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Rockville, MD, United States

Drenkard C.,Emory University | Bao G.,Emory University | Dennis G.,Human Genome science | Kan H.J.,Glaxosmithkline | And 3 more authors.
Arthritis Care and Research | Year: 2014

Objective. To examine the burden of systemic lupus erythematosus (SLE) on work loss, unemployment, and work productivity impairment in an SLE cohort from the southeastern US. Methods. We examined 689 SLE patients ages 18-64 years from the Georgians Organized Against Lupus (GOAL) cohort. GOAL is a longitudinal cohort predominantly derived from the Georgia Lupus Registry, a population-based registry established in metropolitan Atlanta. We used the Kaplan-Meier method to assess the proportion of patients who self-reported work loss since diagnosis. We compared unemployment between SLE patients and the general population from the same geographic area, calculating the standardized unemployment ratio (SUR) within demographic and disease strata. We also calculated the percentage of work productivity impairment by disease outcomes. Results. Of 511 patients employed at diagnosis, 249 (49%) experienced work loss within an average disease duration of 13 years. The proportion of patients who lost their jobs since diagnosis was almost twice for African Americans than for whites. However, the SURs were similar across demographic characteristics, including race. Patients with severe disease activity and severe organ damage had the highest SUR at 4.4 and 5.6, respectively. Among those that remained employed, patients with severe fatigue, neurocognitive symptoms, and musculoskeletal symptoms had the highest impairment of work productivity. Conclusion. SLE imposes a substantial toll on individuals and burden on society. Major factors that negatively impact work outcomes are fatigue, disease activity, and organ damage. More effective treatments along with coping strategies at the workplace are needed to reduce the burden of SLE on work outcomes. Copyright © 2014 by the American College of Rheumatology.

Dennis G.J.,Human Genome science
Clinical Pharmacology and Therapeutics | Year: 2012

Belimumab (Benlysta), which recently received marketing approval, is the first of a new class of immunomodulators with a novel mechanism of action. It is a specific inhibitor of the soluble B-lymphocyte stimulator (BLyS) cytokine, which has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Two large phase III randomized controlled clinical trials evaluated the safety and efficacy of belimumab combined with standard therapy and showed that the efficacy of this treatment was significantly superior to placebo plus standard therapy. Belimumab is an evidence-based therapeutic option for patients with general lupus disease activity and may signal a shift in the existing treatment paradigm from therapeutic selection targeting specific organ involvement to an approach directed at tackling multisystem disease activity and preventing the disease from worsening. © 2012 american Society for Clinical Pharmacology and Therapeutics.

Jacob C.O.,University of Southern California | Guo S.,University of Southern California | Jacob N.,University of Southern California | Pawar R.D.,Yeshiva University | And 5 more authors.
Arthritis and Rheumatism | Year: 2012

Objective To determine the role of APRIL in the development of systemic lupus erythematosus (SLE) in mice. Methods Wild-type (WT) NZM 2328, NZM. April -/-, NZM.Baff -/-, and NZM.Baff -/-. April -/- mice were evaluated for lymphocyte phenotype by flow cytometry, for serum total IgG and IgG autoantibody levels by enzyme-linked immunosorbent assay, for glomerular deposition of IgG and C3 by immunofluorescence, for renal changes by histopathology, and for clinical disease by laboratory assessment (severe proteinuria). Results In comparison to WT mice, NZM.April -/- mice harbored increased spleen B cells, T cells, and plasma cells (PCs), increased serum levels of IgG antichromatin antibodies, and decreased numbers of bone marrow (BM) PCs. Glomerular deposition of IgG and C3 was similar in NZM.April -/- mice and WT mice, renal changes on histopathology tended to be more severe in NZM.April -/- mice than in WT mice, and development of clinical disease was identical in NZM.April -/- mice and WT mice. BM (but not spleen) PCs and serum IgG antichromatin and anti-double-stranded DNA antibody levels were lower in NZM.Baff -/-.April -/- mice than in NZM.Baff -/- mice, whereas renal immunopathology in each cohort was equally mild. Conclusion APRIL is dispensable for the development of full-blown SLE in NZM mice. Moreover, the elimination of both APRIL and BAFF had no discernible effect on the development of renal immunopathology or clinical disease beyond that of elimination of BAFF alone. The reduction in BM PCs in hosts doubly deficient in APRIL and BAFF beyond that in hosts deficient only in BAFF raises concern that combined antagonism of APRIL and BAFF may lead to greater immunosuppression without a concomitant increase in therapeutic efficacy. Copyright © 2012 by the American College of Rheumatology.

