Can rheumatoid arthritis (RA) registries provide contextual safety data for modern RA clinical trials? The case for mortality and cardiovascular disease.

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 57 251 patients with RA (234 089 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.

How comparable are rates of malignancies in patients with rheumatoid arthritis across the world? A comparison of cancer rates, and means to optimise their comparability, in five RA registries.

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.

Association of faecal elastase 1 with non-fasting triglycerides in type 2 diabetes.

AIMS: Intestinal absorption of esterified fatty acids depends on exocrine pancreatic function and influences plasma triglycerides levels. The aim was to investigate the association of reduced exocrine pancreatic function (low fecal elastase-1; FE1) with plasma triglycerides in type 2 diabetes and controls without diabetes. METHODS: FE1 (µg/g stool) and non-fasting plasma triglyceride measurements were undertaken in 544 type 2 diabetes patients (age: 63 ± 8 years) randomly selected from diabetes registers in Cambridgeshire (UK), and 544 matched controls (age, sex, practice) without diabetes. Linear regression models were fitted using FE1 as dependent and log-triglycerides as independent variable adjusting for sex, age, body mass index, alcohol consumption, serum lipase, HbA1c, and smoking. RESULTS: FE1 concentrations were lower (mean ± SD: 337 ± 204 vs. 437 ± 216 µg/g, p < 0.05) and plasma triglycerides were higher (geometric mean */: standard deviation factor: 2.2*/:1.9 vs. 1.6*/:1.8 mmol/l, p < 0.05) in type 2 diabetes compared to controls, respectively. Within the category of type 2 diabetes and controls separately, a 10% increase in plasma triglycerides was associated with 4.5 µg/g higher FE1 concentrations (p < 0.01) after adjusting for confounders. In contrast, in diabetes patients and controls with pathological FE1 (<100 µg/g), low FE1 levels were associated with high plasma triglycerides (significant only in controls). CONCLUSIONS: Non-fasting triglycerides were positively related to FE1 in both type 2 diabetes and controls suggesting that impairment of exocrine pancreas function is influencing plasma triglycerides. Marked loss of exocrine pancreatic function had the opposite effect, resulting in higher levels of plasma triglycerides.

Inverse association of HbA1c with faecal elastase 1 in people without diabetes.

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 (µg/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 (ß-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 (ß-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 µg/g vs. HbA1c ≤ 5.6% [≤37.7 mmol/mol]: 476 ± 219 µg/g; p < 0.0001). The prevalence of FE1<100 µg/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.

Using epidemiological registry data to provide background rates as context for adverse events in a rheumatoid arthritis drug development program: a coordinated approach.

PURPOSE: Observational studies can provide context for adverse events observed in clinical trials, especially for infrequent events or long-term risks. We developed methods to improve safety contextualization for a rheumatoid arthritis drug development program through coordinated analyses of multiple registries. METHODS: We identified and characterized differences and similarities across five registries (Swedish Rheumatology Quality of Care Register, Consortium of Rheumatology Researchers of North America [CORRONA], Norfolk Arthritis Register, Institute of Rheumatology Rheumatoid Arthritis, and the new CORRONA International), harmonized outcome definitions, and investigated whether restricted subcohorts improved comparability with trial populations. To address confounding, we identified risk predictors for outcomes of interest (mortality, cardiovascular disease, infection, and malignancy). We used patient-level analyses at each registry and central analysis of standardized group-level data. RESULTS: Despite data differences, the coordinated approach enabled consistent variable definitions for key baseline characteristics and outcomes. Selection of restricted subcohorts (e.g., using active joint count criteria) improved baseline comparability with trial patients for some rheumatoid arthritis disease activity measures, but less for other characteristics (e.g., age and comorbidity); however, such selection decreased sample size considerably. For most outcomes, age was the most important risk predictor, emphasizing the importance of age/sex standardization to address confounding. The prospective approach enabled use of recent relevant data; the distributed analysis safeguarded confidentiality of registry data. CONCLUSIONS: Compared with reliance on published data alone, a forward-looking coordinated approach across multiple observational data sources can improve comparability and consistency and better support sensitivity analyses and data interpretation, in contextualizing safety data from clinical trials. This approach may have utility to support safety assessments across diverse diseases and drug development programs and satisfy future regulatory requirements.

