ATP-binding cassette G1 membrane transporter-mediated cholesterol efflux capacity influences coronary atherosclerosis and cardiovascular risk in Rheumatoid Arthritis.

OBJECTIVES: Cholesterol efflux capacity (CEC) measures the ability of high-density lipoprotein (HDL) to remove cholesterol from macrophages and reduce the lipid content of atherosclerotic plaques. CEC inversely associated with cardiovascular risk beyond HDL-cholesterol levels. CEC through the ATP-binding-cassette G1 (ABCG1) membrane transporter is impaired in rheumatoid arthritis (RA). We evaluated associations of ABCG1-CEC with coronary atherosclerosis, plaque progression and cardiovascular risk in RA. METHODS: Coronary atherosclerosis (noncalcified, partially, fully-calcified, low-attenuation plaque) was assessed with computed tomography angiography in 140 patients and reevaluated in 99 after 6.9 ± 0.3 years. Cardiovascular events including acute coronary syndromes, stroke, cardiovascular death, claudication, revascularization and hospitalized heart failure were recorded. ABCG1-CEC was measured in Chinese hamster ovary cells as percentage of effluxed over total intracellular cholesterol. RESULTS: ABCG1-CEC inversely associated with extensive atherosclerosis (≥5 plaques) (adjusted odds ratio 0.50 [95% CI 0.28-0.88]), numbers of partially-calcified (rate ratio [RR] 0.71 [0.53-0.94]) and low-attenuation plaques (RR 0.63 [0.43-0.91] per standard deviation increment). Higher ABCG1-CEC predicted fewer new partially-calcified plaques in patients with lower baseline and time-averaged CRP and fewer new noncalcified and calcified plaques in those receiving higher mean prednisone dose. ABCG1-CEC inversely associated with events in patients with but not without noncalcified plaques, with

Serum cholesterol loading capacity of macrophages is regulated by seropositivity and C-reactive protein in rheumatoid arthritis patients.

OBJECTIVE: Excessive cholesterol accumulation in macrophages is the pivotal step underlying atherosclerotic plaque formation. We here explore factors in the serum of patients with RA, and mechanisms through which they interact with and influence cholesterol loading capacity (CLC) of macrophages. METHODS: In a cross-sectional observational cohort of 104 patients with RA, CLC was measured as intracellular cholesterol content in human THP-1-derived macrophages after incubation with patient serum. Low-density lipoprotein (LDL) oxidation was measured in terms of oxidized phospholipids on apoB100-containing particles (oxPL-apoB100). Antibodies against oxidized LDL (anti-oxLDL), proprotein convertase subtilisin/Kexin type-9 (PCSK9) and high-sensitivity CRP were also quantified. All analyses adjusted for atherosclerotic cardiovascular disease (ASCVD) risk score, obesity, total LDL, statin use, age at diagnosis, and anti-oxLDL IgM. RESULTS: OxPL-apoB100, anti-oxLDL IgG and PCSK9 were positively associated with CLC (all P < 0.020). OxPL-apoB100 directly influenced CLC only in dual RF- and ACPA-positive patients [unstandardized b (95% bootstrap CI)=2.08 (0.38, 3.79)]. An indirect effect of oxPL-apoB100 on CLC through anti-oxLDL IgG increased, along with level of CRP [index of moderated mediation = 0.55 (0.05-1.17)]. CRP also moderated yet another indirect effect of oxPL-apoB100 on CLC through upregulation of PCSK9, but only among dual-seropositive patients [conditional indirect effect = 0.64 (0.13-1.30)]. CONCLUSION: Oxidized LDL can directly influence CLC in dual-seropositive RA patients. Two additional and independent pathways-via anti-oxLDL IgG and PCSK9-may mediate the effects of oxPL-apoB100 on CLC, depending on CRP and seropositivity status. If externally validated, these findings may have clinical implications for cardiovascular risk prevention.

Lipoprotein oxidation may underlie the paradoxical association of low cholesterol with coronary atherosclerotic risk in rheumatoid arthritis.

