Eswar Krishnan

Long-term Cardiovascular Mortality Among Middle-aged Men With Gout

BACKGROUND There are limited data available on the association of gouty arthritis (gout) in middle age with long-term cardiovascular disease (CVD) mortality. METHODS We performed a 17-year follow-up study of 9105 men, aged 41 to 63 years and at above-average risk for coronary heart disease, who were randomized to the Multiple Risk Factor Intervention Trial and who did not die or have clinical or electrocardiographic evidence of coronary artery disease during the 6-year trial. Risk of CVD death and other causes subsequent to the sixth annual examination associated with gout was assessed by means of Cox proportional hazards regressions. RESULTS The unadjusted mortality rates from CVD among those with and without gout were 10.3 per 1000 person-years and 8.0 per 1000 person-years, respectively, representing an approximately 30% greater risk. After adjustment for traditional risk factors, use of diuretics and aspirin, and serum creatinine level, the hazard ratio (gout vs no gout) for coronary heart disease mortality was 1.35 (95% confidence interval [CI], 1.06-1.72). The hazard ratio for death from myocardial infarction was 1.35 (95% CI, 0.94-1.93); for death from CVD overall, 1.21 (95% CI, 0.99-1.49); and for death from any cause, 1.09 (95% CI, 1.00-1.19) (P = .04). The association between hyperuricemia and CVD was weak and did not persist when analysis was limited to men with hyperuricemia without a diagnosis of gout. CONCLUSION Among middle-aged men, a diagnosis of gout accompanied by an elevated uric acid level imparts significant independent CVD mortality risk. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00000487.

Hyperuricemia and Incidence of Hypertension Among Men Without Metabolic Syndrome

The aim of this project was to study the risk of developing hypertension over a 6-year follow-up in normotensive men with baseline hyperuricemia (serum uric acid >7.0 mg/dL) but without diabetes/glucose intolerance or metabolic syndrome. We analyzed the data on men without metabolic syndrome or hypertension at baseline from the Multiple Risk Factor Intervention Trial. These men (n=3073; age: 35 to 57 years) were followed for an average of 6 years by annual examinations. Follow-up blood pressure among those with baseline was consistently higher than among those with normal serum uric acid concentration. We used Cox regression models for adjustment for the effects of serum creatinine, body mass index, age, blood pressure, proteinuria, serum cholesterol and triglycerides, alcohol and tobacco use, risk factor interventions, and use of diuretics. In these models, normotensive men with baseline hyperuricemia had an 80% excess risk for incident hypertension (hazard ratio: 1.81; 95% CI: 1.59 to 2.07) compared with those who did not. Each unit increase in serum uric acid was associated with a 9% increase in the risk for incident hypertension (hazard ratio: 1.09; 95% CI: 1.02 to 1.17). We conclude that the hyperuricemia–hypertension risk relationship is present among normotensive middle-aged men without diabetes/glucose intolerance or metabolic syndrome.

Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity

The ability of the human immune system to respond to vaccination declines with age. We identified an age-associated defect in T cell receptor (TCR)-induced extracellular signal–regulated kinase (ERK) phosphorylation in naive CD4+ T cells, whereas other signals, such as ζ chain–associated protein kinase 70 (ZAP70) and phospholipase C-γ1 phosphorylation, were not impaired. The defective ERK signaling was caused by the dual specific phosphatase 6 (DUSP6), whose protein expression increased with age due to a decline in repression by miR-181a. Reconstitution of miR-181a lowered DUSP6 expression in naive CD4+ T cells in elderly individuals. DUSP6 repression using miR-181a or specific siRNA and DUSP6 inhibition by the allosteric inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one improved CD4+ T cell responses, as seen by increased expression of activation markers, improved proliferation and supported preferential T helper type 1 cell differentiation. DUSP6 is a potential intervention target for restoring T cell responses in the elderly, which may augment the effectiveness of vaccination.

Progress in Assessing Physical Function in Arthritis: PROMIS Short Forms and Computerized Adaptive Testing