Ambient air pollution and daily mortality among survivors of 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/cm and 5.1% [1.6%-9.3%] per 10 microg/m, 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.

Rapid effects of air pollution on ventricular arrhythmias.

AIMS: Air pollution has been associated with ventricular arrhythmias in patients with implantable cardioverter defibrillators (ICDs) for exposure periods of 24-48 h. Only two studies have investigated exposure periods <24 h. We aimed to explore such effects during the 2 and 24 preceding hours as well as in relation to distance from the place of the event to the air pollution monitor. METHODS AND RESULTS: We used a case-crossover design to investigate the effects of particulate matter <10 microm in diameter (PM10) and nitrogen dioxide (NO2) in 211 patients with ICD devices in Gothenburg and Stockholm, Sweden. Events interpreted as ventricular arrhythmias were downloaded from the ICDs, and air pollution data were collected from urban background monitors. We found an association between 2 h moving averages of PM10 and ventricular arrhythmia [odds ratio (OR) 1.31, 95% confidence interval (CI) 1.00-1.72], whereas the OR for 24 h moving averages was 1.24 (95% CI 0.87-1.76). Corresponding ORs for events occurring closest to the air pollution monitor were 1.76 (95% CI 1.18-2.61) and 1.74 (95% CI 1.07-2.84), respectively. Events occurring in Gothenburg showed stronger associations than in Stockholm. CONCLUSION: Moderate increases in air pollution appear to be associated with ventricular arrhythmias in ICD patients already after 2 h, although future studies including larger numbers of events are required to confirm these findings. Representative geographical exposure classification seems important in studies of these effects.

Interactions between glutathione S-transferase P1, tumor necrosis factor, and traffic-related air pollution for development of childhood allergic disease.

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 beta2-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 NO(x)) 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(x) 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(x) (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-NO(x) 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.

Aldosterone-to-renin ratio as a marker for disease severity in 21-hydroxylase deficiency congenital adrenal hyperplasia.

CONTEXT: Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency (21 OHD) is classified clinically in decreasing order of severity into salt-wasting, simple-virilizing, and nonclassical forms. Causative mutations in the CYP21A2 gene dictate the degrees of adrenal enzyme defect. Salt-wasting crises due to aldosterone deficiency are clinically apparent in the salt-wasting form but not in other forms of 21 OHD. OBJECTIVES: This study examined the ratio of serum aldosterone to plasma renin activity as an index of sodium wasting in patients with 21 OHD CAH, heterozygotes, and normal individuals. DESIGN: This was a cross-sectional, retrospective, noninterventional study. PATIENTS AND OTHER PARTICIPANTS: A total of 402 individuals were included: 224 patients affected with 21 OHD CAH and 178 unaffected subjects. Classification into each diagnostic group was made primarily on the basis of clinical and hormonal features. Affected or unaffected status was confirmed by genotype of CYP21A2. All subjects were on ad lib diets without restrictions. Salt-wasting status was examined by sodium deprivation testing in 32 salt-wasting subjects and 14 simple virilizing subjects. RESULTS: The ratio of serum aldosterone to plasma renin activity was found to discriminate well between the different groups of disease severity. The lowest ratios, indicative of the least sodium conservation, were seen in the salt-wasting group with increasing ratios in the simple virilizing, nonclassical, and unaffected groups. This ratio remained stable with age. CONCLUSION: The ratio of serum aldosterone to plasma renin activity provides a simple index to compare groups of patients with varying degrees of 21 OHD.

Air pollution and inflammation (interleukin-6, C-reactive protein, fibrinogen) in myocardial infarction survivors.

