Hyperuricemia and coronary heart disease: A systematic review and meta‐analysis

Objective

The role of serum uric acid as an independent risk factor for cardiovascular disease remains unclear, although hyperuricemia is associated with cardiovascular disease such as coronary heart disease (CHD), stroke, and hypertension.

Methods

A systematic review and meta‐analysis using a random‐effects model was conducted to determine the risk of CHD associated with hyperuricemia in adults. Studies of hyperuricemia and CHD were identified by searching major electronic databases using the medical subject headings and keywords without language restriction (through February 2009). Only prospective cohort studies were included if they had data on CHD incidences or mortalities related to serum uric acid levels in adults.

Results

Twenty‐six eligible studies of 402,997 adults were identified. Hyperuricemia was associated with an increased risk of CHD incidence (unadjusted risk ratio [RR] 1.34, 95% confidence interval [95% CI] 1.19–1.49) and mortality (unadjusted RR 1.46, 95% CI 1.20–1.73). When adjusted for potential confounding, the pooled RR was 1.09 (95% CI 1.03–1.16) for CHD incidence and 1.16 (95% CI 1.01–1.30) for CHD mortality. For each increase of 1 mg/dl in uric acid level, the pooled multivariate RR for CHD mortality was 1.12 (95% CI 1.05–1.19). Subgroup analyses showed no significant association between hyperuricemia and CHD incidence/mortality in men, but an increased risk for CHD mortality in women (RR 1.67, 95% CI 1.30–2.04).

Conclusion

Hyperuricemia may marginally increase the risk of CHD events, independently of traditional CHD risk factors. A more pronounced increased risk for CHD mortality in women should be investigated in future research.     

Cardiovascular disease and cognitive dysfunction in systemic lupus erythematosus

Objective

Cognitive dysfunction and cardiovascular disease are common and debilitating manifestations of systemic lupus erythematosus (SLE). In this study, we evaluated the relationship between cardiovascular events, traditional cardiovascular risk factors, and SLE‐specific risk factors as predictors of cognitive dysfunction in a large cohort of participants with SLE.

Methods

Subjects included 694 participants from the Lupus Outcomes Study (LOS), a longitudinal study of SLE outcomes based on an annual telephone survey querying demographic and clinical variables. The Hopkins Verbal Learning Test‐Revised and the Controlled Oral Word Association Test were administered to assess cognitive function. Multiple logistic regression was used to identify cardiovascular events (myocardial infarction, stroke), traditional cardiovascular risk factors (hypertension, hyperlipidemia, diabetes mellitus, obesity, smoking), and SLE‐specific risk factors (antiphospholipid antibodies [aPL], disease activity, disease duration) associated with cognitive impairment in year 7 of the LOS.

Results

The prevalence of cognitive impairment as measured by verbal memory and verbal fluency metrics was 15%. In adjusted multiple logistic regression analyses, aPL (odds ratio [OR] 2.10, 95% confidence interval [95% CI] 1.3–3.41), hypertension (OR 2.06, 95% CI 1.19–3.56), and a history of stroke (OR 2.27, 95% CI 1.16–4.43) were significantly associated with cognitive dysfunction. In additional analyses evaluating the association between these predictors and severity of cognitive impairment, stroke was significantly more prevalent in participants with severe impairment when compared to those with mild or moderate impairment (P = 0.036).

Conclusion

These results suggest that the presence of aPL, hypertension, and stroke are key variables associated with cognitive impairment, which may aid in identification of patients at greatest risk.     

Cardiovascular and disease-related predictors of depression in systemic lupus erythematosus

Objective

Depression and cardiovascular disease are common and debilitating comorbidities associated with systemic lupus erythematosus (SLE). In this study, history of cardiovascular events, cardiovascular risk factors, and SLE disease‐related factors were evaluated as longitudinal predictors of depression in a large cohort of patients with SLE.

Methods

Data were derived from 663 adult participants in the 2004–2008 Lupus Outcomes Study, who were followed for up to 5 annual interviews. Multivariate logistic regression analyses using generalized estimating equations were used to determine predictors of the development of increased depressive symptom severity over a 12‐month period (Center for Epidemiologic Studies Depression Scale [CES‐D] score of 23 or greater), yielding 2,224 paired observations. Predictors included sociodemographics, traditional cardiovascular risk factors (reported presence of heart disease, history of stroke or myocardial infarction, hypertension, hypercholesterolemia, diabetes mellitus, obesity, smoking status, and family history), and SLE‐specific risk factors (glucocorticoid use, renal involvement, disease duration, and disease activity).

