Alfonso Corrales

Carotid ultrasound is useful for the cardiovascular risk stratification of patients with rheumatoid arthritis: results of a population-based study

Objective To determine if the use of carotid ultrasonography (US) may improve the stratification of the cardiovascular (CV) risk in rheumatoid arthritis (RA). Methods A set of 370 consecutive patients without history of CV events were studied to assess carotid intima-media thickness (cIMT) and plaques. As previously proposed, CV risk was calculated according to the modified EULAR systematic coronary risk evaluation (mSCORE) for RA that was adapted by the application of a multiplier factor of 1.5 in those patients fulfilling ≥2 of 3 specific criteria. Results The mean disease duration was 9.8 years, 250 (68%) had rheumatoid factor/anticyclic citrullinated peptide positivity and 61 (17%) extra-articular manifestations. 43 were excluded because they had type 2 diabetes mellitus or severe chronic kidney disease. CV risk was categorised in the remaining 327 RA patients according to the mSCORE: mild (96 cases; 29.3%), moderate (201; 61.5%) and high/very high risk (30; 9.2%). Only five patients were reclassified as having high/very high CV risk when the mSCORE was applied. Severe carotid US abnormalities (cIMT >0.90 mm and/or plaques) were uncommon in patients with low mSCORE (13%). Nevertheless, in patients with moderate mSCORE, severe carotid US abnormalities were observed in 63% of cases. A model that included a chart mSCORE risk ≥5% plus the presence of severe carotid US findings in patients with moderate mSCORE risk (≥1% and <5%) yielded high sensitivity for high/very high CV risk (93 (95% CI 88 to 96)). Conclusions Our results support the use of carotid US in the assessment of CV risk in patients with RA.

Cardiovascular risk stratification in rheumatic diseases: carotid ultrasound is more sensitive than Coronary Artery Calcification Score to detect subclinical atherosclerosis in patients with rheumatoid arthritis

Objective To determine the ability of Coronary Artery Calcification Score (CACS) and carotid ultrasonography in detecting subclinical atherosclerosis in rheumatoid arthritis (RA). Methods A set of 104 consecutive RA patients without history of cardiovascular (CV) events were studied to determine CACS, carotid intima-media thickness (cIMT) and plaques. Systematic Coronary Risk Evaluation (SCORE) modified according to the EULAR recommendations (mSCORE) was also assessed. Results The mean disease duration was 10.8 years, 72.1% had rheumatoid factor and/or anti-CCP positivity and 16.4% extra-articular manifestations. Nine were excluded because they had type 2 diabetes mellitus or chronic kidney disease. CV risk was categorised in the remaining 95 RA patients according to the mSCORE as follows: low (n=21), moderate (n=60) and high/very high risk (n=14). Most patients with low mSCORE (16/21; 76.2%) had normal CACS (zero), and none of them CACS>100. However, a high number of patients with carotid plaques was disclosed in the groups with CACS 0 (23/40; 57.5%) or CACS 1–100 (29/38; 76.3%). 72 (75.8%) of the 95 patients fulfilled definitions for high/very high CV as they had an mSCORE ≥5% or mSCORE <5% plus one of the following findings: severe carotid ultrasonography findings (cIMT>0.9 mm and/or plaques) or CACS>100. A CACS>100 showed sensitivity similar to mSCORE (23.6% vs 19.4%). In contrast, the presence of severe carotid ultrasonography findings allowed identifying most patients who met definitions for high/very high CV risk (70/72; sensitivity 97.2% (95% CI 90.3 to 99.7)). Conclusions Carotid ultrasonography is more sensitive than CACS for the detection of subclinical atherosclerosis in RA.

SCORE and REGICOR function charts underestimate the cardiovascular risk in Spanish patients with rheumatoid arthritis.