BACKGROUND: Numerous studies have found that ambient air pollution has been associated with cardiovascular disease exacerbation. OBJECTIVES: Given previous findings, we hypothesized that particulate air pollution might induce systemic inflammation in myocardial infarction (MI) survivors, contributing to an increased vulnerability to elevated concentrations of ambient particles. METHODS: A prospective longitudinal study of 1,003 MI survivors was performed in six European cities between May 2003 and July 2004. We compared repeated measurements of interleukin 6 (IL-6), fibrinogen, and C-reactive protein (CRP) with concurrent levels of air pollution. We collected hourly data on particle number concentrations (PNC), mass concentrations of particulate matter (PM) < 10 microm (PM(10)) and < 2.5 microm (PM(2.5)), gaseous pollutants, and meteorologic data at central monitoring sites in each city. City-specific confounder models were built for each blood marker separately, adjusting for meteorology and time-varying and time-invariant covariates. Data were analyzed with mixed-effects models. RESULTS: Pooled results show an increase in IL-6 when concentrations of PNC were elevated 12-17 hr before blood withdrawal [percent change of geometric mean, 2.7; 95% confidence interval (CI), 1.0-4.6]. Five day cumulative exposure to PM(10) was associated with increased fibrinogen concentrations (percent change of arithmetic mean, 0.6; 95% CI, 0.1-1.1). Results remained stable for smokers, diabetics, and patients with heart failure. No consistent associations were found for CRP. CONCLUSIONS: Results indicate an immediate response to PNC on the IL-6 level, possibly leading to the production of acute-phase proteins, as seen in increased fibrinogen levels. This might provide a link between air pollution and adverse cardiac events.

Road traffic noise and hypertension.

BACKGROUND: It has been suggested that noise exposure increases the risk of hypertension. Road traffic is the dominant source of community noise exposure. OBJECTIVE: To study the association between exposure to residential road traffic noise and hypertension in an urban municipality. METHODS: The study population comprised randomly selected subjects aged 19-80 years. A postal questionnaire provided information on individual characteristics, including diagnosis of hypertension. The response rate was 77%, resulting in a study population of 667 subjects. The outdoor equivalent traffic noise level (Leq 24 h) at the residence of each individual was determined using noise-dispersion models and manual noise assessments. The individual noise exposure was classified in units of 5 dB(A), from <45 dB(A) to >65 dB(A). RESULTS: The odds ratio (OR) for hypertension adjusted for age, smoking, occupational status and house type was 1.38 (95% confidence interval (CI) 1.06 to 1.80) per 5 dB(A) increase in noise exposure. The association seemed stronger among women (OR 1.71; 95% CI 1.17 to 2.50) and among those who had lived at the address for >10 years (OR 1.93; 95% CI 1.29 to 2.83). Analyses of categorical exposure variables suggested an exposure-response relationship. The strongest association between exposure to traffic noise and hypertension was found among those with the least expected misclassification of true individual exposure, as indicated by not having triple-glazed windows, living in an old house and having the bedroom window facing a street (OR 2.47; 95% CI 1.38 to 4.43). CONCLUSION: The results of our study suggest an association between exposure to residential road traffic noise and hypertension.

Infection rates in patients from five rheumatoid arthritis (RA) registries: contextualising an RA clinical trial programme.

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.

Ambient air pollution is associated with increased risk of hospital cardiac readmissions of myocardial infarction survivors in five European cities.

BACKGROUND: Ambient air pollution has been associated with increases in acute morbidity and mortality. The objective of this study was to evaluate the short-term effects of urban air pollution on cardiac hospital readmissions in survivors of myocardial infarction, a potentially susceptible subpopulation. METHODS AND RESULTS: In this European multicenter cohort study, 22,006 survivors of a first myocardial infarction were recruited in Augsburg, Germany; Barcelona, Spain; Helsinki, Finland; Rome, Italy; and Stockholm, Sweden, from 1992 to 2000. Hospital readmissions were recorded in 1992 to 2001. Ambient nitrogen dioxide, carbon monoxide, ozone, and mass of particles <10 microm (PM10) were measured. Particle number concentrations were estimated as a proxy for ultrafine particles. Short-term effects of air pollution on hospital readmissions for myocardial infarction, angina pectoris, and cardiac causes (myocardial infarction, angina pectoris, dysrhythmia, or heart failure) were studied in city-specific Poisson regression analyses with subsequent pooling. During follow-up, 6655 cardiac readmissions were observed. Cardiac readmissions increased in association with same-day concentrations of PM10 (rate ratio [RR] 1.021, 95% CI 1.004 to 1.039) per 10 microg/m3) and estimated particle number concentrations (RR 1.026 [95% CI 1.005 to 1.048] per 10,000 particles/cm3). Effects of similar strength were observed for carbon monoxide (RR 1.014 [95% CI 1.001 to 1.026] per 200 microg/m3 [0.172 ppm]), nitrogen dioxide (RR 1.032 [95% CI 1.013 to 1.051] per 8 microg/m3 [4.16 ppb]), and ozone (RR 1.026 [95% CI 1.001 to 1.051] per 15 microg/m3 [7.5 ppb]). Pooled effect estimates for angina pectoris and myocardial infarction readmissions were comparable. CONCLUSIONS: The results suggest that ambient air pollution is associated with increased risk of hospital cardiac readmissions of myocardial infarction survivors in 5 European cities.

