Antidiabetogenic effects of hydroxychloroquine on insulin sensitivity and beta cell function: a randomised trial.

AIMS/HYPOTHESIS: Hydroxychloroquine (HCQ), an antimalarial drug with anti-inflammatory properties, is employed in rheumatic diseases. In observational studies, patients with rheumatic diseases treated with HCQ have a lower risk of developing diabetes. However, the physiological mechanisms remain unexplained. We hypothesised that HCQ may have favourable effects on insulin sensitivity and/or beta cell function. METHODS: This was a randomised, double-blind, parallel-arm (placebo vs HCQ 400 mg/day) trial at the University of Pittsburgh. Randomisation was conducted by a computer system with concealment by sealed envelopes. Treatment duration was 13 ± 1 weeks. Randomised participants (HCQ n = 17; placebo n = 15) were non-diabetic volunteers, age >18, overweight or obese, with one or more markers of insulin resistance. All participants were included in intention-to-treat analysis. Outcomes were changes in insulin sensitivity and beta cell function measured by intravenous glucose tolerance tests and minimal model analysis. RESULTS: There was a positive change in insulin sensitivity with HCQ but not placebo (mean ± SEM: +20.0% ± 7.1% vs -18.4% ± 7.9%, respectively; p < 0.01; difference: 38.3% ± 10.6%; 95% CI: 17%, 60%). Improvement in beta cell function was also observed with HCQ but not placebo (+45.4% ± 12.3% vs -19.7% ± 13.6%; p < 0.01; difference: 65% ± 19%; 95% CI: 27%, 103%). There were modest treatment effects on fasting plasma glucose and HbA(1c) (p < 0.05) but circulating markers of inflammation (IL-6, IL-1, TNF-α, soluble intercellular adhesion molecule) were not affected in either group. In contrast, adiponectin levels increased after HCQ treatment but not after placebo (+18.7% vs +0.7%, respectively; p < 0.001). Both low- and high-molecular-weight adiponectin forms accounted for the increase. There were no serious or unexpected adverse effects. CONCLUSIONS/INTERPRETATION: HCQ improves both beta cell function and insulin sensitivity in non-diabetic individuals. These metabolic effects may explain why HCQ treatment is associated with a lower risk of type 2 diabetes. An additional novel observation is that HCQ improves adiponectin levels, possibly being a mediator of the favourable effects on glucose metabolism. Our findings suggest that HCQ is a drug with considerable metabolic effects that warrant further exploration in disorders of glucose metabolism. TRIAL REGISTRATION: Clinicaltrials.gov NCT01326533 FUNDING: This study was funded by National Institutes of Health no. 5R21DK082878, UL1-RR024153 and UL-1TR000005.

Glucocorticoid use is associated with increase in HDL and no change in other lipids in rheumatoid arthritis patients.

The aim of this article was to examine the association of glucocorticoid use and dose and changes in the lipid profile in rheumatoid arthritis (RA) patients. RA patients between January 1, 2001, and November 30, 2011, who received oral or intravenous glucocorticoids and who had lipid levels within 1 year before and 1 year after ongoing (at least 3 months) glucocorticoids use along with RA patients who did not take glucocorticoids (controls) were included. Glucocorticoid exposure was calculated as a weighted daily dose in prednisone equivalents and analyzed using as cutoff dose prednisone equivalent of 7.5 mg/day. Outcomes were changes in high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), triglycerides, and TC/HDL ratio and were calculated in linear regression models adjusting for relevant confounders. In total, 202 subjects on glucocorticoids and 436 controls were included. The glucocorticoid group of ≥7.5 mg/day had the greatest increase in HDL of 6.0 mg/dL (p = 0.003 compared to controls) with lower increases of 3.1 and 2.4 mg/dL in the glucocorticoid group of <7.5 mg/day and controls, respectively. There were no significant differences in other parameters of the lipid profile between the two glucocorticoid groups and controls. In this RA cohort, glucocorticoid dose equivalent of prednisone ≥7.5 mg/day was associated with increased HDL and no change in LDL or TC/HDL ratio compared to no glucocorticoid use These results suggest that this glucocorticoid dose is not associated with an atherogenic lipid profile in RA, a finding that is important in this patient population at high risk for cardiovascular disease.