OBJECTIVE: To compare coronary plaque burden, proatherogenic cytokines, oxidized low-density lipoprotein (oxLDL), anti-oxLDL antibodies, lipoprotein(a)-cholesterol, and their relationships in patients with rheumatoid arthritis with low-density lipoprotein cholesterol (LDL-C)<1.8 mmol/L versus ≥1.8 mmol/L. Also, to study differences in inflammation and proprotein convertase subtilisin/kexin type-9 (PCSK9), which impacts LDL clearance, in patients with low versus high LDL-C. METHODS: Computed tomography angiography evaluated coronary plaque (noncalcified, partially calcified, fully calcified, and high-risk plaque) in 150 patients from a single-center observational cohort. Ox-LDL, anti-oxLDL IgG, lipoprotein(a)-cholesterol, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6, tumor necrosis factor-α (TNF-α) and PCSK9 were measured. Analyses adjusted for Framingham general cardiovascular risk score, statin use, and high-density lipoprotein cholesterol. RESULTS: Patients with LDL-C<1.8 mmol/L versus ≥1.8 mmol/L demonstrated: 1) higher likelihood of per-segment plaque (adjusted-OR = 1.67 [95%CI = 1.10-2.55], p = 0.017) and high-risk plaque presence (adjusted-OR 2.78 [95%CI = 1.06-7.29], p = 0.038); 2) greater anti-oxLDL titers (p = 0.020), which positively associated with TNF-α and likelihood of noncalcified, partially calcified and high-risk plaque presence only in patients with LDL-C<1.8 mmol/L (all p-for-interaction≤0.046); 3) increased lipoprotein(a)-cholesterol content (10.33% [8.11-12.54] versus 6.68% [6.10-7.25], p < 0.001), which positively associated with oxLDL (p < 0.001) and anti-oxLDL (p = 0.036); 4) higher interleukin-6 and PCSK9. No differences in CRP, ESR, or oxLDL were observed. CONCLUSION: RA patients with LDL-C<1.8 mmol/L had more coronary plaque, higher anti-oxLDL titers and anti-oxLDL associated with plaque only in this group. It is possible the observed paradoxical association of low LDL-C with greater atherosclerosis may be related to higher production of the oxidation-prone lipoprotein(a)-cholesterol and anti-oxLDL antibodies, resulting in increased vascular LDL uptake and plaque formation.

The impact of statins on coronary atherosclerosis progression and long-term cardiovascular disease risk in rheumatoid arthritis.

OBJECTIVES: To evaluate whether statins lower cardiovascular disease (CVD) risk in RA and if tentative benefits are related to changes in coronary plaque burden or composition. METHODS: In an observational cohort study, 150 patients without CVD underwent coronary atherosclerosis evaluation (total, noncalcified, partially and fully calcified plaque) with CT angiography. Prespecified cardiovascular events including cardiac death, myocardial infarction, unstable angina, revascularization, stroke, claudication and heart failure were prospectively recorded. Change in plaque burden and composition was re-assessed in 102 patients within 6.9 (0.3) years. RESULTS: Time-varying statin therapy, modeled using inverse probability treatment and censoring weights, did not significantly attenuate CVD risk in RA overall [adjusted odds ratio (OR) = 0.39 (95% CI: 0.15, 1.07), P =0.067]. However, statins associated with lower CVD risk in patients with baseline CRP > 0.5 mg/dl [adjusted OR = 0.09 (95%CI: 0.03, 0.30), P <0.001] but not in those with CRP < 0.5 mg/dl (P-interaction = 0.023), after controlling for Framingham-CVD score and time-varying bDMARD use. In patients treated with statin >50% of follow-up time, CRP did not associate with new plaque formation [adjusted OR = 0.42 (95% CI: 0.09, 1.94)], in contrast to statin-naïve [adjusted OR = 1.89 (95% CI:1.41, 2.54)] and statin-treated <50% time [adjusted-OR = 1.41 (95% CI: 1.03, 1.95), P-interaction = 0.029]. Statin therapy >50% follow-up time predicted dissipation [adjusted-OR = 5.84 (95% CI: 1.29, 26.55)] and calcification of prevalent noncalcified lesions [adjusted-OR = 4.16 (95% CI: 1.11, 15.54)], as well as new calcified plaque formation in segments without baseline plaque [adjusted-OR = 2.84 (95% CI:1.09, 7.41)]. CONCLUSION: Statin therapy associated with lower long-term cardiovascular risk in RA patients with higher inflammation. Moreover, statin therapy modified the impact of inflammation on new coronary plaque formation and predicted both regression and calcification of prevalent noncalcified lesions.

High-sensitivity cardiac troponin I is a biomarker for occult coronary plaque burden and cardiovascular events in patients with rheumatoid arthritis.

Objectives: Patients with RA display greater occult coronary atherosclerosis burden and experience higher cardiovascular morbidity and mortality compared with controls. We here explored whether pro-inflammatory cytokines and high-sensitivity cardiac troponin I (hs-cTnI), a biomarker of myocardial injury, correlated with plaque burden and cardiovascular events (CVEs) in RA. Methods: We evaluated 150 patients with 64-slice coronary CT angiography. Coronary artery calcium, number of segments with plaque (segment involvement score), stenotic severity and plaque burden were assessed. Lesions were described as non-calcified, mixed or fully calcified. Blood levels of hs-cTnI and pro-inflammatory cytokines were assessed during coronary CT angiography. Subjects were followed over 60 (s.d. 26) months for both ischaemic [cardiac death, non-fatal myocardial infarction (MI), stroke, peripheral arterial ischaemia] and non-ischaemic (new-onset heart failure hospitalization) CVEs. Results: Plasma hs-cTnI correlated with all coronary plaque outcomes (P < 0.01). Elevated hs-cTnI (⩾1.5 pg/ml) further associated with significant calcification, extensive atherosclerosis, obstructive plaque and any advanced mixed or calcified plaques after adjustments for cardiac risk factors or Framingham D'Agostino scores (all P < 0.05). Eleven patients suffered a CVE (1.54/100 patient-years), eight ischaemic and three non-ischaemic. Elevated hs-cTnI predicted all CVE risk independent of demographics, cardiac risk factors and prednisone use (P = 0.03). Conversely, low hs-cTnI presaged a lower risk for both extensive atherosclerosis (P < 0.05) and incident CVEs (P = 0.037). Conclusion: Plasma hs-cTnI independently associated with occult coronary plaque burden, composition and long-term incident CVEs in patients with RA. Low hs-cTnI forecasted a lower risk for both extensive atherosclerosis as well as CVEs. hs-cTnI may therefore optimize cardiovascular risk stratification in RA.