IntroductionOur objective was to determine which one of the two function charts available in Spain to calculate cardiovascular (CV) risk, Systematic COronary Risk Evaluation (SCORE) or Framingham-REgistre GIroní del COR (REGICOR), should be used in patients with rheumatoid arthritis (RA).MethodsA series of RA patients seen over a one-year period without history of CV events were assessed. SCORE, REGICOR, modified (m)SCORE and mREGICOR according to the European League Against Rheumatism (EULAR) recommendations were applied. Carotid ultrasonography (US) was performed. Carotid intima-media thickness (cIMT) > 0.90 mm and/or carotid plaques were used as the gold standard test for severe subclinical atherosclerosis and high CV risk (US+). The area under the receiver operating curves (AUC) for the predicted risk for mSCORE and mREGICOR were calculated according to the presence of severe carotid US findings (US+).ResultsWe included 370 patients (80% women; mean age 58.9 ± 13.7 years); 36% had disease duration of 10 years or more; rheumatoid factor (RF) and/or anticyclic citrullinated peptide (anti-CCP) were positive in 68%; and 17% had extra-articular manifestations. The EULAR multiplier factor was used in 122 (33%) of the patients. The mSCORE was 2.16 ± 2.49% and the mREGICOR 4.36 ± 3.46%. Regarding US results, 196 (53%) patients were US+. The AUC mSCORE was 0.798 (CI 95%: 0.752 to 0.844) and AUC mREGICOR 0.741 (95% CI; 0.691 to 0.792). However, mSCORE and mREGICOR failed to identify 88% and 91% of US+ patients. More than 50% of patients with mSCORE ≥1% or mREGICOR >1% were US+.ConclusionsNeither of these two function charts was useful in estimating CV risk in Spanish RA patients.

Study of Association of CD40-CD154 Gene Polymorphisms with Disease Susceptibility and Cardiovascular Risk in Spanish Rheumatoid Arthritis Patients

Objective Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased cardiovascular (CV) mortality. Since CD40-CD154 binding has direct consequences on inflammation process initiation, we aimed to replicate previous findings related to disease susceptibility in Spanish RA population. Furthermore, as the major complication in RA disease patients is the development of CV events due to accelerated atherosclerosis, and elevated levels of CD40L/CD154 are present in patients with acute myocardial infarction, we assessed the potential association of CD40 and CD154/CD40L gene variants with CV risk in Spanish RA patients. Methods One thousand five hundred and seventy-five patients fulfilling the 1987 ACR classification criteria for RA and 1600 matched controls were genotyped for the CD40 rs1883832, rs4810485 and rs1535045 and CD154 rs3092952 and rs3092920 gene polymorphisms, using predesigned TaqMan single nucleotide polymorphism genotyping assays. Afterwards, we investigated the influence of CD40-CD154 gene variants in the development of CV events. Also, in a subgroup of 273 patients without history of CV events, we assessed the influence of these polymorphisms in the risk of subclinical atherosclerosis determined by carotid ultrasonography. Results Nominally significant differences in the allele frequencies for the rs1883832 CD40 gene polymorphism between RA patients and controls were found (p = 0.038). Although we did not observe a significant association of CD40-CD154 gene variants with the development of CV events, an ANCOVA model adjusted for sex, age at the time of the ultrasonography assessment, follow-up time, traditional CV risk factors and anti-cyclic citrullinated peptide antibodies disclosed a significant association (p = 0.0047) between CD40 rs1535045 polymorphism and carotid intima media thickness, a surrogate marker of atherosclerosis. Conclusion Data from our pilot study indicate a potential association of rs1883832 CD40 gene polymorphism with susceptibility to RA. Also, the CD40 rs1535045 gene variant may influence development of subclinical atherosclerosis in RA patients.

Cardiovascular risk assessment in patients with rheumatoid arthritis: The relevance of clinical, genetic and serological markers

Cardiovascular disease (CV) is the most common cause of premature mortality in patients with rheumatoid arthritis (RA). This is the result of an accelerated atherosclerotic process. Adequate CV risk stratification has special relevance in RA to identify patients at risk of CV disease. However, current CV risk screening and management strategies underestimate the actual CV risk in RA. Consequently, the search for additional tools that may help to identify those patients at high CV risk has become a key objective in the last years. In this regard, non-invasive surrogates, such as carotid ultrasonography, have been found to be excellent predictors of future CV events. In addition, several studies have revealed the relevance of a genetic component in the development of CV disease in RA patients. Besides an association with HLA-DRB1* shared epitope alleles other gene polymorphisms located inside and outside the HLA seem to influence the risk of cardiovascular disease in RA. Moreover, serum levels of some metabolic syndrome-related biomarkers, adipokines such as adiponectin and biomarkers of endothelial cell activation and inflammation such as Osteoprotegerin and Asymmetric dimethylarginine have recently been found useful for the prediction of CV disease in these patients. An update of the current knowledge on these potential markers, especially focused on new genetic and serological biomarkers is shown in this review.