Results

The annual incidence of depression was 12% in this cohort. Multivariate predictors of new‐onset depression included younger age (ages 20–39 years: odds ratio [OR] 2.3, 95% confidence interval [95% CI] 1.3–3.9; ages 40–59 years: OR 1.8, 95% CI 1.1–2.7), Hispanic/Latino ethnicity (OR 1.8, 95% CI 1.2–2.8), having some college education (OR 1.8, 95% CI 1.1–3.0), baseline CES‐D score (OR per point 1.1, 95% CI 1.1–1.2), presence of diabetes mellitus (OR 1.8, 95% CI 1.1–2.8), and baseline SLE disease activity (OR 1.2, 95% CI 1.1–1.4).

Conclusion

These results suggest that, in addition to known sociodemographic factors, the presence of diabetes mellitus and SLE disease activity may play a role in the development of depression in SLE.     

Combined oral contraceptive use and the risk of systemic lupus erythematosus

Objective

To assess whether the risk of incident systemic lupus erythematosus (SLE) is associated with the use of combined oral contraceptives (COCs), because studies of the link between exogenous hormonal exposure and the risk of SLE have produced conflicting results.

Methods

We conducted a population‐based nested case–control study among women ages 18–45 years, using the UK's General Practice Research Database. All incident cases of SLE from 1994–2004 (n = 786) were identified in the database and matched with up to 10 controls (n = 7,817) among women without SLE at the time of the case's diagnosis.

Results

The adjusted rate ratio (RR) of incident SLE associated with any use of COC was 1.19 (95% confidence interval [95% CI] 0.98–1.45), whereas with current use it was 1.54 (95% CI 1.15–2.07). The rate was particularly increased in current users who had only recently started COC use (RR 2.52, 95% CI 1.14–5.57) compared with longer‐term current users (RR 1.45, 95% CI 1.06–1.99). The risk appeared to be particularly elevated with current exposure to first‐ or second‐generation contraceptives (RR 1.65, 95% CI 1.20–2.26), and increasing with the dose of ethinyl estradiol (RR 1.42, 1.63, and 2.92 for ≤30 μg, 31–49 μg, and 50 μg, respectively).

Conclusion

The use of COCs is associated with an increased risk of SLE. This risk is particularly elevated in women who recently started contraceptive use, suggesting an acute effect in a small subgroup of susceptible women.     

Use of disease‐modifying antirheumatic drugs during pregnancy and risk of preeclampsia

Objective

To describe patterns of disease‐modifying antirheumatic drug (DMARD) use during pregnancy in a population‐based cohort, and to evaluate the association between autoimmune disease, DMARDs, corticosteroids, and nonsteroidal antiinflammatory drugs (NSAIDs) and preeclampsia.

Methods

Using health care utilization databases from British Columbia (1997–2006), we compared the risk for preeclampsia among 44,786 women with and without autoimmune disease with study drug dispensings before pregnancy (past users) and before and during the first 20 gestational weeks (continuous users). Relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated.

Results

Only 414 women (0.1%) had a DMARD dispensing during pregnancy. The incidence of preeclampsia was 2.3% for past DMARD users, 2.7% for past corticosteroid users, and 2.9% for past NSAID users. Compared to past users, the continuous DMARD user RR was 2.29 (95% CI 0.81–6.44), and was 0.89 (95% CI 0.51–1.56) for corticosteroid and 0.84 (95% CI 0.63–1.10) for NSAID users. Compared to women without autoimmune disease, the delivery year–adjusted RR was 2.02 (95% CI 1.11–3.64) for women with systemic lupus erythematosus (SLE). The DMARD results were attenuated when antimalarials were excluded, and the delivery year–adjusted RR was 0.95 (95% CI 0.25–3.55) when the DMARD analysis was restricted to women with autoimmune disease.

Conclusion

Few women were exposed to DMARDs during pregnancy. We observed a 2‐fold increased risk of preeclampsia among women with SLE and a nonsignificant increase in risk in DMARD users. The DMARD and preeclampsia association was attenuated when antimalarials were excluded and null when restricted to women with autoimmune disease, which suggests the association is likely due to greater autoimmune disease severity in DMARD users.     