Propensity-adjusted association of methotrexate with overall survival in rheumatoid arthritis.

OBJECTIVE: While medications used to treat rheumatoid arthritis (RA) may affect survival in RA, few studies take into account the propensity for medication use, which may reflect selection bias in treatment allocation in survival models. We undertook this study to examine the relationship between methotrexate (MTX) use and mortality in RA, after controlling for individual propensity scores for MTX use. METHODS: We studied 5,626 RA patients prospectively for 25 years to determine the risk of death associated with MTX use, modeled in time-varying Cox regression models. We used the random forest method to generate individual propensity scores for MTX use at study entry and during followup in a time-varying manner; these scores were included in the multivariate model. We also investigated whether selective discontinuation of MTX immediately prior to death altered the risk of mortality, and we examined the association of duration of MTX use with survival. RESULTS: During followup, 666 patients (12%) died. MTX use was associated with reduced risk of death (adjusted hazard ratio 0.30 [95% confidence interval 0.09-1.03]). Selective MTX cessation immediately before death did not account for the protective association of MTX use with mortality. Only MTX use for >1 year was associated with lower risks of mortality, but associations were not stronger with longer durations of use. CONCLUSION: MTX use was associated with a 70% reduction in mortality in RA.

Patterns of preventive health services in rheumatoid arthritis patients compared to a primary care patient population.

To determine the proportion of rheumatoid arthritis (RA) patients receiving preventive health care according to US Preventive Services Task Force recommendations compared with a community-based population sample, with emphasis on dyslipidemia testing, given the increased risk of cardiovascular disease (CVD) in RA patients. Patients with RA (ICD-9 code 714.0 at ≥2 office visits with a rheumatologist) and a primary care physician (PCP) at the Geisinger Health System (GHS) were identified through electronic health records. The records were searched back from 3/31/08 for the length of time required to satisfy each outcome measure. Percentages were compared with population testing rates using the Pearson Chi-square test. Eight hundred and thirty-one RA patients were compared to 169,476 subjects with a PCP at GHS, stratified by gender and age. Patients with RA were more likely to have had dyslipidemia and osteoporosis testing compared with the general population (86 vs. 75 and 75 vs. 55%, respectively, P < 0.0001 for both). The proportion of RA patients receiving breast and cervical cancer testing was similar to the general population. The majority (79%) of lipid testing was ordered by PCPs. Those RA patients with recommended lipid testing had more traditional CVD factors (hypertension, diabetes, coronary artery disease). RA patients are screened more than the general population for two RA-related co-morbidities, i.e. dyslipidemia and osteoporosis. The RA patients with traditional cardiovascular risk factors are more likely to be tested for dyslipidemia. Further work is warranted to improve testing for modifiable CVD risk factors in this group with multiple co-morbidities.

Hydroxychloroquine use and decreased risk of diabetes in rheumatoid arthritis patients.

