Physical activity in rheumatoid arthritis: relationship to cardiovascular risk factors, subclinical atherosclerosis, and disease activity.

Objective: To investigate associations between physical activity and risk factors for cardiovascular disease (CVD), subclinical atherosclerosis, and disease activity in patients with early and long-standing rheumatoid arthritis (RA).Method: This cross-sectional study included 84 patients with early and 37 with long-standing RA (disease duration, mean ± sd: 1.4 ± 0.4 and 16.3 ± 2.3 years, respectively). Physical activity was measured using a combined accelerometer and heart-rate monitor. Further assessments were disease activity (erythrocyte sedimentation rate, Disease Activity Score in 28 joints), functional ability (Health Assessment Questionnaire), risk factors for CVD (blood lipids, i.e. triglycerides, high-density lipoprotein, low-density lipoprotein; blood glucose, blood pressure, sleeping heart rate, waist circumference, body mass index, and body fat), and subclinical atherosclerosis (pulse-wave velocity, augmentation index, and carotid intima-media thickness).Results: Physical activity variables did not differ between patients with early and long-standing RA. However, 37% of the patients with early and 43% of those with long-standing RA did not reach the World Health Organization's recommended levels of moderate to vigorous physical activity (MVPA). In a final multiple regression model, adjusted for age, gender, disease duration, and activity monitor wear time, higher total physical activity was associated with lower body fat and higher functional ability. With the same adjustments, more time spent in MVPA was associated with lower high-density lipoprotein and lower sleeping heart rate.Conclusions: Physical activity was associated with more favourable risk factors for CVD. However, many patients were physically inactive, stressing the importance of promoting physical activity in RA.

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 prevalence of prior malignancies and autoimmune diseases in patients diagnosed with chronic myeloid leukemia.

We recently reported an increased incidence of second malignancies in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKI). To elucidate whether this increase may be linked, not to TKI but rather to a hereditary or acquired susceptibility to develop cancer, we estimated the prevalence of malignancies, autoimmune disease (AD) and chronic inflammatory disease (CID) in CML patients prior to their CML diagnosis. Nationwide population-based registers were used to identify patients diagnosed with CML in Sweden 2002-2012 and to estimate the prevalence of other malignancies, AD and CID prior to their CML diagnosis. For each patient with CML, five matched controls were selected from the general population. Conditional logistic regression was used to calculate odds ratios (OR). Nine hundred and eighty-four CML patients were assessed, representing more than 45 000 person-years of follow-up. Compared with matched controls, the prevalence of prior malignancies and AD was elevated in CML patients: OR 1.47 (95% confidence interval (CI) 1.20-1.82) and 1.55 (95% CI 1.21-1.98), respectively. No associations were detected between CML and previous CID. An increased prevalence of other malignancies and AD prior to the diagnosis of CML suggest that a hereditary or acquired predisposition to cancer and/or autoimmunity is involved in the pathogenesis of CML.

Circulating plasma levels of cathepsin S and L are not associated with disease severity in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is characterized by chronic synovitis and articular cartilage destruction. Increased activities of cathepsin S and cathepsin L, two potent cysteine proteases, are thought to play a role in the pathogenesis of the irreversible articular cartilage destruction. Nevertheless, data regarding the potential importance of the cathepsins as circulating biomarkers in RA patients are limited. METHOD: Subjects enrolled in this study are part of a larger study where patients from the three northern counties of Sweden diagnosed with early RA are followed in an ongoing prospective study. In total, 71 patients were included, along with 44 age- and sex-matched control subjects. Plasma levels of cathepsin S and L were analysed. Disease severity was assessed using the 28-joint count Disease Activity Score (DAS28). RESULTS: Plasma levels of cathepsin S and L were significantly increased in patients with RA compared to healthy controls (p < 0.05 for both). However, in the patients with RA, no association between the cathepsins and the severity of the disease, as characterized by DAS28, was observed (p > 0.51). CONCLUSIONS: Although circulating levels of cathepsin S and L were significantly increased in patients with recently diagnosed RA, our data do not support the notion that circulating levels of cathepsins are relevant biomarkers for disease severity.

