Performance Evaluation and Clinical Associations of Immunoassays That Detect Antibodies to Negatively Charged Phospholipids Other Than Cardiolipin.

OBJECTIVES: We evaluate the performance characteristics of antiphosphatidylserine (anti-PS), antiphosphatidylinositol (anti-PI), and antiphospholipid mixture (APhL) enzyme-linked immunosorbent assays (ELISAs) compared with anticardiolipin (aCL) and anti-ß2 glycoprotein I (anti-ß2GPI) in a large group of patients with antiphospholipid (aPL)-related diseases. METHODS: Serum samples from 548 patients from the Hopkins and Jamaican systemic lupus erythematosus cohorts, the PROMISSE cohort, and the Antiphospholipid Standardization Laboratory were examined for immunoglobulin G (IgG)/immunoglobulin M (IgM) positivity in aCL, anti-ß2GPI, anti-PS, anti-PI, and APhL ELISA assays. RESULTS: All IgG assays were associated with one or more thrombotic and/or obstetric manifestations, with an increased risk associated with higher antibody titers. Analytical performance was similar among assays, but IgG assays performed better than IgM counterparts. CONCLUSIONS: Increasing titers of APhL, anti-PS, and anti-PI antibodies could indicate an increased risk of thrombotic and/or obstetric aPL-related manifestations. These assays may be promising biomarkers for particular APS manifestations.

Educational Health Disparities in Cardiovascular Disease Risk Factors: Findings from Jamaica Health and Lifestyle Survey 2007-2008.

OBJECTIVES: Socioeconomic disparities in health have emerged as an important area in public health, but studies from Afro-Caribbean populations are uncommon. In this study, we report on educational health disparities in cardiovascular disease (CVD) risk factors (hypertension, diabetes mellitus, hypercholesterolemia, and obesity), among Jamaican adults. METHODS: We analyzed data from the Jamaica Health and Lifestyle Survey 2007-2008. Trained research staff administered questionnaires and obtained measurements of blood pressure, anthropometrics, glucose and cholesterol. CVD risk factors were defined by internationally accepted cut-points. Educational level was classified as primary or lower, junior secondary, full secondary, and post-secondary. Educational disparities were assessed using age-adjusted or age-specific prevalence ratios and prevalence differences obtained from Poisson regression models. Post-secondary education was used as the reference category for all comparisons. Analyses were weighted for complex survey design to yield nationally representative estimates. RESULTS: The sample included 678 men and 1,553 women with mean age of 39.4 years. The effect of education on CVD risk factors differed between men and women and by age group among women. Age-adjusted prevalence of diabetes mellitus was higher among men with less education, with prevalence differences ranging from 6.9 to 7.4 percentage points (p < 0.05 for each group). Prevalence ratios for diabetes among men ranged from 3.3 to 3.5 but were not statistically significant. Age-specific prevalence of hypertension was generally higher among the less educated women, with statistically significant prevalence differences ranging from 6.0 to 45.6 percentage points and prevalence ratios ranging from 2.5 to 4.3. Similarly, estimates for obesity and hypercholesterolemia suggested that prevalence was higher among the less educated younger women (25-39 years) and among more educated older women (40-59 and 60-74 years). There were no statistically significant associations for diabetes among women, or for hypertension, high cholesterol, or obesity among men. CONCLUSION: Educational health disparities were demonstrated for diabetes mellitus among men, and for obesity, hypertension, and hypercholesterolemia among women in Jamaica. Prevalence of diabetes was higher among less educated men, while among younger women the prevalence of hypertension, hypercholesterolemia, and obesity was higher among those with less education.

Social determinants of breast cancer in the Caribbean: a systematic review.

