implications for atherosclerosis and autoimmunity

Publisher Copyright: © 2021 John Wiley & Sons Ltd Copyright: Copyright 2021 Elsevier B.V., All rights reserved.Inflammation and immune dysfunction have been increasingly recognized as crucial mechanisms in atherogenesis. Modifications in cell lipid metabolism, plasma dyslipidaemia and particularly low high-density lipoprotein (HDL) levels occur both in atherosclerosis and in autoimmune rheumatic diseases (which are strongly associated with an increased risk of atherosclerosis), suggesting the presence of a crucial link. HDL, the plasma lipoprotein responsible for reverse cholesterol transport, is known for its several protective effects in the context of atherosclerosis. Among these, HDL immunomodulatory effects are possibly the less understood. Through the efflux of cholesterol from plasma cell membranes with the consequent disruption of lipid rafts and the interaction with the cholesterol transporters present in the plasma membrane, HDL affects both the innate and adaptive immune responses. Animal and human studies have demonstrated a predominance of HDL anti-inflammatory effects, despite some pro-inflammatory actions having also been reported. The HDL role on the modulation of the immune response is further suggested by the detection of low levels together with a dysfunctional HDL in patients with autoimmune diseases. Here, we review the current knowledge of the immune mechanisms of atherosclerosis and the modulatory effects HDL may have on them.publishersversionpublishe

A retrospective analysis over 30 years

Publisher Copyright: © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.Objective. To review the likelihood of very long-term remission in patients with biopsy-proven LN attempting to identify good prognostic features. Methods. We reviewed patients with LN whose renal biopsies showed World Health Organization (WHO) classes III, IV and V and who had a follow-up of at least 5 years between 1973 and 2008. We analysed demographic, clinical, laboratory and therapeutic parameters comparing those patients with (group A) and without (group B) 5 year remission. Results. Of 191 LN patients followed, 105 patients met the strict inclusion criteria. Ninety-five patients were female. Mean age at diagnosis of lupus was 24.1 years (s.d. 10.7). ean age at diagnosis of LN was 28.4 years (s.d. 11.3). The mean duration of follow-up was 13.7 years (s.d. 14.1). Forty (38%) patients achieved 5 year remission, of whom 17 (16.2%) had remission for ≥15 years. The incidence of flares per year from 5 to 15 years was 7.9%; however, no flares were observed after 15 years of remission. The only distinguishing feature found in this study was the association of WHO class IV on kidney biopsy with LN progression (P = 0.03).Conclusion. Renal histology with WHO class IV predicted a poor long-term remission rate. Age, sex, ethnicity, serological parameters and treatment received did not predict long-term remission. Renal flares can occur up to 15 years after a patient has gone into remission.publishersversionpublishe

Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-Adjusted life-years for 29 cancer groups, 1990 to 2017 : A systematic analysis for the global burden of disease study

Importance: Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data. Objective: To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning. Evidence Review: We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-Adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence. Findings: In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572000 deaths and 15.2 million DALYs), and stomach cancer (542000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601000 deaths and 17.4 million DALYs), TBL cancer (596000 deaths and 12.6 million DALYs), and colorectal cancer (414000 deaths and 8.3 million DALYs). Conclusions and Relevance: The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care. © 2019 American Medical Association. All rights reserved.Peer reviewe

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019 : a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2·72 (95% uncertainty interval [UI] 2·66–2·79) in 2000 to 2·31 (2·17–2·46) in 2019. Global annual livebirths increased from 134·5 million (131·5–137·8) in 2000 to a peak of 139·6 million (133·0–146·9) in 2016. Global livebirths then declined to 135·3 million (127·2–144·1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2·1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27·1% (95% UI 26·4–27·8) of global livebirths. Global life expectancy at birth increased from 67·2 years (95% UI 66·8–67·6) in 2000 to 73·5 years (72·8–74·3) in 2019. The total number of deaths increased from 50·7 million (49·5–51·9) in 2000 to 56·5 million (53·7–59·2) in 2019. Under-5 deaths declined from 9·6 million (9·1–10·3) in 2000 to 5·0 million (4·3–6·0) in 2019. Global population increased by 25·7%, from 6·2 billion (6·0–6·3) in 2000 to 7·7 billion (7·5–8·0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58·6 years (56·1–60·8) in 2000 to 63·5 years (60·8–66·1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Homogneous time resolved fluorescence: a new technique for detection and quantifications of infliximab in autoimmune patients