Systematic review and meta-analysis: anti-tumor necrosis factor α therapy and cardiovascular events in rheumatoid arthritis

Objective

Control of rheumatoid arthritis (RA) may reduce the risk of cardiovascular events. We sought to systematically assess the association between anti–tumor necrosis factor α (anti‐TNFα) therapy in RA and cardiovascular event rates.

Methods

Observational cohorts and randomized controlled trials (RCTs) reporting on cardiovascular events (all events, myocardial infarction [MI], congestive heart failure, and cerebrovascular accident [CVA]) in RA patients treated with anti‐TNFα therapy compared to traditional disease‐modifying antirheumatic drugs were identified from a search of PubMed (1950 to November 2009), EMBase (1980 to November 2009), and conference abstracts. Relative risks (RRs) or hazard ratios and 95% confidence intervals (95% CIs) were extracted. If the incidence was reported, additional data were extracted to calculate an incidence density ratio and its variance.

Results

The systematic review and meta‐analysis include 16 and 11 publications, respectively. In cohort studies, anti‐TNFα therapy was associated with a reduced risk for all cardiovascular events (pooled adjusted RR 0.46; 95% CI 0.28, 0.77), MI (pooled adjusted RR 0.81; 95% CI 0.68, 0.96), and CVA (pooled adjusted RR 0.69; 95% CI 0.53, 0.89). Meta‐analysis of RCTs also produced a point estimate indicating lower risk of cardiovascular events, but this was not statistically significant (pooled RR 0.85; 95% CI 0.28, 2.59).

Conclusion

Anti‐TNFα therapy is associated with a reduced risk of all cardiovascular events, MI, and CVA in observational cohorts. There was heterogeneity among cohort studies and possible publication bias. The point estimate of the effect from RCTs is underpowered with wide 95% CIs, and cardiovascular events were secondary outcomes, but RCTs also demonstrated a trend toward decreased risk.     

Effect of fluvastatin on cardiac outcomes in kidney transplant patients with systemic lupus erythematosus: A randomized placebo‐controlled study

Objective

Patients with systemic lupus erythematosus (SLE), with or without end‐stage renal failure, are at increased risk of premature cardiovascular disease. Although statin therapy has been found to reduce cardiovascular risk in the general population, its effectiveness in kidney transplant recipients with SLE has not been examined. This study was undertaken to investigate the effect of fluvastatin on cardiac end points in a randomized controlled trial of renal transplant patients with SLE.

Methods

Patients with SLE were identified from among participants in the Assessment of Lescol in Renal Transplantation trial, a randomized, double‐blind, placebo‐controlled study of the effect of fluvastatin (40–80 mg/day) on cardiovascular outcomes in renal transplant recipients. Patients were randomized to either a group receiving fluvastatin or a placebo group for the duration of the 5–6‐year trial, and then invited to continue in a 2‐year open‐label extension during which all participants, regardless of original group, received fluvastatin. Patients were followed up for a total of 7–8 years for assessment of the primary end point of major cardiac events, comprising nonfatal myocardial infarction, cardiac death, and coronary intervention procedures.

Results

Fluvastatin reduced low‐density lipoprotein cholesterol levels by 29.2% (95% confidence interval [95% CI] 18.3–40%), from a mean ± SD of 4.0 ± 0.9 mmoles/liter to 2.8 ± 1.1 mmoles/liter, and total cholesterol by 19.6% (95% CI 11.7–27.5%), from 6.4 ± 0.9 mmoles/liter to 5.1 ± 1.1 mmoles/liter. Compared with placebo‐treated patients, patients randomized to receive fluvastatin exhibited a 73.4% reduction in the risk of major cardiac events (relative risk 26.6 [95% CI 5.9–119.4], P = 0.064).

Conclusion

Our results indicate that the effect of fluvastatin on cardiac events in renal transplant recipients with SLE is similar to that observed with statin therapy in the renal transplant population as a whole.

     

Role of the Fcγ receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: A meta‐analysis

Objective

To assess the impact of the Fcγ receptor type IIa (FcγRIIa)–R/H131 polymorphism on the risk for systemic lupus erythematosus (SLE) and development of lupus nephritis.

