Longitudinal relationships between rheumatoid factor and cytokine expression by immunostimulated peripheral blood lymphocytes from patients with rheumatoid arthritis: New insights into B-cell activation.

To identify associations between immunostimulated cytokine production and disease characteristics, peripheral blood lymphocytes were collected from 155 adult patients with rheumatoid arthritis (RA) before and after a 5-year interval. The lymphocytes were activated in vitro with T-cell stimulants, cytosine-phosphate-guanine (CpG) oligonucleotide, and medium alone (negative control). Expression of 17 cytokines was evaluated with immunoassays, and factor analysis was used to reduce data complexity and identify cytokine combinations indicative of cell types preferentially activated by each immunostimulant. The findings showed that the highest numbers of correlations were between cytokine levels and rheumatoid factor (RF) positivity and between cytokine levels and disease duration. Scores for cytokines driven by CpG and medium alone were negatively associated with RF positivity and disease duration at baseline but positively associated with both at 5 years. Our findings suggest that RF expression sustained over time increases activation of B cells and monocytes without requirements for T-cell functions.

A global perspective on the challenges and opportunities in learning about rheumatic and musculoskeletal diseases in undergraduate medical education : White paper by the World Forum on Rheumatic and Musculoskeletal Diseases (WFRMD).

Rheumatic and musculoskeletal diseases (RMDs) encompass a spectrum of degenerative, inflammatory conditions predominantly affecting the joints. They are a leading cause of disability worldwide and an enormous socioeconomic burden. However, worldwide deficiencies in adult and paediatric RMD knowledge among medical school graduates and primary care physicians (PCPs) persist. In October 2017, the World Forum on Rheumatic and Musculoskeletal Diseases (WFRMD), an international think tank of RMD and related experts, met to discuss key challenges and opportunities in undergraduate RMD education. Topics included needs analysis, curriculum content, interprofessional education, teaching and learning methods, implementation, assessment and course evaluation and professional formation/career development, which formed a framework for this white paper. We highlight a need for all medical graduates to attain a basic level of RMD knowledge and competency to enable them to confidently diagnose, treat/manage or refer patients. The importance of attracting more medical students to a career in rheumatology, and the indisputable value of integrated, multidisciplinary and multiprofessional care are also discussed. We conclude that RMD teaching for the future will need to address what is being taught, but also where, why and to whom, to ensure that healthcare providers deliver the best patient care possible in their local setting.

Increased hospitalization rates following heart failure diagnosis in rheumatoid arthritis as compared to the general population.

OBJECTIVE: To compare the frequency of and trends in hospitalizations after heart failure (HF) diagnosis in patients with and without rheumatoid arthritis (RA) during 1987-2015. METHODS: The study included a retrospectively identified population-based cohort of patients with incident HF and prior RA (age≥18 years, 1987 ACR criteria) and a cohort of incident HF patients without RA matched 3:1 on age, sex, and year of HF diagnosis. Hospitalizations at the time of HF diagnosis were excluded. All subjects were followed until death, migration, or 12/31/2015. RESULTS: The study included 212 patients with RA (mean age at HF diagnosis 78.3 years; 68% female) and 636 non-RA patients (mean age at HF diagnosis 78.6 years; 68% female). The hospitalization rate after HF diagnosis was higher in RA vs non-RA (rate ratio [RR] 1.17; 95%CI 1.08-1.26). Hospitalization rates in both groups have been declining since 2005 and the difference between patients with and without RA may be decreasing after 2010. The magnitude of the increase was similar in both sexes and across all ages. Patients with RA were more likely to be hospitalized for non-cardiovascular causes (RR 1.26; 95%CI 1.14-1.39), but not for HF or other cardiovascular causes compared to non-RA patients. CONCLUSIONS: The hospitalization rate following HF diagnosis was higher in RA versus non-RA patients regardless of sex and age. Increased hospitalization risk in patients with RA was driven by increased rates of non-cardiovascular hospitalization.

Secular trends in the incidence and prevalence of rheumatoid arthritis within members of an integrated health care delivery system.