BACKGROUND/OBJECTIVES: Several studies have associated hydroxychloroquine use with decreased risk of diabetes mellitus (diabetes) or improved glycemic control in rheumatoid arthritis patients, but the studies were small or used data from self-report. The present study sought to replicate this protective relationship in a health system using electronic health records with laboratory data and physician diagnoses. METHODS: This study is a retrospective cohort of 1127 adults with newly diagnosed rheumatoid arthritis and no diabetes within the Geisinger Health System between January 1, 2003, and March 31, 2008. Patients were classified as ever users (n = 333) or never users (n = 794) of hydroxychloroquine. Incident diabetes cases were defined using 2010 American Diabetes Association criteria. RESULTS: The median follow-up times for the ever and never hydroxychloroquine users were 26.0 and 23.0 months, respectively (P = 0.28). The median duration of hydroxychloroquine exposure was 14.0 months. Of the 48 cases developing diabetes during observation, 3 were exposed to hydroxychloroquine at time of development and 45 were nonexposed, yielding incidence rates of 6.2 and 22.0 per 1000 per year (P = 0.03), respectively. In time-varying Cox proportional hazards regression models adjusting for sex, age, body mass index, positive rheumatoid factor and anti-cyclic citrullinated peptide antibodies, erythrocyte sedimentation rate, and nonsteroidal anti-inflammatory drug, glucocorticoid, methotrexate, and tumor necrosis factor α inhibitor use, the hazard ratio for incident diabetes among hydroxychloroquine users was 0.29 (95% confidence interval, 0.09-0.95; P = 0.04) compared with nonusers. CONCLUSIONS: Our findings support the potential benefit of hydroxychloroquine in attenuating the risk of diabetes in rheumatoid arthritis patients. Further work is needed to determine its potential preventive role in other groups at high risk for diabetes.

Exploring the Lipid Paradox Theory in Rheumatoid Arthritis: Associations of Low Circulating Low-Density Lipoprotein Concentration With Subclinical Coronary Atherosclerosis.

OBJECTIVE: Rheumatoid arthritis (RA) patients with the lowest circulating low-density lipoprotein (LDL) concentrations are at heightened risk of cardiovascular events. However, the atherosclerosis burden within this subgroup is unknown. METHODS: RA patients pooled from 4 cohort studies of cardiovascular disease (CVD; n = 546) were compared with non-RA controls from the Multi-Ethnic Study of Atherosclerosis (n = 5,279). Those taking lipid-lowering medications were excluded. Differences in cardiac computed tomography-derived Agatston coronary artery calcium (CAC) scores between the RA and control groups were compared across strata of LDL concentration. RESULTS: Among those with low LDL concentrations (<70 mg/dl), mean adjusted CAC scores were >4-fold higher for RA patients than for controls (18.6 versus 4.6 Agatston units, respectively; P < 0.001), a difference significantly greater than that in any other LDL concentration stratum except LDL concentration ≥160 mg/dl. Similarly, 32% of the RA patients with low LDL concentration had a CAC score of ≥100 Agatston units compared with only 7% of controls in the same LDL concentration stratum (odds ratio 5.97; P < 0.001), a difference significantly greater than that in all of the other LDL concentration strata. Low LDL concentration was most strongly associated with higher CAC score among RA patients who were white, had ever smoked, or were not obese. Other than a higher frequency of current smokers, RA patients with low LDL concentrations did not have more CVD risk factors or higher measures of RA disease activity or severity than RA patients with higher LDL concentrations. CONCLUSION: RA patients with low LDL concentration may represent a group for whom heightened screening and prevention of atherosclerotic CVD is appropriate.

C-reactive protein and coronary artery calcium in asymptomatic women with systemic lupus erythematosus or rheumatoid arthritis.

Patients with systemic lupus erythematosus (SLE) and those with rheumatoid arthritis (RA) have increased risk for atherosclerotic cardiovascular disease. The aims of this study were to compare the presence of coronary artery calcium (CAC) in age- and race-matched women with SLE, those with RA, and healthy controls without diabetes mellitus or history of myocardial infarction, angina pectoris, or stroke and to investigate its relation with traditional risk factors, inflammation, and endothelial activation. Study subjects completed cardiovascular risk factor assessment and electron-beam computed tomography that measured CAC. The 2 patient groups had similar prevalence and extent of CAC as well as significantly increased odds of having any CAC (odds ratio 1.87, 95% confidence interval 1.09 to 3.21) and more extensive CAC (odds ratio 4.04, 95% confidence interval 1.42 to 11.56 for CAC score >100) compared with healthy controls. After controlling for differences in cardiovascular risk factors, including insulin resistance and hypertension, the results remained statistically significant. After adjustment for differences in levels of C-reactive protein and/or soluble intercellular adhesion molecule-1, however, women with chronic inflammatory diseases no longer had significantly increased odds of having any CAC or more extensive CAC compared with controls. In conclusion, asymptomatic and nondiabetic women with chronic inflammatory diseases had significantly increased odds of having CAC and more extensive CAC compared with age- and race-matched healthy controls. The increased odds for CAC may in part result from higher levels of inflammation and endothelial activation in these patients.