Comparison of different methods in analyzing short-term air pollution effects in a cohort study of susceptible individuals.

BACKGROUND: Short-term fluctuations of ambient air pollution have been associated with exacerbation of cardiovascular disease. A multi-city study was designed to assess the probability of recurrent hospitalization in a cohort of incident myocardial infarction survivors in five European cities. The objective of this paper is to discuss the methods for analyzing short-term health effects in a cohort study based on a case-series. METHODS: Three methods were considered for the analyses of the cohort data: Poisson regression approach, case-crossover analyses and extended Cox regression analyses. The major challenge of these analyses is to appropriately consider changes within the cohort over time due to changes in the underlying risk following a myocardial infarction, slow time trends in risk factors within the population, dynamic cohort size and seasonal variation. RESULTS: Poisson regression analyses, case-crossover analyses and Extended Cox regression analyses gave similar results. Application of smoothing methods showed the capability to adequately model the complex time trends. CONCLUSION: From a practical point of view, Poisson regression analyses are less time-consuming, and therefore might be used for confounder selection and most of the analyses. However, replication of the results with Cox models is desirable to assure that the results are independent of the analytical approach used. In addition, extended Cox regression analyses would allow a joint estimation of long-term and short-term health effects of time-varying exposures.

Aerosol particle number concentration measurements in five European cities using TSI-3022 condensation particle counter over a three-year period during health effects of air pollution on susceptible subpopulations.

In this study, long-term aerosol particle total number concentration measurements in five metropolitan areas across Europe are presented. The measurements have been carried out in Augsburg, Barcelona, Helsinki, Rome, and Stockholm using the same instrument, a condensation particle counter (TSI model 3022). The results show that in all of the studied cities, the winter concentrations are higher than the summer concentrations. In Helsinki and in Stockholm, winter concentrations are higher by a factor of two and in Augsburg almost by a factor of three compared with summer months. The winter maximum of the monthly average concentrations in these cities is between 10,000 cm(-3) and 20,000 cm(-3), whereas the summer min is approximately 5000-6000 cm(-3). In Rome and in Barcelona, the winters are more polluted compared with summers by as much as a factor of 4-10. The winter maximum in both Rome and Barcelona is close to 100,000 cm(-3), whereas the summer minimum is > 10,000 cm(-3). During the weekdays the maximum of the hourly average concentrations in all of the cities is detected during the morning hours between 7 and 10 a.m. The evening maxima were present in Barcelona, Rome, and Augsburg, but these were not as pronounced as the morning ones. The daily maxima in Helsinki and Stockholm are close or even lower than the daily minima in the more polluted cities. The concentrations between these two groups of cities are different with a factor of about five during the whole day. The study pointed out the influence of the selection of the measurement site and the configuration of the sampling line on the observed concentrations.

Methodological Challenges When Comparing Demographic and Clinical Characteristics of International Observational Registries.

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.

Prevalence of self-reported hypersensitivity to electric or magnetic fields in a population-based questionnaire survey.