The apoB/apoA1 ratio predicts future cardiovascular events in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) have increased mortality and morbidity due to cardiovascular disease (CVD). A high apolipoprotein (apo)B/apoA1 ratio is known to predict cardiovascular events (CVEs) in the population. apoA1 has, besides anti-atherogenic effects, anti-inflammatory properties. The importance of apolipoproteins in the development of CVEs, in the context of lipids, haemostatic factors, and inflammation, was evaluated over 18 years in patients with RA. METHOD: Seventy-four patients with inflammatory active RA (61 females/13 males, mean age 63.6 years, disease duration 22.1 years) had been previously investigated in a study of haemostatic factors [tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI)-1, von Willebrand factor (vWF)], lipids (cholesterol and triglycerides), apolipoproteins (apoA1 and apoB), lipoprotein(a) [Lp(a)], and markers of inflammation [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and haptoglobin]. After 18 years, the first CVE during follow-up and the presence of traditional CV risk factors, extra-articular disease, and pharmacological treatment were registered. Cox proportional hazards regression was used to identify predictors of a new CVE. RESULTS: A new CVE (n = 34) was predicted by the apoB/apoA1 ratio (p < 0.01), the triglyceride level (p < 0.01), PAI-1 (p < 0.01) and tPA (p < 0.01) activities, vWF (p < 0.001), ESR (< 0.001), CRP (< 0.05), and haptoglobin (p < 0.05). apoA1 (p = 0.056) and apoB (p < 0.05) correlated weakly and inversely with haptoglobin and CRP, respectively. In a multiple Cox regression model, adjusted for gender and previous CVD, the apoB/apoA1 ratio significantly predicted a new CVE, as did vWF, PAI-1, and ESR. CONCLUSIONS: The apoB/apoA1 ratio was a good predictor of CVE during 18 years of follow-up in patients with active RA. Apolipoproteins correlated negatively with inflammation.

A population-based investigation of the autoantibody profile in mothers of children with atrioventricular block.

The objective of the study was to investigate the antigen specificity and occurrence of individual autoantibodies in mothers of children diagnosed with atrioventricular (AV) block in a nation-wide setting. Patients with AV block detected before 15 years of age were identified using national quality registries as well as a network of pediatric and adult cardiologists and rheumatologists at the six university hospitals in Sweden. Patients with gross heart malformations, surgically or infectiously induced blocks were excluded. Blood samples were obtained from the mothers and maternal autoantibody profile, including the occurrence of antibodies against Ro52, Ro60, La, SmB, SmD, RNP-70k, RNP-A, RNP-C, CENP-C, Scl-70, Jo-1, ribosomal RNP and histones was investigated in 193 mothers of children with AV block by immunoblotting and ELISA. Autoantibody reactivity was detected in 48% (93/193) of the mothers of children with AV block. In autoantibody-positive mothers, the vast majority, 95% (88/93), had antibodies against Ro52, while 63% (59/93) had autoantibodies to Ro60 and 58% (54/93) had autoantibodies to La. In addition, 13% (12/93) of the autoantibody-positive mothers had antibodies to other investigated antigens besides Ro52, Ro60 and La, and of these anti-histone antibodies were most commonly represented, detected in 8% (7/93) of the mothers. In conclusion, this Swedish population-based study confirms that maternal autoantibodies may associate with heart block in the child. Further, our data demonstrate a dominant role of Ro52 antibodies in association with AV block.

Atherothrombotic events in rheumatoid arthritis are predicted by homocysteine - a six-year follow-up study.