Rheumatoid arthritis and cardiovascular disease.

An increased risk of cardiovascular events and subclinical atherosclerosis in patients with rheumatoid arthritis (RA) has been attributed to the inflammatory milieu associated with this chronic autoimmune disease and possibly to the independent effects of RA medications on risk. This review provides an update on the most recent epidemiologic studies documenting this relationship and noteworthy publications examining RA-related factors that could influence the role of traditional cardiovascular risk factors and expression of atherosclerotic disease in patients with RA.

Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis.

CONTEXT: Hydroxychloroquine, a commonly used antirheumatic medication, has hypoglycemic effects and may reduce the risk of diabetes mellitus. OBJECTIVE: To determine the association between hydroxychloroquine use and the incidence of self-reported diabetes in a cohort of patients with rheumatoid arthritis. DESIGN, SETTING, AND PATIENTS: A prospective, multicenter observational study of 4905 adults with rheumatoid arthritis (1808 had taken hydroxychloroquine and 3097 had never taken hydroxychloroquine) and no diagnosis or treatment for diabetes in outpatient university-based and community-based rheumatology practices with 21.5 years of follow-up (January 1983 through July 2004). MAIN OUTCOME MEASURES: Diabetes by self-report of diagnosis or hypoglycemic medication use. RESULTS: During the observation period, incident diabetes was reported by 54 patients who had taken hydroxychloroquine and by 171 patients who had never taken hydroxychloroquine, with incidence rates of 5.2 per 1000 patient-years of observation compared with 8.9 per 1000 patient-years of observation, respectively (P < .001). In time-varying multivariable analysis with adjustments for possible confounding factors, the hazard ratio for incident diabetes among patients who had taken hydroxychloroquine was 0.62 (95% confidence interval, 0.42-0.92) compared with those who had not taken hydroxychloroquine. In Poisson regression, the risk of incident diabetes was significantly reduced with increased duration of hydroxychloroquine use (P < .001 for trend); among those taking hydroxychloroquine for more than 4 years (n = 384), the adjusted relative risk of developing diabetes was 0.23 (95% confidence interval, 0.11-0.50; P < .001), compared with those who had not taken hydroxychloroquine. CONCLUSION: Among patients with rheumatoid arthritis, use of hydroxychloroquine is associated with a reduced risk of diabetes.

Hydroxychloroquine Use Is Associated With Decreased Incident Cardiovascular Events in Rheumatoid Arthritis Patients.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in rheumatoid arthritis (RA) patients. This study is the first to report the association of hydroxychloroquine (an antirheumatic medication that has been associated with decreased risk of diabetes, a less atherogenic lipid profile, and antithrombotic properties) with CVD in RA. METHODS AND RESULTS: A retrospective incident RA cohort from January 1, 2001, to October 31, 2013, excluding patients with CVD prior to RA diagnosis, was constructed. Patients were categorized as hydroxychloroquine users versus nonusers and were allowed to contribute time to either group according to hydroxychloroquine exposure. The primary outcome was adjudicated incident CVD defined as a composite of coronary artery disease, stroke, transient ischemic attack, sudden cardiac death, and peripheral artery disease with arterial revascularization procedure. The secondary outcome was a composite of incident coronary artery disease, stroke, and transient ischemic attack. Cox time-varying regression models were used to estimate the association between hydroxychloroquine exposure and development of CVD, after adjusting for propensity score and relevant confounders, including demographics, CVD-related comorbidities, RA severity, and activity indicators and medications. We included 1266 RA patients, 547 hydroxychloroquine users, and 719 nonusers. During the observation period, 102 CVD events occurred, 3 in hydroxychloroquine users and 99 in nonusers. The fully adjusted Cox model showed a hazard ratio of 0.28 (95% CI 0.12-0.63, P=0.002) for incident CVD and 0.30 (95% CI 0.13-0.68, P=0.004) for incident composite coronary artery disease, stroke, and transient ischemic attack for hydroxychloroquine users versus nonusers, respectively. CONCLUSION: In this hypothesis-generating study, hydroxychloroquine use was associated with a 72% decrease in the risk of incident CVD in RA patients. If these preliminary results are confirmed in larger studies, our findings may be used as a rationale for a randomized study of hydroxychloroquine use for primary prevention of CVD in RA or nonrheumatic high-risk patients.

