Maria Majdan

Cardiovascular disease in patients with rheumatoid arthritis: results from the QUEST-RA study

IntroductionWe analyzed the prevalence of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA) and its association with traditional CV risk factors, clinical features of RA, and the use of disease-modifying antirheumatic drugs (DMARDs) in a multinational cross-sectional cohort of nonselected consecutive outpatients with RA (The Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis Program, or QUEST-RA) who were receiving regular clinical care.MethodsThe study involved a clinical assessment by a rheumatologist and a self-report questionnaire by patients. The clinical assessment included a review of clinical features of RA and exposure to DMARDs over the course of RA. Comorbidities were recorded; CV morbidity included myocardial infarction, angina, coronary disease, coronary bypass surgery, and stroke. Traditional risk factors recorded were hypertension, hyperlipidemia, diabetes mellitus, smoking, physical inactivity, and body mass index. Unadjusted and adjusted hazard ratios (HRs) (95% confidence interval [CI]) for CV morbidity were calculated using Cox proportional hazard regression models.ResultsBetween January 2005 and October 2006, the QUEST-RA project included 4,363 patients from 48 sites in 15 countries; 78% were female, more than 90% were Caucasian, and the mean age was 57 years. The prevalence for lifetime CV events in the entire sample was 3.2% for myocardial infarction, 1.9% for stroke, and 9.3% for any CV event. The prevalence for CV risk factors was 32% for hypertension, 14% for hyperlipidemia, 8% for diabetes, 43% for ever-smoking, 73% for physical inactivity, and 18% for obesity. Traditional risk factors except obesity and physical inactivity were significantly associated with CV morbidity. There was an association between any CV event and age and male gender and between extra-articular disease and myocardial infarction. Prolonged exposure to methotrexate (HR 0.85; 95% CI 0.81 to 0.89), leflunomide (HR 0.59; 95% CI 0.43 to 0.79), sulfasalazine (HR 0.92; 95% CI 0.87 to 0.98), glucocorticoids (HR 0.95; 95% CI 0.92 to 0.98), and biologic agents (HR 0.42; 95% CI 0.21 to 0.81; P < 0.05) was associated with a reduction of the risk of CV morbidity; analyses were adjusted for traditional risk factors and countries.ConclusionIn conclusion, prolonged use of treatments such as methotrexate, sulfasalazine, leflunomide, glucocorticoids, and tumor necrosis factor-alpha blockers appears to be associated with a reduced risk of CV disease. In addition to traditional risk factors, extra-articular disease was associated with the occurrence of myocardial infarction in patients with RA.

Remission and rheumatoid arthritis: Data on patients receiving usual care in twenty-four countries

OBJECTIVE To compare the performance of different definitions of remission in a large multinational cross-sectional cohort of patients with rheumatoid arthritis (RA). METHODS The Questionnaires in Standard Monitoring of Patients with RA (QUEST-RA) database, which (as of January 2008) included 5,848 patients receiving usual care at 67 sites in 24 countries, was used for this study. Patients were clinically assessed by rheumatologists and completed a 4-page self-report questionnaire. The database was analyzed according to the following definitions of remission: American College of Rheumatology (ACR) definition, Disease Activity Score in 28 joints (DAS28), Clinical Disease Activity Index (CDAI), clinical remission assessed using 42 and 28 joints (Clin42 and Clin28), patient self-report Routine Assessment of Patient Index Data 3 (RAPID3), and physician report of no disease activity (MD remission). RESULTS The overall remission rate was lowest using the ACR definition of remission (8.6%), followed by the Clin42 (10.6%), Clin28 (12.6%), CDAI (13.8%), MD remission (14.2%), and RAPID3 (14.3%); the rate of remission was highest when remission was defined using the DAS28 (19.6%). The difference between the highest and lowest remission rates was >or=15% in 10 countries, 5-14% in 7 countries, and <5% in 7 countries (the latter of which had generally low remission rates [<5.5%]). Regardless of the definition of remission, male sex, higher education, shorter disease duration, smaller number of comorbidities, and regular exercise were statistically significantly associated with remission. CONCLUSION The use of different definitions of RA remission leads to different results with regard to remission rates, with considerable variation among countries and between sexes. Reported remission rates in clinical trials and clinical studies have to be interpreted in light of the definition of remission that has been used.