Methods

A meta‐analysis was performed based on the Medline and Embase databases (last retrieval August 2001), assessment of bibliographies of pertinent articles, and additional data gathered after contact with primary investigators.

Results

A total of 25 comparisons from 17 studies involving R/H131 genotyping of 1,405 patients with lupus nephritis, 1,709 SLE patients without nephritis, and 2,580 non‐SLE controls were included. No association between RR genotype and risk of lupus nephritis relative to both other genotypes (odds ratio [OR] 1.05, 95% confidence interval [95% CI] 0.88–1.27) was demonstrated in the total meta‐analysis or in any racial subgroup. The RR genotype was more frequent in SLE patients as a whole (OR 1.30, 95% CI 1.10–1.52) and in SLE patients without nephritis (OR 1.27, 95% CI 1.04–1.55) compared with disease‐free controls. A potential dose–response relation between the R131 allele and the risk of SLE was also identified, with an OR of 1.23 for RR versus RH (95% CI 1.03–1.46). The OR was 1.55 for RR versus HH (95% CI 1.21–1.98). There was no significant heterogeneity between racial subgroups. The population‐attributable fractions of SLE cases due to the FcγRIIa‐R131 allele were 13%, 40%, and 24% in subjects of European, African, and Asian descent, respectively.

Conclusion

The FcγRIIa‐R/H131 polymorphism represents a significant risk factor for SLE but has no clear effect on susceptibility for lupus nephritis.

     

Perinatal factors and adult‐onset lupus

Objective

Some evidence suggests that perinatal factors, including birth weight and breastfeeding, may influence the occurrence of autoimmune rheumatic diseases. However, few studies have investigated these factors in patients with systemic lupus erythematosus (SLE). Therefore, we evaluated the role of birth weight, being breastfed, and preterm birth on the incidence of SLE in participants in the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHSII).

Methods

We studied 87,411 NHS participants and 98,413 NHSII participants without SLE at baseline who provided information on perinatal exposures. Among these women, during 26 (NHS) and 14 (NHSII) years of followup, 222 incident SLE cases were confirmed (136 NHS and 86 NHSII) by medical record review using American College of Rheumatology criteria. We used stratified Cox models to estimate the association of perinatal factors with SLE, adjusting for race, early passive cigarette smoke exposure, and parents' occupation. A random‐effects meta‐analysis was used to compute combined estimates across the 2 cohorts.

Results

After adjustment for multiple potential confounders, high birth weight (≥10 pounds) was associated with increased rates of SLE compared with normal birth weight (7–8.5 pounds; rate ratio [RR] 2.7, 95% confidence interval [95% CI] 1.2–5.9), as was being born ≥2 weeks preterm (RR 1.9, 95% CI 1.2–3.0); however, being breastfed was not (RR 0.8, 95% CI 0.6–1.1).

Conclusion

Birth weight ≥10 pounds and preterm birth were both positively associated with incident SLE among women.     

Low‐dose aspirin in the primary prevention of rheumatoid arthritis: The women's health study

Objective

Low‐dose aspirin may reduce the risk of developing rheumatoid arthritis (RA) through its effect on cyclooxygenase activity and its antioxidant pathways. Previous randomized trial data have demonstrated a beneficial effect of low‐dose aspirin in reducing other inflammatory diseases, such as asthma and colorectal adenomas, but no trial has evaluated the role of aspirin in RA prevention.

Methods

The Women's Health Study is a randomized, double‐blind, placebo‐controlled trial conducted between 1992 and 2004 designed to evaluate the risks and benefits of low‐dose aspirin (100 mg every other day) and vitamin E in the primary prevention of cardiovascular disease and cancer among 39,876 female health care professionals age ≥45 years throughout the US. After excluding women with RA at baseline, 39,144 women were evaluated for the present study. A definite diagnosis of RA was assessed during followup by self‐report and confirmed using a connective tissue disease screening questionnaire, followed by a medical record review by a rheumatologist for American College of Rheumatology criteria.

Results

During an average followup of 10 years, 106 women developed definite RA (48 women in the aspirin group and 58 in the placebo group). There was a nonsignificant risk for RA (relative risk [RR] 0.83, 95% confidence interval [95% CI] 0.56–1.21; P = 0.33) associated with aspirin. There were 64 seropositive RA cases (60%) and 42 seronegative RA cases (40%). Aspirin also had no significant effect on either seropositive RA (RR 1.0, 95% CI 0.61–1.63) or seronegative RA (RR 0.62, 95% CI 0.33–1.15).

