Aikaterini Arida

Anti-TNF agents for Behçet's disease: analysis of published data on 369 patients.

OBJECTIVE Off-label use of anti-tumor necrosis factor (TNF) agents for Behçets disease (BD) is increasing. We evaluated published data on their efficacy and safety for patients with unmet medical needs due to severe disease manifestations, including ocular, gastrointestinal, and central nervous system involvement. METHODS Peer-reviewed articles on anti-TNF agents for BD appearing in Medline/PubMed through March 2010 were identified using the appropriate indexing terms. RESULTS We found 88, 12, and 13 primary articles from 20 countries on infliximab, etanercept, and adalimumab, reporting on 325, 37, and 28 patients, respectively. All patients were inadequately controlled with, or intolerant to, other immunosuppressive regimens, including interferon; 20 patients received more than 1 anti-TNF agent. In the only randomized placebo-controlled trial, 4-week administration of etanercept was effective in suppressing most of the mucocutaneous manifestations. In 16 open prospective studies evaluating the effect of repetitive infliximab injections (174 patients in total, men:women = 3:1, median follow-up = 16.2 months), sustained organ-specific, clinical responses were evident in 90%, 89%, 100%, and 91% of patients with resistant mucocutaneous, ocular, gastrointestinal, and central nervous system involvement, respectively. Combination of infliximab with azathioprine and/or cyclosporine-A appeared superior to monotherapy for sustained ocular remission. However, due to the fact that necessary data were lacking, formal estimation of anti-TNF treatment effect on the disease activity indexes for different organ involvement was not possible. CONCLUSIONS Although more controlled data are needed, there is enough published experience to suggest that TNF blockade represents an important therapeutic advancement for patients with severe and resistant, or intolerant, to standard immunosuppressive regimens BD.

The diagnostic value of ultrasonography-derived edema of the temporal artery wall in giant cell arteritis: a second meta-analysis

BackgroundUltrasonography of temporal arteries is not commonly used in the approach of patients with suspected giant cell arteritis (GCA) in clinical practice. A meta-analysis of primary studies available through April 2004 concluded that ultrasonography could indeed be helpful in diagnosing GCA. We specifically re-examined the diagnostic value of the ultrasonography-derived halo sign, a dark hypoechoic circumferential thickening around the artery lumen, indicating vasculitic wall edema, in GCA.MethodsOriginal, prospective studies in patients with suspected GCA that examined ultrasonography findings of temporal arteries using the ACR 1990 classification criteria for GCA as reference standard, published through 2009, were identified. Only eight studies involving 575 patients, 204 of whom received the final diagnosis of GCA, fulfilled technical quality criteria for ultrasound. Weighted sensitivity and specificity estimates of the halo sign were assessed, their possible heterogeneity was investigated and pooled diagnostic odds ratio was determined.ResultsUnilateral halo sign achieved an overall sensitivity of 68% (95% CI, 0.61-0.74) and specificity of 91% (95% CI, 0.88-0.94) for GCA. The values of inconsistency coefficient (I2) of both sensitivity and specificity of the halo sign, showed significant heterogeneity concerning the results between studies. Pooled diagnostic odds ratio, expressing how much greater the odds of having GCA are for patients with halo sign than for those without, was 34 (95% CI, 8.21-138.23). Diagnostic odds ratio was further increased to 65 (95% CI, 17.86-236.82) when bilateral halo signs were present (sensitivity/specificity of 43% and 100%, respectively). In both cases, it was found that DOR was constant across studies.ConclusionTemporal artery edema demonstrated as halo sign should be always looked for in ultrasonography when GCA is suspected. Providing that currently accepted technical quality criteria are fulfilled, halo signs sensitivity and specificity are comparable to those of autoantibodies used as diagnostic tests in rheumatology. Validation of revised GCA classification criteria which will include the halo sign may be warranted.