The study objective was to estimate secular trends in the overall incidence rate (IR) and prevalence rate (PR) of rheumatoid arthritis (RA); and subgroup-specific IR and PR by race, ethnicity, and sex in a multi-ethnic population of a large integrated health care delivery system. An ecological study was conducted within the adult population of Kaiser Permanente Southern California health plan. From January 1995 up to and including December 2014, annual IR and PR were calculated separately by race, ethnicity, sex and pooled overall. Depending on the stationarity of each ecological series, annual percentage change in IR and PR was evaluated using auto-regressive integrated moving average models. Average overall IR was 53 [95% confidence interval (CI) 46, 61] per 100,000 person-years. The overall as well as subgroup-specific annual IR of RA were unchanged from 1995 to 2014. In 1995, the overall PR of RA was 59 (44, 74) per 100,000 person-years which increased by 14% (7%, 21%) annually thereafter. The increase in PR in Caucasians was lower as compared to African American, Asian and other race (13% vs 15%, 15%, and 18%, respectively). Compared to non-Hispanic ethnicity, the increase in PR among Hispanic was higher (17% vs 14%). Over the past 2 decades, while the incidence of RA was unchanged, the prevalence had increased significantly overall as well as within every subgroup of race, ethnicity, and sex.

Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) have an excess risk of cardiovascular disease (CVD). We aimed to assess the impact of CVD risk factors, including potential sex differences, and RA-specific variables on CVD outcome in a large, international cohort of patients with RA. METHODS: In 13 rheumatology centres, data on CVD risk factors and RA characteristics were collected at baseline. CVD outcomes (myocardial infarction, angina, revascularisation, stroke, peripheral vascular disease and CVD death) were collected using standardised definitions. RESULTS: 5638 patients with RA and no prior CVD were included (mean age: 55.3 (SD: 14.0) years, 76% women). During mean follow-up of 5.8 (SD: 4.4) years, 148 men and 241 women developed a CVD event (10-year cumulative incidence 20.9% and 11.1%, respectively). Men had a higher burden of CVD risk factors, including increased blood pressure, higher total cholesterol and smoking prevalence than women (all p<0.001). Among the traditional CVD risk factors, smoking and hypertension had the highest population attributable risk (PAR) overall and among both sexes, followed by total cholesterol. The PAR for Disease Activity Score and for seropositivity were comparable in magnitude to the PAR for lipids. A total of 70% of CVD events were attributable to all CVD risk factors and RA characteristics combined (separately 49% CVD risk factors and 30% RA characteristics). CONCLUSIONS: In a large, international cohort of patients with RA, 30% of CVD events were attributable to RA characteristics. This finding indicates that RA characteristics play an important role in efforts to reduce CVD risk among patients with RA.

Decreased Cardiovascular Mortality in Patients with Incident Rheumatoid Arthritis (RA) in Recent Years: Dawn of a New Era in Cardiovascular Disease in RA?

OBJECTIVE: To assess trends in cardiovascular (CV) mortality in patients with incident rheumatoid arthritis (RA) in 2000-07 versus the previous decades, compared with non-RA subjects. METHODS: The study population consisted of Olmsted County, Minnesota, USA residents with incident RA (age ≥ 18 yrs, 1987 American College of Rheumatology criteria was met in 1980-2007) and non-RA subjects from the same underlying population with similar age, sex, and calendar year of index. All subjects were followed until death, migration, or December 31, 2014. Followup was truncated for comparability. Aalen-Johansen methods were used to estimate CV mortality rates, adjusting for competing risk of other causes. Cox proportional hazards models were used to compare CV mortality by decade. RESULTS: The study included 813 patients with RA and 813 non-RA subjects (mean age 55.9 yrs; 68% women for both groups). Patients with incident RA in 2000-07 had markedly lower 10-year overall CV mortality (2.7%, 95% CI 0.6-4.9%) and coronary heart disease (CHD) mortality (1.1%, 95% CI 0.0-2.7%) than patients diagnosed in 1990-99 (7.1%, 95% CI 3.9-10.1% and 4.5%, 95% CI 1.9-7.1%, respectively; HR for overall CV death: 0.43, 95% CI 0.19-0.94; CHD death: HR 0.21, 95% CI 0.05-0.95). This improvement in CV mortality persisted after accounting for CV risk factors. Ten-year overall CV mortality and CHD mortality in 2000-07 RA incidence cohort was similar to non-RA subjects (p = 0.95 and p = 0.79, respectively). CONCLUSION: Our findings suggest significantly improved overall CV mortality, particularly CHD mortality, in patients with RA in recent years. Further studies are needed to examine the reasons for this improvement.