Conclusion

One hundred milligrams of aspirin taken every other day was not associated with a significant reduction in the risk of developing RA among women in a randomized, double‐blind, placebo‐controlled trial.     

Brachial Pulse Pressure and Cardiovascular or All‐Cause Mortality in the General Population: A Meta‐Analysis of Prospective Observational Studies

This study aimed to quantitatively evaluate the predictive value of brachial pulse pressure and cardiovascular or all‐cause mortality in the general population based on prospective observational studies by conducting a meta‐analysis. Only prospective observational studies investigating baseline brachial pulse pressure and cardiovascular or all‐cause mortality risk were selected from PubMed and Embase databases until July 2013. Fourteen studies involving 510,456 participants were analyzed. Pooled risk ratio (RR) of cardiovascular and all‐cause mortality for the highest vs lowest brachial pulse pressure category was 1.80 (95% confidence interval [CI], 1.49–2.17) and 1.32 (95% CI, 1.23–1.41), respectively. Pooled RR of cardiovascular and all‐cause mortality per 10 mm Hg pulse pressure increment was 1.13 (95% CI, 1.10–1.17) and 1.09 (95% CI, 1.07–1.11), respectively. Wide brachial pulse pressure is associated with greater risk of cardiovascular and all‐cause mortality. However, more well‐designed studies specifically on age and sex are needed to further confirm these findings.     

Baseline serum uric acid level as a predictor of cardiovascular disease related mortality and all-cause mortality: A meta-analysis of prospective studies

Objective

Serum uric acid (SUA) levels have been used to predict cardiovascular and all-cause mortality event, but the data have yielded conflicting results. We investigated whether SUA was an independent predictor for cardiovascular or all-cause mortality with prospective studies by meta-analysis.

Methods

Pubmed and Embase were searched without language restrictions for publications available till April 2013. Only prospective studies on cardiovascular or all-cause mortality related to SUA levels were included. Pooled adjust relative risk (RR) and corresponding 95% confidence intervals (CI) were calculated separately for the highest vs. lowest category or the lowest vs. middle category.

Results

For the highest SUA, eleven studies with 172,123 participants were identified and analyzed. Elevated SUA increased risk of all-cause mortality (RR 1.24; 95% CI 1.09–1.42) and cardiovascular mortality (RR 1.37; 95% CI 1.19–1.57). Subgroup analyses showed that elevated SUA significantly increase the risk of all-cause mortality among men (RR 1.23; 95% CI 1.08–1.42), but not in women (RR 1.05; 95% CI 0.79–1.39). Risk of cardiovascular mortality appeared to be more pronounced among women (RR 1.35; 95% CI 1.06–1.72). The association between extremely low SUA and mortality was reported in three studies; we did not perform a pooled analysis because of high degree of heterogeneity in these studies.

Conclusions

Baseline SUA level is an independent predictor for future cardiovascular mortality. Elevated SUA appears to significantly increase the risk of all-cause mortality in men, but not in women. Whether low SUA levels are predictors of mortality is still inconclusive.     

Insecticide use and risk of rheumatoid arthritis and systemic lupus erythematosus in the Women's Health Initiative Observational Study

Objective

Farming and agricultural pesticide use has been associated with 2 autoimmune rheumatic diseases, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, risk associated with other residential or work place insecticide use is unknown.

Methods

We analyzed data from the Women's Health Initiative Observational Study (n = 76,861 postmenopausal women, ages 50–79 years). Incident cases (n = 213: 178 for RA, 27 for SLE, and 8 for both) were identified based on self‐report and use of disease‐modifying antirheumatic drugs at year 3 of followup. We examined self‐reported residential or work place insecticide use (personally mixing/applying by self and application by others) in relation to RA/SLE risk, overall and in relation to farm history. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were adjusted for age, race, region, education, occupation, smoking, reproductive factors, asthma, other autoimmune diseases, and comorbidities.