Adalimumab or Cyclosporine as Monotherapy and in Combination in Severe Psoriatic Arthritis: Results from a Prospective 12-month Nonrandomized Unblinded Clinical Trial

Objective. To assess the efficacy and safety of adalimumab or cyclosporine (CYC) as monotherapy or combination therapy for patients with active psoriatic arthritis (PsA), despite methotrexate (MTX) therapy. Methods. A prospective 12-month, nonrandomized, unblinded clinical trial of 57, 58, and 55 patients who received CYC (2.5–3.75 mg/kg/day), adalimumab (40 mg every other week), or combination, respectively. Lowering of concomitant nonsteroidal antiinflammatory drugs (NSAID) and corticosteroids and reductions of adalimumab and/or CYC doses in responding patients were not restricted. Results. Mean numbers of tender/swollen joints at baseline were 9.7/6.7 in CYC-treated, 13.0/7.8 in adalimumab-treated, and 14.5/9.4 in combination-treated patients, indicating lesser disease severity of patients assigned to the first group. The Psoriatic Arthritis Response Criteria at 12 months were met by 65% of CYC-treated (p = 0.0003 in favor of combination treatment), 85% of adalimumab-treated (p = 0.15 vs combination treatment), and 95% of combination-treated patients, while the American College of Rheumatology-50 response rates were 36%, 69%, and 87%, respectively (p < 0.0001 and p = 0.03 in favor of combination treatment). A significantly greater mean improvement in Health Assessment Questionnaire Disability Index was achieved by combination treatment (−1.11) vs CYC (−0.41) or adalimumab alone (−0.85). Combination therapy significantly improved Psoriasis Area and Severity Index-50 response rates beyond adalimumab, but not beyond the effect of CYC monotherapy. Doses of NSAID and corticosteroids were reduced in combination-treated patients; CYC doses and frequency of adalimumab injections were also reduced in 51% and 10% of them, respectively. No new safety signals were observed. Conclusion. The combination of adalimumab and CYC is safe and seemed to produce major improvement in both clinical and serological variables in patients with severely active PsA and inadequate response to MTX.

Subclinical Atherosclerosis Is Not Accelerated in Patients with Ankylosing Spondylitis with Low Disease Activity: New Data and Metaanalysis of Published Studies.

Objective. Chronic inflammatory rheumatic diseases are associated with accelerated atherosclerosis, but data in ankylosing spondylitis (AS) are limited and the relative contribution of inflammation versus classical cardiovascular (CV) risk factors remains a matter of controversy. We addressed this in an original study and a metaanalysis of previous studies. Methods. Atheromatic plaques in carotid and femoral arteries, carotid hypertrophy [intima-media thickness (IMT), cross-sectional area], and carotid stiffness by ultrasound, as well as aortic stiffness by pulse wave velocity, were examined in consecutive nondiabetic, CV disease (CVD)-free patients with AS. Healthy individuals carefully matched 1:1 with patients for age, sex, smoking habits, hyperlipidemia, and hypertension served as controls. A metaanalysis of original studies that examined subclinical atherosclerosis in patients with AS versus controls with comparable CVD risk factors was also performed. Results. Carotid and femoral atheromatic plaques were slightly less prevalent compared with controls in a contemporary cohort consisting of 67 patients with AS (82% men), aged 47.5 ± 12.5 years (mean ± SD), with a median disease duration of 12 years and a Bath AS Disease Activity Index (BASDAI) of 1.8 (interquartile range 0.4–3.6), of whom 66% were receiving anti-tumor necrosis factor (TNF) treatment. Carotid hypertrophy and stiffness, as well as aortic stiffness, were similar between patients and their matched controls. Metaanalysis of all published studies revealed a significantly increased carotid IMT, but not plaque burden, in AS versus controls. Notably, however, increased IMT was not evident in studies involving patients with low disease activity (mean BASDAI < 4) or in those studies that included > 50% of patients treated with anti-TNF. Conclusion. Low AS disease activity is not associated with accelerated atherosclerosis.