Five-year changes in cardiac structure and function in patients with rheumatoid arthritis compared with the general population.

BACKGROUND: Patients with rheumatoid arthritis (RA) have increased risk of heart failure with preserved ejection fraction. The development and progression of left ventricular dysfunction before onset of clinical heart failure are unknown. The objective of this study was to evaluate longitudinal changes in cardiac structure and function of patients with RA compared with persons in the general population. METHODS: A prospective longitudinal study of a population-based cohort of 160 patients with RA and a population-based cohort of 1391 persons without RA (non-RA cohort) was performed. Each participant underwent 2-dimensional, pulsed-wave tissue Doppler echocardiography at baseline and after 4 to 5years of follow-up. Age- and sex-adjusted linear regression models were used to test for differences between the RA and non-RA cohorts in annualized rates of change for echocardiographic parameters. RESULTS: Mitral A velocity increased more rapidly among the patients with RA than the non-RA cohort (age- and sex-adjusted parameter estimate, 0.030; P<0.001). Correspondingly, the mean mitral inflow E/A ratio decreased faster in the RA cohort than the non-RA cohort (adjusted parameter estimate, -0.096; P<0.001). The left atrial volume index increased at a higher rate in the RA cohort than the non-RA cohort (adjusted parameter estimate, 0.150; P<0.001). CONCLUSIONS: This pattern of echocardiographic findings confirms previous cross-sectional studies and indicates that subclinical changes in diastolic function occur more rapidly over 5years in RA patients than in the general population. Further research into the mechanisms of myocardial disease in these patients and the relationship with disease activity and treatment is warranted.

Correction: Challenges of developing a cardiovascular risk calculator for patients with rheumatoid arthritis.

[This corrects the article DOI: 10.1371/journal.pone.0174656.].

Rheumatoid arthritis-specific cardiovascular risk scores are not superior to general risk scores: a validation analysis of patients from seven countries.

Objectives: Cardiovascular disease (CVD) risk calculators developed for the general population do not accurately predict CVD events in patients with RA. We sought to externally validate risk calculators recommended for use in patients with RA including the EULAR 1.5 multiplier, the Expanded Cardiovascular Risk Prediction Score for RA (ERS-RA) and QRISK2. Methods: Seven RA cohorts from UK, Norway, Netherlands, USA, South Africa, Canada and Mexico were combined. Data on baseline CVD risk factors, RA characteristics and CVD outcomes (including myocardial infarction, ischaemic stroke and cardiovascular death) were collected using standardized definitions. Performance of QRISK2, EULAR multiplier and ERS-RA was compared with other risk calculators [American College of Cardiology/American Heart Association (ACC/AHA), Framingham Adult Treatment Panel III Framingham risk score-Adult Treatment Panel (FRS-ATP) and Reynolds Risk Score] using c-statistics and net reclassification index. Results: Among 1796 RA patients without prior CVD [mean ( s . d .) age: 54.0 (14.0) years, 74% female], 100 developed CVD events during a mean follow-up of 6.9 years (12430 person-years). Estimated CVD risk by ERS-RA [mean ( s . d .) 8.8% (9.8%)] was comparable to FRS-ATP [mean ( s . d .) 9.1% (8.3%)] and Reynolds [mean ( s . d .) 9.2% (12.2%)], but lower than ACC/AHA [mean ( s . d .) 9.8% (12.1%)]. QRISK2 substantially overestimated risk [mean ( s . d .) 15.5% (13.9%)]. Discrimination was not improved for ERS-RA (c-statistic = 0.69), QRISK2 or EULAR multiplier applied to ACC/AHA compared with ACC/AHA (c-statistic = 0.72 for all) or for FRS-ATP (c-statistic = 0.75). The net reclassification index for ERS-RA was low (-0.8% vs ACC/AHA and 2.3% vs FRS-ATP). Conclusion: The QRISK2, EULAR multiplier and ERS-RA algorithms did not predict CVD risk more accurately in patients with RA than CVD risk calculators developed for the general population.

Challenges of developing a cardiovascular risk calculator for patients with rheumatoid arthritis.

