Sex differences in cardiovascular and disease-related features in axial spondyloarthritis. A multicenter study of 912 patients.

OBJECTIVES: To determine the potential impact of sex-specific disease-related characteristics on cardiovascular (CV) disease in axial spondyloarthritis (axSpA). METHODS: Cross-sectional study of the Spanish AtheSpAin cohort to study CV disease in axSpA. Data on carotid ultrasound and CV disease and disease-related features were collected. RESULTS: 611 men and 301 women were recruited. Classic CV risk factors were significantly less prevalent in women, who also showed a lower frequency of carotid plaques (p = 0.001), lower carotid intima-media thickness (IMT) values ​​(p<0.001) and CV events (p = 0.008). However, after adjustment for classic CV risk factors, only the differences with respect to carotid IMT remained statistically significant. Women showed higher ESR at diagnosis (p = 0.038), and more active disease (ASDAS, p = 0.012, and BASDAI, p<0.001). They had shorter disease duration (p<0.001), lower prevalence of psoriasis (p = 0.008), less structural damage (mSASSS, p<0.001), and less mobility limitation (BASMI, p = 0.033). To establish whether these findings could lead to sex differences in CV disease burden, we compared the prevalence of carotid plaques in men and women with the same level of CV risk stratified according to the Systematic Coronary Risk Evaluation (SCORE). Men included in the low-moderate CV risk SCORE category had more carotid plaques (p = 0.050), along with longer disease duration (p = 0.004), higher mSASSS (p = 0.001) and psoriasis (p = 0.023). In contrast, in the high-very high-risk SCORE category, carotid plaques were observed more frequently in women (p = 0.028), who were characterized as having worse BASFI (p = 0.011), BASDAI (p<0.001) and ASDAS (p = 0.027). CONCLUSION: Disease-related features may influence the expression of atherosclerosis in patients with axSpA. This may be especially applicable to women at high CV risk, characterized by greater disease severity and more severe subclinical atherosclerosis than men, suggesting a stronger interaction between disease activity and atherosclerosis in women with axSpA.

Cardiovascular and disease-related features associated with extra-articular manifestations in axial spondyloarthritis. A multicenter study of 888 patients.

OBJECTIVES: To determine the potential impact of extra-articular manifestations (EAMs) on disease characteristics and cardiovascular (CV) risk in patients with axial spondylarthritis (axSpA). METHODS: This is a cross-sectional study from the AtheSpAin cohort, a Spanish multicenter cohort to study atherosclerosis in axSpA. Data on the history of CV events, subclinical carotid atherosclerosis, and disease-related features, including EAMs, were collected. RESULTS: 888 axSpA patients were recruited. Concomitant acute anterior uveitis (AAU), psoriasis (PSO), and inflammatory bowel disease (IBD) were present in 177 (19.9%), 96 (10.8%), and 57 (6.4%) patients, respectively. When compared with axSpA patients without EAMs, a significant increase in past CV events was observed in patients with PSO (9% versus 4%, p = 0.048) and in those with at least one EAM (7% versus 4%, p = 0.032) or with more than one EAM (11% versus 4%, p = 0.022). The frequency of carotid plaques and the values of cIMT were higher in patients with EAMs than in those without EAMs, although only the univariable analysis for carotid plaques in patients with PSO (39% versus 30%, p = 0.038) and for cIMT in patients with AAU (665 ± 156 µm versus 637 ± 139 µm, p = 0.042) and those with at least one EAM (661 ± 155 µm versus 637 ± 139 µm, p = 0.024) showed significant results. In addition, patients with PSO or IBD were found to have specific disease-related features, such as higher ESR at diagnosis, and more frequent use of glucocorticoids and TNF inhibitors than those without EAMs. Also, PSO patients had more commonly peripheral involvement and those with AAU more severe radiographic damage than those without EAMs. The frequency of HLA B27 was higher in patients with AAU and lower in those with PSO or IBD compared to those without EAMs. CONCLUSION: Patients with axSpA and EAMs, in addition to displaying their own disease-related features, are likely to have an increased CV risk that appears proportional to the number of EAMs and could be related to proatherogenic factors other than traditional CV risk factors, such as the inflammatory load and the use of glucocorticoids.

