Mihaela Taylor

Cholesterol efflux by high density lipoproteins is impaired in patients with active rheumatoid arthritis

Objectives Reverse cholesterol transport (RCT) is a major antiatherogenic function of high density lipoprotein (HDL). In the current work, the authors evaluated whether the RCT capacity of HDL from rheumatoid arthritis (RA) patients is impaired when compared to healthy controls. Methods HDL was isolated from 40 patients with RA and 40 age and sex matched healthy controls. Assays of cholesterol efflux, HDLs antioxidant function and paraoxanase-1 (PON-1) activity were performed as described previously. Plasma myeloperoxidase (MPO) activity was assessed by a commercially available assay. Results Mean cholesterol efflux capacity of HDL was not significantly different between RA patients (40.2%±11.1%) and controls (39.5%±8.9%); p=0.75. However, HDL from RA patients with high disease activity measured by a disease activity score using 28 joint count (DAS28>5.1), had significantly decreased ability to promote cholesterol efflux compared to HDL from patients with very low disease activity/clinical remission (DAS28<2.6). Significant correlations were noted between cholesterol efflux and the DAS28 (r=−0.39, p=0.01) and erythrocyte sedimentation rate, (r=−0.41, p=0.0009). Higher plasma MPO activity was associated with worse HDL function (r=0.41/p=0.009 (antioxidant capacity); r=0.35, p=0.03 (efflux)). HDLs ability to promote cholesterol efflux was modestly but significantly correlated with its antioxidant function (r=−0.34, p=0.03). Conclusions The cholesterol efflux capacity of HDL is impaired in RA patients with high disease activity and is correlated with systemic inflammation and HDLs antioxidant capacity. Attenuation of HDL function, independent of HDL cholesterol levels, may suggest a mechanism by which active RA contributes to increased cardiovascular (CV) risk.

A Panel of Biomarkers Is Associated With Increased Risk of the Presence and Progression of Atherosclerosis in Women With Systemic Lupus Erythematosus

An increased frequency of atherosclerosis (ATH) in systemic lupus erythematosus (SLE) is well‐documented but not fully explained by the presence of traditional cardiac risk factors. Several nontraditional biomarkers, including proinflammatory high‐density lipoprotein (piHDL) and leptin, have been individually associated with subclinical ATH in SLE. The aim of this study was to examine whether these and other biomarkers can be combined into a risk profile, the Predictors of Risk for Elevated Flares, Damage Progression, and Increased Cardiovascular Disease in Patients with SLE (PREDICTS), that could be used to better predict future progression of ATH.

Antibodies against the Activated Coagulation Factor X (FXa) in the Antiphospholipid Syndrome That Interfere with the FXa Inactivation by Antithrombin

Antiphospholipid Ab have been shown to promote thrombosis and fetal loss in the antiphospholipid syndrome (APS). Previously, we found IgG anti-thrombin Ab in some APS patients that could interfere with inactivation of thrombin by antithrombin (AT). Considering that activated coagulation factor X (FXa) is homologous to thrombin in the catalytic domains and is also regulated primarily by AT, we hypothesized that some thrombin-reactive Ab may bind to FXa and interfere with AT inactivation of FXa. To test these hypotheses, we studied reactivity of eight patient-derived monoclonal IgG antiphospholipid Ab with FXa and the presence of IgG anti-FXa Ab in APS patients and investigated the effects of FXa-reactive mAb on AT inactivation of FXa. The results revealed that six of six thrombin-reactive IgG mAb bound to FXa and that the levels of plasma IgG anti-FXa Ab in 38 APS patients were significantly higher than those in 30 normal controls (p < 0.001). When the mean plus 3 SDs of the 30 normal controls was used as the cutoff, 5 of 38 APS patients (13.2%) had IgG anti-FXa Ab. Importantly, three of six FXa-reactive mAb significantly inhibited AT inactivation of FXa. Combined, these results indicate that anti-FXa Ab may contribute to thrombosis by interfering with the anticoagulant function of AT on FXa in some APS patients.

