Older patients with nonspecific complaints at the Emergency Department are at risk of adverse health outcomes.

OBJECTIVE: Older adults at the Emergency Department (ED) often present with nonspecific complaints (NSC) such as 'weakness' or 'feeling unwell'. Health care workers may underestimate illness in patients with NSC, leading to adverse health outcomes. This study compares characteristics and outcomes of NSC-patients versus specific complaints (SC) patients. METHODS: Cohort study in patients ≥ 70 years in two Dutch EDs. NSC was classified according to the BANC-study-framework based on the medical history in the ED letter, before additional diagnostics took place. A second classification was performed at the end of the ED visit/hospital admission. Primary outcomes were functional decline, institutionalization, and mortality at 30 days. RESULTS: 26% (n = 228) of a total of 888 included patients presented with NSC. Compared with SC-patients, NSC-patients were older, more frail, and more frequently female. NSC-patients had a higher risk of functional decline and institutionalization at 30 days (adjusted ORs 1.84, 95% CI 1.27 - 2.72, and 2.46, 95% CI 1.51-4.00, respectively), but not mortality (adjusted OR 1.26, 95% CI 0.58 - 2.73). Reclassification to a specific complaint after the ED visit or hospital admission occurred in 54% of NSC-patients. CONCLUSION: NSC occur especially in older, frail female patients and are associated with an increased risk of functional decline and institutionalization, even after adjustment for worse baseline status. In half of the patients, a specific complaint revealed during ED or hospital stay. Physicians at the ED should consider NSC as a red flag needing appropriate observation and evaluation of underlying serious conditions and needs of this vulnerable patient group.

In RA patients without prevalent CVD, incident CVD is mainly associated with traditional risk factors: A 20-year follow-up in the CARRÉ cohort study.

OBJECTIVES: To extend our investigation of cardiovascular diseases (CVD) in rheumatoid arthritis (RA) patients to a follow up of more than 20 years, with a special focus on patients without prevalent CVD. METHODS: The CARRÉ study is an ongoing prospective cohort study on CV endpoints in RA patients. Results were compared to those of a reference cohort (n = 2484) enriched for type 2 diabetes mellitus (DM). Hazard ratios (HR) for RA and DM patients compared to non-RA/-DM controls were calculated with cox proportional hazard models, and adjusted for baseline SCORE1 (estimated 10-year CVD mortality risk based on CV risk factors). RESULTS: 238 RA patients, 117 DM patients and 1282 controls, without prevalent CVD at baseline were included. Analysis of events in these patients shows that after adjustment, no relevant 'RA-specific' risk remains (HR 1.16; 95%CI 0.88 - 1.53), whereas a 'DM-specific' risk is retained (1.73; 1.24 - 2.42). In contrast, adjusted analyses of all cases confirm the presence of an 'RA-specific' risk (1.50; 1.19 - 1.89). CONCLUSIONS: In RA patients without prevalent CVD the increased CVD risk is mainly attributable to increased presence of traditional risk factors. After adjustment for these factors, an increased risk attributable to RA only was thus preferentially seen in the patients with prevalent CVD at baseline. As RA treatment has improved, this data suggests that the 'RA-specific' effect of inflammation is preferentially seen in patients with prevalent CVD. We suggest that with modern (early) treatment of RA, most of the current increased CVD risk is mediated through traditional risk factors.

The effect of anti-TNF treatment on body composition and insulin resistance in patients with rheumatoid arthritis.