Results

Compared with never used, personal use of insecticides was associated with increased RA/SLE risk, with significant trends for greater frequency (HR 2.04, 95% CI 1.17–3.56 for ≥6 times/year) and duration (HR 1.97, 95% CI 1.20–3.23 for ≥20 years). Risk was also associated with long‐term insecticide application by others (HR 1.85, 95% CI 1.07–3.20 for ≥20 years) and frequent application by others among women with a farm history (HR 2.73, 95% CI 1.10–6.78 for ≥6 times/year).

Conclusion

These results suggest residential and work place insecticide exposure is associated with the risk of autoimmune rheumatic diseases in postmenopausal women. Although these findings require replication in other populations, they support a role for environmental pesticide exposure in the development of autoimmune rheumatic diseases.     

Decreased live births in women with systemic lupus erythematosus

Objective

Multiple disease‐related factors may limit the number of children born to women with systemic lupus erythematosus (SLE). We calculated live births in women with SLE and compared this with general population rates.

Methods

We studied women with SLE from a subset of centers participating in the Systemic Lupus International Collaborating Clinics Prospective Inception Cohort Study of SLE. Women diagnosed as having SLE before age 50 years were included. Using age, calendar‐period, and country‐specific general population birth rates, we calculated the standardized incidence ratio (SIR) of observed to expected live births. We also performed a multivariate analysis with the SIR as the dependent variable to explore potential predictors of live births.

Results

A total of 339 women with SLE were studied. The number of live births over the interval (n = 313) was substantially below that which would be expected (n = 479; SIR 0.65, 95% confidence interval [95% CI] 0.58–0.73). In the multivariate analyses, black race/ethnicity (SIR 1.47, 95% CI 1.08–2.00) and being married or living common‐law (SIR 2.04, 95% CI 1.52–2.74) were associated with increased live births (relative to what would be expected). There were trends for fewer live births in women exposed to cyclophosphamide (SIR 0.88, 95% CI 0.56–1.38) and in those with high disease activity (mean SLE Disease Activity Index 2000 update score ≥5; SIR 0.82, 95% CI 0.54–1.25).

Conclusion

Overall, we found that women with SLE have fewer live births compared with the general population. Marital status, race/ethnicity, and possibly clinical factors may mediate this effect.     

Do breast‐feeding and other reproductive factors influence future risk of rheumatoid arthritis?: Results from the Nurses' Health Study

Objective

To explore the contribution of female hormonal factors occurring prior to the onset of rheumatoid arthritis (RA), such as age at menarche, parity, age at first birth, breast‐feeding, use of oral contraceptives (OCs), irregular menstrual cycles, and postmenopausal hormone (PMH) use, to the subsequent development of RA in a large female cohort.

Methods

We studied female reproductive and hormonal risk factors for RA in a cohort of 121,700 women enrolled in the longitudinal Nurses' Health Study. The diagnosis of incident RA (between 1976 and 2002) in 674 women was confirmed by a connective tissue disease screening questionnaire and blinded medical record review for American College of Rheumatology criteria. Sixty percent of the patients with RA were rheumatoid factor positive. The relationship between potential risk factors, including age, age at menarche, parity, age at first birth, total lifetime history of breast‐feeding, use of OCs, and irregular menstrual cycles and the multivariate‐adjusted risk of RA was estimated using Cox proportional hazards models.

Results

Using a multivariate model that adjusted for age, body mass index, smoking, parity, and other hormonal factors, we observed a strong trend for decreasing risk of RA with increasing duration of breast‐feeding (P for trend = 0.001). For women who breast‐fed (compared with parous women who did not breast‐feed), the risk ratios (RRs) and 95% confidence intervals (95% CIs) were as follows: breast‐feeding for ≤3 total months, RR 1.0 (95% confidence interval [95% CI] 0.8‐1.2); for 4–11 total months, RR 0.9 (95% CI 0.7–1.1); for 12–23 total months, RR 0.8 (95% CI 0.6–1.0); and for ≥24 total months, RR 0.5 (95% CI 0.3–0.8). Very irregular menstrual cycles were associated with an increased risk of RA (RR 1.4, 95% CI 1.0–2.0). Age at menarche ≤10 years was associated with an increased risk of seropositive RA (RR 1.6, 95% CI 1.1–2.4) but not significantly associated with risk of RA. Parity, total number of children, age at first birth, and OC use were not associated with an increased risk of RA in this cohort.

