Diss. (sammanfattning) Stockholm : Karol. inst., 2001. / Härtill 6 uppsatser.

Background: Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease characterised by autoantibody production and variable clinical features, ranging from mild to severe disease. Patients with SLE are at increased risk of developing accelerated atherosclerosis. Biomarkers have potential utility in SLE as markers of disease or predictors of future clinical events and mortality. Objective The aim of this thesis was to identify serological biomarkers predictive for erosive arthritis (EA), cardiovascular events (CVEs), mortality and subclinical atherosclerosis in SLE. Methods: In chapters 2 to 4, study subjects were SLE patients from Bath. Anti-cyclic citrullinated peptide antibodies (ACPA) and HLA-DR and -DQ were studied for markers of EA, and anticardiolipin (aCL) and lipoprotein profiles for markers of CVEs and mortality. In chapters 5 and 6, study subjects were women with SLE from Manchester. B-mode ultrasound scans of subjects' carotid arteries were performed at baseline and follow-up time-points to detect atherosclerotic plaque. Baseline IgG and IgM antiphospholipid (aPL) antibodies and CV risk factors were studied for markers of subclinical atherosclerosis. Clinical data collected for all studies included SLE features and auto-antibody profiles. Results: ACPA was identified as a marker of a SLE phenotype with EA - "rhupus". Patients with major erosive arthritis were HLA-DQB1*0302 carriers. Increased aCL GPL levels and total cholesterol : high density lipoprotein-C (TC : HDL-C) ratio were markers for future CVEs, and increased TC : HDL ratio, aCL GPL and lipoprotein(a) concentrations were markers for increased mortality. Lower HDL-C concentrations and anti-annexin A5 (anti-AnxA5) GPL were markers of carotid plaque progression. Conclusion: This thesis identified new markers for EA, subclinical atherosclerosis and future CVE and mortality risk in SLE. Strategies to incorporate these new CV markers into clinical CV risk assessments may assist in distinguishing the subset of SLE patients most at risk of developing accelerated atherosclerosis.

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No. of bitstreams: 1 Tese - Sandra Lúcia Euzébio Ribeiro.pdf: 2096473 bytes, checksum: f91d4ac32c47ec6b75b46a090c06dd46 (MD5) Previous issue date: 2014-09-02 / SUFRAMA - Superintendência da Zona Franca de Manaus / Antiphospholipid (aPL) antibodies may be detected during the course of many infections, but are usually transient. In leprosy, however, these antibodies are found to linger for longer periods. The aim of this study was to evaluate the persistence of anticardiolipin (aCL) and anti-β2 glycoprotein I (anti-β2GPI) antibodies in leprosy patients, and disclose epidemiologic, immunologic and clinical features associated with it. Thirty-eight APL antibody positive leprosy patients completed polychemotherapy and were followed for an average of 66,9 months, when a second sample was drawn for a new aPL testing. Enzima -linked immunosorbent assay (ELISA) was used to measure aCL and anti-β2GPI antibodies. Epidemiologic and clinical data were analyzed with logistic regression. Persistence of aPL antibodies was demonstrated in 32 out of 38 leprosy patients thoroughly treated and considered cured, studied after an average of 66,9 months of follow up. All of these sera were IgM isotype. Sixteen of these patients (50%) presented lepromatous clinical form. Reactional state was present in three patients (9,4%). Seventeen (53,1%) were in use of prednisone and/or thalidomide. Observed median values of aPL antibodies were rather high (64U/mL for aCL and 62U/mL for aβ2GP). Occurrence of vascular thrombosis, gestational morbidity, diabetes, tobacco use and alcoholism were not different in positive and negative