OBJECTIVES: The prevalence of medically unexplained symptoms attributed to exposure to electromagnetic fields is still largely unknown. Previous studies have investigated reported hypersensitivity to electricity in selected groups recruited from workplaces or outpatient clinics. The aim of this study was to estimate the prevalence of self-reported hypersensitivity to electric or magnetic fields in the general population and to describe characteristics of the group reporting such hypersensitivity with regard to demographics, other complaints, hypersensitivities, and traditional allergies. METHODS: A cross-sectional questionnaire survey was conducted in 1997 among 15,000 men and women between 19 and 80 years of age in Stockholm County. The response rate was 73%. RESULTS: One and a half percent of the respondents reported hypersensitivity to electric or magnetic fields. Prevalence was highest among women and in the 60- to 69-year age group. The hypersensitive group reported all symptoms, allergies, and other types of hypersensitivities included in the survey (as well as being disturbed by various factors in the home) to a significantly greater extent than the rest of the respondents. No specific symptom profile set off the hypersensitive group from the rest of the respondents. CONCLUSIONS: The results should be interpreted with caution. But they suggest that there is widespread concern among the general population about risks to health posed by electric and magnetic fields. More research is warranted to explore ill health among people reporting hypersensitivity to electric or magnetic fields.

Prevalence of self-reported allergic and non-allergic rhinitis symptoms in Stockholm: relation to age, gender, olfactory sense and smoking.

OBJECTIVE: To estimate the prevalence of isolated self-reported allergic and non-allergic rhinitis symptoms in an adult population and to explore the relations to age, gender, olfaction and smoking habits. MATERIAL AND METHODS: Self-judged health and environmental exposures were investigated by means of a questionnaire survey administered to a stratified random sample of 15,000 adults in Stockholm County. RESULTS: A total of 10,670 individuals were included in the analysis, corresponding to a response rate of 73%. The results revealed a high prevalence of self-reported non-allergic rhinitis, 19%, almost as high as the prevalence of self-reported allergic rhinoconjunctivitis, 24%. In contrast to current clinical opinion, we did not find a significant increase in the prevalence of non-allergic symptoms with increased age. There were no statistically significant gender differences in the prevalence of either allergic or non-allergic symptoms. A reduced sense of smell was twice as common in the non-allergic group, 23%, as in the healthy population. The prevalence of rhinitis symptoms differed according to smoking habits. CONCLUSION: Both self-reported allergic rhinitis symptoms and non-allergic nasal symptoms are frequent in the population sample. Self-reported non-allergic nasal symptoms seem to occur independent of age and reduced olfactory sense is a common complaint among these subjects. The prevalence of self-reported allergic and non-allergic nasal symptoms did not differ much between men and women or between individuals with different smoking habits.

The efficacy and safety of the dipeptidyl peptidase-4 inhibitor saxagliptin in treatment-naïve patients with type 2 diabetes mellitus: a randomized controlled trial.

BACKGROUND: 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. METHODS: 365 treatment-naïve patients with T2DM (HbA1c 7.0%-10.0%) were treated with saxagliptin 2.5 mg q.A.M., saxagliptin 2.5 mg q.A.M. with possible titration to saxagliptin 5 mg, saxagliptin 5 mg q.A.M., saxagliptin 5 mg q.P.M., or placebo. After week 24, patients in all groups were eligible for titration to saxagliptin 10 mg based on HbA1c ≥7%, and all unrescued placebo patients began blinded metformin 500 mg/day. Rescue with open-label metformin was available for patients with inadequate glycemic control. RESULTS: At week 24, placebo-subtracted mean HbA1c reduction from baseline (LOCF) was significantly greater in the saxagliptin treatment groups vs placebo, and remained greater through week 76. Serious adverse events (AEs) and discontinuations due to AEs were similar in saxagliptin and control groups; incidence of confirmed hypoglycemia was low across all treatment groups (saxagliptin-treated, 2 [0.7]; control, 1 [1.4]). CONCLUSIONS: In treatment-naïve patients with T2DM, saxagliptin monotherapy demonstrated statistically significant improvement in HbA1c compared with placebo at 24 weeks and was generally well tolerated for up to 76 weeks. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00316082.

Saxagliptin and metformin XR combination therapy provides glycemic control over 24 hours in patients with T2DM inadequately controlled with metformin.

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.