Anti-TNF-α therapy improves insulin sensitivity in non-diabetic patients with psoriasis: a 6-month prospective study.

Psoriasis is a chronic inflammatory disease associated with increased risk of cardiovascular death. Several studies have shown a beneficial effect of anti‐TNF‐α therapy on the mechanisms associated with accelerated atherogenesis in patients with inflammatory arthritis, including an improvement of insulin sensitivity. In this study, we aimed to determine for the first time whether the anti‐TNF‐α monoclonal antibody adalimumab may improve insulin sensitivity in non‐diabetic patients with psoriasis.

Multi-examiner reliability of automated radio frequency-based ultrasound measurements of common carotid intima–media thickness in rheumatoid arthritis

OBJECTIVES To assess the reliability of the automated radio frequency (RF)-based US measurement of carotid intima-media thickness (IMT) performed by rheumatologists and to evaluate the variability between this method and the conventional B-mode US measurement of carotid IMT in RA patients. METHODS Twelve rheumatologists measured in two blinded rounds the IMT of both common carotid arteries (CCAs) of seven RA patients with an automated RF-based method. At each round, a cardiologist measured both CCA-IMTs of the patients using an automated B-mode method. Inter-observer reliability for RF-based IMT measurements was evaluated by the intra-class correlation coefficient (ICC). Intra-observer reliability for RF-based IMT measurements was assessed using the root mean square coefficient of variation (RMS-CV), Bland-Altman method and ICC. Agreement between the two US methods was evaluated by the Bland-Altman method, ICC and RMS-CV. RESULTS Inter-observer ICCs for the RF-based CCA-IMT measurements were 0.85 (95% CI 0.69, 0.94) for the first round, and 0.77 (95% CI 0.55, 0.91) for the second round. RMS-CVs for the RF-based CCA-IMT measurements varied from 5.6 to 11.7%. The mean intra-observer ICC for the RF-based CCA-IMT measurements was 0.61 (95% CI 0.46, 0.71). In the Bland-Altman analysis for agreement between RF-based and B-mode CCA-IMT measurements, the mean difference varied from -0.6 to -19.7 μm. Inter-method ICCs varied from 0.57 to 0.83 for 11 rheumatologists. Inter-method RMS-CVs varied from 11.3 to 13.7%. CONCLUSIONS Our results suggest that automated RF-based CCA-IMT measurement performed by rheumatologists can be a reliable method for assessing cardiovascular risk in RA patients.

The ZC3HC1 rs11556924 polymorphism is associated with increased carotid intima-media thickness in patients with rheumatoid arthritis

IntroductionRheumatoid arthritis (RA) is a complex polygenic disease associated with chronic inflammation, accelerated atherosclerosis and increased cardiovascular (CV) mortality. A recent meta-analysis has described the ZC3HC1 rs11556924 polymorphism as one of the most important signals associated with coronary artery disease (CAD) in non-rheumatic Caucasian individuals. In this study we evaluated the potential association of this gene polymorphism with subclinical atherosclerosis assessed by the evaluation of carotid intima-media thickness (cIMT) in RA patients.MethodsThis study included 502 RA patients from Northern Spain. The ZC3HC1 rs11556924 polymorphism was genotyped with TaqMan single-nucleotide polymorphism (SNP) genotyping assays (C__31283062_10) in a 7900HT real-time polymerase chain reaction (PCR) system. cIMT was also assessed in these patients by carotid ultrasonography (US) technology.ResultsRA patients carrying the TT genotype had significantly higher cIMT values than those homozygous for the CC genotype (mean ± standard deviation (SD): 0.76 ± 0.18 mm and mean ± SD: 0.71 ± 0.16 mm respectively; P = 0.03) even after adjusting the results for sex, age at the time of US study, follow-up time and traditional CV risk factors (P = 0.04) evidencing that the effect conferred by ZC3HC1 rs11556924 polymorphism is independent of the traditional CV risk factors.ConclusionOur results indicate that ZC3HC1 rs11556924 polymorphism is associated with subclinical atherosclerosis in RA.