Factors associated with atherosclerosis in radiographic and non-radiographic axial spondyloarthritis. A multicenter study on 838 patients.

OBJECTIVES: To identify disease-related factors associated with subclinical atherosclerosis and cardiovascular (CV) events in a large series of patients with axial spondyloarthritis (axSpA) and to identify possible differences in the effect of the potential pro-atherogenic factors between ankylosing spondylitis (AS) non-radiographic axSpA (nr-axSpA). METHODS: This is a cross-sectional observational study of the AtheSpAin cohort, a Spanish multicenter cohort to study atherosclerosis in axSpA. Subclinical atherosclerosis determined by carotid ultrasound included assessment of carotid intima-media thickness (cIMT) and plaque detection. RESULTS: 639 AS and 167 nr-axSpA patients were recruited. CV risk factors (CRF) and several disease-related factors showed a statistically significant association with subclinical atherosclerosis in the crude analysis. After adjustment for age, sex, and smoking (model 1), associations remained statistically significant for spinal mobility, inflammatory bowel disease, use of prednisone, and Disease-modifying antirheumatic drugs (DMARD) when assessing carotid plaques and for acute phase reactants (APR) at diagnosis, use of prednisone, DMARD, and TNF-inhibitors when measuring cIMT. In model 2, which also included classic CRF as confounding factors to identify axSpA features with a potential independent pro-atherogenic effect, the functional status was the only variable significantly associated with plaques and the use of prednisone and APR at diagnosis with cIMT. No association differences were found between both subtypes of patients. Besides, APR at diagnosis were also associated with subsequent development of CV events that had occurred in 33 patients. CONCLUSION: Apart from CRF, atherosclerotic disease in AxSpA is associated with disease-related factors such as inflammatory response and disease severity, with no differences between AS and nr-axSpA.

Potential relation of cardiovascular risk factors to disease activity in patients with axial spondyloarthritis.

BACKGROUND: Axial spondyloarthritis (axSpA) patients are known to have a higher prevalence of several comorbidities, including, among others, an increased risk of atherosclerosis, hypertension, dyslipidemia, and diabetes. The purpose of the present study was to determine whether the sum of traditional cardiovascular (CV) risk factors is related to disease characteristics, such as disease activity, in patients with axSpA. METHODS: A cross-sectional study that encompassed 804 patients with axSpA was conducted. Patients were assessed for the presence of five traditional CV risk factors (diabetes mellitus, dyslipidemia, hypertension, obesity, and smoking status), and disease activity measurements. A multivariable regression analysis was performed to evaluate whether the number of classic CV risk factors was independently associated with specific features of the disease, to include disease activity. RESULTS: A multivariable analysis showed that Ankylosing Spondylitis Disease Activity Score-C reactive protein (ASDAS-CRP) activity score was significantly higher in patients with 1 [beta coefficient 0.3 (95% confidence interval (CI) 0.1-0.5), p = 0.001] and ⩾2 [beta coefficient 0.5 (95% CI 0.3-0.7), p = 0.000] CV risk factors compared with those without CV risk factors. Similarly, patients with 1 [OR 2.00 (95%CI 0.99-4.02), p = 0.053] and ⩾2 [OR 3.39 (95%CI 1.82-6.31), p = 0.000] CV risk factors had a higher odds ratio for the presence of high disease activity compared with the zero CV category. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) activity score was significantly associated with the number of CV risk factors, being higher in patients with more CV risk factors. These relationships showed a CV risk factor-dependent effect being beta coefficients and ORs higher for the effect of ⩾2 over 1 CV risk factor. CONCLUSION: Among patients with axSpA, as the number of traditional CV risk factors increased, disease activity similarly increases in an independent manner.