Objective. Assessing self-reported physical function/disability with the Health Assessment Questionnaire Disability Index (HAQ) and other instruments has become central in arthritis research. Item response theory (IRT) and computerized adaptive testing (CAT) techniques can increase reliability and statistical power. IRT-based instruments can improve measurement precision substantially over a wider range of disease severity. These modern methods were applied and the magnitude of improvement was estimated. Methods. A 199-item physical function/disability item bank was developed by distilling 1865 items to 124, including Legacy Health Assessment Questionnaire (HAQ) and Physical Function-10 items, and improving precision through qualitative and quantitative evaluation in over 21,000 subjects, which included about 1500 patients with rheumatoid arthritis and osteoarthritis. Four new instruments, (A) Patient-Reported Outcomes Measurement Information (PROMIS) HAQ, which evolved from the original (Legacy) HAQ; (B) “best” PROMIS 10; (C) 20-item static (short) forms; and (D) simulated PROMIS CAT, which sequentially selected the most informative item, were compared with the HAQ. Results. Online and mailed administration modes yielded similar item and domain scores. The HAQ and PROMIS HAQ 20-item scales yielded greater information content versus other scales in patients with more severe disease. The “best” PROMIS 20-item scale outperformed the other 20-item static forms over a broad range of 4 standard deviations. The 10-item simulated PROMIS CAT outperformed all other forms. Conclusion. Improved items and instruments yielded better information. The PROMIS HAQ is currently available and considered validated. The new PROMIS short forms, after validation, are likely to represent further improvement. CAT-based physical function/disability assessment offers superior performance over static forms of equal length.

Epidemiology of gout in women: Fifty-two–year followup of a prospective cohort

OBJECTIVE Despite the recent doubling of the incidence of gout among women and its substantial prevalence particularly in the aging female population, the risk factors for gout among women remain unknown. We undertook this study to evaluate purported risk factors for incident gout among women and to compare them with those among men. METHODS Using prospective data from the Framingham Heart Study, we examined over a 52-year period (1950-2002) the relationship between purported risk factors and the incidence of gout in 2,476 women and 1,951 men. RESULTS We documented 304 incident cases of gout, 104 of them among women. The incidence rates of gout for women per 1,000 person-years according to serum uric acid levels of <5.0, 5.0-5.9, 6.0-6.9, 7.0-7.9, and > or = 8.0 mg/dl were 0.8, 2.5, 4.2, 13.1, and 27.3, respectively (P for trend < 0.0001). The magnitude of this association was lower than that among men (P for interaction = 0.0002). Multivariate relative risks conferred by increasing age (per 5 years), obesity (body mass index > or = 30 kg/m(2)), alcohol intake (> or = 7 ounces of pure alcohol/week), hypertension, and diuretic use were 1.24, 2.74, 3.10, 1.82, and 2.39, respectively (all P < 0.05), for women. CONCLUSION These prospective data with long-term followup provide evidence that higher levels of serum uric acid increase the risk of gout in a graded manner among women, but the rate of increase is lower than that among men. Increasing age, obesity, alcohol consumption, hypertension, and diuretic use were associated with the risk of incident gout among women.

Gout and the risk of type 2 diabetes among men with a high cardiovascular risk profile

OBJECTIVE Our objective was to evaluate the independent relation between a history of gout and the future risk of type 2 diabetes among men with a high cardiovascular risk profile. METHODS We prospectively examined over a 6-yr period the relation between gout and the risk of incident type 2 diabetes in 11 351 male participants from the Multiple Risk Factor Intervention Trial (MRFIT). Incident diabetes was defined based on the American Diabetes Association (ADA) criteria for epidemiological studies. Cox proportional hazards regression was used to adjust for potential confounders. RESULTS We documented 1215 new cases of type 2 diabetes. After adjusting for age, BMI, smoking, family history of type 2 diabetes, alcohol intake, dietary factors and presence of individual components of the metabolic syndrome, the multivariate relative risk (RR) for incident type 2 diabetes among men with gout at baseline, as compared with men without gout, was 1.34 (95% CI 1.09, 1.64). When we further adjusted for serum uric acid levels, the association remained significant (RR 1.26; 95% CI 1.02, 1.54). When we updated the status of gout annually during follow-up as a time-varying covariate, the association remained similar. The association also remained similar in our subgroup analyses by major covariates (P-values for interaction >0.16). CONCLUSIONS These findings from men with a high cardiovascular risk profile suggest that men with gout are at a higher future risk of type 2 diabetes independent of other known risk factors. These data expand on well-established, cross-sectional associations between hyperuricaemia, gout and the metabolic syndrome, and extend the link to the future risk of type 2 diabetes.

Declines in Mortality From Acute Myocardial Infarction in Successive Incidence and Birth Cohorts of Patients With Rheumatoid Arthritis

Background—Patients with rheumatoid arthritis are at high risk for acute myocardial infarction (AMI). The treatment of rheumatoid arthritis has become more intensive over the past 2 decades, resulting in tighter control of inflammation and lower levels of disability. The impact of this on atherosclerotic cardiovascular diseases is not known. Methods and Results—Death rates from AMI in a cohort of 3862 patients with rheumatoid arthritis followed up from 1980 to 1997 were studied. Time trends in AMI mortality among successive incidence and birth cohorts were examined by use of multivariable Poisson regression models and by comparing standardized mortality ratios. The mean age was 56 years in this predominantly female cohort (76%), and median disease duration was 6.5 years. During the period of observation, the use of methotrexate increased substantially, whereas that of prednisone was relatively stable. Over the 22 209 person-years of observation, there were 157 deaths as a result of AMI, with a death rate of 7.06 per 1000 person-years. Mortality rates were higher in older age groups and in men. After adjustment for age, sex, race, and disease duration, the risk of AMI declined in successive incidence years (relative risk, 0.94; 95% CI, 0.92 to 0.96). Patients with rheumatoid arthritis incident after 1990 did not have excess AMI mortality compared with general population. Declines in mortality trends were observed in successive birth cohorts as well. Conclusions—Mortality as a result of AMI among patients with rheumatoid arthritis has declined over time.