Patient's global assessment of disease activity and patient's assessment of general health for rheumatoid arthritis activity assessment: are they equivalent?

Objectives To assess (A) determinants of patients global assessment of disease activity (PTGL) and patients assessment of general health (GH) scores of rheumatoid arthritis (RA) patients; (B) whether they are equivalent as individual variables; and (C) whether they may be used interchangeably in calculating common RA activity assessment composite indices. Methods Data of 7023 patients from 30 countries in the Quantitative Standard Monitoring of Patients with RA (QUEST-RA) was analysed. PTGL and GH determinants were assessed by mixed-effects analyses of covariance models. PTGL and GH equivalence was determined by Bland-Altman 95% limits of agreement (BALOA) and Lins coefficient of concordance (LCC). Concordance between PTGL and GH based Disease Activity Score 28 (DAS28), Clinical Disease Activity Index (CDAI) and Routine Assessment of Patient Index Data 3 (RAPID3) indices were calculated using LCC, and the level of agreement in classifying RA activity in four states (remission, low, moderate, high) using κ statistics. Results Significant differences in relative and absolute contribution of RA and non-RA related variables in PTGL and GH ratings were noted. LCC of 0.64 and BALOA of −4.41 to 4.54 showed that PTGL and GH are not equivalent. There was excellent concordance (LCC 0.95–0.99) for PTGL and GH based DAS28, CDAI and RAPID3 indices, and >80% absolute agreement (κ statistics 0.75–0.84) in RA activity state classification for all three indices. Conclusions PTGL and GH ratings differ in their determinants. Although they are individually not equivalent, they may be used interchangeably for calculating composite indices for RA activity assessment.

Adiponectin and leptin serum concentrations in patients with rheumatoid arthritis

Adipose tissue is regarded as an active metabolic and endocrine organ producing adipokines. The purpose of the study was to evaluate adiponectin and leptin concentrations in rheumatoid arthritis (RA) patients (pts) in relation to disease duration and activity. The study group consisted of 80 RA pts. Serum adiponectin and leptin concentrations remained within normal ranges. Adiponectin concentration correlated positively both with the age and disease duration. Both adipokines levels correlated negatively with glomerular filtration rate. There were significant positive correlations between adipokines’ concentrations and lipid profile components (between adiponectin and HDL-cholesterol, leptin and total cholesterol and LDL-cholesterol). In pts with long-standing RA, there was a negative correlation between adiponectin and numbers of tender, swollen joints and a positive relationship between leptin level and DAS28. The results confirm adipokines’ involvement in the process of inflammation and atherosclerosis: protective and antiinflammatory adiponectin effect and proatherogenic and proinflammatory leptin function.

Lack of association between three vascular endothelial growth factor gene polymorphisms and systemic sclerosis: results from a multicenter EUSTAR study of European Caucasian patients

Introduction: Systemic sclerosis (SSc) is characterised by disturbed vessel morphology and an overproduction of vascular endothelial growth factor (VEGF). The VEGF gene located on chromosome 6p21.3 has several polymorphisms. Objective: To test the hypothesis that disturbed angiogenesis may be related to the genetic background of the VEGF gene. Materials and methods: EUSTAR centres included European Caucasian patients with SSc and matched controls with osteoarthritis. The VEGF gene was genotyped by polymerase chain reaction, followed by restriction enzyme analysis. The 634 C/T and 936 C/G mutations and an 18-base pair insertion/deletion at −2549 of the VEGF promoter region were tested. Results: 416 patients with SSc and 249 controls were included in the study population. Of the patients with SSc, 42% had a diffuse cutaneous subtype, 16% had increased pulmonary arterial pressure and 61% had decreased carbon monoxide diffusion capacity. The genotype frequencies in the patients with SSc and in controls were in Hardy–Weinberg equilibrium. The allele and genotype frequencies of the polymorphisms did not differ between patients with SSc and controls. No association was found between these polymorphisms and disease phenotypes. Conclusion: This study shows that there is no association between the three selected functional VEGF polymorphisms and SSc.