Subclinical atherosclerotic disease in ankylosing spondylitis and non-radiographic axial spondyloarthritis. A multicenter study on 806 patients.

OBJECTIVES: To compare the atherosclerosis disease burden between ankylosing spondylitis (AS) and non-radiographic (nr) axial spondyloarthritis (axSpA) and establish a model that allows to identify high-cardiovascular (CV) risk in axial spondyloarthritis patients. METHODS: Cross-sectional study from the AtheSpAin cohort, a Spanish multicenter cohort aimed to study atherosclerosis in axSpA. Carotid ultrasound (US) was performed to determine the carotid intima-media wall thickness (cIMT) and detect the presence of carotid plaques. The European cardiovascular disease risk assessment model, the Systematic COronary Risk Evaluation (SCORE), was also applied. RESULTS: A set of 639 patients with AS and 167 patients with nr-axSpA without history of CV events were recruited. AS patients were older showing more CV risk factors and higher values of C reactive protein and erythrocyte sedimentation rate (ESR) than those with nr-axSpA. However, no difference in the prevalence of carotid plaques or in the cIMT was found between both groups in the adjusted analysis. The percentage of patients reclassified from the low and moderate CV risk categories to the very high-risk category due to the presence of carotid plaques was comparable in AS and nr-axSpA (10.7% versus 10.1% and 40.5% versus 45.5%, respectively). A model containing age, BASFI and ESR applied to moderate risk axSpA patients identified 41% of these patients as having very high-risk patients with high specificity (88%). CONCLUSION: The atherosclerosis burden is similar in nr-axSpA and AS. As occurred for AS, more than 40% of axSpA patients included in the category of moderate CV risk according to the SCORE are reclassified into very high risk after carotid US, and a clinically relevant proportion of them can be detected by applying a model containing age, BASFI and ESR.

Treatment of polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is an inflammatory disease characterized by bilateral pain involving predominantly the shoulders and proximal aspects of the arms and less commonly the neck and the pelvic girdle. This review discusses briefly the main epidemiological data and clinical features of this condition. Especial attention is paid in the management of the disease. For this reason, both the classic management and the impact of new therapies are discussed in depth. In general, patients with PMR experience a rapid response to 12.5-25 mg/prednisone/day in less than a week. Patients with poor response to glucocorticoids or with relapsing disease require other therapies aimed mainly to spare glucocorticoids. Among them, methotrexate is the most commonly used. Nevertheless, different studies indicate that this agent yields only a modest effect. Biologic therapies against the main cytokines involved in the pathogenesis of the disease have been used in refractory patients. However, randomized controlled trials do not support the use of anti-tumor necrosis factor agents in PMR. In contrast, several case series and retrospective studies highlight the efficacy of the anti-interleukin-6 receptor tocilizumab in PMR. Nonetheless, controlled trials are needed to fully establish the beneficial effect of this agent. The potential favorable effect of the Janus-kinase inhibitors and new anti-interleukin-6 antagonists remains to be determined.

Identification of a 3'-Untranslated Genetic Variant of RARB Associated With Carotid Intima-Media Thickness in Rheumatoid Arthritis: A Genome-Wide Association Study.

OBJECTIVE: To investigate the genetic background influencing the development of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA). METHODS: We performed a genome-wide association study (GWAS) in which, after quality control and imputation, a total of 6,308,944 polymorphisms across the whole genome were analyzed in 2,989 RA patients of European origin. Data on subclinical atherosclerosis, obtained through assessment of carotid intima-media thickness (CIMT) and presence/absence of carotid plaques by carotid ultrasonography, were available for 1,355 individuals. RESULTS: A genetic variant of the RARB gene (rs116199914) was associated with CIMT values at the genome-wide level of significance (minor allele [G] ß coefficient 0.142, P = 1.86 × 10-8 ). Interestingly, rs116199914 overlapped with regulatory elements in tissues related to CV pathophysiology and immune cells. In addition, biologic pathway enrichment and predictive protein-protein relationship analyses, including suggestive GWAS signals of potential relevance, revealed a functional enrichment of the collagen biosynthesis network related to the presence/absence of carotid plaques (Gene Ontology no. 0032964; false discovery rate-adjusted P = 4.01 × 10-3 ). Furthermore, our data suggest potential influences of the previously described candidate CV risk loci NFKB1, MSRA, and ZC3HC1 (P = 8.12 × 10-4 , P = 5.94 × 10-4 , and P = 2.46 × 10-4 , respectively). CONCLUSION: The present findings strongly suggest that genetic variation within RARB contributes to the development of subclinical atherosclerosis in patients with RA.