Clark P.J.,Duke University | Clark P.J.,University of New South Wales | Thompson A.J.,Duke University | Vock D.M.,Duke University | And 8 more authors.
Hepatology | Year: 2012

Hepatitis C virus (HCV) subverts host cholesterol metabolism for key processes in its lifecycle. How this interference results in the frequently observed, genotype-dependent clinical sequelae of hypocholesterolemia, hepatic steatosis, and insulin resistance (IR) remains incompletely understood. Hypocholesterolemia typically resolves after sustained viral response (SVR), implicating viral interference in host lipid metabolism. Using a targeted cholesterol metabolomic platform we evaluated paired HCV genotype 2 (G2) and G3 patient sera for changes in in vivo HCV sterol pathway metabolites. We compared HCV genotypic differences in baseline metabolites and following antiviral treatment to assess whether sterol perturbation resolved after HCV eradication. We linked these metabolites to IR and urine oxidative stress markers. In paired sera from HCV G2 (n = 13) and G3 (n = 20) patients, baseline sterol levels were lower in G3 than G2 for distal metabolites (7-dehyrocholesterol (7DHC) 0.017 versus 0.023 mg/dL; P adj = 0.0524, cholesterol 140.9 versus 178.7 mg/dL; P adj = 0.0242) but not the proximal metabolite lanosterol. In HCV G3, SVR resulted in increased levels of distal metabolites (cholesterol [Δ55.2 mg/dL; P adj = 0.0015], 7DHC [Δ0.0075 mg/dL; P adj = 0.0026], lathosterol [Δ0.0430 mg/dL P adj = 0.0405]). In contrast, lanosterol was unchanged after SVR (P = 0.9515). Conclusion: HCV G3, but not G2, selectively interferes with the late cholesterol synthesis pathway, evidenced by lower distal sterol metabolites and preserved lanosterol levels. This distal interference resolves with SVR. Normal lanosterol levels provide a signal for the continued proteolysis of 3-hydroxyl-3-methylglutaryl coenzyme A reductase, which may undermine other host responses to increase cholesterol synthesis. These data may provide a hypothesis to explain why hypocholesterolemia persists in chronic HCV infection, particularly in HCV G3, and is not overcome by host cholesterol compensatory mechanisms. © 2012 American Association for the Study of Liver Diseases.

Sarnes E.,Xcenda | Crofford L.,University of Kentucky | Watson M.,Glaxosmithkline | Dennis G.,Human Genome science | And 2 more authors.
Clinical Therapeutics | Year: 2011

Objective: The objective of this systematic literature review was to evaluate the incidences and risks for adverse events (AEs) associated with oral and parenteral corticosteroids. An assessment was performed to estimate the costs of such AEs. Methods: A systematic review of literature published from 2007 to 2009 was conducted to identify the incidence rates and risk ratios of corticosteroid-related AEs. The review protocol was developed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The literature search was expanded to include additional search terms for psychiatric conditions, infections, and peptic ulcers. Costs obtained from a separate narrative literature review were applied to AEs likely to affect third-party payers in the United States. Results: A total of 357 publications were identified from the primary (n = 323) and secondary (n = 34) searches. Of these, 310 were excluded because they did not evaluate AEs related to corticosteroids, were an excluded publication type, or for other reasons. A final list of 47 studies were used for data extraction. Across patient populations, the most frequently reported corticosteroid-associated AEs were psychiatric events, infections, gastric conditions, and fractures. Corticosteroid-associated AEs reported to occur at an incidence >30% were sleep disturbances, lipodystrophy, adrenal suppression, metabolic syndrome, weight gain, and hypertension. Vertebral fractures were reported at an incidence of 21% to 30%. Dose-response relationships were documented for fractures, acute myocardial infarction, hypertension, and peptic ulcer. The costs of managing AEs that may occur with corticosteroids can be substantial. The literature reported 1-year per-patient costs of up to $26,471.80 for nonfatal myocardial infarction, and per-event costs as high as $18,357.90 for fracture. The findings from the present review should be interpreted cautiously due to several limitations, including the retrospective design of most of the studies identified, risk for confounding due to underlying disease activity or patient population, and the relatively small number of studies that reported each AE association. As this cost analysis was preliminary, a comprehensive pharmacoeconomic analysis should be undertaken to confirm the findings. Conclusion: Based on the findings from this review, systemic corticosteroids are a common cause of AEs that may be costly to payers. © 2011 Elsevier HS Journals, Inc..

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