Tumor necrosis factor α inhibitor use and decreased risk for incident coronary events in rheumatoid arthritis.

OBJECTIVE: To determine the association of tumor necrosis factor α (TNFα) inhibitors with risk for cardiovascular disease (CVD) in rheumatoid arthritis (RA) patients. METHODS: A retrospective cohort of 2,101 incident RA patients was established. Medication exposure was categorized into the following groups: TNFα inhibitors alone or in combination with methotrexate (MTX; aTNF group); MTX alone or in combination with other nonbiologic disease-modifying antirheumatic drugs (DMARDs; MTX group); and no MTX, nonbiologic DMARDs (reference group). Primary outcome was adjudicated incident coronary artery disease (CAD), defined as myocardial infarction, unstable angina, or coronary revascularization procedure. Secondary outcome was adjudicated incident CVD, defined as a composite of CAD, stroke, transient ischemic attack, abdominal aortic aneurysm, peripheral arterial disease, or arterial revascularization procedure. Cox regression models were used to calculate the hazard ratio for CAD and CVD for the aTNF and MTX groups compared to the reference group. RESULTS: There were 46 incident CAD and 82 incident CVD events. Adjusting for covariates associated with CAD and CVD, the hazard ratio for incident CAD was 0.45 (95% confidence interval [95% CI] 0.21-0.96) for the aTNF group and 0.54 (95% CI 0.27-1.09) for the MTX group compared to the reference group. Use of TNFα inhibitors for >16.1 months was associated with a relative risk for CAD of 0.18 (95% CI 0.06-0.50) and for CVD of 0.31 (95% CI 0.15-0.65) compared to the reference group. A similar, although not significant, trend was seen with the MTX group. CONCLUSION: Use of TNFα inhibitors is associated with a decreased risk for CAD in RA; the risk decreases further with long-term use. This should be considered when weighing the risks versus benefits of these medications.

Diabetes mellitus risk in rheumatoid arthritis: reduced incidence with anti-tumor necrosis factor α therapy.

OBJECTIVE: To examine the association of tumor necrosis factor α (TNFα) inhibitor use and the risk of developing diabetes mellitus in a rheumatoid arthritis (RA) inception cohort. METHODS: Adults diagnosed with RA between January 1, 2001, and December 31, 2009, were identified (n = 1,881). Prevalent cases of diabetes mellitus (n = 294) were excluded. Information on sociodemographic data, medical history, body mass index (BMI), laboratory measures, and medications was collected from the electronic health record. Incident diabetes mellitus was defined using the 2010 American Diabetes Association criteria or physician-established diagnosis. Time-varying Cox proportional hazards regression models were used to adjust for age, sex, race, BMI, rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP), erythrocyte sedimentation rate (ESR), and use of nonsteroidal antiinflammatory drugs (NSAIDs), glucocorticoids, hydroxychloroquine, and methotrexate. RESULTS: A total of 1,587 incident RA patients without diabetes mellitus were included. The anti-TNFα users (n = 522) had a lower median age but greater baseline BMI; maximum ESR, RF, and anti-CCP positivity; and NSAID, glucocorticoid, or methotrexate use. The median followup time for the ever and never TNFα inhibitor users was 44.9 months (interquartile range [IQR] 23.7-73.0 months) and 37.1 months (IQR 16.3-65.1 months), respectively (P < 0.001). Of the 91 patients developing diabetes mellitus, 16 were ever and 75 were never TNFα inhibitor users, yielding incidence rates of 8.6 and 17.2 per 1,000 person-years (P = 0.048), respectively. Adjusting for covariates, the hazard ratio for incident diabetes mellitus in TNFα inhibitor users was 0.49 (95% confidence interval 0.24-0.99, P = 0.049) compared to the never users. CONCLUSION: In this inception RA cohort, anti-TNFα use was associated with a 51% reduction in risk of developing diabetes mellitus.