OBJECTIVE: The aim of this study was to investigate whether homocysteine is linked to atherothrombotic (AT) events in patients with rheumatoid arthritis (RA). METHODS: Analysis of homocysteine (Hcy) levels was carried out in 235 consecutive RA patients. They were followed-up for 6.5 years or until death, with analysis of AT risk factors and the type and length of DMARD and corticosteroid treatment. The disease history before inclusion was collected. Six categories of AT events were defined. In addition, the diagnosis of the patients at follow-up was co-analyzed with the nationwide population-based Swedish Inpatient Register and Death Register to certify all events. RESULTS: The Hcy level was found to be higher in males (p<0.05) and increased with age (p<0.001). Patients with folic acid supplementation had significantly lower levels, while those on corticosteroids had higher levels. High Hcy levels predicted AT events (n=48) during a 6.5-year follow-up adjusted for age and male sex in a logistic regression analysis. CONCLUSION: In this study, RA patients on folic acid had lower Hcy levels. High Hcy levels (in addition to age, sex and diabetes) predicted AT event prospectively.

Increased incidence of stroke and impaired prognosis after stroke among patients with seropositive rheumatoid arthritis.

OBJECTIVE: To examine the incidence of, and outcome after, a stroke in patients with rheumatoid arthritis (RA) compared with the general population. METHODS: The northern Sweden MONICA register was used to compare the incidence of stroke in a cohort of RA patients with the general population. Forty RA patients who had also suffered a stroke were identified. For each patient with RA, three controls with a history of stroke but without RA were randomly collected from the same register, and matched for age and sex. RESULTS: The standardised incidence ratio (SIR) for stroke was 2.7 in RA patients compared with the general population (p<0.05). During the follow-up, RA patients had a higher overall case fatality (CF) following stroke compared with controls (hazard ratio (HR) =1.70, p<0.05). CONCLUSIONS: Both the incidence of a stroke, and the subsequent CF, were higher among RA patients compared with the general population. The results emphasize the necessity of optimising the prevention of stroke and follow-up care after a stroke in RA.

Increased arterial stiffness and indication of endothelial dysfunction in long-standing rheumatoid arthritis.

OBJECTIVE: Atherosclerotic progression is accelerated in rheumatoid arthritis (RA). We evaluated arterial stiffness and endothelial dysfunction in RA patients and controls by pulse wave analysis (PWA). METHODS: Thirty RA patients with long-standing disease and 30 age- and sex-matched controls were examined using applanation tonometry of the radial artery before and after vasodilation by terbutaline (endothelium dependent) and nitroglycerin (endothelium independent). The aortic augmentation index (AIx) and time to reflected wave (transit time, Tr) were measured. Using the peripheral pulse curve, the stiffness index (SI) and the reflectance index (RI) were calculated. Tr and SI predominantly reflect large artery stiffness, whereas Aix and RI also reflect small vessel resistance. The PWA measurements were assessed in relation to adhesion molecules [soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble intracellular adhesion molecule-1 (sICAM-1)], selectins (E, L and P), and inflammation [erythrocyte sedimentation rate (ESR), haptoglobin, interleukin (IL)-6, IL-1 receptor antagonist (IL-1-Ra), IL-2-soluble receptor (IL-2sR), and tumour necrosis factor receptors-I and -II (TNFR-I and TNFR-II)]. RESULTS: RA patients had shorter Tr (p<0.05) and higher SI (p<0.001) than controls, indicating impaired large vessel compliance. After terbutaline, Tr remained shorter (p<0.05), while SI (p<0.01) and AIx (p<0.01) were higher. The post-terbutaline changes in AIx and RI (DeltaAIx, DeltaRI), suggested to be the best PWA measurements of endothelial function, were smaller in RA patients (p = 0.06). In RA, L-selectin and sVCAM-1 correlated with DeltaRI and L-selectin also with DeltaAIx. Both RI and AIx correlated at baseline with a retrospective inflammatory activity score. CONCLUSION: Arterial stiffness was increased in RA patients. Endothelial dysfunction was implicated and correlated with levels of soluble adhesion molecules. Small vessel resistance correlated with the long-standing inflammatory load in RA.

Interleukin-1 receptor antagonist is associated with both lipid metabolism and inflammation in rheumatoid arthritis.