Prevalence, extent and composition of coronary plaque in patients with rheumatoid arthritis without symptoms or prior diagnosis of coronary artery disease.

OBJECTIVES: Accelerated cardiovascular morbidity and mortality occur in patients with rheumatoid arthritis (RA). We evaluated the presence, burden and compositional differences of coronary plaque in patients with RA without symptoms or diagnosis of coronary artery disease (CAD) compared against controls. METHODS: One hundred and fifty patients with RA and 150 matched controls underwent 64-slice CT angiography (CTA) for evaluation of coronary plaque. Numbers of segments with plaque per patient (Segment involvement score (SIS)), degree of segment stenosis (stenosis severity score (SSS)), plaque size (plaque burden score (PBS)), and composition were assessed using a standardised American Heart Association 15-segment model. Lesions were classified as non-calcified plaque (NCP), mixed (MP), and fully calcified plaque (CP). RESULTS:  Higher proportion of patients with RA had plaque when compared with controls (71% vs 45%, p<0.0001); 13.5% of total RA segments harboured plaque compared with 6% in controls (p<0.0001), and all plaque types were higher (p<0.001). Multivessel disease, both non-obstructive and obstructive, was more prevalent, and quantitative measures of stenotic plaque severity (SSS) and extent (PBS) were higher in RA, even after adjustments for cardiac risk factors (p<0.01 for all). A steeper progression of plaque with age was seen in RA. Disease activity associated only with presence of NCP and MP, whereas patient age was the only predictor of fully CP. CONCLUSIONS: RA patients without CAD have higher prevalence, extent, and severity of all types of coronary plaque. Residual disease activity associates with presence of higher risk NCP and MP potentially contributing to future adverse cardiac events.

Decision Impact Analysis to Measure the Influence of Molecular Signature Response Classifier Testing on Treatment Selection in Rheumatoid Arthritis.

INTRODUCTION: Clinical guidelines offer little guidance for treatment selection following inadequate response to conventional synthetic disease-modifying antirheumatic drug (csDMARD) in rheumatoid arthritis (RA). A molecular signature response classifier (MSRC) was validated to predict tumor necrosis factor inhibitor (TNFi) inadequate response. The decision impact of MSRC results on biologic and targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) selection was evaluated. METHODS: This is an analysis of AIMS, a longitudinal, prospective database of patients with RA tested using the MSRC. This study assessed selection of b/tsDMARDs class after MSRC testing by surveying physicians, the rate of b/tsDMARD prescriptions aligning with MSRC results, and the percentage of physicians utilizing MSRC results for decision-making. RESULTS: Of 1018 participants, 70.7% (720/1018) had treatment selected after receiving MSRC results. In this MSRC-informed cohort, 75.6% (544/720) of patients received a b/tsDMARD aligned with MSRC results, and 84.6% (609/720) of providers reported using MSRC results to guide treatment selection. The most prevalent reason reported (8.2%, 59/720) for not aligning treatment selection with MSRC results from the total cohort was health insurance coverage issues. CONCLUSION: This study showed that rheumatologists reported using the MSRC test to guide b/tsDMARD selection for patients with RA. In most cases, MSRC test results appeared to influence clinical decision-making according to physician self-report. Wider adoption of precision medicine tools like the MSRC could support rheumatologists and patients in working together to achieve optimal outcomes for RA.

Efficacy and safety of JAK inhibitors in rheumatoid arthritis: update for the practising clinician.