Nailfold Capillaroscopy Characteristics of Antisynthetase Syndrome and Possible Clinical Associations: Results of a Multicenter International Study.

OBJECTIVE: To describe nailfold videocapillaroscopy (NVC) features of patients with antisynthetase syndrome (AS) and to investigate possible correlations with clinical and serological features of the disease. METHODS: We retrospectively analyzed NVC images of 190 patients with AS [females/males 3.63, mean age 49.7 ± 12.8 yrs, median disease duration 53.7 mos (interquartile range 82), 133 anti-Jo1 and 57 non-anti-Jo1-positive patients]. For each patient, we examined number of capillaries, giant capillaries, microhemorrhages, avascular areas, ramified capillaries, and the presence of systemic sclerosis (SSc)-like pattern. Finally, we correlated NVC features with clinical and serological findings of patients with AS. Concomitantly, a historical cohort of 75 patients with antinuclear antibody-negative primary Raynaud phenomenon (RP) and longterm followup was used as a control group (female/male ratio 4.13/1, mean age 53.9 ± 17.6 yrs) for NVC measures. RESULTS: NVC abnormalities were observed in 62.1% of AS patients compared with 29.3% of primary RP group (p < 0.001). An SSc-like pattern was detected in 67 patients (35.3%) and it was associated with anti-Jo1 antibodies (p = 0.002) and also with a longer disease duration (p = 0.004). Interestingly, there was no significant correlation between the presence of SSc-like pattern and RP, and only 47% of patients with SSc-like pattern had RP. CONCLUSION: NVC abnormalities are commonly observed in AS, independently from the occurrence of RP. The presence of an SSc-like pattern could allow identification of a more defined AS subtype, and prospective studies could confirm the association with clinical and serological features of AS.

Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility.

OBJECTIVE: The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc). PATIENTS AND METHODS: The case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays. RESULTS: We observed evidence of association of the rs6822844 and rs907715 variants with global SSc (pc=6.6E-4 and pc=7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (pc=1.7E-03 and pc=8E-4, respectively). CONCLUSIONS: These results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases.

Role of the rs6822844 gene polymorphism at the IL2-IL21 region in biopsy-proven giant cell arteritis.

OBJECTIVES: To assess the influence of the interleukin (IL)2-IL21 rs6822844 G/T polymorphism in the susceptibility to biopsy-proven giant cell arteritis (GCA) and in the clinical spectrum of manifestations of this vasculitis. METHODS: Two hundred and seventy-two biopsy-proven GCA patients were included in this study. DNA from patients and matched controls (n=791) was obtained from peripheral blood. Samples were genotyped for the rs6822844 polymorphism using a predesigned TaqMan allele discrimination assay and by polymerase chain reaction amplification. RESULTS: No significant differences in the allele and genotype frequencies between biopsy-proven GCA patients and controls were observed. However, the stratification of GCA patients disclosed some differences according to gender and ischemic manifestations of the disease. In this regard, the frequency of the minor allele T was increased in males (14.8%) compared to females (8.4%) (odds ratio-OR:1.89 (95% confidence interval-CI: 1.09-3.28); p=0.02; Bonferroni adjustment p=0.12). Also, minor allele T frequency was increased in GCA patients with severe ischemic complications (12.8%) compared to those without severe ischemic complications (7.7%) (OR:1.72 (95% CI: 0.97-3.05); p=0.05; Bonferroni adjustment p=0.30), and specifically in patients with jaw claudication (13.7% versus 8.2% in those without jaw claudication; OR:1.76 (95% CI: 1.02-3.04); p=0.04; Bonferroni adjustment p=0.24). CONCLUSIONS: IL2-IL21 rs6822844 polymorphism does not appear to be a genetic risk factor for susceptibility to biopsy-proven GCA. However, this gene polymorphism may contribute to the different phenotypic expression of this vasculitis, in particular in the development of ischemic complications of the disease.