Given the link between systemic inflammation, body composition and insulin resistance (IR), anti-inflammatory therapy may improve IR and body composition in inflammatory joint diseases. This study assesses the IR and beta cell function in rheumatoid arthritis (RA) patients with active disease compared to osteoarthritis (OA) patients and investigates the effect of anti-TNF treatment on IR, beta cell function and body composition in RA. 28 Consecutive RA patients starting anti-TNF treatment (adalimumab), and 28 age, and sex-matched patients with OA were followed for 6 months. Exclusion criteria were use of statins, corticosteroids, and cardiovascular or endocrine co-morbidity. Pancreatic beta cell function and IR, using the homeostasis model assessment (HOMA2), and body composition, using dual-energy X-ray absorptiometry (DXA) were measured at baseline and 6 months. At baseline, IR [1.5 (1.1-1.8) vs. 0.7 (0.6-0.9), 100/%S] and beta cell function (133% vs. 102%) were significantly (p < 0.05) higher in RA patients with active disease as compared to OA patients. After 6 months of anti-TNF treatment, IR [1.5 (1.1-1.8) to 1.4 (1.1-1.7), p = 0.17] slightly improved and beta cell function [133% (115-151) to 118% (109-130), p <0.05] significantly improved. Improvement in IR and beta cell function was most pronounced in RA patients with highest decrease in CRP and ESR. Our observations indicate that IR and increased beta cell function are more common in RA patients with active disease. Anti-TNF reduced IR and beta cell function especially in RA patients with highest decrease in systemic inflammation and this effect was not explained by changes in body composition.

Prescription patterns of lipid lowering agents among older patients in general practice: an analysis from a national database in the Netherlands.

BACKGROUND: Dutch cardiovascular risk management guidelines state almost every older adult (≥70 years) is eligible for a lipid lowering drug (LLD). However, life expectancy, frailty or comorbidities may influence this treatment decision. OBJECTIVE: investigate how many older adults, according to age, frailty (Drubbel-frailty index) and comorbidities were prescribed LLDs. METHODS: data of 244,328 adults ≥70 years from electronic health records of 415 Dutch general practices from 2011-15 were used. Number of LLD prescriptions in patients with (n = 55,309) and without (n = 189,019) cardiovascular disease (CVD) was evaluated according to age, frailty and comorbidities. RESULTS: about 69% of adults ≥70 years with CVD and 36% without CVD were prescribed a LLD. LLD prescriptions decreased with age; with CVD: 78% aged 70-74 years and 29% aged ≥90 years were prescribed a LLD, without CVD: 37% aged 70-74 years and 12% aged ≥90 years. In patients with CVD and within each age group, percentage of LLD prescriptions was 20% point(pp) higher in frail compared with non-frail. In patients without CVD, percentage of LLD prescriptions in frail patients was 11pp higher in adults aged 70-74 years and 40pp higher in adults aged ≥90 years compared to non-frail. Similar trends were seen in the analyses with number of comorbidities. CONCLUSION: in an older population, LLD prescriptions decreased with age but-contrary to our expectations-LLD prescriptions increased with higher frailty levels.

EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update.

Patients with rheumatoid arthritis (RA) and other inflammatory joint disorders (IJD) have increased cardiovascular disease (CVD) risk compared with the general population. In 2009, the European League Against Rheumatism (EULAR) taskforce recommended screening, identification of CVD risk factors and CVD risk management largely based on expert opinion. In view of substantial new evidence, an update was conducted with the aim of producing CVD risk management recommendations for patients with IJD that now incorporates an increasing evidence base. A multidisciplinary steering committee (representing 13 European countries) comprised 26 members including patient representatives, rheumatologists, cardiologists, internists, epidemiologists, a health professional and fellows. Systematic literature searches were performed and evidence was categorised according to standard guidelines. The evidence was discussed and summarised by the experts in the course of a consensus finding and voting process. Three overarching principles were defined. First, there is a higher risk for CVD in patients with RA, and this may also apply to ankylosing spondylitis and psoriatic arthritis. Second, the rheumatologist is responsible for CVD risk management in patients with IJD. Third, the use of non-steroidal anti-inflammatory drugs and corticosteroids should be in accordance with treatment-specific recommendations from EULAR and Assessment of Spondyloarthritis International Society. Ten recommendations were defined, of which one is new and six were changed compared with the 2009 recommendations. Each designated an appropriate evidence support level. The present update extends on the evidence that CVD risk in the whole spectrum of IJD is increased. This underscores the need for CVD risk management in these patients. These recommendations are defined to provide assistance in CVD risk management in IJD, based on expert opinion and scientific evidence.

Increased progression of carotid intima media thickness in thyroid peroxidase antibodies-positive rheumatoid arthritis patients.