BACKGROUND: Breast cancer is the leading cause of cancer deaths among women in the Caribbean and accounts for >1 million disability adjusted life years. Little is known about the social inequalities of this disease in the Caribbean. In support of the Rio Political Declaration on addressing health inequities, this article presents a systematic review of evidence on the distribution, by social determinants, of breast cancer risk factors, frequency, and adverse outcomes in Caribbean women. METHODS: MEDLINE, EMBASE, SciELO, CINAHL, CUMED, LILACS, and IBECS were searched for observational studies reporting associations between social determinants and breast cancer risk factors, frequency, or outcomes. Based on the PROGRESS-plus checklist, we considered 8 social determinant groups for 14 breast cancer endpoints, which totalled to 189 possible ways ('relationship groups') to explore the role of social determinants on breast cancer. Studies with >50 participants conducted in Caribbean territories between 2004 and 2014 were eligible for inclusion. The review was conducted according to STROBE and PRISMA guidelines and results were planned as a narrative synthesis, with meta-analysis if possible. RESULTS: Thirty-four articles were included from 5,190 screened citations. From these included studies, 75 inequality relationships were reported examining 30 distinct relationship groups, leaving 84% of relationship groups unexplored. Most inequality relationships were reported for risk factors, particularly alcohol and overweight/obesity which generally showed a positive relationship with indicators of lower socioeconomic position. Evidence for breast cancer frequency and outcomes was scarce. Unmarried women tended to have a higher likelihood of being diagnosed with breast cancer when compared to married women. While no association was observed between breast cancer frequency and ethnicity, mortality from breast cancer was shown to be slightly higher among Asian-Indian compared to African-descent populations in Trinidad (OR 1.2, 95% CI 1.1-1.4) and Guyana (OR 1.3, 95% CI 1.0-1.6). CONCLUSION: Study quantity, quality, and variability in outcomes and reporting limited the synthesis of evidence on the role of social determinants on breast cancer in the Caribbean. This report represents important current evidence on the region, and can guide future research priorities for better describing and understanding of Caribbean breast cancer inequalities.

Educational health disparities in hypertension and diabetes mellitus among African descent populations in the Caribbean and the USA: a comparative analysis from the Spanish town cohort (Jamaica) and the Jackson heart study (USA).

BACKGROUND: Studies have suggested that social inequalities in chronic disease outcomes differ between industrialized and developing countries, but few have directly compared these effects. We explored inequalities in hypertension and diabetes prevalence between African-descent populations with different levels of educational attainment in Jamaica and in the United States of America (USA), comparing disparities within each location, and between countries. METHODS: We analyzed baseline data from the Jackson Heart Study (JHS) in the USA and Spanish Town Cohort (STC) in Jamaica. Participants reported their highest level of educational attainment, which was categorized as 'less than high school' (HS). Educational disparities in the prevalence of hypertension and diabetes were examined using prevalence ratios (PR), controlling for age, sex and body mass index (BMI). RESULTS: Analyses included 7248 participants, 2382 from STC and 4866 from JHS, with mean age of 47 and 54 years, respectively (p < 0.001). Prevalence for both hypertension and diabetes was significantly higher in the JHS compared to STC, 62% vs. 25% (p < 0.001) and 18% vs. 13% (p < 0.001), respectively. In bivariate analyses there were significant disparities by education level for both hypertension and diabetes in both studies; however, after accounting for confounding or interaction by age, sex and BMI these effects were attenuated. For hypertension, after adjusting for age and BMI, a significant education disparity was found only for women in JHS, with PR of 1.10 (95% CI 1.04-1.16) for < HS vs > HS and 1.07 (95% CI 1.01-1.13) for HS vs > HS. For diabetes; when considering age-group and sex specific estimates adjusted for BMI, among men: significant associations were seen only in the 45-59 years age-group in JHS with PR 1.84 (95% CI 1.16-2.91) for < HS vs > HS. Among women, significant PR comparing < HS to > HS was seen for all three age-groups for JHS, but not in STC; PR were 3.95 (95% CI 1.94-8.05), 1.53 (95% CI 1.10-2.11) and 1.32 (95% CI 1.06-1.64) for 25-44, 45-59 and 60-74 age-groups, respectively. CONCLUSION: In Jamaica, educational disparities were largely explained by age, sex and BMI, while in the USA these disparities were larger and persisted after accounting these variables.

Antibodies to Phosphatidylserine/Prothrombin Complex in Antiphospholipid Syndrome: Analytical and Clinical Perspectives.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy-related morbidity accompanied by persistently positive antiphospholipid antibodies (aPL). Current laboratory criteria for APS classification recommend testing for lupus anticoagulant as well as IgG and IgM anticardiolipin, and beta-2 glycoprotein I (anti-ß2GPI) antibodies. However, there appears to be a subset of patients with classical APS manifestations who test negative for the recommended criteria aPL tests. While acknowledging that such patients may have clinical features that are not of an autoimmune etiology, experts also speculate that these "seronegative" patients may test negative for relevant autoantibodies as a result of a lack of harmonization and/or standardization. Alternatively, they may have aPL that target other antigens involved in the pathogenesis of APS. In the latter, autoantibodies that recognize a phosphatidylserine/prothrombin (PS/PT) complex have been reported to be associated with APS and may have diagnostic relevance. This review highlights analytical and clinical attributes associated with PS/PT antibodies, taking into consideration the performance characteristics of criteria aPL tests in APS with specific recommendations for harmonization and standardization efforts.

