supplement clinical trial analyses for drug development programmes.

BACKGROUND:The overall incidence of cancer in patients with rheumatoid arthritis (RA) is modestly elevated. The extent to which cancer rates in RA vary across clinical cohorts and patient subsets, as defined by disease activity or treatment is less known but critical for understanding the safety of existing and new antirheumatic therapies. We investigated comparability of, and means to harmonise, malignancy rates in five RA registries from four continents. METHODS:Participating RA registries were Consortium of Rheumatology Researchers of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (SRR) (Sweden), Norfolk Arthritis Register (NOAR) (UK), CORRONA International (several countries) and Institute of Rheumatology, Rheumatoid Arthritis (IORRA) (Japan). Within each registry, we analysed a main cohort of all patients with RA from January 2000 to last available data, and sensitivity analyses of sub-cohorts defined by disease activity, treatment change, prior comorbidities and restricted by calendar time or follow-up, respectively. Malignancy rates with 95% CIs were estimated, and standardised for age and sex, based on the distributions from a typical RA clinical trial programme population (fostamatinib). RESULTS:There was a high consistency in rates for overall malignancy excluding non-melanoma skin cancer (NMSC), for malignant lymphomas, but not for all skin cancers, across registries, in particular following age/sex standardisation. Standardised rates of overall malignancy excluding NMSC varied from 0.56 to 0.87 per 100 person-years. Within each registry, rates were generally consistent across sensitivity analyses, which differed little from the main analysis. CONCLUSION:In real-world RA populations, rates of both overall malignancy and of lymphomas are consistent.

Objective Comparisons of data from different registries can be helpful in understanding variations in many aspects of rheumatoid arthritis (RA). The study aim was to assess and improve the comparability of demographic, clinical, and comorbidity data from 5 international RA registries. Methods Using predefined definitions, 2 subsets of patients (main cohort and subcohort) from 5 international observational registries (Consortium of Rheumatology Researchers of North America Registry [CORRONA], the Swedish Rheumatology Quality of Care Register [SRR], the Norfolk Arthritis Register [NOAR], the Institute of Rheumatology Rheumatoid Arthritis cohort [IORRA], and CORRONA International) were evaluated and compared. Patients ages >18 years with RA, and present in or recruited to the registry from January 1, 2000, were included in the main cohort. Patients from the main cohort with positive rheumatoid factor and/or erosive RA who had received ≥1 synthetic disease‐modifying antirheumatic drug (DMARD), and switched to or added another DMARD, were included in the subcohort at time of treatment switch. Results Age and sex distributions were fairly similar across the registries. The percentage of patients with a high Disease Activity Score in 28 joints score varied between main cohorts (17.5% IORRA, 18.9% CORRONA, 24.7% NOAR, 27.7% CORRONA International, and 36.8% SRR), with IORRA, CORRONA, and CORRONA International including more prevalent cases of RA; the differences were smaller for the subcohort. Prevalence of comorbidities varied across registries (e.g., coronary artery disease ranged from 1.5% in IORRA to 7.9% in SRR), partly due to the way comorbidity data were captured and general cultural differences; the pattern was similar for the subcohorts. Conclusion Despite different inclusion criteria for the individual RA registries, it is possible to improve the comparability and interpretability of differences across RA registries by applying well‐defined cohort definitions.

Background/objectives: Faecal elastase 1 (FE1) was inversely correlated with diabetes duration and HbA1c in type 2 diabetes. The association of FE1 and HbA1c has not been investigated in people without diabetes.Methods: Type 2 diabetes patients (oral antidiabetic drugs or insulin: n = 391; medically untreated: n = 145) and matched (age, sex, practice) people without diabetes (n = 529) from general practices in Cambridgeshire (UK) were included. FE1 measurements (mu g/g stool) were performed centrally (ScheBo-Tech Institute, Wettenberg, Germany). Linear regression models were fitted using FE1 as dependent variable and HbA1c, diabetes (no, untreated diabetes, treated diabetes) and interactions as independent variables. Potential confounders were sex, age, BMI, current alcohol consumption, smoking, triglycerides, and amylase.Results: In univariate linear regression models, HbA1c was significantly inversely related to FE1 in controls (beta-coefficient: -108.74, p < 0.0001), whereas no significant associations were found for the diabetes groups. The inverse relationship of HbA1c with FE1 concentrations in people without diabetes persisted after adjusting for potential confounders in multivariate regression (beta-coefficient: -109.18, p < 0.0001). In people without diabetes, there were lower FE1 concentrations among those with increased diabetes risk (HbA1c 5.7%-6.4% [38.8-46.4 mmol/mol]: 395 +/- 204 mu g/g vs. HbA1c <= 5.6% [<= 37.7 mmol/mol]: 476 +/- 219 mu g/g; p < 0.0001). The prevalence of FE1 < 100 mu g/g was significantly increased among persons with an HbA1c of 5.7%-6.4% (38.8-46.4 mmol/mol) compared with those with a normal HbA1c <= 5.6% (<= 37.7 mmol/mol) (6.1% vs. 1.4%; p = 0.004).Conclusion/interpretation: The present study suggests that pancreatic exocrine dysfunction might be an early disturbance that develops in parallel with hyperglycemia. Copyright (C) 2015, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

The aim of this study was to assess efficacy and safety of saxagliptin monotherapy for up to 76 weeks in patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control, with main efficacy assessment at 24 weeks.