aPL patients. Logistic regression showed significant association of aPL antibodies persistence and age (p=0,045, OR=0,91 e IC 95% 0,82 - 1,00), lepromatous clinical form (p=0,034; OR=0,02 e IC 95% = 0,0 - 0,76) and bacillary index (p=0,044; OR=2,74 e IC 95% = 1,03 – 7,33). aPL antibodies in leprosy patients do persist many years after treatment. Patients’ age, lepromatous clinical form and bacillary index were factors that influence persistence. No thromboembolic events were registred. / Anticorpos antifosfolipídeos (aFL) podem ser detectados no curso de diversas infecções, mas costumam ser transitórios. Entretanto, na hanseníase tem-se observado que esses autoanticorpos persistem por mais tempo. Os objetivos do presente estudo foram verificar a persistência de anticorpos anticardiolipina (aCL) e anti-β2glicoproteína  (anti-β2GP) em pacientes com hanseníase, e avaliar as características epidemiológicas, clínicas e imunológicas associadas. Trinta e oito pacientes com diagnóstico de hanseníase e positivos para anticorpos aFL completaram o tratamento de poliquimioterapia (PQT) e foram acompanhados por um tempo médio de 66,9 meses, quando coletou-se outra amostra para nova pesquisa da anticorpos aFL. A detecção de anticorpos aCL e anti-β2GP foi feita pela a técnica de ELISA. A análise dos dados epidemiológicos e clínicos foi feita por regressão logística binária multivariada. Persistência de anticorpos aFL foi demonstrada em 32 (84%) dos 38 pacientes com hanseníase, tratados com PQT e em alta do tratamento PQT, seguidos por um tempo médio de 66,9 meses. Todos os soros positivos eram do isotipo IgM, sendo que 16 desses pacientes (50%) apresentavam a forma virchowiana (VV). Episódios reacionais estavam presentes em três pacientes (9,4%). Dezessete (53,1%) continuavam usando medicação (prednisona e/ou talidomida). Os valores médios de IgM foram altos, 64U/mL para aCL e 62U/mL para anti-β2GP. Em relação às variáveis trombose vascular, morbidade gestacional, diabetes, tabagismo e etilismo não foram observadas diferenças significativas entre os pacientes positivos e negativos para aFL. Na regressão logística demonstrou-se significância estatística para as variáveis idade: (p=0,045, OR=0,91 e IC 95% 0,82-1,00), forma clínica VV (p=0,034; OR=0,02 e IC 95% = 0,0-0,76) e índice baciloscópico (p=0,044; OR=2,74 e IC 95% = 1,03 - 7,33). Portanto, anticorpos aFL na hanseníase, diferentemente de outras infecções, persistem anos após o tratamento em pacientes considerados “curados”. Essa persistência foi influenciada pela idade, forma clínica VV e índice baciloscópico. Não houve associação com fenômenos trombóticos.

No / Objectives It is hypothesised that endothelial cell reactive antibodies (ECRA) play a role in the progression of PAD through activation of endothelial cells and the release of inflammatory cytokines. We aimed to test this hypothesis by assessing levels of ECRA, E-selectin and IL-6 in patients with PAD of varying severity in a case controlled study. Design, materials, methods Patients were assessed clinically and with ankle¿brachial pressure indices. Patients with critical ischaemia (CI, n=30), stable claudicants (SC, n=30), and age-matched controls (AMC, n=20) were studied. Antibody, E-selectin and IL-6 levels were measured using ELISA. Results ECRA levels were significantly raised in the CI group over AMC. IL-6 levels were significantly elevated in both SC and CI over the control group and in CI over SC. There were no significant differences in E-selectin levels between the AMC, SC and CI. Conclusion Our findings support the hypothesis that autoantibodies play a role in promoting PAD by elevating IL-6. The absence of an elevation in E-selectin in this study may be due to its short half-life, and casts doubt on its value as a marker of inflammation in atherosclerosis.