OBJECTIVE: Autoimmune diseases such as rheumatoid arthritis (RA) and hypothyroidism tend to cluster, and this coexistence amplifies the elevated cardiovascular risk in RA. Whether thyroid peroxidase antibodies (TPOabs) are associated with increased cardiovascular disease (CVD) risk has not been studied extensively. Therefore, this study determined firstly the prevalence of TPOabs in RA and secondly whether TPOabs were associated with CVD. Moreover, this study explored whether TPOabs were related to RA characteristics. DESIGN AND METHODS: Data from the CARRÉ Study, an ongoing study investigating CVDs and its risk factors in RA (n=322), was used to ascertain the prevalence of TPOabs in RA patients. In addition, cardiovascular and RA disease characteristics were compared between TPOabs-positive and -negative patients at baseline and at a second visit after 3 years. RESULTS: TPOabs were present in 47/322 (15%) RA patients and TSH levels were higher in TPOabs-positive patients (1.40 mU/l) compared with TPOabs-negative patients (1.26 mU/l, P=0.048). At baseline and after 3 years no association was observed between TPOabs and (risk factors for) CVD. Regression analyses revealed a significantly larger progression of carotid intima media thickness (cIMT; ß=0.13 mm) in TPOabs-positive compared with TPOabs-negative patients independent of risk factors for cIMT progression. RA disease activity scores (DAS28) were higher in TPOabs-positive compared with TPOabs-negative patients (4.4 vs 3.8 P=0.018). CONCLUSIONS: TPOabs were associated with increased cIMT progression. Moreover, an association between TPOabs and DAS28 was observed. Hence, TPOabs seems to have a role in the amplified cardiovascular risk in RA patients.

Subclinical renal dysfunction is independently associated with cardiovascular events in rheumatoid arthritis: the CARRÉ Study.

BACKGROUND: Patients with rheumatoid arthritis (RA) have double the risk of cardiovascular (CV) disease, largely independently of traditional CV risk factors. Renal dysfunction is associated with CV morbidity and mortality in the general population, but data on this association in RA are lacking. OBJECTIVE: To investigate the association between renal function and CV events in RA. METHODS: The CARRÉ Study is an ongoing prospective cohort study of Dutch patients with RA, which records CV events. Glomerular filtration rate (GFR) was estimated with the abbreviated Modification of Diet in Renal Disease formula. Logistic regression determined the association between estimated GFR and the occurrence of CV events. RESULTS: 353 patients were followed for 3 years, and 23 (7%) had a CV event. Patients who had an event had a significantly lower baseline GFR than those who did not (59 vs 79 ml/min, p=0.001). This association remained significant after adjustment for traditional risk factors: in this analysis, a decrease in GFR of 5 ml/min was associated with a 30% (95% CI 7% to 59%) increase in the occurrence of CV events. During follow-up, an unfavourable change in GFR was noted in patients who later had a CV event compared with those who did not. CONCLUSION: These data confirm that, in RA, renal dysfunction is associated with a higher risk of CV disease independently of traditional CV risk factors.

The interplay between inflammation, lipids and cardiovascular risk in rheumatoid arthritis: why ratios may be better.

BACKGROUND: There is abundant evidence that patients with rheumatoid arthritis (RA) are at elevated cardiovascular (CV) risk. The contribution of lipids in general is well recognised, but is as yet unclear in inflammatory diseases such as RA in part because inflammation appears inversely associated with lipid levels in RA. METHODS: The CARRE study is a cohort study of 353 randomly selected RA outpatients followed since their enrollment in 2001-2002. We used data from this cohort to (i) evaluate the relationship at baseline between lipid levels [total cholesterol (TC), high-density lipoprotein (HDL)-cholesterol and the TC:HDLc ratio] and inflammation [by means of C-reactive protein (CRP)]; and (ii) determine the association of baseline TC and TC:HDLc ratio with incident (fatal and non-fatal) CV events. RESULTS: C-reactive protein correlated negatively with TC (r = -0.184, p = 0.002), more so with HDLc (r = -0.327, p = 0.001) and therefore positively with TC:HDLc ratio (r = 0.204, p = 0.001). These associations were most evident when CRP exceeded 10 mg/l. Furthermore, the TC:HDLc ratio, but not TC, was positively related to event risk, again most marked in those with elevated CRP. CONCLUSION: Our observations support use of TC:HDLc ratio rather than TC alone in assessing cardiovascular risk in RA patients, especially in those with high inflammatory activity.