Interleukin 15 levels in serum may predict a severe disease course in patients with early arthritis.

BACKGROUND: Interleukin-15 (IL-15) is thought to be involved in the physiopathological mechanisms of RA and it can be detected in the serum and the synovial fluid of inflamed joints in patients with RA but not in patients with osteoarthritis or other inflammatory joint diseases. Therefore, the objective of this work is to analyse whether serum IL-15 (sIL-15) levels serve as a biomarker of disease severity in patients with early arthritis (EA). METHODOLOGY AND RESULTS: Data from 190 patients in an EA register were analysed (77.2% female; median age 53 years; 6-month median disease duration at entry). Clinical and treatment information was recorded systematically, especially the prescription of disease modifying anti-rheumatic drugs. Two multivariate longitudinal analyses were performed with different dependent variables: 1) DAS28 and 2) a variable reflecting intensive treatment. Both included sIL-15 as predictive variable and other variables associated with disease severity, including rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACPA). Of the 171 patients (638 visits analysed) completing the follow-up, 71% suffered rheumatoid arthritis and 29% were considered as undifferentiated arthritis. Elevated sIL-15 was detected in 29% of this population and this biomarker did not overlap extensively with RF or ACPA. High sIL-15 levels (ß Coefficient [95% confidence interval]: 0.12 [0.06-0.18]; p<0.001) or ACPA (0.34 [0.01-0.67]; p = 0.044) were significantly and independently associated with a higher DAS28 during follow-up, after adjusting for confounding variables such as gender, age and treatment. In addition, those patients with elevated sIL-15 had a significantly higher risk of receiving intensive treatment (RR 1.78, 95% confidence interval 1.18-2.7; p = 0.007). CONCLUSIONS: Patients with EA displaying high baseline sIL-15 suffered a more severe disease and received more intensive treatment. Thus, sIL-15 may be a biomarker for patients that are candidates for early and more intensive treatment.

Role of BANK1 gene polymorphisms in biopsy-proven giant cell arteritis.

OBJECTIVE: Giant cell arteritis (GCA) is a complex polygenic disease in which more than 1 genetic locus is likely to contribute to disease susceptibility and clinical expression. BANK, an adaptor molecule, has been suggested to participate in the B cell antigen receptors-mediated calcium homeostasis. We assessed for the first time the implication of BANK1 functional variants in susceptibility to GCA. METHODS: Two hundred twenty-two patients with biopsy-proven GCA and 534 matched controls were assessed. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for 3 putative functional BANK1 gene polymorphisms (rs17266594 T/C, rs10516487 G/A, rs3733197 G/A) using a TaqMan allele discrimination assay. RESULTS: No significant differences were observed in genotype distribution between patients with biopsy-proven GCA and controls for these 3 gene polymorphisms. A trend for a decreased risk of having GCA was observed in individuals carrying the BANK1 rs3733197 GG genotype (patients with GCA 43.9% compared to 51.6% in controls; p = 0.06, OR 0.73, 95% CI 0.53-1.02). The frequency of BANK1 rs3733197 allele G was marginally decreased in patients with biopsy-proven GCA compared to controls (p = 0.09, OR 0.82, 95% CI 0.64-1.04). Haplotype analysis of 3-single-nucleotide polymorphisms found no statistically significant differences between patients with GCA and controls. No significant differences for the BANK1 gene polymorphisms were found when patients were stratified according to specific clinical features of the disease. CONCLUSION: Our results do not support a major implication of the BANK1 locus in susceptibility to GCA.