The relationship between carotid intima-media thickness and the activity of rheumatoid arthritis.

Background:Cardiovascular (CV) disease, the most common cause of mortality in patients with rheumatoid arthritis (RA), is largely attributable to accelerated atherosclerosis. Carotid intima-media thickness (cIMT) has been approved as a surrogate marker of early atherosclerosis. Objectives:The aim of the study was to assess cIMT in RA patients lacking concomitant comorbidities potentially influencing cIMT value. Methods:The study group consisted of 74 RA patients, without diagnosed heart or kidney disease, hypertension, diabetes, obesity, or current smoking (mean age, 46.4 [SD, 10.6] years; range, 19-70 years). Assessment of cIMT was determined by high-resolution B-mode ultrasonography in RA patients and 31 control subjects (mean age, 42.6 [SD, 8.0] years; range, 27-59 years). Results:The mean maximum cIMT value was significantly greater in RA patients than in control subjects (0.73 [SD, 0.14] vs 0.59 [SD, 0.12] mm; P < 0.0001). In RA patients, cIMT correlated positively with a number of immunological and inflammatory parameters and also with amino-terminal pro-brain natriuretic peptide (NT-proBNP), age, metabolic variables (serum cholesterol, creatinine, cystatin C). In multiple linear regression analysis, significant association was found between cIMT and NT-proBNP and age. Patients without atherosclerosis (cIMT <0.6 mm) were younger and had significantly lower concentrations of NT-proBNP and total cholesterol, as well as higher estimated glomerular filtration rate. The course of RA in patients without atherosclerosis was characterized by shorter disease duration, lower tender joint count, and C-reactive protein. Conclusions:Values of cIMT were significantly greater in RA compared with control subjects. Features of RA, such as extra-articular manifestations, erosions, high inflammatory parameters, and long disease duration, even in the absence of traditional clinical CV risk factors, were associated with greater cIMT, suggesting an unfavorable CV risk profile.

Coexistence of five autoimmune diseases: diagnostic and therapeutic difficulties

We report the case of coexistence of five autoimmune diseases in a 36-year-old woman, who initially developed psoriasis. Several years later, the patient was diagnosed with a mixed connective tissue disease and primary biliary cirrhosis (PBC). On admission to the Department of Rheumatology and Connective Tissue Diseases, the patient fulfilled classification criteria of an overlap syndrome systemic lupus erythematosus (SLE) with secondary antiphospholipid syndrome/systemic sclerosis (SSc)/Sjogren’s syndrome (SS) with coexisting PBC and psoriasis. The SLE symptoms included discoid lupus erythematosus, arthritis, pancytopenia, antinuclear antibodies and anticardiolipin antibodies. Moreover, the patient met the criteria of antiphospholipid syndrome diagnosed based on preterm delivery before week 34, and high values of anticardiolipin antibodies were found at repeated determinations. The SSc symptoms included sclerodactyly, pulmonary fibrosis with pulmonary hypertension and esophageal dysfunction. The SS syndrome involved xerostomia, xerophthalmia, the positive Schirmer’s test and presence of anti-SS antibodies. The literature reports overlap syndromes in various combinations; however, the coexistence of five autoimmune diseases is extremely rare.

Serum amyloid A as a marker of persistent inflammation and an indicator of cardiovascular and renal involvement in patients with rheumatoid arthritis.