The Additive Value of Femoral Ultrasound for Subclinical Atherosclerosis Assessment in a Single Center Cohort of 962 Adults, Including High Risk Patients with Rheumatoid Arthritis, Human Immunodeficiency Virus Infection and Type 2 Diabetes Mellitus

Background Presence of femoral atheromatic plaques, an emerging cardiovascular disease (CVD) biomarker additional to carotid plaques, is poorly investigated in conditions associating with accelerated atherosclerosis such as Rheumatoid Arthritis (RA), Human Immunodeficiency Virus (HIV) infection and Type 2 Diabetes Mellitus (T2DM). Objective/Methods To assess the frequency of femoral/carotid subclinical atheromatosis phenotypes in RA, HIV and T2DM and search for each disease-specific probability of either femoral and/or carotid subclinical atheromatosis, we examined by ultrasound a single-center cohort of CVD-free individuals comprised of consecutive non-diabetic patients with RA (n=226) and HIV (n=133), T2DM patients (n=109) and non-diabetic individuals with suspected/known hypertension (n=494) who served as reference group. Results Subclinical atheromatosis - defined as local plaque presence in at least on arterial bed - was diagnosed in 50% of the overall population. Among them, femoral plaques only were found in 25% of either RA or HIV patients, as well as in 16% of T2DM patients and 35% of reference subjects. After adjusting for all classical CVD risk factors, RA and HIV patients had comparable probability to reference group of having femoral plaques, but higher probability (1.75; 1.17 - 2.63 (odds ratio; 95% confidence intervals), 2.04; 1.14 - 3.64, respectively) of having carotid plaques, whereas T2DM patients had higher probability to have femoral and carotid plaques, albeit, due to their pronounced dyslipidemic profile. Conclusion RA and HIV accelerate predominantly carotid than femoral. A “two windows” carotid/femoral, rather than carotid alone ultrasound, screening improves substantially subclinical atheromatosis detection in patients at high CVD risk.

Brief Report: Drug-Free Long-Term Remission in Severe Behçet's Disease Following Withdrawal of Successful Anti–Tumor Necrosis Factor Treatment

To test the hypothesis that remission of Behçets disease (BD) in patients with severe vital organ involvement is maintained after withdrawal of successful anti–tumor necrosis factor (anti‐TNF) treatment.

Systemic Inflammatory Response and Atherosclerosis: The Paradigm of Chronic Inflammatory Rheumatic Diseases

Patients with Chronic Inflammatory Rheumatic diseases (CIRD) are at increased risk of cardiovascular disease (CVD), ascribed not only to classical risk factors, but also to the presence of chronic systemic inflammatory response. Αtherosclerosis, the cornerstone of CVD, is known to be accelerated in CIRD; rheumatoid arthritis promotes atheromatosis and associates with preclinical atherosclerosis equivalent to Diabetes Mellitus, which also seems to apply for systemic lupus erythematosus. Data on ankylosing spondylitis and psoriatic arthritis, albeit more limited, also support an increased CV risk in these patients. The association between inflammation and atherosclerosis, has been thoroughly investigated in the last three decades and the role of inflammation in the pathogenesis and progression of atherogenesis has been well established. Endothelial dysfunction, oxidative stress in vascular endothelial cells and macrophage accumulation, toll-like receptor signaling, NLPR-3 formation and subsequent pro-inflammatory cytokine production, such as TNFa, IL-1β, IL-6, and TNF-like cytokine 1A, are few of the mechanisms implicated in the atherogenic process. Moreover, there is evidence that anti-inflammatory biologic drugs, such as anti-TNF and anti-IL1β agents, can decelerate the atherogenic process, thus setting new therapeutic targets for early and effective disease control and suppression of inflammation, in addition to aggressive management of classical CV risk factors.