OBJECTIVE:To assess 24-hour glycemic control with saxagliptin compared with placebo as add-on treatment to metformin in patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control. RESEARCH DESIGN AND METHODS:This was a 4-week, multicenter, randomized, double-blind, placebo-controlled Phase IIIb trial comparing the antihyperglycemic activity of saxagliptin 5 mg once daily in combination with a stable dose of metformin extended release (XR) vs. placebo in combination with metformin XR in patients with T2DM inadequately controlled (screening glycated hemoglobin [HbA(1c)] 7-10%) with stable doses of metformin immediate release or metformin XR ≥ 1500 mg/day. Ninety-three adult patients were randomized and received treatment. The primary outcome measure was change from baseline to week 4 in 24-hour mean weighted glucose (MWG). RESULTS:The reduction from baseline in 24-hour MWG was significantly greater for saxagliptin 5 mg + metformin XR (-13.8 mg/dL; -0.77 mmol/L) compared with placebo + metformin XR (3.0 mg/dL; 0.17 mmol/L) (p = 0.0001). At week 4, the mean decrease in plasma glucose was sustained through a 24-hour period in saxagliptin-treated patients. Treatment with saxagliptin 5 mg + metformin XR resulted in significant mean reductions from baseline in 4-hour mean weighted postprandial glucose (PPG), 2-hour PPG, 3-day average mean daily glucose, and fasting plasma glucose levels compared with placebo + metformin XR (p ≤ 0.001). The proportion of adverse events (AEs) was similar in the two treatment groups, with no reported hypoglycemic AEs in saxagliptin-treated patients. The 4-week evaluation period may have been insufficient to evaluate longer term effects on hyperglycemia or to identify additional AEs. CONCLUSIONS:In patients with T2DM treated with metformin XR, saxagliptin 5 mg orally administered once daily in the evening for 4 weeks effectively lowered plasma glucose concentrations through the 24-hour dosing interval and was well tolerated.

OBJECTIVE:The objective was to assess the relative risk (RR) for cardiovascular (CV) events across all 8 randomized phase 2/3 trials evaluating saxagliptin in patients with type 2 diabetes mellitus.METHODS:Cardiovascular events (death, myocardial infarction [MI], stroke, revascularization procedures, and cardiac ischemia) were reported by investigators through standard adverse event reporting procedures and were systematically identified. Post hoc blinded adjudication of all deaths, MIs, and strokes was performed using prespecified endpoint definitions by an independent clinical events committee (CEC).RESULTS:A total of 4607 randomized and treated patients (n = 3356 treated with saxagliptin [2.5-100 mg/d]; n = 1251, comparator [n = 656, placebo; n = 328, metformin; n = 267, uptitrated glyburide]) were included. The median ages were 54 years (saxagliptin) and 55 years (comparator) (interquartile range, 47-61 each); 51% were female, 73% were white, 52% were hypertensive, 44% had hypercholesterolemia, 39% had a smoking history, 20% had a first-degree family member with premature coronary heart disease, and 12% had prior CV disease. Cardiovascular events were experienced by 61 patients (38 [1.1%], saxagliptin; 23 [1.8%], comparator), and CV death/MI/stroke events were reported by investigators in 41 patients: 23 (0.7%), saxagliptin; 18 (1.4%), comparator (relative risk, 95% confidence interval [CI], 0.44 [0.24-0.82]). The CEC reviewed 147 patients with potential CV events and identified a total of 40 patients with CV death/MI/stroke: 22 (0.7%), saxagliptin; 18 (1.4%), comparator (RR, 0.43 [0.23-0.80]). Component proportions for CV death, MI, and stroke were (saxagliptin vs comparator): 7 (0.2%) vs 10 (0.8%), 8 (0.2%) vs 8 (0.6%), and 11 (0.3%) vs 5 (0.4%), respectively.CONCLUSION:No increased risk of CV death/MI/stroke was observed in patients randomly assigned saxagliptin across a broad drug development program. Although this systematic overview has inherent and important limitations, the data support a potential reduction in CV events with saxagliptin. The hypothesis of CV protection with saxagliptin will be tested prospectively in a large randomized clinical outcome trial evaluating saxagliptin compared with standard of care in patients with type 2 diabetes at increased risk for CV events.