Disparities in cardiovascular disease among Caribbean populations: a systematic literature review.

BACKGROUND: Cardiovascular diseases (CVD) are the predominant cause of death globally. The large health disparities in the distribution of the burden of disease seen in developed and developing countries are of growing concern. Central to this concern is the poor outcome which is seen disproportionately in socially disadvantaged groups and racial/ethnic minorities. The aim of the study was to conduct a systematic literature review to investigate the nature of cardiovascular disease health disparities among Afro-Caribbean origin populations and identify current knowledge gaps. METHODS: A systematic literature review including a detailed search strategy was developed to search MEDLINE and other research databases. Using an a priori protocol peer-reviewed publications and grey literature articles were retrieved and screened and relevant data extracted by two independent review authors. Thematic analysis was done according to CVD outcomes and measures of disparity including age, sex, ethnicity and socioeconomic status. RESULTS: The search retrieved 665 articles of which 22 met the inclusion criteria. Most studies were conducted in the United Kingdom and centered on the prevalence of CVD by ethnicity, age and sex. An important sub-theme identified was the disparities in health service utilization/hospital admission. Coronary Heart Disease (CHD) and Peripheral Arterial Disease (PAD) were less prevalent among Afro-Caribbeans compared to Caucasian and South East Asian ethnic groups. The prevalence of CHD ranged from 0-7% in Afro-Caribbean to 2-22% in Caucasians. Strokes were more common among Afro-Caribbeans. There are inadequate data on morbidity and mortality from CVD, particularly across the socio-economic gradient, in Afro-Caribbean populations. CONCLUSIONS: There are important differences in morbidity and mortality from CVD across ethnic groups. Important knowledge gaps remain in understanding the social determinants of these disparities in CVD. More research exploring these gaps by varying disparity indicators needs to be undertaken.

Trends in Longevity in the Americas: Disparities in Life Expectancy in Women and Men, 1965-2010.

OBJECTIVE: We describe trends in life expectancy at birth (LE) and between-country LE disparities since 1965, in Latin America and the Caribbean. METHODS & FINDINGS: LE trends since 1965 are described for three geographical sub-regions: the Caribbean, Central America, and South America. LE disparities are explored using a suite of absolute and relative disparity metrics, with measurement consensus providing confidence to observed differences. LE has increased throughout Latin America and the Caribbean. Compared to the Caribbean, LE has increased by an additional 6.6 years in Central America and 4.1 years in South America. Since 1965, average reductions in between-country LE disparities were 14% (absolute disparity) and 23% (relative disparity) in the Caribbean, 55% and 51% in Central America, 55% and 52% in South America. CONCLUSIONS: LE in Latin America and the Caribbean is exceeding 'minimum standard' international targets, and is improving relative to the world region with the highest human longevity. The Caribbean, which had the highest LE and the lowest between-country LE disparities in Latin America and the Caribbean in 1965-70, had the lowest LE and the highest LE disparities by 2005-10. Caribbean Governments have championed a collaborative solution to the growing burden of non-communicable disease, with 15 territories signing on to the Declaration of Port of Spain, signalling regional commitment to a coordinated public-health response. The persistent LE inequity between Caribbean countries suggests that public health interventions should be tailored to individual countries to be most effective. Between- and within-country disparity monitoring for a range of health metrics should be a priority, first to guide country-level policy initiatives, then to contribute to the assessment of policy success.

Cause-of-death disparities in the African diaspora: exploring differences among shared-heritage populations.

OBJECTIVES: We investigated changes in life expectancy (LE) and cause-specific mortality over time, directly comparing African-descent populations in the United States and the Caribbean. METHODS: We compared LE at birth and cause-specific mortality in 6 disease groups between Caribbean countries with a majority (> 90%) African-descent population and US African Americans. RESULTS: The LE improvement among African Americans exceeded that of Afro-Caribbeans so that the LE gap, which favored the Caribbean population by 1.5 years in 1990, had been reversed by 2009. This relative improvement among African Americans was mainly the result of the improving mortality experience of African American men. Between 2000 and 2009, Caribbean mortality rates in 5 of the 6 disease groups increased relative to those of African Americans. By 2009, mortality from cerebrovascular diseases, cancers, and diabetes was higher in Afro-Caribbeans relative to African Americans, with a diabetes mortality rate twice that of African Americans and 4 times that of White Americans. CONCLUSIONS: The Caribbean community made important mortality reductions between 2000 and 2009, but this progress fell short of African American health improvements in the same period, especially among men.