Conclusion

In this large cohort, breast‐feeding for >12 months was inversely related to the development of RA. This apparent effect was dose‐dependent, with a significant trend toward lower risk with longer duration of breast‐feeding. Irregular menstrual cycles and earlier age at menarche increased the risk of RA. Other reproductive hormonal factors were not associated with RA risk.

     

Sedentary time in adults and the association with diabetes, cardiovascular disease and death: systematic review and meta-analysis

Aims/hypothesis

Sedentary (sitting) behaviours are ubiquitous in modern society. We conducted a systematic review and meta-analysis to examine the association of sedentary time with diabetes, cardiovascular disease and cardiovascular and all-cause mortality.

Methods

Medline, Embase and the Cochrane Library databases were searched for terms related to sedentary time and health outcomes. Cross-sectional and prospective studies were included. RR/HR and 95% CIs were extracted by two independent reviewers. Data were adjusted for baseline event rate and pooled using a random-effects model. Bayesian predictive effects and intervals were calculated to indicate the variance in outcomes that would be expected if new studies were conducted in the future.

Results

Eighteen studies (16 prospective, two cross-sectional) were included, with 794,577 participants. Fifteen of these studies were moderate to high quality. The greatest sedentary time compared with the lowest was associated with a 112% increase in the RR of diabetes (RR 2.12; 95% credible interval [CrI] 1.61, 2.78), a 147% increase in the RR of cardiovascular events (RR 2.47; 95% CI 1.44, 4.24), a 90% increase in the risk of cardiovascular mortality (HR 1.90; 95% CrI 1.36, 2.66) and a 49% increase in the risk of all-cause mortality (HR 1.49; 95% CrI 1.14, 2.03). The predictive effects and intervals were only significant for diabetes.

Conclusions/interpretation

Sedentary time is associated with an increased risk of diabetes, cardiovascular disease and cardiovascular and all-cause mortality; the strength of the association is most consistent for diabetes.     

Impact of lung‐function measures on cardiovascular disease events in older adults with metabolic syndrome and diabetes

Background

Individuals with metabolic syndrome (MetS) and diabetes (DM) are more likely to have decreased lung function and are at greater risk of cardiovascular disease (CVD).

Hypothesis.

Lung‐function measures can predict CVD events in older persons with MetS, DM, and neither condition.

Methods

We followed 4114 participants age ≥ 65 years with and without MetS or DM in the Cardiovascular Health Study. Cox regression examined the association of forced vital capacity (FVC) and 1‐second forced expiratory volume (FEV₁; percent of predicted values) with incident coronary heart disease and CVD events over 12.9 years.

Results

DM was present in 537 (13.1%) and MetS in 1277 (31.0%) participants. Comparing fourth vs first quartiles for FVC, risk of CVD events was 16% (HR: 0.84, 95% CI: 0.59–1.18), 23% (HR: 0.77, 95% CI: 0.60–0.99), and 30% (HR: 0.70, 95% CI: 0.58–0.84) lower in DM, MetS, and neither disease groups, respectively. For FEV₁, CVD risk was lower by 2% (HR: 0.98, 95% CI: 0.70–1.37), 26% (HR: 0.74, 95% CI: 0.59–0.93), and 31% (HR: 0.69, 95% CI: 0.57–0.82) in DM. Findings were strongest for predicting congestive heart failure (CHF) in all disease groups. C‐statistics increased significantly with addition of FEV₁ or FVC over risk factors for CVD and CHF among those with neither MetS nor DM.

Conclusions

FEV₁ and FVC are inversely related to CVD in older adults with and without MetS, but not DM (except for CHF); however, their value in incremental risk prediction beyond standard risk factors is limited mainly to metabolically healthier persons.     

Hyperuricemia and incident hypertension: A systematic review and meta‐analysis

Objective

A novel rodent model and a recent randomized trial of hyperuricemic adolescents with hypertension suggest a pathogenetic role of uric acid in hypertension, but it remains unknown whether these findings would be applicable to adult populations where the larger disease burden exists. We conducted a systematic review and meta‐analysis to determine if hyperuricemia was associated with incident hypertension, particularly in various demographic subgroups.

Methods

We searched major electronic databases using medical subject headings and keywords without language restrictions (through April 2010). We included prospective cohort studies with data on incident hypertension related to serum uric acid levels. Data abstraction was conducted in duplicate. We analyzed age, sex, and race subgroups.