BACKGROUND: There is a relationship between cardiovascular morbidity, inflammatory activity, and changes in the lipid profile in rheumatoid arthritis (RA), although the mechanisms are not fully elaborated. Recent know-ledge that white adipose tissue (WAT) is a producer of immunologically and metabolically active substances gives another perspective to study. OBJECTIVE: To evaluate the relationship between interleukin-1 receptor antagonist (IL-1Ra) and variables associated with WAT and inflammation in RA. METHODS: Anthropometric, inflammatory and metabolic variables were assessed in 23 women with RA and 23 matched controls. Spearman, partial correlation and factor analyses were performed. RESULTS: Inflammatory markers were increased in patients. In both groups, IL-1Ra correlated with leptin independent of age and BMI. IL-1Ra also correlated with haptoglobin and apolipoprotein (Apo) B in patients and with soluble TNF receptor (sTNFR) 1 in controls. In factor analysis, three latent factors were identified among patients. The first loaded on IL-1Ra, leptin, BMI, ApoB and body fat content (BF%), the second loaded on IL1-Ra and sTNF-receptors and the third showed inverse loadings on ApoA-I together with loadings on ESR, haptoglobin, orosomucoid, BF% and BMI. CONCLUSION: IL-1Ra was associated with markers of inflammation and with fat-related factors in RA patients, suggesting a dualistic relationship of IL-1Ra in RA. IL-1Ra correlated independently with leptin in both patients and controls, indicating a relationship between inflammation and leptin.

Polymorphism of genes related to cardiovascular disease in patients with rheumatoid arthritis.

OBJECTIVE: To analyze candidate genes, related to cardiovascular disease (CVD) in general, and potentially involved in the inflammatory process, in RA patients from northern Sweden. METHODS: Four hundred and sixty-seven individuals (345 females; 122 males) with RA (ACR criteria), having a mean age of 61.8 +/- 13.0 years and mean disease duration of 16.2 +/- 12.1 years, were consecutively recruited and followed-up for 3 years. The prevalence of CVD, [(ischemic heart disease (IHD), deep vein thromboses/pulmonary embolism (DVT/PE) and/or stroke/TIA] and hypertension was registered. Candidate genes encoding for Beta-fibrinogen (G-455A), Factor XIIIA (Val34Leu), plasminogen activator inhibitor type-1 (PAI-1 4G/5G), and tumor necrosis factor receptor (TNFR)II (M196R) were analysed. Controls (n = 672) were randomly selected according to age and gender from the Medical Biobank of Northern Sweden. Polymorphisms were genotyped using a TaqMan 9700HT and the 5'nuclease allelic discrimination assay. RESULTS: The genotypes, carriers and alleles did not differ in distribution between patients and controls. Carriage of the TNFRII R variant was more frequent among patients with hypertension (p = 0.018). The genotype distribution of PAI-1 in patients with IHD differed significantly (p = 0.002) because carriage of 4G was more frequent (p = 0.024). Combined carriage of TNFRII 196R variant and Beta-fibrinogen-455A was a stronger predictor for hypertension than each genotype separately. The distribution of FXIIIA genotypes deviated significantly in RA patients with DVT/PE (p = 0.028) with an increased frequency of the Leu34 variant. CONCLUSION: The unusual alleles of TNFRII, PAI-1 and FXIIIA were associated with CVD in RA patients. The combination of several of the rare types further increased the predictive values for CVD.

Which factors are related to the presence of atherosclerosis in rheumatoid arthritis?