Sleep quality and functional disability in patients with rheumatoid arthritis.

STUDY OBJECTIVES: Disturbed sleep is a common complaint in patients with rheumatoid arthritis (RA). The majority of the research investigating relationships between sleep and patient-reported outcomes in RA has focused on pain and depression. Poor sleep may also affect disability, though this association has not been explored in RA. The present study represents a cross-sectional examination of the relationship between sleep quality and functional disability in 162 patients with RA. Depression, pain severity, and fatigue were examined as separate mediators of the relationship between sleep quality and disability. METHODS: The sample had an average age of 58.47 years, and 76% were female. Participants completed the following questionnaires as part of a medication adherence intervention study: Pittsburgh Sleep Quality Index, Beck Depression Inventory-II, Medical Outcomes Study Short Form-36, and the Health Assessment Questionnaire. RESULTS: Poor sleep quality was significantly correlated with higher levels of depressive symptoms, greater pain severity, increased fatigue, and greater functional disability. Hierarchical regression analyses showed that sleep quality was not associated with functional disability when depression, pain severity, and fatigue were entered into the model. Separate mediation analyses of depression, pain severity, and fatigue revealed that pain severity and fatigue were mediators of the relationship between sleep quality and disability. CONCLUSIONS: Sleep quality has an indirect effect on functional disability through its relationship with pain severity and fatigue. Future research should investigate whether improvements in sleep can reduce disability in patients with RA.

Physical activity measured by the SenseWear Armband in women with rheumatoid arthritis.

BACKGROUND: Individuals with rheumatoid arthritis (RA) often are sedentary and have an increased risk of developing comorbid conditions. Women with RA are more likely to experience challenges in maintaining an active lifestyle over their life span than men with RA or people who are healthy. As the benefits of physical activity (PA) are well known, measuring PA accurately in this population is important. OBJECTIVES: The purposes of this study were: (1) to characterize PA as measured with the SenseWear Armband (SWA) in women with RA and (2) to determine the measurement time frame to obtain consistent estimates of PA and daily energy expenditure (EE) in women with RA. DESIGN: This was a cross-sectional study. METHODS: Participants wore the SWA for 7 days. Measurements of daily total energy expenditure (TEE), physical activity energy expenditure (PAEE) during activities at or above 1 metabolic equivalent (MET) level (PAEE≥1MET), PAEE during activities at or above 2 METs (PAEE≥2METs), PAEE during activities at or above 3 METs (PAEE≥3METs), and number of steps were obtained. RESULTS: Fifty-three women participated. Complete data were obtained for 47 participants (89%). Daily usage of the SWA was 98% of the time (23:31 hours/24 hours). Means (SD) were 2,099 (340) kcal/d for TEE, 1,050 (331) kcal/d for PAEE≥1MET, 642 (309) kcal/d for PAEE≥2METs, 239 (178) kcal/d for PAEE≥3METs, and 7,260 (2,710) for number of steps. Results of intraclass correlation coefficient analyses and multiple linear regressions indicated that 2 days were needed to reliably estimate TEE; 3 days for PAEE≥1MET, PAEE≥2METs, and number of steps; and 4 days for PAEE≥3METs. LIMITATIONS: The sample was composed of well-educated women with RA who had mild to moderate difficulty performing daily activities. CONCLUSION: The SWA may be useful to quantify PA in women with RA and to monitor effectiveness of interventions aiming to increase PA levels. Minimizing the number of days necessary for data collection will reduce the individual's burden and may improve adherence in studies of PA behaviors.