Janus kinase (JAK) inhibitors, including tofacitinib, baricitinib, upadacitinib and filgotinib, are increasingly used in the treatment of rheumatoid arthritis (RA). There has been debate about their safety, particularly following the issuance of guidance by regulatory agencies advising caution in their use in certain patients. The registrational clinical trials and registry data of JAK inhibitors did not identify a difference in the risk of major adverse cardiovascular events (MACEs), venous thromboembolism, malignancies or infections (other than herpes zoster) with a JAK inhibitor versus a biologic DMARD. In the ORAL Surveillance trial, which enrolled patients >50 years of age with ≥1 cardiovascular risk factor, tofacitinib was statistically inferior to TNF inhibitors for the occurrence of MACEs and malignancy. Further post hoc analysis of the data revealed that an age of ≥65 years, a high baseline cardiovascular risk, a history of smoking, sustained inflammation, disease activity and suboptimal treatment of cardiovascular comorbidities all increase the risk of these outcomes. The guidance issued by regulatory agencies should be carefully considered to ensure appropriate and safe treatment of patients with RA without undertreatment of patients who might benefit from JAK inhibitor, as well as biologic, treatment. As always, the risks associated with the use of these agents, treatment goals, costs and patient preferences should be discussed with the patient.

Identification of Gaps in Quality of Care and Good Practice Interventions in Rheumatoid Arthritis: Insights From a Literature Review and Qualitative Study of Nine Centers in North America.

OBJECTIVE: Quality of care (QoC) delivery in rheumatoid arthritis (RA) continues to suffer from various challenges (eg, delay in diagnosis and referral) that can lead to poor patient outcomes. This study aimed to identify good practice interventions that address these challenges in RA care in North America. METHODS: The study was conducted in three steps: (1) literature review of existing publications and guidelines (April 2005 to April 2021) on QoC in RA; (2) in-person visits to >50 individual specialists and health care professionals across nine rheumatology centers in the United States and Canada to identify challenges in RA care and any corresponding good practice interventions; and (3) collation and organization of findings of the two previous methods by commonalities to identify key good practice interventions, followed by further review by RA experts to ensure key challenges and gaps in RA care were captured. RESULTS: Several challenges and eight good practice interventions were identified in RA care. The interventions were prioritized based on the perceived positive impact on the challenges in care and ease of implementation. High-priority interventions included the use of technology to improve care, streamlining specialist treatment, and facilitating comorbidity assessment and care. Other interventions included enabling patient access to optimal medication regimens and improving patient self-management strategies. CONCLUSION: Learnings from the study can be implemented in other rheumatology centers throughout North America to improve RA care. Although the study was completed before the COVID-19 pandemic, the findings remain relevant.

Prevalence and target attainment of traditional cardiovascular risk factors in patients with systemic lupus erythematosus: a cross-sectional study including 3401 individuals from 24 countries.

BACKGROUND: Systemic lupus erythematosus (SLE) is characterised by increased cardiovascular morbidity and mortality risk. We aimed to examine the prevalence of traditional cardiovascular risk factors and their control in an international survey of patients with systemic lupus erythematosus. METHODS: In this multicentre, cross-sectional study, cardiovascular risk factor data from medical files of adult patients (aged ≥18) with SLE followed between Jan 1, 2015, and Jan 1, 2020, were collected from 24 countries, across five continents. We assessed the prevalence and target attainment of cardiovascular risk factors and examined potential differences by country income level and antiphospholipid syndrome coexistence. We used the Systemic Coronary Risk Evaluation algorithm for cardiovascular risk estimation, and the European Society of Cardiology guidelines for assessing cardiovascular risk factor target attainment. People with lived experience were not involved in the research or writing process. FINDINGS: 3401 patients with SLE were included in the study. The median age was 43·0 years (IQR 33-54), 3047 (89·7%) of 3396 patients were women, 349 (10.3%) were men, and 1629 (48·1%) of 3390 were White. 556 (20·7%) of 2681 patients had concomitant antiphospholipid syndrome. We found a high cardiovascular risk factor prevalence (hypertension 1210 [35·6%] of 3398 patients, obesity 751 [23·7%] of 3169 patients, and hyperlipidaemia 650 [19·8%] of 3279 patients), and suboptimal control of modifiable cardiovascular risk factors (blood pressure [target of <130/80 mm Hg], BMI, and lipids) in the entire SLE group. Higher prevalence of cardiovascular risk factors but a better blood pressure (target of <130/80 mm Hg; 54·9% [1170 of 2132 patients] vs 46·8% [519 of 1109 patients]; p<0·0001), and lipid control (75·0% [895 of 1194 patients] vs 51·4% [386 of 751 patients], p<0·0001 for high-density lipoprotein [HDL]; 66·4% [769 of 1158 patients] vs 60·8% [453 of 745 patients], p=0·013 for non-HDL; 80·9% [1017 of 1257 patients] vs 61·4% [486 of 792 patients], p<0·0001 for triglycerides]) was observed in patients from high-income versus those from middle-income countries. Patients with SLE with antiphospholipid syndrome had a higher prevalence of modifiable cardiovascular risk factors, and significantly lower attainment of BMI and lipid targets (for low-density lipoprotein and non-HDL) than patients with SLE without antiphospholipid syndrome. INTERPRETATION: High prevalence and inadequate cardiovascular risk factor control were observed in a large multicentre and multiethnic SLE cohort, especially among patients from middle-income compared with high-income countries and among those with coexistent antiphospholipid syndrome. Increased awareness of cardiovascular disease risk in SLE, especially in the above subgroups, is urgently warranted. FUNDING: None.