Smoking-gender interaction and risk for rheumatoid arthritis.

The present case–control study was conducted to investigate the relationship between smoking and rheumatoid arthritis, and to investigate formally the interaction between sex, smoking, and risk for developing rheumatoid arthritis. The study was performed in the Central District of Finland. Cases were patients with rheumatoid arthritis and the control group was a random sample of the general population. Logistic regression models were used to evaluate the effect of smoking on risk for rheumatoid arthritis, after adjusting for the effects of age, education, body mass index, and indices of general health and pain. Overall, 1095 patients with rheumatoid arthritis and 1530 control individuals were included. Patients were older, less well educated, more disabled, and had poorer levels of general health as compared with control individuals (all P < 0.01). Preliminary analyses revealed the presence of substantial statistical interaction between smoking and sex (P < 0.001). In separate multivariable analyses, past history of smoking was associated with increased risk for rheumatoid arthritis overall in men (odds ratio 2.0, 95% confidence interval 1.2–3.2) but not in women. Among men, this effect was seen only for rheumatoid factor-positive rheumatoid arthritis. There were significant interactions between smoking and age among women but not among men. We conclude that sex is a biologic effect modifier in the association between smoking and rheumatoid arthritis. The role of menopause in the etiology of rheumatoid arthritis merits further research.

Factors Associated With Patients Who Leave Acute-Care Hospitals Against Medical Advice

OBJECTIVES We examined hospital- and patient-related factors associated with discharge against medical advice (termed self-discharge) after emergency admission to acute-care hospitals. METHODS We analyzed data from the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project using logistic regression models to assess the relationship between self-discharge and a set of patient and hospital characteristics. RESULTS Of 3,039,050 discharges in the sample, 43 678 were against medical advice (1.44%). In multivariable modeling, predictors of self-discharge included having Medicaid insurance (adjusted odds ratio [AOR]=3.32; 95% confidence interval [CI]=3.22, 3.42), having Medicare insurance (AOR=1.64; 95% CI=1.59, 1.70), urban location (AOR=1.66; 95% CI=1.61, 1.72), medium (AOR=1.25; 95% CI=1.20, 1.29) or large (AOR=1.08, 95% CI=1.05, 1.12) hospital (defined by the number of beds), shorter hospital stay (OR=0.84; 95% CI=0.84, 0.85), and African American race (AOR=1.10; 95% CI=1.07, 1.14). Teaching hospitals had fewer self-discharges (AOR=0.90; 95% CI=0.88, 0.92). Other predictors of discharge against medical advice included age, gender, and income. CONCLUSIONS Approximately 1 in 70 hospital discharges in the United States are against medical advice. Both hospital and patient characteristics were associated with these decisions.

Reduction in long-term functional disability in rheumatoid arthritis from 1977 to 1998:a longitudinal study of 3035 patients

PURPOSE If newer, more aggressive treatment strategies in rheumatoid arthritis are more effective, long-term outcomes in rheumatoid arthritis should be improving substantially. We therefore assessed trends in disability over time in a large cohort of patients with rheumatoid arthritis. METHODS We examined functional disability data from 3035 patients with rheumatoid arthritis whose disease onset was from 1977 to 1998. Disability data were collected semiannually with the Health Assessment Questionnaire disability index. We then estimated average disability for each patient. We also computed mean disability for each calendar year by averaging the values from all patients in that year. We examined the relation of successive annual cohorts and subsequent disability, adjusting for age, sex, race, education, clinical center, disease duration, follow-up, and attrition. We used two regression approaches: ordinary and generalized least squares. RESULTS Average disability declined by about 2% to 3% per calendar year of disease onset (2.7% to 2.8% per year [P <0.001] in univariable models and 2.0% to 2.1% per year [P <0.001] in multivariable models). This trend was consistent by age, sex, race, disease duration, clinical center, and baseline disability. CONCLUSION After accounting for potential confounders, average disability levels in rheumatoid arthritis have declined by approximately 40% in the 20+ years since 1977. This decline is consistent with a beneficial effect of the associated changes in treatment strategies.