Standardization of antiphospholipid antibody testing--historical perspectives and ongoing initiatives.

The measurement of antiphospholipid antibodies (aPL) has been an important aspect of antiphospholipid syndrome (APS) characterization since the disease was first described in the 1980s. Despite significant efforts geared toward the standardization of immunoassays that measure anticardiolipin antibodies and anti-ß2-glycoprotein I spanning three decades, there are still reports of significant interassay and interlaboratory variation in the results of these assays. At the recent 13th International Congress on Antiphospholipid Antibodies (APLA 2010, April 13-16, 2010, Galveston, TX), a task force composed of internationally recognized experts in the field of APS was formed to address these issues. In this review, we discuss approaches that have been used in the past to achieve harmonization among aPL immunoassays as well as the ongoing efforts of the APLA task force. Our review also highlights the importance of cutoff determination in aPL assays and the clinical significance of positive aPL results of varying magnitudes.

Current international initiatives in antiphospholipid antibody testing.

Positive results in the anticardiolipin antibody (aCL), anti-ß2-glycoprotein I antibody (aß2GPI), and/or lupus anticoagulant (LA) assays constitute the laboratory criteria for the definite diagnosis of the antiphospholipid syndrome (APS). These tests became available from as early as the1980s, and since then several novel assays have become available that have varied usefulness in the diagnosis and prognosis of APS patients. For almost three decades there has been an ongoing effort to standardize the aCL, aß2GPI, and LA assays, but there are still reports of significant intra- and interlaboratory variation in the results of all three assays. There have also been numerous issues with the implementation of novel (noncriteria) antiphospholipid antibody (aPL) tests in standard testing panels, due to either lack of standardized testing methods or limited evidence of their clinical utility in APS patients. At the recent 13th International Congress on Antiphospholipid Antibodies (APLA 2010, 13-16 April 2010, Galveston, TX), two task forces were set up to address these problems. This review gives a general description of current problems hindering the standardization of aPL tests and the implementation of novel assays as standard components of aPL testing panels. It also highlights the approach used by APLA 2010 Task Forces to address these problems and presents their recommendations.

Pathogenesis of the antiphospholipid syndrome.

The presence of pathogenic antiphospholipid antibodies (aPL) is the characterizing feature of the antiphospholipid syndrome (APS), mediating the recurrent pregnancy loss and thrombosis typical of the disease, through their action on various antigenic targets. Despite the available knowledge regarding the mechanisms by which aPL induce a procoagulant phenotype in the vasculature and abnormal cellular proliferation and differentiation in placental tissues to cause the typical clinical features, these processes still remain incompletely understood. It is also known that inflammation serves as a necessary link between the observed procoagulant phenotype and actual thrombus development, and is an important mediator of the placental injury in APS patients. Even less well understood are the processes underlying the ontogeny of these pathogenic antibodies. This review seeks to highlight what is known about the mechanisms that contribute to the origin of pathogenic aPL and to the action of these antibodies on target antigens that produce the pathological features of APS. We will also examine the feasibility of classifying patients in clinical phenotypes related to underlying pathophysiological mechanisms, and how this could impact the management of patients with novel "targeted" therapeutic strategies.

Standards and reference materials for the anticardiolipin and anti-ß2glycoprotein I assays: a report of recommendations from the APL Task Force at the 13th International Congress on Antiphospholipid Antibodies.

BACKGROUND: The confirmation of diagnosis of the Antiphospholipid Syndrome (APS) relies on laboratory tests. Current classification criteria for definite APS mandate the use of three "standardized" laboratory assays to detect antiphospholipid antibodies (aPL) [viz: anticardiolipin (aCL) IgG and IgM, anti-ß(2)glycoprotein I (anti-ß(2)GPI) antibodies IgG and IgM and/or a lupus anticoagulant (LAC)], when at least one of the two major clinical manifestations (thrombosis or pregnancy losses) are present. Several attempts have been made to standardize the aCL and anti-ß(2)GPI tests, though, a considerable degree of inconsistencies still exist, limiting the clinical and diagnostic value of aPL tests. Among the areas of concern are the type and source of calibrant material, the lack of proper validated reference material and of universal units of measurement, particularly for anti-ß(2)GPI antibodies. CONTENT: A Task Force of scientists and leaders in the field from different countries - discussed and analyzed those critical questions in an evidence-based manner and further discussed and made recommendations at a workshop that was conducted during 13th International Congress on Antiphospholipid Antibodies (APLA 2010, April 13-16, 2010, Galveston, TX). SUMMARY: This concise report summarizes the findings, conclusions and recommendations of the task force and preconference workshop. The group recommended to ensure the availability of properly prepared and validated polyclonal and monoclonal antibody reference materials for both assays, to continue reporting the aCL assay in GPL/MPL units and to establish consensus international units of measurement for anti-ß(2)GPI antibodies.