Hydroxychloroquine use associated with improvement in lipid profiles in rheumatoid arthritis patients.

OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of death in patients with rheumatoid arthritis (RA). Disease-modifying therapies that improve risk factors for CVD, such as dyslipidemia, are desired. This study used an electronic health record to determine if hydroxychloroquine (HCQ) use was associated with an improvement in lipid levels in an inception RA cohort. METHODS: All adult individuals with the initial diagnosis of RA between January 1, 2001, and March 31, 2008, were identified (n=1,539). Only patients with at least one lipid level post-RA diagnosis were included (n=706). Information on demographics, medical history, body mass index (BMI), laboratory measures, and medications were collected at office visits. Potential risk and protective factors for dyslipidemia were controlled for in linear mixed-effects regression models for low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol, triglycerides, LDL/HDL, and total cholesterol/HDL. RESULTS: Patients were 69% women and 98% white, with a median age of 65 years and a median BMI of 29.8 kg/m2. In the adjusted regression models, HCQ use was associated with the following average differences in lipids: LDL decrease of 7.55 mg/dl (P<0.001), HDL increase of 1.02 mg/dl (P=0.20), total cholesterol decrease of 7.70 mg/dl (P=0.002), triglycerides decrease of 10.91 mg/dl (P=0.06), LDL/HDL decrease of 0.136 (P=0.008), and total cholesterol/HDL decrease of 0.191 (P=0.006), which were stable over time. CONCLUSION: Use of HCQ in this RA cohort was independently associated with a significant decrease in LDL, total cholesterol, LDL/HDL, and total cholesterol/HDL. Considering these results, its safety profile, and low cost, HCQ remains a valuable initial or adjunct therapy in this patient population at high risk for CVD.

Association of physical function and physical activity in women with rheumatoid arthritis.

OBJECTIVE: To explore the associations between measures of physical activity (PA) and measures of physical function (PF) in women with rheumatoid arthritis (RA). We hypothesized that the strength of the associations between PA and PF would be moderate, and that after controlling for social and biomedical characteristics, the associations would decrease. METHODS: Women with RA (n = 47, mean +/- SD age 56.5 +/- 7.0 years) participated in the cross-sectional analysis of this study. Social and biomedical characteristics explored included age, ethnicity, disease duration, marital and educational status, height, weight, comorbidity, and disease activity. PF was measured by the self-reported Health Assessment Questionnaire (HAQ) and by a battery of performance-based measures that included self-selected gait speed, the 5 chair rise test, and the single leg stance test. PA was measured by a portable activity monitor worn for 10 days, and was characterized in 2 ways: daily average number of steps and daily energy expenditure during moderate levels of PA. RESULTS: Correlations between measures of PA and PF were small to moderate (zero-order correlations = 0.189-0.479). After controlling for social and biomedical characteristics, the correlations became smaller (semi-partial correlations = 0.095-0.277) and only HAQ score remained significantly associated with PA. CONCLUSION: Associations between measures of PA and measures of PF were explained, in part, by social and biomedical characteristics in women with RA. The results indicate that measures of PF and PA may represent different constructs and support the need to measure PA in rehabilitation research in RA.

Hydroxychloroquine and glycemia in women with rheumatoid arthritis and systemic lupus erythematosus.