Introduction: Au moins 30% des AVC ischémiques chez les jeunes demeurent inexpliqués malgré une investigation extensive. Le rôle de certains états prothrombotiques (ÉP) dans la thrombose artérielle reste incertain, possiblement à cause du petit nombre de patients, de populations hétérogènes ou d’ÉP analysés individuellement dans les études antérieures, alors que leur prévalence est basse. Méthodologie : Étude cas-témoins sur une cohorte rétrospective (2002-2011). Les patients âgés de ≤50ans lors d’un AVC ischémique furent identifiés sur une base de données hospitalière. Après exclusion des individus ayant une investigation étiologique incomplète, un syndrome antiphospholipide ou aucun ÉP testé, la cohorte fut divisée en groupes cas (AVC idiopathique) et témoins (étiologie identifiée). La prevalence de chaque ÉP fut comparée entre les groupe, ainsi que la présence de ≥2 ÉP (analyse primaire), sans et avec ajustement pour les facteurs de risque non-prothrombotiques (régression logistique). En analyse de sous-groupe, la présence de ≥1 ÉP fut comparée entre les cas avec versus sans foramen ovale perméable (FOP), entre les cas ou contrôles porteurs d’un FOP avec versus sans migraine, de même qu’entre les cas versus témoins de sexe féminin en incluant la contraception orale parmi les ÉP. Résultats : 502 jeunes avec AVC ischémique furent identifiés. Après exclusion de 108 patients, 184 cas et 210 témoins furent comparés, (âge moyen : 39,2 ans, 51% hommes). La prévalence des ÉP ne différait pas entre les cas et contrôles : déficits en protéine S (0,6%), protéine C (3,4%), antithrombine (1,2%), mutation de la prothrombine (2,5%), facteur V Leiden (4,6%), et anticardiolipines (titre 15-40 unités GPL ou MPL; 3,3%). La présence de ≥2 ÉP n’était pas associée à l’AVC idiopathique, avant (p=0,48) ou après ajustement (p=0,74). La présence de ≥1 ÉP ne différait pas entre les sous-groupes étudiés. Conclusion: Il n’y a pas d’association entre les ÉP, isolés ou en association, avec l’AVC ischémique idiopathique chez les jeunes, même en presence de FOP ou de migraine. / Background: Despite extensive workup, more than 30% of ischemic strokes in young adults remain idiopathic. The role of some prothrombotic factors (PF) in arterial thrombosis remains unclear in previous studies. This may be due to small sample sizes, heterogeneous characteristics of populations studied, or analyzing individual PF with low prevalence. Methods: We conducted a case-control study using a retrospective cohort (2002-2011). From a hospital database, we identified patients with ischemic stroke at age ≤50 years. We excluded patients with incomplete baseline investigation or antiphospholipid syndrome, and those without prothrombotic testing. We compared the prevalence of each PF, as well as the presence of ≥2 PF (primary analysis) between cases with idiopathic stroke and controls with defined stroke etiology, before and after adjusting for non-prothrombotic risk factors. By subgroup analysis, we compared the presence of ≥1 PF between cases with versus without patent foramen ovale (PFO), between cases or controls with PFO with versus without migraine, as well as between women (cases versus controls), including oral contraceptives among PF. Results: 502 young ischemic stroke patients were identified. We excluded 108 patients. We analyzed 184 cases and 210 controls (Mean age : 39.2 y-o, 51% male). Prevalence of individual PF did not differ between cases and controls : protein S (0.6%), protein C (3.4%), antithrombin (1.2%) deficiencies, mutant prothrombin (2.5%), factor V Leiden (4.6%), and total anticardiolipin (titers 15-40 units GPL or MPL; 3,3%). There was no association between the presence of ≥2 PF and idiopathic stroke, before (p=0,48) and after adjusting for non-prothrombotic risk factors (p= 0,74). No differences were observed between subgroups for the presence of ≥1 PF. Conclusion: There is no association between prothrombotic risk factors (analyzed individually or as a group) and idiopathic ischemic stroke in the young, even in those with a PFO or with migraine.