Cardiovascular risk in vasculitis.

The present review summarizes the burden, risk factors, biomarkers of and therapeutic consideration for cardiovascular disease in systemic vasculitis. Ischemic heart disease (IHD) and stroke are intrinsic features of Kawasaki disease, Takayasu arteritis, Giant Cell Arteritis (GCA), and Behcet's disease. The risk of IHD and stroke is increased in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and cryoglobulinemic vasculitis. Behcet's disease could present with venous thromboembolism. The risk of venous thromboembolism is increased in AAV, polyarteritis nodosa, and GCA. The risk of cardiovascular events is greatest at or immediately after the diagnosis of AAV or GCA, therefore, controlling vasculitis disease activity is of utmost importance. Traditional as well as disease-related risk factors drive the heightened cardiovascular risk in vasculitis. Aspirin or statins reduce the risk of IHD or stroke in GCA or the risk of IHD in Kawasaki Disease. Venous thromboembolism in Behcet's disease should be treated with immunosuppressive therapy rather than with anticoagulation.

Role of Lipoprotein Levels and Function in Atherosclerosis Associated with Autoimmune Rheumatic Diseases.

Immune and inflammatory mediators in autoimmune rheumatic diseases induce modification in the activity of enzymes pivotal for lipid metabolism and promote a proatherogenic serum lipid profile. However, disturbances in low- and high-density lipoprotein composition and increased lipid oxidation also occur. Therefore, lipoprotein dysfunction causes intracellular cholesterol accumulation in macrophages, smooth muscle cells, and platelets. Overall, both plaque progression and acute cardiovascular events are promoted. Single rheumatic diseases may present a particular pattern of lipid disturbances so that standard methods to evaluate cardiovascular risk may not be accurate enough. In general, antirheumatic drugs positively affect lipid metabolism in these patients.

Statins influence the relationship between ATP-binding cassette A1 membrane transporter-mediated cholesterol efflux capacity and coronary atherosclerosis in rheumatoid arthritis.

Objectives: Cholesterol efflux capacity (CEC) is the main antiatherogenic function of high-density lipoprotein (HDL). ATP-binding-cassette A1 (ABCA1) membrane transporter initiates cholesterol export from arterial macrophages to pre-ß HDL particles fostering their maturation; in turn, those accept cholesterol through ABCG1-mediated export. Impaired pre-ß HDL maturation may disrupt the collaborative function of the two transporters and adversely affect atherosclerosis. Statins exert atheroprotective functions systemically and locally on plaque. We here evaluated associations between ABCA1-CEC, coronary atherosclerosis and cardiovascular risk and the influence of statins on those relationships in rheumatoid arthritis (RA). Methods: Evaluation with computed tomography angiography was undertaken in 140 patients and repeated in 99 after 6.9 ± 0.3 years. Events comprising cardiovascular death, acute coronary syndromes, stroke, claudication, revascularization and heart failure were recorded. ABCA1-CEC and ABCG1-CEC were evaluated in J774A.1 macrophages and Chinese hamster ovary (CHO) cells respectively and expressed as percentage of effluxed over total intracellular cholesterol. Covariates in all cardiovascular event risk and plaque outcome models included atherosclerotic cardiovascular disease (ASCVD) risk score and high-density lipoprotein cholesterol. Results: ABCA1-CEC negatively correlated with ABCG1-CEC (r = -0.167, p = 0.049). ABCA1-CEC associated with cardiovascular risk (adjusted hazard ratio 2.05 [95%CI 1.20-3.48] per standard deviation [SD] increment). There was an interaction of ABCA1-CEC with time-varying statin use (p = 0.038) such that current statin use inversely associated with risk only in patients with ABCA1-CEC below the upper tertile. ABCA1-CEC had no main effect on plaque or plaque progression; instead, ABCA1-CEC (per SD) associated with fewer baseline total plaques (adjusted rate ratio [aRR] 0.81, [95%CI 0.65-1.00]), noncalcified plaques (aRR 0.78 [95%CI 0.61-0.98]), and vulnerable low-attenuation plaques (aRR 0.41 [95%CI 0.23-0.74]) in statin users, and more low-attenuation plaques (aRR 1.91 [95%CI 1.18-3.08]) in nonusers (p-for-interaction = 0.018, 0.011, 0.025 and < 0.001 respectively). Moreover, ABCA1-CEC (per SD) associated with greater partially/fully-calcified plaque progression (adjusted odds ratio 3.07 [95%CI 1.20-7.86]) only in patients not exposed to statins during follow-up (p-for-interaction = 0.009). Conclusion: In patients with RA, higher ABCA1-CEC may reflect a proatherogenic state, associated with enhanced cardiovascular risk. Statin use may unmask the protective impact of ABCA1-mediated cholesterol efflux on plaque formation, progression and cardiovascular risk.