OBJECTIVE: Cardiovascular disease (CVD) risk calculators designed for use in the general population do not accurately predict the risk of CVD among patients with rheumatoid arthritis (RA), who are at increased risk of CVD. The process of developing risk prediction models involves numerous issues. Our goal was to develop a CVD risk calculator for patients with RA. METHODS: Thirteen cohorts of patients with RA originating from 10 different countries (UK, Norway, Netherlands, USA, Sweden, Greece, South Africa, Spain, Canada and Mexico) were combined. CVD risk factors and RA characteristics at baseline, in addition to information on CVD outcomes were collected. Cox models were used to develop a CVD risk calculator, considering traditional CVD risk factors and RA characteristics. Model performance was assessed using measures of discrimination and calibration with 10-fold cross-validation. RESULTS: A total of 5638 RA patients without prior CVD were included (mean age: 55 [SD: 14] years, 76% female). During a mean follow-up of 5.8 years (30139 person years), 389 patients developed a CVD event. Event rates varied between cohorts, necessitating inclusion of high and low risk strata in the models. The multivariable analyses revealed 2 risk prediction models including either a disease activity score including a 28 joint count and erythrocyte sedimentation rate (DAS28ESR) or a health assessment questionnaire (HAQ) along with age, sex, presence of hypertension, current smoking and ratio of total cholesterol to high-density lipoprotein cholesterol. Unfortunately, performance of these models was similar to general population CVD risk calculators. CONCLUSION: Efforts to develop a specific CVD risk calculator for patients with RA yielded 2 potential models including RA disease characteristics, but neither demonstrated improved performance compared to risk calculators designed for use in the general population. Challenges encountered and lessons learned are discussed in detail.

Fragility Fractures Are Associated with an Increased Risk for Cardiovascular Events in Women and Men with Rheumatoid Arthritis: A Population-based Study.

OBJECTIVE: Women and men with rheumatoid arthritis (RA) have an increased risk for fragility fractures and cardiovascular disease (CVD), each of which has been reported to contribute to excess morbidity and mortality in these patients. Fragility fractures share similar risk factors for CVD but may occur at relatively younger ages in patients with RA. We aimed to determine whether a fragility fracture predicts the development of CVD in women and men with RA. METHODS: We studied a population-based cohort with incident RA from 1955 to 2007 and compared it with age- and sex-matched non-RA subjects. We identified fragility fractures and CVD events following the RA incidence/index date, along with relevant risk factors. We used Cox models to examine the association between fractures and the development of CVD, in which fractures and CVD risk factors were modeled as time-dependent covariates. RESULTS: There were 1171 subjects (822 women; 349 men) in each of the RA and non-RA cohorts. Over followup, there were 406 and 346 fragility fractures and 286 and 225 CVD events, respectively. The overall CVD risk was increased significantly for RA subjects following a fragility fracture (HR 1.81, 95% CI 1.38-2.37) but not for non-RA subjects (HR 1.18, 95% CI 0.85-1.63). Results were similar for women and men with RA. CONCLUSION: Fragility fractures in both women and men with RA are associated with an increased risk for CVD events and should raise an alert to clinicians to target these individuals for further screening and preventive strategies for CVD.

Predictors of Dissection in Aortic Aneurysms From Giant Cell Arteritis.

BACKGROUND: Factors associated with dissection from inflammatory aortic aneurysms may be different from those in the general population. OBJECTIVE: The aim of this study was to evaluate the risk factors for aortic dissection/rupture in patients with giant cell arteritis (GCA) and aortic aneurysms. METHODS: A population-based incident cohort of patients with a diagnosis of GCA from 1950 to 2004 was used. All patients with aortic aneurysms diagnosed 1 year prior to GCA diagnosis or any time thereafter were included. Cox proportional hazard models were used to evaluate risk factors for aortic dissection/rupture. RESULTS: The study included 33 patients (91% women) with GCA and aortic aneurysms. Mean age at diagnosis of aortic aneurysm was 83.6 years. There were 27 thoracic aneurysms and 19 abdominal aneurysms. Eight patients developed aortic dissection/rupture (both thoracic and abdominal aorta in 5 cases, thoracic aorta only in 2 cases, and isolated abdominal aorta in 1 case).Older age (hazard ratio [HR], 0.27 per 10 years; 95% confidence interval [CI], 0.09-0.86) and later calendar year at diagnosis of aortic aneurysm (HR, 0.29 per 10 years; 95% CI, 0.13-0.69) were associated with decreased risk of dissection/rupture. Size of the thoracic aneurysm (HR, 1.17; 95% CI, 0.69-1.99) was not associated with dissection/rupture. Histopathology showed active aortitis in 4 of 7 patients with aortic dissection/rupture compared with 0 of 7 patients with aortic aneurysm without dissection/rupture. CONCLUSIONS: Aneurysm size was not a predictor of aortic dissection/rupture in this cohort of patients with GCA. The higher frequency of active aortitis in patients with dissection suggests that active inflammation may play a role.