Association of paraoxonase 1 gene polymorphism and enzyme activity with carotid plaque in rheumatoid arthritis.

OBJECTIVE To investigate the relationship of genetic and biochemical determinants of paraoxonase 1 activity to carotid plaque as a surrogate marker of cardiovascular (CV) risk in patients with rheumatoid arthritis (RA). METHODS The relationships between paraoxonase 1 activity, PON1 genotype (for the functional polymorphism at position 192), and carotid plaque presence were determined in 168 RA patients. After an overnight fast, blood was collected for lipoprotein analysis, and paraoxonase 1 activity was measured using paraoxon as the substrate. The PON1 Q192R genotype was determined for all patients. Lipoprotein cholesterol levels, traditional CV risk factors, medication use, and RA disease characteristics were assessed for all patients. RESULTS Paraoxonase 1 activity values in the RA patients were highest for the RR genotype, intermediate for the QR genotype, and lowest for the QQ genotype (P < 0.0001). Compared to patients with either the QQ genotype or the QR genotype, patients with the RR genotype demonstrated decreased risk of carotid plaque on multivariate analysis, controlling for traditional CV risk factors, high-sensitivity C-reactive protein levels, prednisone use, and cholesterol-lowering medication use (P < 0.05). Additional multivariate logistic regression analysis controlling for the above factors also revealed a significant association of plasma paraoxonase 1 activity with carotid plaque in RA patients. Lower plasma paraoxonase 1 activity was associated with increased risk of carotid plaque (P < 0.05). CONCLUSION The current findings suggest a relationship of the genetic determinants and activity of paraoxonase 1 to CV risk in RA patients, as assessed by the presence or absence of carotid plaque. Further CV outcome studies are warranted to validate the utility of paraoxonase 1 as a biomarker of CV risk in patients with RA.

Using the antinuclear antibody test to diagnose rheumatic diseases: when does a positive test warrant further investigation?

Abstract The anti-nuclear antibody (ANA) test is ordered commonly as a screening test for rheumatic diseases. Although ANA positivity is highly sensitive for certain rheumatic diseases, the presence of ANA is nonspecific and can be associated with numerous nonrheumatic factors, including environmental exposures, malignancies, drugs, and infections. This article describes a practical approach for physicians when evaluating patients using a positive ANA test. In the absence of connective tissue disease symptoms, the ANA test has minimal clinical significance in diagnosing rheumatic diseases. Understanding how to use ANA test results appropriately may reduce unnecessary referrals and costly workups.

An OMERACT reliability exercise of inflammatory and structural abnormalities in patients with knee osteoarthritis using ultrasound assessment

Objective To assess whether ultrasonography (US) is reliable for the evaluation of inflammatory and structural abnormalities in patients with knee osteoarthritis (OA). Methods Thirteen patients with early knee OA were examined by 11 experienced sonographers during 2 days. Dichotomous and semiquantitative scoring was performed on synovitis characteristics in various aspects of the knee joint. Semiquantitative scoring was done of osteophytes at the medial and lateral femorotibial joint space or cartilage damage of the trochlea and on medial meniscal damage bilaterally. Intra- and interobserver reliability were computed by use of unweighted and weighted κ coefficients. Results Intra- and interobserver reliability scores were moderate to good for synovitis (mean κ 0.67 and 0.52, respectively) as well as moderate to good for the global synovitis (0.70 and 0.50, respectively). Mean intra- and interobserver reliability κ for cartilage damage, medial meniscal damage and osteophytes ranged from fair to good (0.55 and 0.34, 0.75 and 0.56, 0.73 and 0.60, respectively). Conclusions Using a standardised protocol, dichotomous and semiquantitative US scoring of pathological changes in knee OA can be reliable.

Saline breast implant fluid collection and reactive arthritis in a patient with streptococcal toxic shock syndrome.