Beneficial effect of 1-year etanercept treatment on the lipid profile in responding patients with rheumatoid arthritis: the ETRA study.

BACKGROUND: Effective anti-inflammatory treatment with tumour necrosis factor α (TNFα) inhibitors may have favourable effects on the lipid profile. Available evidence is derived from short-term studies, and it is not clear whether TNFα inhibitors have a similar effect on the lipid profile in responders and non-responders to the treatment. OBJECTIVES: To investigate the effect of long-term etanercept treatment on the lipid profile in a large sample of patients with rheumatoid arthritis (RA), stratified for European League Against Rheumatism (EULAR) response. METHODS: Between 2004 and 2008, 292 consecutive patients with active RA (DAS28 >3.2) and a new etanercept prescription were included in an observational cohort. Clinical response variables and lipid samples were collected at baseline and after 4 months and 1 year of etanercept treatment. Generalised estimating equation analyses were used to investigate the longitudinal course of lipid levels in relation to clinical response variables. RESULTS: According to the EULAR response criteria, 76% of the patients were good or moderate responders at 4 months, and 85% of the remainder at 1 year. Significant changes in apoA-I (increased by 3.5% (p=0.002) at 4 months and 3.1% (p=0.005) at 1 year) and apoB/apoA-I ratio (decreased by 6.2% (p<0.001) at 4 months and 3.6% (p=0.025) at 1 year) were observed in EULAR responders. No significant differences were observed in EULAR non-responders at all time points. CONCLUSIONS: Treatment with etanercept resulted in a significant and sustained decrease in the apoB/apoA-I ratio in patients with good or moderate EULAR response. This may have a beneficial effect on the cardiovascular risk in patients with RA.

The relationship between disease-related characteristics and conduction disturbances in ankylosing spondylitis.

OBJECTIVES: Ankylosing spondylitis (AS) is associated with an increased cardiovascular (CV) risk. Conduction disturbances (CD) may explain the CV burden, as they are independently associated with cardiac disease. The aim of this study was (i) to determine the prevalence of CD in AS, and (ii) to evaluate the relationship between CD and demographic and AS-related characteristics. METHODS: A rheumatological evaluation assessing demographic and AS-related characteristics and a resting standard 12-lead electrocardiogram (ECG) were performed in 131 consecutive AS patients. RESULTS: A first-degree atrioventricular (AV) block was found in six (4.6%) patients. One (0.8%) patient suffered from a complete right bundle branch block (RBBB) and one (0.8%) patient had a left anterior hemiblock. A prolonged QRS (pQRS) interval was observed in 38 (29.2%) patients, including those with a complete or incomplete BBB. Age, disease duration, and body mass index (BMI) were significantly associated with the PR interval, and male gender, disease duration, and the Bath Ankylosing Spondylitis Metrology Index (BASMI) with the QRS interval. In multivariate analyses, disease duration remained independently associated with both the PR and the QRS intervals. CONCLUSION: Intraventricular CD is highly prevalent in AS, particularly in patients with long-standing disease. Further research is needed to determine whether intraventricular CD contribute to the increased CV risk and long-term CV mortality in AS.

Ankylosing spondylitis: a risk factor for myocardial infarction?

OBJECTIVE: To ascertain the prevalence of myocardial infarction (MI) in ankylosing spondylitis (AS) relative to that in the general population. METHODS: A questionnaire was sent to 593 patients with AS, aged between 50 and 75 years and registered at the Jan van Breemen Institute or VU University Medical Centre. A total of 383 (65%) patients with AS returned their questionnaire that covered the primary outcome, (non-fatal) MI. The prevalence of MI was calculated with data from the general population provided by Netherlands Information Network of General Practice databases as reference. RESULTS: The overall prevalence for MI was 4.4% in patients with AS versus 1.2% in the general population, resulting in an age- and gender-adjusted odds ratio of 3.1 (95% CI 1.9 to 5.1) for patients with AS. When non-responders (35%) were considered as non-MI the odds ratio decreased to 1.9 (95% CI 1.2 to 3.2). CONCLUSIONS: These observations indicate that the prevalence of MI is increased in patients with AS.