AB0333 Central Aortic Systolic Blood Pressure Measurements in Rheumatoid Arthritis: Towards the Optimization of the Blood Pressure-Associated Cardiovascular Risk Assessment

Background Rheumatoid Arthritis (RA) associates with increased risk of cardiovascular disease (CVD) and high prevalence of arterial hypertension [1]. Central aortic systolic blood pressure (SBP), assessed non-invasively, is a better predictor of CVD and a better guide for anti-hypertensive treatment compared to brachial SBP [2,3]. Data on the prevalence of central aortic SBP-based hypertension [3] are lacking in RA. Objectives Since abnormal/uncontrolled central aortic SBP might refine CVD risk classification in RA we aimed to describe its frequency in the presence or absence of, (i) abnormal/uncontrolled office brachial SBP, and (ii) “white coat” and masked systolic hypertension phenomena, which are frequently observed in these patients [1] Methods Consecutive RA patients referred to out cardiovascular laboratory for CVD risk stratification underwent office brachial SBP (triplicate oscillometric recording) and central aortic SBP (with Sphygmocor device) assessments, as well as out- of-office 24-hour ambulatory, or home monitoring of brachial SBP. Results Among 263 patients (median age 60 years IQR [52-67], women 80%), 27% and 30% had abnormal/uncontrolled brachial or central aortic measurements at office, respectively. Of all patients, 69% had both brachial and central aortic normal/controlled measurements, 25% had both brachial and central aortic abnormal/uncontrolled measurements, whereas the remaining 6% presented intermediate phenotypes (1.5% and 4.5% only brachial or only central aortic abnormal/uncontrolled measurements, respectively). Notably, abnormal central aortic measurements were noted in 100% of patients with systolic “white coat” hypertension phenomenon, as well as in 45% of patients with systolic masked hypertension phenomenon. Conclusions Given the fact that modern technologies provide the possibility to measure simultaneously office brachial and central aortic SBP, whereas the latter guides more efficiently blood pressure management, incorporation of central aortic measurement in clinical practice might help to optimize hypertension treatment in 6% of RA patients and particularly to detect the presence of masked hypertension almost in half of them without the use of out-of-office blood pressure monitoring. References Protogerou AD et al. Arterial hypertension assessed “out-of-office” in a contemporary cohort of rheumatoid arthritis patients free of cardiovascular disease is characterized by high prevalence, low awareness, poor control and increased vascular damage-associated “white coat” phenomenon. Arthritis Res Ther. 2013; 15(5):R142. Sharman JE, et al. Randomized trial of guiding hypertension management using central aortic blood pressure compared with best-practice care: principal findings of the BP GUIDE study. Hypertension. 2013; 62:1138-45. Cheng HM et al. Derivation and validation of diagnostic thresholds for central blood pressure measurements based on long-term cardiovascular risks. J Am Coll Cardiol. 2013; 62:1780-7. Disclosure of Interest None declared

AB0758 Subclinical Atherosclerosis is not Accelerated in Well-Controlled Ankylosing Spondylitis: Original Data and Meta-Analysis of Published Studies