RESUMO:As terapias biológicas revolucionaram o tratamento das doenças autoimunes nos últimos anos. Tipicamente têm como alvos mediadores importantes no mecanismo das doenças. Os antagonistas do fator de necrose tumoral-α (TNF-α) são um grupo de agentes biológicos muito prescrito, pois estão indicados no tratamento de doenças imuno-mediadas comuns, tais como artrite reumatoide, artrite idiopática juvenil, artrite psoriática, espondilite anquilosante, doença de Crohn e colite ulcerosa. Com o uso frequente de inibidores do TNF-α, tem-se tornado evidente que estes agentes têm um potencial imunogénico importante, que pode comprometer o prognóstico a longo prazo dos doentes cronicamente tratados. A produção de anticorpos anti-fármaco parece causar falência terapêutica secundária em muitos doentes. Um dos efeitos dos anticorpos anti-fármaco é o aumento da eliminação do fármaco. A eliminação do fármaco, por sua vez, varia entre indivíduos, refletindo diferentes perfis farmacocinéticos. A determinação dos níveis séricos mínimos do agente anti-TNF-α é assim muito informativa e pode auxiliar nas decisões terapêuticas. Contudo, os testes imunológicos para determinar as concentrações séricas do fármaco não estão facilmente disponíveis na prática clínica. De forma a investigar uma nova técnica potencialmente fidedigna e prática para a deteção e quantificação dos agentes biológicos anti-TNF-α, foi testada a técnica por HTRF (homogeneous time-resolved fluorescence resonance energy transfer) para a determinação de concentrações séricas de infliximab. Apesar de apresentar algumas limitações relacionadas com as condições de leitura da fluorescência, esta técnica provou obter resultados próximos das concentrações obtidas por ELISA (enzyme-linked immunosorbent assay) bridging. Adicionalmente, tem a vantagem de ser de execução muito mais fácil e rápida. Deste modo, a técnica por HTRF poderá ser otimizada e tornar-se uma valiosa ferramenta laboratorial para orientar as decisões terapêuticas em doentes autoimunes com falência da terapêutica anti-TNF-α.--------- ABSTRACT: Biologic therapies revolutionized the treatment of autoimmune diseases in the last years. Typically, they target important disease mediators. Tumor necrosis factor-alpha (TNF-α) antagonists constitute a very prescribed group of biologic agents as they are indicated for the treatment of common immune-mediated diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease and ulcerative colitis. With the increasing use of TNF-α inhibitors it has been noticed that they have an important immunogenic potential that can compromise long-term outcomes in chronically treated patients. The production of anti-drug antibodies seems to cause secondary therapeutic failure in many patients. One of the effects of anti-drug antibodies is the enhancement of drug clearance. Drug clearance, in turn, varies among individuals, reflecting different pharmacokinetic profiles. Determination of serum anti-TNF-α drug trough levels is though very informative and could support treatment decisions. However, immunologic assays to determine drug serum concentrations are not readily available in clinical practice. In order to investigate a potentially reliable and practical new technique for detection and quantification of anti-TNF-α biologic agents, homogeneous time-resolved fluorescence resonance energy transfer (HTRF) technique was tested for determination of serum infliximab concentrations. Although presenting some limitations related with fluorescence reading conditions, this technique proved to give results close to the concentrations obtained by the widely used bridging enzyme-linked immunosorbent assay (ELISA). In addition, it has the advantage of being much easier and faster to perform. Thus, HTRF technique can be optimized and become a valuable laboratorial tool to guide treatment decisions in autoimmune patients with anti-TNF-α therapy failure

The role of high-density lipoproteins in the activation of T lymphocytes and regulation of immune response