The metabolic syndrome is amplified in hypothyroid rheumatoid arthritis patients: a cross-sectional study.

OBJECTIVES: Rheumatoid arthritis (RA) patients are at increased risk of cardiovascular disease (CVD), which is even more pronounced in hypothyroid RA patients. An unfavourable cardiovascular risk profile conferred by a higher prevalence of the metabolic syndrome (MetS) and a higher Framingham risk score might explain this amplified cardiovascular morbidity. This study compared first, MetS (features) and second, the Framingham 10-year CVD risk in RA patients with hypothyroidism compared with euthyroid RA patients. METHODS: RA patients participating in the CARRE investigation were divided into two groups: hypothyroid and euthyroid RA patients. MetS according to the National Cholesterol Education Program Third Adult Treatment Panel criteria and the Framingham risk score was compared between hypothyroid and non-hypothyroid CVD event-free RA patients. RESULTS: In total, 257 RA patients were included: 236 with RA (91.8%) and 21 with hypothyroid RA (8.2%), respectively. The prevalence of the MetS was significantly higher in hypothyroid RA patients (43%) compared with RA patients (20%). Moreover, female hypothyroid RA patients had a higher Framingham risk score compared with euthyroid RA patients. With RA patients as the reference category, the age and gender-adjusted prevalence odds ratio for the MetS was 3.5 (95% CI 1.3 to 9.1) in hypothyroid RA. CONCLUSIONS: Hypothyroid RA patients, particularly female patients, have a more unfavourable cardiovascular risk profile, reflected by an increased prevalence of the MetS and higher Framingham score, than euthyroid RA patients, suggesting a greater need for cardiovascular risk management in these patients to prevent future CVD events.

EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis.

OBJECTIVES: To develop evidence-based EULAR recommendations for cardiovascular (CV) risk management in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). METHODS: A multidisciplinary expert committee was convened as a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), comprising 18 members including rheumatologists, cardiologists, internists and epidemiologists, representing nine European countries. Problem areas and related keywords for systematic literature research were identified. A systematic literature research was performed using MedLine, Embase and the Cochrane library through to May 2008. Based on this literature review and in accordance with the EULAR's "standardised operating procedures", the multidisciplinary steering committee formulated evidence-based and expert opinion-based recommendations for CV risk screening and management in patients with inflammatory arthritis. RESULTS: Annual CV risk assessment using national guidelines is recommended for all patients with RA and should be considered for all patients with AS and PsA. Any CV risk factors identified should be managed according to local guidelines. If no local guidelines are available, CV risk management should be carried out according to the SCORE function. In addition to appropriate CV risk management, aggressive suppression of the inflammatory process is recommended to further lower the CV risk. CONCLUSIONS: Ten recommendations were made for CV risk management in patients with RA, AS and PsA. The strength of the recommendations differed between RA on the one hand, and AS and PsA, on the other, as evidence for an increased CV risk is most compelling for RA.

Improvement of lipid profile is accompanied by atheroprotective alterations in high-density lipoprotein composition upon tumor necrosis factor blockade: a prospective cohort study in ankylosing spondylitis.

OBJECTIVE: Cardiovascular mortality is increased in ankylosing spondylitis (AS), and inflammation plays an important role. Inflammation deteriorates the lipid profile and alters high-density lipoprotein cholesterol (HDL-c) composition, reflected by increased concentrations of serum amyloid A (SAA) within the particle. Anti-tumor necrosis factor (anti-TNF) treatment may improve these parameters. We therefore undertook the present study to investigate the effects of etanercept on lipid profile and HDL composition in AS. METHODS: In 92 AS patients, lipid levels and their association with the inflammation markers C-reactive protein (CRP), erythrocyte sedimentation rate, and SAA were evaluated serially during 3 months of etanercept treatment. HDL composition and its relationship to inflammation markers was determined in a subgroup of patients, using surface-enhanced laser desorption/ionization time-of-flight analysis. RESULTS: With anti-TNF treatment, levels of all parameters of inflammation decreased significantly, whereas total cholesterol, HDL-c, and apolipoprotein A-I (Apo A-I) levels increased significantly. This resulted in a better total cholesterol:HDL-c ratio (from 3.9 to 3.7) (although the difference was not statistically significant), and an improved Apo B:Apo A-I ratio, which decreased by 7.5% over time (P=0.008). In general, increases in levels of all lipid parameters were associated with reductions in inflammatory activity. In addition, SAA was present at high levels within HDL particles from AS patients with increased CRP levels and disappeared during treatment, in parallel with declining plasma levels of SAA. CONCLUSION: Our results show for the first time that during anti-TNF therapy for AS, along with favorable changes in the lipid profile, HDL composition is actually altered whereby SAA disappears from the HDL particle, increasing its atheroprotective ability. These findings demonstrate the importance of understanding the role of functional characteristics of HDL-c in cardiovascular diseases related to chronic inflammatory conditions.

Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a cross-sectional study, the CARRE Investigation.

OBJECTIVES: Patients with rheumatoid arthritis (RA) have an increased cardiovascular risk, but the magnitude of this risk is not known precisely. A study was undertaken to investigate the associations between RA and type 2 diabetes (DM2), a well-established cardiovascular risk factor, on the one hand, and cardiovascular disease (CVD) on the other. METHODS: The prevalence of CVD (coronary, cerebral and peripheral arterial disease) was determined in 353 randomly selected outpatients with RA (diagnosed between 1989 and 2001, aged 50-75 years; the CARRE study) and in participants of a population-based cohort study on diabetes and CVD (the Hoorn study). Patients with RA with normal fasting glucose levels from the CARRE study (RA, n = 294) were compared with individuals from the Hoorn study with normal glucose metabolism (non-diabetic, n = 258) and individuals with DM2 (DM2, n = 194). RESULTS: The prevalence of CVD was 5.0% (95% CI 2.3% to 7.7%) in the non-diabetic group, 12.4% (95% CI 7.5% to 17.3%) in the DM2 group and 12.9% (95% CI 8.8% to 17.0%) in those with RA. With non-diabetic individuals as the reference category, the age- and gender-adjusted prevalence odds ratio (OR) for CVD was 2.3 (95% CI 1.1 to 4.7) for individuals with DM2 and 3.1 (95% CI 1.6 to 6.1) for those with RA. There was an attenuation of the prevalences after adjustment for conventional cardiovascular risk factors (OR 2.0 (95% CI 0.9 to 4.5) and 2.7 (95% CI 1.2 to 5.9), respectively). CONCLUSIONS: The prevalence of CVD in RA is increased to an extent that is at least comparable to that of DM2. This should have implications for primary cardiovascular prevention strategies in RA.

Immunogenicity does not influence treatment with etanercept in patients with ankylosing spondylitis.

BACKGROUND: Immunogenicity, specifically the onset of antibodies against tumour necrosis factor (TNF) blocking agents, seems to play an important role in non-response to treatment with these drugs. OBJECTIVES: To assess the relation of clinical response of ankylosing spondylitis (AS) to etanercept with etanercept levels, and the presence of antibodies to etanercept. METHODS: Patients with AS were treated with etanercept 25 mg twice weekly, according to the international Assessment in Ankylosing Spondylitis (ASAS) working group consensus statement. Sera were collected at baseline and after 3 and 6 months of treatment. Clinical response was defined as a 50% improvement or as an absolute improvement of 2 points on a (0-10 scale) Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score. Functional etanercept levels were measured by a newly developed ELISA, measuring the binding of etanercept to TNF. Antibodies against etanercept were measured with a two-site assay and antigen binding test. Clinical data were used to correlate disease activity with serum etanercept levels. RESULTS: In all, 53 consecutive patients were included. After 3 months of treatment 40 patients (76%) fulfilled the response criteria. Mean etanercept levels were 2.7 mg/litre and 3.0 mg/litre after 3 and 6 months respectively. Characteristics and etanercept levels of responders and non-responders were similar. No antibodies to etanercept were detected with any of the assays. CONCLUSION: Etanercept levels of responders and non-responders were similar and no antibodies to etanercept were detected with any of the assays. This study indicates that etanercept is much less immunogenic compared with the other TNF-blocking agents.