Background Chronic inflammatory rheumatic diseases associate with increased risk of cardiovascular disease (CVD) in part due to accelerated atherosclerosis. While this is well established for rheumatoid arthritis (1), data on ankylosing spondylitis (AS) is limited and the relative contribution of inflammation versus classical cardiovascular risk factors remains a matter of controversy (2). Objectives To address this controversy in an original, carefully designed study of subclinical atherosclerosis in AS patients, as well as in a meta-analysis of previous studies. Methods Atheromatic plaques in carotid and femoral arteries, carotid hypertrophy (intima-media thickness-IMT; cross sectional area) and carotid stiffness by ultrasound, as well as aortic stiffness by pulse wave velocity were examined in consecutive non-diabetic CVD-free, AS patients. Apparently healthy individuals carefully matched 1:1 with patients for age, gender, smoking, dyslipidemia and hypertension served as controls. A meta-analysis of those studies that examined subclinical atherosclerosis in AS patients versus controls with comparable CVD risk factors, published up to June 2014, was also performed. Studies were subsequently stratified according to the mean level of disease activity (BASDAI> or <4), and the proportion of patients receiving anti-TNF biological therapy (> or <50%). Results In this contemporary cohort comprising of 67 AS patients (82% men), aged 47.5+12.5 years (mean ± SD), with median disease duration of 12 years and BASDAI of 1.8 (IQR 0.4-3.6), of whom 66% were receiving anti-TNF treatment, atheromatic plaques were slightly less prevalent compared to controls. Moreover, carotid hypertrophy and stiffness, as well as aortic stiffness, were comparable between patients and their matched controls. Meta-analysis and meta-regression analysis of 14 studies, including the present study, revealed that carotid IMT is significantly increased in AS patients versus controls. On the other hand, analysis of those studies examining also the presence of carotid plaques revealed no statistical difference in the relative risk of the presence of carotid plaques between AS patients and their matched controls. Interestingly, however, increased IMT was not evident in studies involving well-controlled patients (mean BASDAI <4) or in those studies which included >50% of anti-TNF-treated patients. Conclusions Subclinical atherosclerosis is not accelerated in well-controlled AS patients. References Peters MJ, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 2010;69:325-31. Mathieu S, et al. Cardiovascular profile in ankylosing spondylitis: a systematic review and meta-analysis. Arthritis Care Res 2011;4:557-63. Disclosure of Interest None declared

SAT0109 Accelerated Subclinical Atheromatosis, but not Arterial Stiffness or Hypertrophy, in Rheumatoid Arthritis Patients Free of Classical Risk Factors

Background Several lines of evidence indicate that classical cardiovascular disease (CVD) risk factors, such as arterial hypertension, diabetes mellitus, smoking and dyslipidemia, are significantly increased in rheumatoid arthritis (RA), which, in turn, is associated with 1.5- to 2-fold increased prevalence of CVD. The exact contribution of the RA disease per se in this association, in terms of systemic inflammation, drugs, disease-related genetics and/or other factors, remains under study. Objectives We aimed to test the hypothesis that RA per se in patients free of classical CVD risk factors is associated with accelerated subclinical arterial disease. Methods Consecutive patients with RA (n=267) were comprehensively studied by ultrasound for, a) subclinical atheromatosis assessed by the presence of carotid artery and/or femoral artery plaques, b) stiffness of common carotid artery and aortic stiffness by pulse wave velocity, and, c) hypertrophy of common carotid artery assessed by intimal-medial thickness and cross sectional area (calculated adjacent to plaques, when plaques were present). Of all patients, we identified those who were CVD-free, non-smokers, without hypertension, diabetes and dyslipidemia (only 18%). Of them, 41 (aged 49±13 years, 36 women, median disease duration of 7 years, range 3-19 years) were compared to 41 healthy non-smokers, without hypertension, diabetes and dyslipidemia who were effectively matched 1:1 for age and gender and studied in parallel. Results Patients had more than 2-fold higher prevalence of carotid and/or femoral atheromatic plaques than healthy controls (29% vs. 12%, p=0.05). All patients with plaques had an acceptable functional status of class I or II. Moreover, body mass index, as well as family history of CVD, was similar between patients with plaques and their matched controls. Multi-arterial subclinical atheromatosis, defined as plaque presence at more than 1 of 8 arterial sites evaluated, was by far more prevalent in RA patients than controls (22% vs. 2%, p=0.007). Notably, plaque burden in the subgroup of RA patients with less than 5 years of disease duration was comparable to their matched controls. Either arterial stiffness or hypertrophy, however, was not significantly increased compared to controls, even in patients with long-standing RA. Conclusions These data directly show for the first time an acceleration of atheromatosis in RA, but not of arterial stiffness or hypertrophy, independently of the classical CVD risk factors. This phenomenon is not evidenced during the first 5 years after disease onset and seems to be chronic inflammation-dependent. Also, the dissociation between atheromatosis and arterial stiffness in this selected population suggests a minimal, if any, effect of chronic inflammation in arterial remodeling. Studies testing whether early and effective RA clinical disease control prevents the development of arterial damage in the long-term are ongoing. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5811