High-density lipoproteins (HDL) are the densest plasma lipoproteinsand theircomplex protein and lipid constitution interfereswith several physiological mechanisms. The most well characterized HDL functionis reverse cholesterol transport,but other functions have also been attributed to HDL, namelyanti-oxidative, vasodilatoryand anti-inflammatory properties. However, the HDL immunomodulatoryfunction is poorly understood. HDL mediation of cholesterol efflux and consequent lipid raft disruption is one of the main mechanisms by which HDL modulatestheimmune response, but other mechanisms are also involved.Most ofthe existent knowledge comes from animal studies, withlimitations related to the animal model lipid metabolism. Thefew human studiesare heterogeneous and demonstrate both anti-inflammatory and pro-inflammatory effects.Paradoxically, HDL can also suffer transformation to dysfunctional particles, by many different mechanisms. One of these mechanisms is related with the production of antibodies to HDL particles, with themain target beingapolipoprotein A-I (ApoA-I).In this thesis, I questioned the role ofHDL in immune functionwitha specialfocus on the HDL effects on T celllipid metabolism and T cell response, using cells from patients with systemic lupus erythematosus and healthy controls.This work studied: 1)the conditions in which HDL induces cholesterol depletion from CD4+T cells in vitro; 2)the HDL influence on ABCA1 and lipid raft organization inthe plasma membrane (PM)of cultured CD4+T cells; 3) the HDL effect on immune conjugate formation; 4) CD4+T cell lipid metabolismin relation toanti-HDL antibodies; 5)the presence of anti-ABCA1 antibodies; 6) the HDL modulation of T cell response in vitro.The main methodologies used in this thesiswere peripheral blood mononuclear cells (PBMCs)isolation by density gradient separation, immune-based assays such as ELISA, cell culture experimentsandflow cytometry.The results give importantclues to the importance of HDL to T cell metabolism and response: 1)HDL depletes cholesterol from the PM of CD4+T cellsin 24hourcultures, suggesting that this is the ideal time-lapse for in vitrostudies; 2)cholesterol content in the PM of healthy CD4+T cells varies between different T cell subsets, with effector memory (EM)T cells showing the highestlevels of PM cholesteroland less abundant glycosphingolipids (lipid raft constituents); 3) anti-HDL antibodies associate with an increase in the prevalence of EM T cells and a decrease in naïve and regulatory T cells (Treg). The presence of anti-HDL antibodies is also associated withanincreased expression of lipid rafts in CD4+T cells from SLE patients and withaderegulated membrane cholesterol and lipid transporter ABCA1; 4)anti-ABCA1 antibodies are presentin some patients with SLE; 5)24 hour culture with HDL induces the expression of TGF-β1 in CD4+T cellswithout affecting inflammatory cytokines; 6)HDL inhibited the proliferation of CD4+T cells from patients with SLE but did not affect the proliferation in healthy T cells; 7)in the presence of HDL,TCRzeta phosphorylation is reduced. In conclusion, this worksupports the conceptthat HDL has essentially regulatory functions in the immune system, with a notorious effect in the production of TGF-β1 in CD4+T cells. HDL seems toreduceexaggerated inflammation and maintain normal immune function, withimmune modulatory effects that are context dependent. Modifications in lipid metabolism occur in lymphocytes from patients with SLE, reinforcing the importance ofthelipid metabolism for the immune response. These discoveries add new information to the current knowledge on HDL immune functionin humansthat will hopefully be further studied in the research of atherosclerosis, autoimmune diseases and other pathologiesin which lipid metabolism anomalies concurwith immune dysfunction

Assessment of long-term remission in lupus nephritis patients: a retrospective analysis over 30 years

Publisher Copyright: © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.Objective. To review the likelihood of very long-term remission in patients with biopsy-proven LN attempting to identify good prognostic features. Methods. We reviewed patients with LN whose renal biopsies showed World Health Organization (WHO) classes III, IV and V and who had a follow-up of at least 5 years between 1973 and 2008. We analysed demographic, clinical, laboratory and therapeutic parameters comparing those patients with (group A) and without (group B) 5 year remission. Results. Of 191 LN patients followed, 105 patients met the strict inclusion criteria. Ninety-five patients were female. Mean age at diagnosis of lupus was 24.1 years (s.d. 10.7). ean age at diagnosis of LN was 28.4 years (s.d. 11.3). The mean duration of follow-up was 13.7 years (s.d. 14.1). Forty (38%) patients achieved 5 year remission, of whom 17 (16.2%) had remission for ≥15 years. The incidence of flares per year from 5 to 15 years was 7.9%; however, no flares were observed after 15 years of remission. The only distinguishing feature found in this study was the association of WHO class IV on kidney biopsy with LN progression (P = 0.03).Conclusion. Renal histology with WHO class IV predicted a poor long-term remission rate. Age, sex, ethnicity, serological parameters and treatment received did not predict long-term remission. Renal flares can occur up to 15 years after a patient has gone into remission.publishersversionpublishe