INTRODUCTION: Patients with systemic lupus erythematosus (SLE) are at increased risk of the metabolic syndrome (MetS) and its complications. In the absence of published studies from sub-Saharan Africa, we investigated the prevalence and associations of the MetS amongst recent-onset SLE patients. METHODS: A cross-sectional study of recent onset (<5 years disease duration) patients with SLE meeting the SLICC SLE classification criteria. The MetS was defined by Joint Interim Statement criteria. Clinical and demographic data and a Functional Assessment of Chronic Illness Therapy score and the 36-Item Short-Form Healthy Survey were completed. RESULTS: Of 75 patients, the mean age was 37.1 (11.7) years, disease duration was 30.8 (23.6) months, 65 (86.7%) were female, 68.0% were of mixed ethnic ancestry and 29.3% were Black Africans. The mean SLEDAI score was 0.9 (1.6). The prevalence of MetS was 40.0%, and age and body mass index were the only significant features associated with MetS (p = 0.003 and 0.001 respectively). Increased waist circumference (WC) was the most frequently observed feature, present in 92.9% of MetS patients. Patients with an elevated WC were 32.5 times more likely to have MetS. CONCLUSION: This study shows a high prevalence of MetS amongst South Africans with recently diagnosed SLE. This calls for aggressive strategies to reduce the prevalence of Mets and atherosclerotic cardiovascular disease. Waist circumference is a useful and costeffective screening tool to identify SLE patients at risk of MetS.

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京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20270号 / 医博第4229号 / 新制||医||1021(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山田 亮, 教授 福原 俊一, 教授 小川 修 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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京都大学 / 新制・論文博士 / 博士(医学) / 乙第13536号 / 論医博第2276号 / 新制||医||1065(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 河本 宏, 教授 妹尾 浩, 教授 中川 一路 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

No description available.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease requiring a genetic predisposition coupled with an environmental trigger in order for initiation of disease. While the exact pathoaetiology has yet to be determined, both B and T cell dysregulation are thought to contribute to disease. Histone deacetylases (HDACs) are a class of enzymes that hydrolyze the lysine bound acetyl group in both histone and non-histone proteins thereby altering protein structure and function. While the use of pan-HDAC inhibitors has proven to be effective for the treatment of a number of acute diseases, they may not be viable as therapeutics for chronic disease due to cytotoxicity and adverse side effects following long term treatment. We sought to determine whether treatment with a class I and II HDAC inhibitor (HDACi) or a specific HDAC6i would be able to ameliorate disease in lupus-prone NZB/W mice. We found that both the class I and II HDACi (ITF2357) and the HDAC6i (ACY-738) were able to decrease SLE markers of disease including splenomegaly, proteinuria, and anti-dsDNA and IgG production in the sera. Treatment with ITF2357 resulted in an increase in the number of immunosuppressive regulatory T (Treg) cells and a decrease in the pro-inflammatory Th17 phenotype. Furthermore, ITF2357 was found to increase Foxp3 acetylation leading to increased Foxp3 stability allowing for differentiation into the Treg phenotype. ACY-738 treatment was able to correct aberrant bone marrow B cell differentiation while also increasing the number of splenic Treg cells in NZB/W mice. These results suggest that HDAC inhibition is able to ameliorate SLE in NZB/W mice by altering aberrant T and B cell differentiation. Additional studies were performed to further examine the expression and function of different HDAC isoforms in immune cells. Due to the ability of HDAC inhibition to decrease markers of SLE disease as well as alter B and T cell development and differentiation, we sought to determine if specific HDAC isoforms are altered in lupus vs non lupus mice in early and late disease states. We determined the level of class IIb HDAC (HDACs 6, 9, and 10) expression in bone marrow B cells, splenic B and T cells, and glomerular cells from early- and late-disease MRL/lpr lupus-prone mice compared to healthy, age-matched C57BL/6 control mice. Expression of HDAC6 and HDAC9 were significantly increased in all of the tissues tested from MRL/lpr mice. Furthermore, both cytoplasmic and nuclear HDAC activity was increased in diseased MRL/lpr mice, and HDAC activity and expression continued to increase as disease progressed. In vitro treatment with ACY-738, a selective HDAC6i, was able to decrease cytoplasmic HDAC activity and inhibit iNOS production. Furthermore, ACY-738 was able to alter apoptosis through increased Bax expression in B cells. Treatment with ACY-738 was also able to inhibit Hsp90 expression and decrease NF-κB nuclear translocation, which are both upregulated during active SLE. Our studies indicate that HDAC activity contributes to SLE pathogenesis and that the use of isoform-selective HDAC inhibitors may be a viable treatment for SLE. / Ph. D.