OBJECTIVE: An accelerated progression of atherosclerosis may contribute to the increased mortality due to cardiovascular disease reported in rheumatoid arthritis (RA). The aim of this study was to identify variables, related to disease onset as well as to disease progression, of importance for the presence of atherosclerosis, as diagnosed by B-mode ultrasonography, in patients with medium-term RA. The results are based on the co-analysis of retrospective data as well as cross-sectional data. The impact of RA per se on atherosclerosis was evaluated relative to age- and sex-matched controls. METHODS: Thirty-nine RA patients, with a maximum age of 65 years, who had previously been included in a large retrospective cohort study, were assessed by duplex scanning after a disease duration of 19-23 years. In the present study, factors identified in the two earlier studies were assessed for their potential relationship with intima-media wall thickness (IMT) of the common carotid artery (CCA), and the presence and grade of atherosclerotic plaques of the CCA and the common femoral artery, in regression models. The candidate co-variates were: variables reflecting inflammatory activity at disease onset and at the time of ultrasound assessment, established cardiovascular risk factors, pharmacological treatment [corticosteroids, disease-modifying anti-rheumatic drugs (DMARDs)], and the presence of complications and co-morbidity identified during disease progression, as well as lipid levels, anti-lipid antibodies, haemostatic factors, and markers of immune activation measured at ultrasound assessment. RESULTS: In patients with RA, analysis of simple linear regression models revealed those variables significantly associated with IMT-CCA to be age, tissue plasminogen activator (tPA) antigen, cholesterol, low density lipoprotein (LDL)-cholesterol, triglycerides, and atherosclerotic plaques while neither inflammatory status at disease onset, traditional cardiovascular risk factors, or pharmacological treatment during disease had any significant impact on IMT. In an estimated multiple linear regression model, variables associated with increasing log of IMT-CCA were the log of cholesterol and of soluble intracellular adhesion molecule 1 (sICAM-1), while methotrexate treatment tended to have a decreasing effect. In simple binary logistic regression, atherosclerotic plaques were associated with age, IMT-CCA, smoking, and the levels of sICAM-1, sE-selectin, interleukin-2 soluble receptor alpha (IL-2sRalpha), plasminogen activator inhibitor-1 (PAI-1) mass, cholesterol, LDL-cholesterol, and the LDL/high density lipoprotein (HDL) ratio. A multiple approach indicated that plaques were associated with age, cholesterol, and sE-selectin. Severe plaques were associated with LDL-cholesterol and disease duration. Logistic regression in the age- and sex-matched case-control study revealed that IMT-CCA was, together with the D-dimer, associated with RA per se. CONCLUSION: Levels of lipids and adhesion molecules were associated with the presence of atherosclerosis in RA. IMT-CCA was associated with RA per se. Disease duration could predict severe atherosclerotic plaques. Treatment with methotrexate seemed to decrease the IMT-CCA.

Homocysteine in patients with rheumatoid arthritis in relation to inflammation and B-vitamin treatment.

OBJECTIVES: To investigate the effects of treatment with B vitamins on homocysteine (Hcy) levels in patients with RA, and to analyse the relationship between Hcy levels and inflammatory variables, and/or MTX treatment. METHODS: Sixty-two patients with RA and levels of Hcy > or = 12 mumol/L were randomized to receive placebo or a combination of vitamins B6, B12 and folic acid. The patients were treated and evaluated in a double-blind manner over 12 months. RESULTS: The Hcy level decreased significantly in the B-vitamin treated patients compared with the placebo treated patients. In a simple regression model, the Hcy level at inclusion was associated with IL-2sR alpha. In a multiple regression model there was an association between the alteration in Hcy level over 0-12 months and MTX treatment, as well as the alteration in CRP, adjusted for B-vitamin treatment. CONCLUSIONS: In patients with RA, Hcy levels can be reduced by treatment with B-vitamins. The Hcy levels were related to markers of inflammation and MTX treatment.

Increased levels of autoantibodies against copper-oxidized low density lipoprotein, malondialdehyde-modified low density lipoprotein and cardiolipin in patients with rheumatoid arthritis.