A quarter of a century in anticardiolipin antibody testing and attempted standardization has led us to here, which is?

The anticardiolipin (aCL) test has been widely used by physicians since the mid-1980s for diagnosing patients with antiphospholipid syndrome (APS). Establishment of this diagnosis has enabled effective management of patients with recurrent thrombosis and recurrent pregnancy losses. The test was first established in 1983 as a radioimmunoassay and soon thereafter converted into an enzyme-linked immunosorbent assay (ELISA). The other test commonly used in the diagnosis of APS is the lupus anticoagulant (LA) test. The aCL ELISA is sensitive for the diagnosis of APS but lacks specificity. On the other hand, the LA assay, although more specific, is not as sensitive as the aCL ELISA. More specific tests are now available such as the anti-beta2 glycoprotein I (anti-beta2GPI) assay, the antiprothrombin assay, and other ELISAs that use negatively charged phospholipids instead of cardiolipin to coat the plates. In the past 25 years, there have been numerous efforts to standardize aCL, LA, and anti-beta2GPI tests but there are still reports of significant intra- and interlaboratory variation in results for all three assays. This article discusses in detail the clinical value of these tests, technical problems associated with their use, the current laboratory classification criteria for diagnosis of APS, and possible new and better assays that will be available in the near future for diagnosis of APS.

Primary, secondary, and catastrophic antiphospholipid syndrome: what's in a name?

The association of the lupus anticoagulant with thrombosis and recurrent pregnancy loss was first recognized over a 20-year period between the early 1960s and early 1980s. The introduction of the anticardiolipin test in 1983 and the recognition of its association with clinical features similar to the lupus anticoagulant led to an exponential growth of interest in this disorder. The belief that anticardiolipin antibodies and lupus anticoagulant belonged to the family of antiphospholipid antibodies led to the disorder being named the antiphospholipid syndrome (APS). Efforts by individual investigators to introduce criteria for classification of APS and to standardize anticardiolipin antibody and lupus anticoagulant tests were started in the mid-1980s to ensure more reliable recognition and treatment of affected patients. Another layer of complexity was introduced with recognition that many anticardiolipin antibody-positive sera also bound the antigen beta (2) glycoprotein I. With increasingly sophisticated epidemiologic and prospective studies in the 1990s, more structured and better-documented criteria for APS were introduced in 1999 and modified in 2006. These criteria have been widely adopted. Whereas data supporting subclassification of APS into primary and secondary subgroups remain tenuous, a small percentage of patients do appear subject to clinical features termed the catastrophic antiphospholipid syndrome. Introduction of classification criteria for APS has enabled more reliable prospective studies, the promise of better management, and more valid tests for recognition of the disorder.

Antiphospholipid antibodies and the antiphospholipid syndrome: pathogenic mechanisms.

Antiphospholipid antibodies (Abs) are associated with thrombosis and are a risk factor for recurrent pregnancy loss and obstetric complications in patients with the antiphospholipid syndrome. It is generally accepted that the major autoantigen for aPL Abs is beta (2) glycoprotein I, which mediates the binding of aPL Abs to target cells (i.e., endothelial cells, monocytes, platelets, trophoblasts, etc.) leading to thrombosis and fetal loss. This article addresses molecular events triggered by aPL Abs on endothelial cells, platelets, and monocytes and complement activation, as well as a review of the current knowledge with regard to the putative receptor(s) recognized by aPL Abs on target cells as well as novel mechanisms that involve fibrinolytic processes. A section is devoted to the description of thrombotic and inflammatory processes that lead to obstetric complications mediated by aPL Abs. Based on experimental evidence using in vitro and in vivo models, new targeted therapies for treatment and/or prevention of thrombosis and pregnancy loss in antiphospholipid syndrome are proposed.

Rheumatic diseases in minority populations.

Rheumatic diseases are expressed in all ethnic populations, but differ in prevalence, genetic associations, clinical features, and responses to interventions. Most data describing these differences do so in reference to and comparisons with white populations. These are sparse data that evaluate differences within minority populations where there is more homogeneity of external factors, such as social, cultural, and behavioral attitudes. This article reviews the features that are unique to various rheumatic diseases within minority populations.