Objectives. Rheumatoid arthritis (RA) is a systemic, inflammatory disease. Serum amyloid A (SAA) is an acute-phase protein, involved in pathogenesis of atherosclerosis. The aim of the study was to assess serum concentration of SAA in RA patients, with reference to other inflammatory parameters and markers of extra-articular involvement. Methods. The study population consisted of 140 RA patients, low/moderate disease activity (L/MDA) in 98 (70%) patients and high disease activity (HDA) in 42 (30%). Comprehensive clinical and laboratory assessment was performed with evaluation of electrocardiogram and carotid intima-media thickness. Results. The mean SAA concentration [327.0 (263.4) mg/L] was increased highly above the normal value, even in patients with L/MDA. Simultaneously, SAA was significantly higher in patients with HDA versus L/MDA. The mean SAA concentration was significantly higher in patients treated with glucocorticoids, was inversely associated with QTc duration, and was markedly higher in patients with atherosclerotic plaques, emphasizing increased CV risk. SAA was significantly higher in patients with increased cystatin-C level. Conclusions. In RA patients, high serum SAA concentration was strongly associated with activity of the disease and risk of CV and renal involvement. Recurrent assessment of SAA may facilitate searching patients with persistent inflammation and risk of extra-articular complications.

Identification of latent tuberculosis infection in rheumatic patients under consideration for treatment with anti-TNF-α agents

Introduction Immunosuppressive therapy with anti-tumour necrosis factor-α (TNF-α) agents in rheumatic patients modulates the immune system and may increase the risk of reactivating infections that are normally maintained in a latent state, such as tuberculosis. The purpose of this study was to analyse the value of QuantiFERON TB Gold In-Tube (QFT IT) and tuberculin skin test (TST) in BCG vaccinated patients with rheumatoid arthritis and ankylosing spondylitis who were qualified to receive TNF-α blockers. Material and methods Ninety patients with rheumatoid arthritis and ankylosing spondylitis were included in the study. The control group consisted of 20 healthy participants. Chest X-ray, TST and QFT IT were carried out in all persons. Results In rheumatic patients positive results of QFT IT and TST tests were identified in 15 cases (16.7%) whereas negative results of both tests were detected in 56 cases (62.2%). In the group of examined patients, 11 (12.2%) had QFT IT-/TST+ test results. In patients with QFT IT+/TST– status one active tuberculosis case was detected. In the control group QFT IT positive results were found in 4 cases (20%) and TST positive in 11 cases (55%). Treatment with TNF-α blockers was introduced in 26 rheumatology patients with the following test status: 3 with QFT IT+/TST+; 20 with QFT IT-/TST-; 3 with QFT IT-/TST+. Conclusions In the BCG vaccinated population the QFT IT assay may potentially improve the identification and selection for therapy for latent TB infection before treatment with anti-TNF agents.

Antiphospholipid antibodies and kidney involvement in patients with systemic sclerosis

Antiphospholipid (aPL) antibodies are often detected in systemic autoimmune diseases. The aim of the study was to examine the correlation between the presence of aPL and certain markers of renal function in systemic sclerosis (SSc). Fifty patients (pts) with SSc were examined for the presence of antibodies to cardiolipin (aCL) and to anti-beta 2 glycoprotein I (a-B2GPI) in immunoglobulin M (IgM) and IgG class. Moreover, serum levels of creatinine, cystatin C, and glomerular filtration rate (GFR) were determined in all patients. In all studied pts together, three multiple-regression analyses were performed with one set cystatin C as a dependent variable, in the second GFR according to the Cockcroft–Gault formula and in the third creatinine clearance by Modification of Diet in Renal Disease (MDRD) formula. As independent variables, aPL of either type were inserted in addition to disease duration and age. IgG aCL was significantly positively associated with serum cystatin C (p = 0.002), significantly negatively associated with creatinine clearance according to the Cockcroft–Gault and MDRD formula (p = 0.01 and 0.02, respectively). IgG a-B2GPI was significantly negatively associated with creatinine clearance according to the Cockcroft–Gault (p = 0.03) and MDRD (p = 0.01) formula. IgM aCL and IgM a-B2GPI were not associated with any markers of the renal function. Our study suggests the relationship between kidney involvement and the positivity for some aPL in patients with SSc. Positivity for IgG aCL and IgG a-B2GPI in patients with SSc without secondary antiphospholipid syndrome seems to be connected with decrease of glomerular filtration.