OBJECTIVES: To analyse the association of autoantibodies against cardiolipin (CL) and oxidized low density lipoproteins [copper-oxidized low density lipoprotein (oxLDL), malondialdehyde-modified LDL (MDA-LDL)] with rheumatoid arthritis (RA) and cardiovascular complications. METHODS: One hundred and twenty-one patients with RA were consecutively included. Autoantibodies were determined by ELISA. Healthy individuals from the same region were used as controls. RESULTS: Levels of IgG, IgM and IgA antibodies against MDA-LDL and CL, as well as IgG and IgA antibodies against oxLDL were increased in the patients (P<0.01). The prevalence of IgG, IgM and IgA antibodies against CL was higher than in the normal population (74, 82 and 14%, respectively). The prevalence of IgG and IgA antibodies against oxLDL was also significantly increased (35 and 25%, respectively) and so was the prevalence of IgG and IgM antibodies against MDA-LDL (17 and 26%, respectively) compared with controls. The levels of IgM and IgA antibodies against aCL and IgM against MDA-LDL were increased in patients with extra-articular manifestations. Patients who developed myocardial infarction had a higher prevalence of IgG antibodies against MDA-LDL (P=0.04). There were substantial correlations between the levels of antibodies against oxLDL, MDA-LDL and CL. CONCLUSIONS: RA patients had increased levels and prevalence of autoantibodies against CL, oxLDL and MDA-LDL, with associations to severity of disease and cardiovascular complications.

Increased content of bombesin/GRP in human synovial fluid in early arthritis: different pattern compared with substance P.

OBJECTIVE: Bombesin (BN) and the mammalian homologue gastrin-releasing peptide (GRP) are known trophic factors, neurotransmitters and paracrine hormones. BN/GRP has not previously been demonstrated in synovial fluid. In this study, the amounts of BN/GRP and substance P (SP) present in synovial fluid from the knee joints of patients with rheumatoid arthritis (RA) and of healthy controls were measured. METHODS: Synovial fluid from the knee joint was collected from patients with either longstanding RA (n = 32) or early arthritis (symptoms for < 12 months; n = 9) and from control subjects, i.e., individuals without known joint disease (n = 10). These samples were analyzed using radioimmunoassays. RESULTS: Levels of BN/GRP-like peptide were below the assay detection limits in synovial fluid from controls. Detectable levels of immunoreactive BN/GRP were present in the majority of patients with either longstanding RA or early arthritis. The levels were significantly higher in the synovial fluid from patients classified as having early arthritis compared with those with longstanding RA (p < 0.05). There was a strong correlation between BN/GRP levels and the number of leukocytes in the synovial fluid in the patients with early arthritis. The levels of SP-like peptide in the patients, whether with early arthritis or longstanding RA, were significantly elevated compared with controls. However, there was no difference in the levels between these two patient groups. CONCLUSIONS: These observations show that BN/GRP-like peptide is present in the synovial fluid of joints affected by arthritis and that the pattern of BN/GRP increase differs from that of SP. It appears as if the presence of BN/GRP is particularly related to the early processes of joint involvement. These observations are of interest because BN/GRP has well-known trophic and paracrine effects and chondrocytes have recently been shown to produce neuropeptides such as BN/GRP.

Hemostatic factors and cardiovascular disease in active rheumatoid arthritis: an 8 year followup study.

OBJECTIVE: To investigate the prospective effect of hemostatic factors and inflammatory variables on the progression of cardiovascular disease in rheumatoid arthritis (RA). METHODS: Von Willebrand factor (vWF) and the fibrinolytic factors tissue plasminogen activator (tPA), measured as tPA capacity, and plasminogen activator inhibitor 1 (PAI-1), platelets, fibrinogen, and inflammatory markers were measured in 74 patients with active seropositive RA. Lipid levels, lipoprotein(a), and cardiolipin antibodies were also analyzed. Cardiovascular disease, measured by past cardiovascular events including thrombotic events, was registered in an 8 year followup. RESULTS: Patients with a cardiovascular event during the followup period (n = 26) had significantly higher levels of vWF, PAI-1, erythrocyte sedimentation rate (ESR), and haptoglobin at entry to the study. In a multiple logistic regression model controlling for several conventional cardiovascular risk factors and pharmacological treatment at sampling, PAI-1 and tPA were significantly associated with cardiovascular disease progression. CONCLUSION: The altered levels of vWF, PAI-1, and, in logistic regression, tPA in RA patients with cardiovascular disease progression indicates a status of hypofibrinolysis in these patients. Higher levels of ESR and haptoglobin may reflect the importance of the inflammatory process for the development of cardiovascular disease in RA.