Results

A total of 18 prospective cohort studies representing data from 55,607 participants were included. Hyperuricemia was associated with an increased risk for incident hypertension (adjusted risk ratio [RR] 1.41, 95% confidence interval [95% CI] 1.23–1.58). For a 1 mg/dl increase in uric acid level, the pooled RR for incident hypertension after adjusting for potential confounding was 1.13 (95% CI 1.06–1.20). These effects were significantly larger in younger study populations (P = 0.02) and tended to be larger in women (P = 0.059). Two studies suggested that the effect may also be larger among African American individuals. Furthermore, later publication year and US‐based studies were significantly associated with a lower effect estimate (P values <0.02).

Conclusion

Hyperuricemia is associated with an increased risk for incident hypertension, independent of traditional hypertension risk factors. This risk appears more pronounced in younger individuals and women.     

Childhood‐onset disease as a predictor of mortality in an adult cohort of patients with systemic lupus erythematosus

Objective

To examine childhood‐onset disease as a predictor of mortality in a cohort of adult patients with systemic lupus erythematosus (SLE).

Methods

Data were derived from the University of California Lupus Outcomes Study, a longitudinal cohort of 957 adult subjects with SLE that includes 98 subjects with childhood‐onset SLE. Baseline and followup data were obtained via telephone interviews conducted in 2002–2007. The number of deaths during 5 years of followup was determined and standardized mortality ratios (SMRs) for the cohort, and across age groups, were calculated. Kaplan‐Meier life table analysis was used to compare mortality rates between childhood‐ (defined as SLE diagnosis at <18 years of age) and adult‐onset SLE. Multivariate Cox proportional hazard models were used to determine predictors of mortality.

Results

During the median followup period of 48 months, 72 deaths (7.5% of subjects) occurred, including 9 deaths (12.5%) in subjects with childhood‐onset SLE. The overall SMR was 2.5 (95% confidence interval [95% CI] 2.0–3.2). In Kaplan‐Meier survival analysis, after adjusting for age, childhood‐onset subjects were at increased risk for mortality throughout the followup period (P< 0.0001). In a multivariate model adjusting for age, disease duration, and other covariates, childhood‐onset SLE was independently associated with an increased mortality risk (hazard ratio [HR] 3.1, 95% CI 1.3–7.3), as was low socioeconomic status measured by education (HR 1.9, 95% CI 1.1–3.2), and end stage renal disease (HR 2.1, 95% CI 1.1–4.0).

Conclusion

Childhood‐onset SLE was a strong predictor of mortality in this cohort. Interventions are needed to prevent early mortality in this population.     

Intensive glucose control and macrovascular outcomes in type 2 diabetes

Aims/hypothesis

Improved glucose control in type 2 diabetes is known to reduce the risk of microvascular events. There is, however, continuing uncertainty about its impact on macrovascular disease. The aim of these analyses was to generate more precise estimates of the effects of more-intensive, compared with less-intensive, glucose control on the risk of major cardiovascular events amongst patients with type 2 diabetes.

Methods

A prospectively planned group-level meta-analysis in which characteristics of trials to be included, outcomes of interest, analyses and subgroup definitions were all pre-specified.

Results

A total of 27,049 participants and 2,370 major vascular events contributed to the meta-analyses. Allocation to more-intensive, compared with less-intensive, glucose control reduced the risk of major cardiovascular events by 9% (HR 0.91, 95% CI 0.84–0.99), primarily because of a 15% reduced risk of myocardial infarction (HR 0.85, 95% CI 0.76–0.94). Mortality was not decreased, with non-significant HRs of 1.04 for all-cause mortality (95% CI 0.90–1.20) and 1.10 for cardiovascular death (95% CI 0.84–1.42). Intensively treated participants had significantly more major hypoglycaemic events (HR 2.48, 95% CI 1.91–3.21). Exploratory subgroup analyses suggested the possibility of a differential effect for major cardiovascular events in participants with and without macrovascular disease (HR 1.00, 95% CI 0.89–1.13, vs HR 0.84, 95% CI 0.74–0.94, respectively; interaction p?=?0.04).

Conclusions/interpretation

Targeting more-intensive glucose lowering modestly reduced major macrovascular events and increased major hypoglycaemia over 4.4 years in persons with type 2 diabetes. The analyses suggest that glucose-lowering regimens should be tailored to the individual.