OBJECT:Chordomas are rare malignant neoplasms arising predominantly at the sacrum and skull base. They are uniformly lethal unless treated with aggressive resection and proton beam irradiation. The authors present results of the surgical management of a large number of patients with clivus chordomas. Factors that influence the surgeon's ability to achieve radical tumor resection are also evaluated.METHODS:Between 1991 and 2005, 71 patients with clivus chordomas underwent surgery. The average follow-up was 66 months (median 60 months, range 3-189 months). Sixty-five patients had complete records that were analyzed in the present report. Thirty-five percent of them had undergone surgery before being treated by the authors. They were evaluated with MR imaging and CT scanning and underwent surgery utilizing a variety of skull base techniques aimed at achieving radical excision. Many also underwent postoperative radiation, usually in the form of proton beam therapy. The patients were followed up with serial imaging at regular intervals as well as with neurological evaluation.RESULTS:Radical tumor resection was achieved in 58% of the group. The overall 5-year survival rate was 75%. Radical resection had a positive impact on survival. The ability to achieve radical resection was dependent on the preoperative tumor volume and the number of anatomical areas involved by the tumor. Cranial nerve impairment and CSF leakage were the most frequent postoperative complications.CONCLUSIONS:Radical excision is the ideal surgical goal in the treatment of clival chordomas and can be achieved with reasonable risks. Several different surgical approaches may be necessary to accomplish this.

The association between ambient air pollution exposure and hospitalization for cardiovascular events has been reported in several studies with conflicting results. A case-crossover design was used to investigate the effects of air pollution in 660 first-time myocardial infarction cases in Stockholm in 1993–1994, interviewed shortly after diagnosis using a standard protocol. Air pollution data came from central urban background monitors. No associations were observed between the risk for onset of myocardial infarction and two-hour or 24-hour air pollution exposure. No evidence of susceptible subgroups was found. This study provides no support that moderately elevated air pollution levels trigger first-time myocardial infarction.

Background: Certain subgroups in the general population, such as persons with existing cardiovascular or respiratory disease, may be more likely to experience adverse health effects from air pollution. Methods: In this European multicenter study, 25,006 myocardial infarction (MI) survivors in 5 cities were recruited from 1992 to 2002 via registers, and daily mortality was followed for 6 to 12 years in relation to ambient particulate and gaseous air pollution exposure. Daily air pollution levels were obtained from central monitor sites, and particle number concentrations were measured in 2001 and estimated retrospectively based on measured pollutants and meteorology. City-specific effect estimates from time-series analyses with Poisson regression were pooled over all 5 cities. Results: Particle number concentrations and PM10 averaged over 2 days (lag 0–1) were associated with increased total nontrauma mortality for patients of age 35 to 74 (5.6% [95% confidence interval, 2.8%–8.5%] per 10,000/cm3 and 5.1% [1.6%–9.3%] per 10 &mgr;g/m3, respectively). For longer averaging times (5 and 15 days), carbon monoxide and nitrogen dioxide were also associated with mortality. There were no clear associations with ozone or sulfur dioxide. Conclusion: Exposure to traffic-related air pollution was associated with daily mortality in MI survivors. Point estimates suggest a stronger effect of air pollution in MI survivors than among the general population.

BACKGROUND: Air pollutants may induce airway inflammation and sensitization due to generation of reactive oxygen species. The genetic background to these mechanisms could be important effect modifiers.OBJECTIVE: Our goal was to assess interactions between exposure to air pollution and single nucleotide polymorphisms (SNPs) in the beta 2-adrenergic receptor (ADRB2), glutathione S-transferase P1 (GSTP1), and tumor necrosis factor (TNF) genes for development of childhood allergic disease.METHODS: In a birth cohort originally of 4,089 children, we assessed air pollution from local traffic using nitrogen oxides (traffic NOx) as an indicator based on emission databases and dispersion modeling and estimated individual exposure through geocoding of home addresses. We measured peak expiratory flow rates and specific IgE for inhalant and food allergens at 4 years of age, and selected children with asthma symptoms up to 4 years of age (n = 542) and controls (n = 542) for genotyping.RESULTS: Interaction effects on allergic sensitization were indicated between several GSTP1 SNPs and traffic NO. exposure during the first year of life (P-nominal < 0.001-0.06). Children with Ile105Val/Val105Val genotypes were at increased risk of sensitization to any allergen when exposed to elevated levels of traffic NO, (for a difference between the 5th and 95th percentile of exposure: odds ratio = 2.4; 95% confidence interval, 1.0-5.3). In children with TNF-308 GA/AA genotypes, the GSTP1-NOx interaction effect was even more pronounced. We observed no conclusive interaction effects for ADRB2.CONCLUSION: The effect of air pollution from traffic on childhood allergy appears to be modified by GSTP1 and TNF variants, supporting a role of genes controlling the antioxidative system and inflammatory response in allergy.