OBJECTIVE: To determine the relationship between current hydroxychloroquine (HCQ) use and 2 indicators of glycemic control, fasting glucose and insulin sensitivity, in nondiabetic women with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). METHODS: Nondiabetic women with SLE (n = 149) or RA (n = 177) recruited between 2000 and 2005 for a cross-sectional evaluation of cardiovascular risk factors were characterized by HCQ usage status. Unadjusted and multivariately adjusted mean fasting glucose, median insulin, and insulin resistance [assessed by the homeostasis model assessment (HOMA-IR) calculation] were compared among HCQ users and nonusers for disease-specific groups. RESULTS: More women with SLE were taking HCQ than those with RA (48% vs 18%; p < 0.0001; mean dose ~ 400 mg vs ~ 200 mg). For women with SLE or RA, after adjustment for age, waist circumference, disease duration, prednisone dosage, C-reactive protein, menopausal status, nonsteroidal antiinflammatory drugs, and disease-specific indicators, serum glucose was lower in HCQ users than in nonusers (SLE: 85.9 vs 89.3 mg/dl, p = 0.04; RA: 82.5 vs 86.6 mg/dl, p = 0.05). In women with SLE, HCQ use also was associated with lower (log)HOMA-IR (0.97 vs 1.12, p = 0.09); in those with RA, no differences in (log)HOMA-IR were seen. HCQ usage was not associated with fasting insulin levels in either patient group. CONCLUSION: HCQ use was associated with lower fasting glucose in women with SLE or RA and also lower (log)HOMA-IR in the SLE group. The use of HCQ may be beneficial for reducing cardiovascular risk by improving glycemic control in these patients.

Association between C-reactive protein and depressive symptoms in women with rheumatoid arthritis.

Converging lines of evidence support an association between systemic inflammation and depressive symptoms. Neuroimmune pathways may account for the high prevalence of depression in individuals with inflammatory conditions such as rheumatoid arthritis (RA). However, this relationship is complicated by factors linked to both inflammatory disease activity and mood, such as pain and physical disability. The goal of this cross-sectional study was to examine the relationship between C-reactive protein (CRP) and depressive symptoms among 173 women with RA. Somatic symptoms of depression and circulating CRP were significantly associated in regression analyses adjusted for body mass index (beta=.19, p<.05), but this relationship was attenuated when pain and disability were included as covariates (beta=.09, p=.24). CRP was not significantly associated with negative mood symptoms of depression. Findings suggest that depression in the context of RA may result from the overlap of somatic depressive and RA symptoms rather than neuroimmune pathways.

Do carotid artery diameters manifest early evidence of atherosclerosis in women with rheumatoid arthritis?

OBJECTIVE: Given the high incidence of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA), we examined the associations between RA diagnosis and characteristics and evidence of carotid atherosclerosis. We take a unique approach by evaluating lumen and interadventitial diameters in addition to intima-media thickness and plaque. METHODS: Ninety-three women with RA were matched with 93 healthy women by age, race, and menopause status. In cross-sectional analyses, we compared common carotid artery measures between groups and examined their relationships with measures of RA severity and activity. RESULTS: Mean age was 53.3 years, and median RA duration was 14 years. Lumen diameter in patients was significantly greater than in healthy women (5.50 vs. 5.19 mm, p < 0.001), as was interadventitial diameter (6.92 vs. 6.61 mm, p < 0.001). Having RA also was independently associated with greater lumen (beta = 0.256, p < 0.01) and interadventitial (beta = 0.261, p < 0.01) diameters, after controlling for cardiovascular risk factors and intima-media thickness. Carotid intima-media thickness (0.70 vs. 0.71 mm) was similar, and the prevalence of carotid plaque in patients (21%) was higher but not statistically different from healthy women (15%). In patients with RA, we found positive associations between methotrexate dose and interadventitial diameter, between hypothyroidism and intima-media thickness, and between hypothyroidism and soluble endothelial adhesion molecule and plaque, independent of cardiovascular risk factors. CONCLUSIONS: Women with RA have increased carotid artery diameters compared with healthy women. This may reflect premature vascular aging and may be an early indicator of increased cardiovascular risk.