No / Our objectives were to obtain monoclonal anti-endothelial cell antibodies (AECA) from systemic lupus erythematosus (SLE) patients, to characterize their antigen specificity, and their capability to induce a pro-inflammatory and pro-adhesive endothelial phenotype, and to investigate the mechanism of endothelial cell (EC) activation in vitro. Monoclonal IgG AECA were generated by hybridoma formation with human SLE B cells. Antigen specificity was characterized by immunoblotting with enriched cell membrane fractions, by cytofluorimetry and by cell solid-phase ELISA. Endothelial activation was evaluated by measuring increases in U937 cell adhesiveness, adhesion molecule (E-selectin and ICAM-1) expression and IL-6 production. In addition, mechanisms of endothelial activation were investigated by assessment of NF-B by measuring the loss of its inhibitor I-B. mAb E-3 bound live EC and recognized a 42 kDa EC membrane protein, it enhanced U937 adhesiveness, E-selectin and ICAM-1 expression and IL-6 production, and caused the loss of I-B. We conclude this is the first in vitro demonstration that a human monoclonal AECA from a SLE patient reacts with a constitutive endothelial membrane antigen and induces a pro-inflammatory endothelial phenotype through NF-B activation.

A cohort of 306 patients was recruited. Questionnaire interview, review of medical records and clinical assessments were performed to obtain information regarding disease status, healthcare resources utilization and HRQoL. / Cost-of-illness studies measure the monetary burden that a disease imposes on society or individuals. The substantial financial burden of SLE has been demonstrated in a modest number of studies and a restricted number of countries. However, there is no study investigating the relationship between disease costs and NPSLE/flare. / In summary, this study has provided support for our hypotheses. The socioeconomic impact of SLE in Hong Kong is considerable. The presence of NPSLE and flare are significantly associated increase disease costs but not impaired HRQoL. These suggest that management, which can lead to early diagnosis and effectively control disease activity and prevent lupus flares, may reduce disease costs due to both healthcare consumption and loss of productivity. / Systemic lupus erythematosus (SLE) is a multi-factorial autoimmune disease that primarily affects young women, characterized by a chronic remitting-relapsing (flare) disease course. Central nervous system is one of the most common affect systems in SLE. Neuropsychiatrie SLE (NPSLE) is associated with impairment of quality of life, accumulated disease damage, disability and employment. Flare, an increase in disease activity over a defined period, is an important outcome in the assessment of SLE. Uncontrolled disease activity results in cumulative organ damage which is associated with increased mortality. / The main findings were as follows. 1. The average annual total costs were USD 13,307 (2006 US dollars) per patient. The direct costs dominated the total costs (62%), and the costs of inpatient care contributed 52% of the direct costs. Costs of SLE per subject are higher than those of other chronic diseases in Hong Kong. 2. Patients with NPSLE incurred significantly higher direct and indirect costs compared to those without NPSLE. The number of NPSLE event was an independent explanatory variable associated with both increased direct and indirect costs. 3. Annual direct costs and indirect costs were significantly higher in those with flares. The number of flare was an independent explanatory variable associated with increased direct costs. Patients with multi-organ flares or renal/neuropsychiatric flares incurred higher direct costs than those with single organ flare or those with minor organ flares. 4. Patients with SLE had significantly lower level of HRQoL compared with Hong Kong general population. The presence of NPSLE and flare only weakly associated with impairment of HRQoL. / The present thesis was a retrospective cost-of-illness study on Chinese patients in Hong Kong with SLE within working age, aiming to 1. estimate the direct and indirect costs of SLE from a societal perspective; 2. ascertain the relationship between NPSLE and direct and indirect costs; 3. ascertain the relationship between flare and direct and indirect costs; 4. investigate the relationship between HRQoL and NPSLE/flares. / We hypothesized that: I. SLE is associated with substantial socioeconomic burden as a result of NPSLE and flare; 2. patients with NPSLE or flares may experience more compromised health-related quality of life (HRQoL). / Zhu, Yaner. / Adviser: Edmund K. Li. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 190-214). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.