Extent of inflammation predicts cardiovascular disease and overall mortality in seropositive rheumatoid arthritis. A retrospective cohort study from disease onset.

OBJECTIVE: To identify predictors for cardiovascular disease (CVD) and for overall survival in patients with rheumatoid arthritis (RA) followed from disease onset. METHODS: A retrospective cohort of patients with seropositive RA and disease onset between 1974 and 1978 (n = 211) was followed up at the end of 1995. Potential predictors for CVD, as measured by "the first cardiovascular event," and for overall survival were registered. The predictors were identified by extended Cox regression models. RESULTS: In simple Cox regression analysis, male sex, higher age at disease onset, HLA-B27, high disease activity, corticosteroid treatment early in disease, and hypertension significantly increased risk of cardiovascular event. Higher educational level, extensive disease modifying antirheumatic drug (DMARD) treatment, and corticosteroids > or =1 yr before event decreased the risk. In multiple Cox regression analysis, male sex, high age at disease onset, hypertension, higher haptoglobin level at disease onset, and corticosteroid treatment early in disease increased risk of CVD. In a multiple model comprising only patients with CVD, corticosteroids delayed the event. A high last registered erythrocyte sedimentation rate (ESR) value before event increased CVD risk, in particular when early in disease progression. Decreased life span was predicted by higher age at disease onset, male sex, low education level, high disease activity, hypertension, and CVD. HLA-B27 was associated with decreased life span, as was early, but not extensive corticosteroid treatment. DMARD treatment was associated with decreased mortality risk, as was the presence of joint prosthesis. In multiple regression, male sex, higher age at disease onset, atlantoaxial subluxation early in disease, hypertension, and cardiovascular event increased mortality. A high last registered ESR value before event or death added to that risk. CONCLUSION: The study emphasizes the importance of inflammation as an important risk indicator for CVD and mortality in RA. The positive impact of disease activity reducing treatment on CVD risk and survival is suggested.

Cardiovascular morbidity and mortality in patients with seropositive rheumatoid arthritis in Northern Sweden.

OBJECTIVE: To investigate the overall and the cardiovascular mortality in rheumatoid arthritis (RA) in Northern Sweden. To analyze the effect of traditional risk factors and factors associated with rheumatoid disease and its treatment on the progression of cardiovascular disease (CVD) and on mortality by all causes. METHODS: A cohort of 606 patients with seropositive RA were followed from 1979 to the end of 1994 or to the death of the patient. Standardized mortality ratio and survival curves were estimated with the population of Vasterbotten as reference. Sex, age at disease onset, treatment with corticosteroids, use of disease modifying antirheumatic drugs (DMARD) and hormone replacement therapy (HRT), hypertension, diabetes mellitus, HLA types, and cause of death were recorded from disease onset. Cox's proportional hazards regression was used to identify important predictors for death and cardiovascular event during followup. RESULTS: The standardized mortality ratio in both sexes was significantly higher (1.57) for all underlying causes together, for CVD (1.46) and for ischemic heart disease (IHD) (1.54) compared to the reference population. The death rate increased over time. In multiple Cox regression analyses, male sex, higher age at disease onset, and former cardiovascular event increased the death rate. Male sex, high age at disease onset, and hypertension increased the risk of cardiovascular event. Diabetes mellitus, treatment with corticosteroids, DMARD, or HRT did not influence the risks of death or first cardiovascular event. CONCLUSION: The overall mortality and death due to CVD and IHD were in both sexes increased in seropositive RA. Male sex and high age at disease onset predicted death and cardiovascular event. Except for hypertension, which increased the risk for cardiovascular event, neither of these traditional cardiovascular risk factors nor corticosteroid treatment influenced mortality by all causes or by cardiovascular event.