Streptococcal toxic shock syndrome is a potentially lethal condition with an increasing incidence over the last 30 years. We present the case of a 55-year-old patient with signs and symptoms of streptococcal toxic shock syndrome. This patients presentation was unique in that it was followed by an accumulation of fluid at her breast implant in addition to a polyarticular reactive arthritis. We propose that the patients reactive arthritis is consistent with the diagnosis of post-streptococcal reactive arthritis, a variant of acute rheumatic fever, which similarly to its variant is immunologically driven. We hypothesize that the fluid collection around the patients breast implant was triggered by her infection and was also immunologically mediated.

Elevated baseline power Doppler discriminates an RA subgroup highly responsive to therapy

SIR, Recent systematic literature reviews and expert panel recommendations by the ACR and the EULAR support the use of musculoskeletal US (MSUS) in monitoring RA disease activity [1, 2]. MSUS is inexpensive and enables multiple point-of-care assessments. Power Doppler US (PDUS) score measures synovitis and may be useful in assessing response to therapy, where studies have reported suppression of PDUS signal after administration of RA treatment [3, 4]. This study evaluates the predictive value of baseline PDUS measures on response to drug by the DAS28 and clinical disease activity index (CDAI) in RA. Few studies have evaluated the association between MSUS and co-morbidities, and we investigate this concept as well. This report describes the results of a pilot 12 month open-label s.c. abatacept study of 25 RA patients naive to biologics. The study was approved by the University of California, Los Angeles institutional review board, registered on clinicaltrials.gov (NCT01299961), and all patients signed an informed consent form. Inclusion criteria were as follows: ACR 1987 RA diagnostic criteria; age 518 years; stable DMARDs; no prior exposure to biologics; DAS28/ESR >3.2; prednisone 410 mg; and total PDUS 51 for at least two MCP joints. Patients completed detailed questionnaires regarding their demographics, function and comorbidities. MSUS assessment of PDUS was performed at baseline, 3 weeks, 3, 6 and 12 months. A GE Logic E9 machine with ML6-15 probe (GE Healthcare) was used. Seven joints were scanned by MSUS of the most affected side (wrist, MCP joint 2/3, PIP joint 2/3 and MTP joint 2/5) according to Backhaus et al. [5]. PDUS was scored semiquantitatively according to published consensus definitions [6]. The clinical assessor was blinded to the US data and vice versa. In addition, when scoring images, the ultrasonographer was blinded to the sequence of the visits and patient. All 25 patients enrolled in the study completed at least 3 months of therapy with s.c. abatacept. Nineteen of the 25 patients completed the 12 month visit. Six patients dropped out for the following reasons: lack of efficacy (two patients); adverse events [three patients (recurrent oral ulcers, erythema nodosum, chronic obstructive pulmonary disease exacerbation), no serious adverse events]; and lost to follow-up (one patient). Patients were separated into two groups based on median baseline PDUS of complete cases: patients with baseline PDUS <5 and patients with baseline PDUS 55 (Table 1). Interestingly, the changes between baseline and 12 months for DAS28/ESR, CDAI and the HAQ disability index (HAQ-DI) for the PDUS 55 group were significantly greater than seen in the PDUS <5 group, where patients in the PDUS 55 group experienced more than twice the magnitude of improvement (DAS28 change of 1.1 vs change of 2.7, CDAI change of 12.8 vs change of 28.0, and HAQ-DI change of 0.3 vs change of 0.8). Baseline PDUS was significantly correlated with change in DAS28/ESR at 12 months (DAS28/ESR = 0.65, P< 0.01). We also performed a multivariate linear regression for change in DAS28/ESR as the outcome, with baseline PDUS and baseline DAS28/ESR as the predictors. Baseline PDUS was almost significantly associated with change in DAS28/ESR (P = 0.06), after accounting for baseline DAS28/ESR (P = 0.52). The number of comorbidities was significantly higher in those with PDUS< 5 (P = 0.02). Lastly, we found that lower baseline