Progression of Nonradiographic Axial Spondyloarthritis to Ankylosing Spondylitis: A Population-Based Cohort Study.

OBJECTIVE: The long-term outcome of patients with nonradiographic axial spondyloarthritis (SpA) is unclear, particularly whether few or most progress to ankylosing spondylitis (AS). Our objective was to examine the progression to AS in a population-based inception cohort of patients with nonradiographic axial SpA. METHODS: The Rochester Epidemiology Project (REP) is a longstanding population-based study of health in the residents of Olmsted County, Minnesota. We searched the REP from 1985 to 2010 using diagnostic and procedural codes for back pain, HLA-B27, and magnetic resonance imaging of the pelvis, and we performed detailed chart reviews to identify subjects who fulfilled the Assessment of SpondyloArthritis international Society classification criteria for axial SpA but did not have AS. We followed these subjects from disease onset to March 15, 2015, and used survival analysis to measure the time to progression to AS. RESULTS: After screening 2,151 patients, we identified 83 subjects with new-onset nonradiographic axial SpA. Over a mean follow-up of 10.6 years, progression to AS occurred in 16 patients. The probability that the condition would remain as nonradiographic axial SpA at 5, 10, and 15 years was 93.6%, 82.7%, and 73.6%, respectively. There was more frequent and more rapid progression among subjects in the imaging arm (n = 18) than among those in the clinical arm (n = 65) (28% versus 17%; hazard ratio 3.50 [95% confidence interval 1.15-10.6], P = 0.02). CONCLUSION: Progression to AS occurred in a minority (26%) of patients with nonradiographic axial SpA over as long as 15 years of follow-up. This suggests that the classification criteria for nonradiographic axial SpA identifies many patients in whom the condition is unlikely to progress to AS or that nonradiographic axial SpA represents a prolonged prodromal state that takes longer to evolve to AS and thus requires longer follow-up.

A novel measure of socioeconomic status using individual housing data to assess the association of SES with rheumatoid arthritis and its mortality: a population-based case-control study.

OBJECTIVES: To assess whether HOUSES (HOUsing-based index of socioeconomic status (SES)) is associated with risk of and mortality after rheumatoid arthritis (RA). DESIGN: We conducted a population-based case-control study which enrolled population-based RA cases and their controls without RA. SETTING: The study was performed in Olmsted County, Minnesota. PARTICIPANTS: Study participants were all residents of Olmsted County, Minnesota, with RA identified using the 1987 American College of Rheumatology criteria for RA from 1 January 1988, to 31 December 2007, using the auspices of the Rochester Epidemiology Project. For each patient with RA, one control was randomly selected from Olmsted County residents of similar age and gender without RA. PRIMARY AND SECONDARY OUTCOME MEASURE: The disease status was RA cases and their matched controls in relation to HOUSES as an exposure. As a secondary aim, post-RA mortality among only RA cases was an outcome event. The associations of SES measured by HOUSES with the study outcomes were assessed using logistic regression and Cox models. HOUSES, as a composite index, was formulated based on a summed z-score for housing value, square footage and number of bedrooms and bathrooms. RESULTS: Of the eligible 604 participants, 418 (69%) were female; the mean age was 56±15.6 years. Lower SES, as measured by HOUSES, was associated with the risk of developing RA (0.5±3.8 for controls vs -0.2±3.1 for RA cases, p=0.003), adjusting for age, gender, calendar year of RA index date, smoking status and BMI. The lowest quartile of HOUSES was significantly associated with increased post-RA mortality compared to higher quartiles of HOUSES (HR 1.74; 95% CI 1.10 to 2.74; p=0.017) in multivariate analysis. CONCLUSIONS: Lower SES, as measured by HOUSES, is associated with increased risk of RA and mortality after RA. HOUSES may be a useful tool for health disparities research concerning rheumatological outcomes when conventional SES measures are unavailable.