Coronary plaque progression is greater in systemic lupus erythematosus than rheumatoid arthritis.

BACKGROUND: Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are associated with a high incidence of cardiovascular disease. Coronary atherosclerosis, particularly total plaque and noncalcified plaque on coronary computed tomography angiography (CCTA) has been correlated with cardiovascular events. We compared baseline coronary plaque burden and progression by serial CCTA in SLE and RA patients. METHODS: We prospectively evaluated 44 patients who underwent serial CCTA examinations to quantify coronary plaque progression, 22 SLE patients, and 22 age- and sex-matched RA patients. Semiautomated plaque software was used for quantitative plaque assessment. Linear regression examined the effect of SLE diagnosis (versus RA) on annualized change in natural log-transformed total normalized atheroma volume (ln-TAV norm ) for low-attenuation, fibrofatty, fibrous, total noncalcified, densely calcified, and total plaque. RESULTS: No quantitative differences for any plaque types were observed at baseline between SLE and RA patients ( P = 0.330-0.990). After adjustment for baseline plaque and cardiovascular risk factors, the increase in ln-TAV norm was higher in SLE than RA patients for fibrous [Exp-ß: 0.202 (0.398), P = 0.0003], total noncalcified [Exp-ß: 0.179 (0.393), P = 0.0001], and total plaque volume [Exp-ß: 0.154 (0.501), P = 0.0007], but not for low-attenuation, fibrofatty, or densely calcified plaque ( P = 0.103-0.489). Patients with SLE had 80% more fibrous, 82% more noncalcified, and 85% more total plaque increase than those with RA. CONCLUSION: Coronary plaque volume was similar in RA and SLE at baseline. Progression was greater in SLE, which may explain the greater cardiovascular risk in this disease. Further research to evaluate screening and management strategies for cardiovascular disease in these high-risk patients is warranted.

Atherosclerotic Cardiovascular Risk Stratification in the Rheumatic Diseases:: An Integrative, Multiparametric Approach.

Cardiovascular disease (CVD) risk is increased in most inflammatory rheumatic diseases (IRDs), reiterating the role of inflammation in the initiation and progression of atherosclerosis. An inverse association of CVD risk with body weight and lipid levels has been described in IRDs. Coronary artery calcium scores, plaque burden and characteristics, and carotid plaques on ultrasound optimize CVD risk estimate in IRDs. Biomarkers of cardiac injury, autoantibodies, lipid biomarkers, and cytokines also improve risk assessment in IRDs. Machine learning and deep learning algorithms for phenotype and image analysis hold promise to improve CVD risk stratification in IRDs.

Inflammation and immunomodulatory therapies influence the relationship between ATP-binding cassette A1 membrane transporter-mediated cholesterol efflux capacity and coronary atherosclerosis in rheumatoid arthritis.

Objectives: High-density lipoprotein (HDL) removes cholesterol from cells in atherosclerotic lesions, a function known as cholesterol efflux capacity (CEC). ATP-binding-cassette A1 (ABCA1) membrane transporter starts cholesterol transfer from macrophages to HDL particles. In rheumatoid arthritis (RA), methotrexate and biologic disease modifying drugs (bDMARDs) are atheroprotective whereas corticosteroids and C-reactive protein (CRP) are proatherogenic. We evaluated the influence of these factors on the relationship of ABCA1-CEC with atherosclerosis and cardiovascular events. Methods: Atherosclerosis was evaluated with computed tomography angiography in 140 patients with RA and repeated in 99 after 6.9 ± 0.3 years. Events including acute coronary syndromes, stroke, cardiovascular death, claudication, revascularization, and heart failure were recorded. ABCA1-CEC was quantified in J774A.1 murine macrophages and reported as percentage of effluxed over intracellular cholesterol. Results: Higher ABCA1-CEC associated with (i) more calcified plaques at baseline only in patients with CRP>7 mg/L (median) (p-interaction = 0.001) and methotrexate nonusers (p-interaction = 0.037), and more partially-calcified plaques only in bDMARD nonusers (p-interaction = 0.029); (ii) fewer new calcified plaques in patients with below-median but not higher time-averaged CRP (p-interaction = 0.028); (iii) fewer new total and calcified plaques in prednisone unexposed but not patients exposed to prednisone during follow-up (p-interaction = 0.034 and 0.004) and (iv) more new plaques in baseline bDMARD nonusers and fewer in bDMARD users (p-interaction ≤ 0.001). Also, ABCA1-CEC associated with greater cardiovascular risk only in baseline prednisone users (p-interaction = 0.027). Conclusion: ABCA1-CEC associated with decreased atherosclerosis in patients with below-median baseline and time-averaged CRP and bDMARD use. Conversely, ABCA1-CEC associated with increased plaque in those with higher CRP, corticosteroid users, methotrexate nonusers, and bDMARD nonusers. While in well-treated and controlled disease ABCA1-CEC appears atheroprotective, in uncontrolled RA its action may be masked or fail to counteract the inflammation-driven proatherogenic state.