Anti-tumor necrosis factor-alpha therapy improves endothelial function and arterial stiffness in patients with moderate to severe psoriasis: A 6-month prospective study.

The aim of the present study was to determine if the use of the anti‐tumor necrosis factor (TNF)‐α monoclonal antibody adalimumab could improve endothelial function and arterial stiffness in patients with moderate to severe psoriasis. This was a prospective study on a series of consecutive patients with moderate to severe psoriasis who completed 6 months of therapy with adalimumab. Patients with history of cardiovascular events, diabetes mellitus, kidney disease, hypertension or body mass index of 35 kg/m2 or more were excluded. Assessment of endothelial function by brachial artery reactivity measuring flow‐mediated endothelial dependent vasodilatation (FMD%), and carotid arterial stiffness by pulse wave velocity (PWV) was performed at the onset of treatment (time 0) and at month 6. Twenty‐nine patients were studied. Anti‐TNF‐α adalimumab therapy yielded a significant improvement of endothelial function. The mean ± standard deviation (SD) FMD% values increased from 6.19 ± 2.44% at the onset of adalimumab to 7.46 ± 2.43% after 6 months of treatment with this biologic agent (P = 0.008). Likewise, following the use of adalimumab, PWV levels decreased from 6.28 ± 1.04 m/s at the onset of adalimumab to 5.69 ± 1.31 m/s at 6 months (P = 0.03). In conclusion, patients with moderate to severe psoriasis exhibit improvement of endothelial function and arterial stiffness following anti‐TNF‐α therapy. These findings are of potential relevance due to increased risk of cardiovascular disease in patients with severe psoriasis.

Carotid artery plaque in women with rheumatoid arthritis and low estimated cardiovascular disease risk: a cross-sectional study

IntroductionWe previously reported that most patients with rheumatoid arthritis (RA) and moderate cardiovascular disease (CVD) risk according to the Systematic COronary Evaluation score (SCORE) experience carotid artery plaque. In this study, we aimed to identify patient characteristics that can potentially predict carotid plaque presence in women with RA and a concurrent low CVD risk according to the SCORE.MethodsA cohort of 144 women with an evaluated low risk of CVD (SCORE value of zero) was assembled amongst 550 consecutive patients with RA that underwent CVD risk factor recording and carotid artery ultrasound. Participants had no established CVD, moderate or severe chronic kidney disease, or diabetes. We assessed carotid plaque(s) presence and its associated patient characteristics.ResultsCarotid artery plaque was present in 35 (24.3%) of women with RA. Age, the number of synthetic disease-modifying agents (DMARDs) and total cholesterol concentrations were independently associated with plaque in multivariable stepwise backward regression analysis (odds ratio (95% confidence interval) = 1.15 (1.07 to 1.24), P <0.0001, 1.51 (1.05 to 2.17), P = 0.03 and 1.66 (1.00 to 2.73) P = 0.04), respectively). The area under the curve (AUC) of the receiver operating curve (ROC) for the association with plaque was 0.807 (P <0.0001), 0.679 (P = 0.001) and 0.599 (P = 0.08) for age, total cholesterol concentrations and number of synthetic DMARDs used, respectively. The optimal cutoff value in predicting plaque presence for age was 49.5 years with a sensitivity and specificity of 74% and 75%, respectively, and for total cholesterol concentration, it was 5.4 mmol/l with a sensitivity and specificity of 63% and 70%, respectively. The plaque prevalence was 37.5% in patients (n = 80; 55.6%) with age >49.5 years or/and total cholesterol concentration of >5.4 mmol/l, respectively, compared to only 7.8% in those (n = 64; 44.4%) with age ≤49.5 years or/and total cholesterol concentration of ≤5.4 mmol/l, respectively.ConclusionsApproximately one-third of women with RA who experience a low SCORE value and are aged >49.5 years or/and have a total cholesterol concentration of >5.4 mmol/l, experience high-risk atherosclerosis, which requires intensive CVD risk management.