Do solar cycles influence giant cell arteritis and rheumatoid arthritis incidence?

OBJECTIVE: To examine the influence of solar cycle and geomagnetic effects on the incidence of giant cell arteritis (GCA) and rheumatoid arthritis (RA). METHODS: We used data from patients with GCA (1950-2004) and RA (1955-2007) obtained from population-based cohorts. Yearly trends in age-adjusted and sex-adjusted incidence were correlated with the F10.7 index (solar radiation at 10.7 cm wavelength, a proxy for the solar extreme ultraviolet radiation) and AL index (a proxy for the westward auroral electrojet and a measure of geomagnetic activity). Fourier analysis was performed on AL, F10.7, and GCA and RA incidence rates. RESULTS: The correlation of GCA incidence with AL is highly significant: GCA incidence peaks 0-1 year after the AL reaches its minimum (ie, auroral electrojet reaches a maximum). The correlation of RA incidence with AL is also highly significant. RA incidence rates are lowest 5-7 years after AL reaches maximum. AL, GCA and RA incidence power spectra are similar: they have a main peak (periodicity) at about 10 years and a minor peak at 4-5 years. However, the RA incidence power spectrum main peak is broader (8-11 years), which partly explains the lower correlation between RA onset and AL. The auroral electrojets may be linked to the decline of RA incidence more strongly than the onset of RA. The incidences of RA and GCA are aligned in geomagnetic latitude. CONCLUSIONS: AL and the incidences of GCA and RA all have a major periodicity of about 10 years and a secondary periodicity at 4-5 years. Geomagnetic activity may explain the temporal and spatial variations, including east-west skewness in geographic coordinates, in GCA and RA incidence, although the mechanism is unknown. The link with solar, geospace and atmospheric parameters need to be investigated. These novel findings warrant examination in other populations and with other autoimmune diseases.

Increased incidence of atrial fibrillation in patients with rheumatoid arthritis.

OBJECTIVE: To investigate the incidence of atrial fibrillation (AF) among patients with rheumatoid arthritis (RA) compared to the general population. METHODS: A population-based inception cohort of Olmsted County, Minnesota, residents with incident RA in 1980-2007 and a cohort of non-RA subjects from the same population base were assembled and followed until 12/31/2008. The occurrence of AF was ascertained by medical record review. RESULTS: The study included 813 patients with RA and 813 non-RA subjects (mean age 55.9 (SD:15.7) years, 68% women in both cohorts). The prevalence of AF was similar in the RA and non-RA cohorts at RA incidence/index date (4% versus 3%; P = 0.51). The cumulative incidence of AF during follow-up was higher among patients with RA compared to non-RA subjects (18.3% versus 16.3% at 20 years; P = 0.048). This difference persisted after adjustment for age, sex, calendar year, smoking, and hypertension (hazard ratio: 1.46; 95% CI: 1.07, 2.00). There was no evidence of a differential impact of AF on mortality in patients with RA compared to non-RA subjects (hazard ratio 2.5 versus 2.8; interaction P = 0.31). CONCLUSION: The incidence of AF is increased in patients with RA, even after adjustment for AF risk factors. AF related mortality risk did not differ between patients with and without RA.