Rheumatoid arthritis disease activity and adverse events in patients receiving tofacitinib or tumor necrosis factor inhibitors: a post hoc analysis of ORAL Surveillance.

Background: In patients with rheumatoid arthritis (RA), persistent inflammation and increasing disease activity are associated with increased risk of adverse events (AEs). Objectives: To assess relationships between RA disease activity and AEs of interest in patients treated with tofacitinib or tumor necrosis factor inhibitors (TNFi). Design: This was a post hoc analysis of a long-term, postauthorization safety endpoint trial of tofacitinib versus TNFi. Methods: In ORAL Surveillance, 4362 patients aged ⩾50 years with active RA despite methotrexate, and ⩾1 additional cardiovascular (CV) risk factor, were randomized 1:1:1 to tofacitinib 5 or 10 mg twice daily or TNFi for up to 72 months. Post hoc time-dependent multivariable Cox analysis evaluated the relationships between disease activity [Clinical Disease Activity Index (CDAI)], inflammation [C-reactive protein (CRP)], and AEs of interest. The AEs included major adverse CV events (MACE), malignancies excluding nonmelanoma skin cancer (NMSC), venous thromboembolism (VTE), serious infections, herpes zoster (HZ), nonserious infections excluding HZ (NSI), and death. Results: Across treatments, risk for NSI was higher when patients had CDAI-defined active disease versus remission; MACE and VTE risks trended higher, but did not reach significance. Hazard ratios for MACE, malignancies excluding NMSC, VTE, infections, and death rose by 2-9% for each 5-mg/L increment in serum CRP. The interaction terms evaluating the impact of treatment assignment on the relationship between disease activity and AEs were all p > 0.05. Conclusion: In ORAL Surveillance, higher NSI risk was observed in the presence of active RA versus remission. The risk of MACE and VTE directionally increased in active disease versus remission, although statistical power was limited due to small event numbers in these categories. The relationship between active disease and AEs was not impacted by treatment with tofacitinib versus TNFi. Registration: NCT02092467.

The link between disease activity and adverse medical events in people with rheumatoid arthritis taking tofacitinib or tumor necrosis factor inhibitors. Why was the study done? • People with rheumatoid arthritis (RA) who have uncontrolled symptoms (high disease activity) have a higher chance of having adverse medical events (medical problems that occur during treatment with a medication) than people who have mild symptoms (low disease activity). • We looked at the link between levels of disease activity and the risk of having adverse medical events in people with RA who took tofacitinib or a tumor necrosis factor inhibitor (TNFi) medication. What did the researchers do? • We used the results of ORAL Surveillance, a long-term safety trial in people with RA. ○ In this study, people with RA were 50 years or older and at high risk of a major cardiovascular event such as heart attack or stroke. • For up to 6 years, people took tofacitinib 5 or 10mg tablets two times a day or TNFi injections. • We used statistical tests to examine the link between different levels of RA disease activity or inflammation and different adverse medical events, such as: ○ major cardiovascular events (such as heart attack, stroke, or death due to heart failure) ○ cancers ○ blood clots ○ infections ○ deaths. What did the researchers find? • In people who took tofacitinib or TNFi: ○ People with active disease (those with RA symptoms) had a higher risk of infections that did not lead to hospitalization (nonserious infections) than people in remission (those with very mild symptoms or no symptoms at all). ○ People with active disease also had a slightly higher risk of major cardiovascular events and blood clots than those in remission. ○ Higher levels of inflammation led to increased risk of major cardiovascular events, cancers, blood clots, infections, and deaths. What do the findings mean? • Active RA disease leads to higher risk of adverse medical events. • The medication used (tofacitinib or TNFi) did not affect the link between levels of RA disease activity and adverse medical events. • This study was limited by the low number of adverse medical events recorded.

Beta-2-glycoprotein-I IgA antibodies predict coronary plaque progression in rheumatoid arthritis.