Population-based study of QT interval prolongation in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular morbidity and mortality. Heart rate corrected QT interval (QTc) (which is obtained from a 12-lead electrocardiogram (ECG) and reflects ventricular repolarisation duration) is a strong predictor of cardiovascular mortality. Our primary purpose is to determine the impact of QTc prolongation on mortality in RA patients. METHODS: A population-based inception cohort of patients with RA fulfilling the 1987 ACR criteria in 1988-2007 was identified, with an age- and sex-matched comparison cohort and followed until death, migration or until the end of 2008. Data were collected on ECG variables, medications known to prolong QT interval, electrolytes, cardiovascular risk factors and disease status and RA disease characteristics. Cox proportional hazards models were used to examine QTc prolongation as predictor of mortality. RESULTS: QTc prolongation prior to RA incidence/index date was similar in RA (15%) and non-RA (18%) subjects. During follow-up, the cumulative incidence of QTc prolongation was higher among RA (48% at 20 years after RA incidence) than non-RA (38% at 20 years after index date; p=0.004). Idiopathic QTc prolongation (excluding prolongations explained by ECG changes, medications, etc.) was marginally associated with all-cause mortality (HR: 1.28; 95% CI: 0.91-1.81, p=0.16), but was not associated with cardiovascular mortality (HR: 1.10; 95% CI:0.43-2.86, p=0.83) in RA. CONCLUSIONS: RA patients have a significantly elevated risk of developing QTc prolongation. However, idiopathic prolonged QTc was only marginally associated with all-cause mortality in RA patients. The clinical implications of these findings in RA require further study.

Elevation of serum immunoglobulin free light chains during the preclinical period of rheumatoid arthritis.

OBJECTIVE: Immunoglobulin free light chains (FLC) represent biomarkers of B cell activity in rheumatoid arthritis (RA) and are associated with all-cause mortality in the general population. Our objective was to evaluate the relationships of serum FLC to preclinical disease, RA characteristics, and mortality in RA compared to non-RA subjects. METHODS: A population-based study in Olmsted County, Minnesota, USA, was performed by crosslinking a large cohort in the general population having available serum FLC measurements with established RA incidence and prevalence cohorts. Serum κ, λ, and total FLC and their trends relative to RA incidence were compared between RA and non-RA subjects. Regression models were used to determine the associations between FLC, disease characteristics, and mortality, testing for differential effects of FLC on mortality in RA. RESULTS: Among 16,609 subjects, 270 fulfilled the criteria for RA at the time of FLC measurement. Mean total FLC were significantly higher in RA compared to non-RA subjects (4.2 vs 3.3 mg/dl, p < 0.001). FLC became elevated 3-5 years before the clinical onset of RA and remained elevated during followup. Polyclonal FLC were found to predict higher mortality in persons with RA, though elevation to the highest decile had a relatively lower effect on mortality in RA compared to non-RA subjects. CONCLUSION: Elevation of serum FLC precedes the development of RA and may be useful in monitoring B cell activity and disease progression. FLC are associated with mortality among patients with RA as well as the general population.

Medication adherence and attrition to biologic treatment in rheumatoid arthritis patients.

PURPOSE: The objectives of this study were to assess medication adherence rate and attrition rate in first-time adalimumab (ADA) or etanercept (ETA) users in rheumatoid arthritis (RA) patients. This study also identified the risk factors associated with nonadherence and treatment abandonment. METHODS: This was a retrospective study with a 2-year follow-up. A total 2151 adult RA patients (18 years of age and older) who initiated ADA or ETA treatment in the Kaiser Permanente Southern California health plan between 2002 and 2009 were identified. Among those on treatment in the first year, continuous treatment receipt was determined by having at least 1 medication refill in the second year; otherwise treatment was considered as abandoned. Medication adherence was measured through proportion of days covered (PDC) and compared between patients continuously on treatment and those abandoning treatment. Risk factors of nonadherence (PDC <80%) and treatment abandonment were estimated by a multinomial logistic regression model. FINDINGS: Patients who abandoned treatment had significantly lower PDC (37.3%) and lower average number of refills (5.1) than adherers (PDC = 88.8%; average number of refills = 12.4) and nonadherers (PDC = 53.3%; average refills = 8.2). Age, African Americans (odds ratio [OR], 1.49; 95% CI, 1.03-2.17), corticosteroids use (OR, 0.80; 95% CI, 0.63-0.98), and history of physical/occupational therapy (OR = 0.66; 95% CI, 0.46-0.93) were associated with nonadherence, whereas having a comorbidity (OR, 1.24; 95% CI, 1.01-1.57) was associated with treatment abandonment. The difference in PDC between ADA and ETA was no longer statistically significant after excluding the treatment abandonment group. A higher proportion of ADA users abandoned treatment than ETA users (42.9% vs 32.2%). IMPLICATIONS: Taking into account treatment abandonment when measuring medication adherence in ADA and ETA use in RA patients can provide a fair and clinically meaningful view of patients' medication-taking behavior.