OBJECTIVES: To evaluate whether anti-Beta-2-Glycoprotein-I (anti-ß2GPI) IgA antibodies associate with progression of coronary atherosclerosis and cardiovascular disease (CVD) events in rheumatoid arthritis (RA). METHODS: One hundred-fifty patients underwent plaque evaluation (total, non-calcified, mixed and calcified) with coronary computed tomography angiography; 101 were re-imaged within 6.9±0.3 years to assess progression. The Framingham-D'Agostino score assessed cardiovascular risk. Coronary artery calcium (CAC) and segment involvement score quantified plaque burden. RESULTS: Anti-ß2GPI IgA were seen in 45 (30%) patients. Despite no link to baseline plaque burden, anti-ß2GPI IgA associated with segment involvement score increase (adjusted-RR=1.64 [95%CI 1.02-2.63]), CAC change (adjusted-ß=0.33 [95%CI 0.002-0.656]) and developing new extensive or obstructive plaque at follow-up (adjusted-OR=4.24 [95%CI 1.30-13.87]). Adding anti-ß2GPI IgA to logistic regression models with conventional risk factors predicting plaque progression outcomes increased Area under the receiver-operator curve and improved Net Reclassification and Integrated Discrimination Improvement indices (all P<0.05). In per-segment analyses, anti-ß2GPI IgA predicted mixed plaque formation (adjusted-OR=3.20 [95%CI 1.01-10.09]) and lower likelihood of transition of mixed to calcified plaque (adjusted-OR=0.19 [95%CI 0.04-0.96]). Anti-ß2GPI IgA moderated the effect of C-reactive protein on CAC change such that C-reactive protein associated with CAC change (ß=0.26 [95%CI 0.14-0.38]) and CVD risk (adjusted-HR=1.89 [95%CI 1.02-3.51]) only in anti-ß2GPI IgA positive patients. CONCLUSION: Anti-ß2GPI IgA addition to clinical risk models improved prediction accuracy of CAC, plaque progression and transition to extensive/obstructive disease. They associated with new high-risk mixed plaques and delayed healing to calcified lesions. Anti-ß2GPI IgA further modified the effect of inflammation on plaque progression and CVD events.

Epicardial Adipose Tissue Volume As a Marker of Subclinical Coronary Atherosclerosis in Rheumatoid Arthritis.

OBJECTIVE: To assess epicardial adipose tissue volume (EATV) and its link to coronary atherosclerosis and plaque morphology in patients with rheumatoid arthritis (RA) and in age- and sex-matched controls. METHODS: Computed tomography angiography was used to evaluate EATV and coronary plaque in 139 RA patients and 139 non-RA controls. All models assessing the effect of EATV on plaque were adjusted for age, sex, hypertension, diabetes, dyslipidemia, smoking status, family history of coronary artery disease, and obesity (body mass index of ≥30 kg/m2 ). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: Mean ± SD log-transformed EATV was similar in patients with RA (4.69 ± 0.36) and controls (4.70 ± 0.42). EATV was higher in RA patients with atherosclerosis compared to those without atherosclerosis (P = 0.046). In stratified analyses, EATV was associated with the number of segments with plaque in RA patients (rate ratio 1.20 [95% CI 1.01-1.41] per 1-SD increment of log-unit increase in EATV) but not in controls (P for interaction = 0.089). Likewise, EATV (per 1-SD log-unit increase) was related to the presence of multivessel or obstructive disease (OR 1.63 [95% CI 1.04-2.61]), noncalcified plaque (OR 1.78 [95% CI 1.17-2.70]), and vulnerable plaque (OR 1.77 [95% CI 1.03-3.04]) in RA patients but not in controls (P for interaction ≤ 0.048 for each). Among RA patients, EATV was associated with the number of segments with plaque in those with RA for <10 years who did not develop any cardiovascular risk factors and who were not obese (P for interaction ≤ 0.017). CONCLUSION: Despite similar EATVs in RA patients and controls, EATVs were associated with greater plaque burden and presence of plaques with a noncalcified component and vulnerability features only in RA patients. EAT may be more pathogenic in RA and play a role in early-stage atherosclerosis. Its value as a biomarker of subclinical atherosclerosis and cardiovascular risk in RA warrants further studies.

Biologics and atherosclerotic cardiovascular risk in rheumatoid arthritis: a review of evidence and mechanistic insights.

Introduction: Cardiovascular disease is a leading comorbidity in rheumatoid arthritis. Timely introduction of biologic therapies in a treat-to-target approach has optimized disease-related outcomes and attenuated accrual of comorbidities, including cardiovascular risk.Areas covered: A literature search in MEDLINE (via PubMed) was performed between January 2009 and November 2020. This manuscript explores recent developments in atherosclerotic cardiovascular risk in RA compared with non-RA individuals; it synopsizes differences in vascular function and inflammation, prevalence, burden, vulnerability, and progression of atherosclerotic plaque and their underlying cellular and molecular mechanisms. Finally, it reviews the recent literature on cardioprotective benefits of biologics and draws mechanistic links with inhibition of new plaque formation, stabilization of high-risk lesions and improvement in endothelial function, arterial stiffness, lipid metabolism, and traditional cardiac risk factors.Expert opinion: Increasing evidence points to a solid cardioprotective influence of earlier, longer, and ongoing use of biologic treatments in RA. Nevertheless, the precise mechanistic effects of plaque progression and remodeling, vascular stiffness, endothelial dysfunction, lipid metabolism, and traditional cardiac risk factors are less rigorously characterized.