Human Genome science
Human Genome science
Manzi S.,Allegheny Singer Research Institute |
Sanchez-Guerrero J.,Instituto Nacional Of Ciencias Medicas Y Nutricion Salvador Zubiran |
Merrill J.T.,Oklahoma Medical Research Foundation |
Furie R.,North Shore LIJ Health System |
And 10 more authors.
Annals of the Rheumatic Diseases | Year: 2012
Objective: To evaluate the effects of belimumab versus placebo, plus standard systemic lupus erythematosus (SLE) therapy, on organ domain-specific SLE disease activity. Methods: Data obtained after 52 weeks of treatment from two phase III trials (BLISS-52 and BLISS-76) comparing belimumab 1 and 10 mg/kg versus placebo, plus standard therapy, in 1684 autoantibody-positive patients were analysed post hoc for changes in British Isles Lupus Assessment Group (BILAG) and Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) organ domain scores. Results: At baseline, the domains involved in the majority of patients were musculoskeletal and mucocutaneous by both BILAG and SELENA-SLEDAI, and immunological by SELENA-SLEDAI. At 52 weeks, significantly more patients treated with belimumab versus placebo had improvement in BILAG musculoskeletal and mucocutaneous domains (1 and 10 mg/kg), and in SELENA-SLEDAI mucocutaneous (10 mg/ kg), musculoskeletal (1 mg/kg) and immunological (1 and 10 mg/kg) domains. Improvement was also observed in other organ systems with a low prevalence (≤16%) at baseline, including the SELENA-SLEDAI vasculitis and central nervous system domains. Significantly fewer patients treated with belimumab versus placebo had worsening in the BILAG haematological domain (1 mg/kg) and in the SELENA-SLEDAI immunological (10 mg/kg), haematological (10 mg/kg) and renal (1 mg/kg) domains. Conclusions: Belimumab treatment improved overall SLE disease activity in the most common musculoskeletal and mucocutaneous organ domains. Less worsening occurred in the haematological, immunological and renal domains.
Navarra S.V.,University of Santo Tomas of Philippines |
Guzman R.M.,SaludCoop Clinic |
Gallacher A.E.,Hospital Britanico Of Buenos Aires |
Hall S.,Emeritus Research Cabrini Hospital |
And 13 more authors.
The Lancet | Year: 2011
Background: Systemic lupus erythematosus is a heterogeneous autoimmune disease that is associated with B-cell hyperactivity, autoantibodies, and increased concentrations of B-lymphocyte stimulator (BLyS). The efficacy and safety of the fully human monoclonal antibody belimumab (BLyS-specific inhibitor) was assessed in patients with active systemic lupus erythematosus. Methods: Patients (aged ≥18 years) who were seropositive with scores of at least 6 on the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) were enrolled in a multicentre phase 3 study, which was done in Latin America, Asia-Pacific, and eastern Europe. Patients were randomly assigned by use of a central interactive voice response system in a 1:1:1 ratio to belimumab 1 mg/kg or 10 mg/kg, or placebo by intravenous infusion in 1 h on days 0, 14, and 28, and then every 28 days until 48 weeks, with standard of care. Patients, investigators, study coordinators, and sponsors were masked to treatment assignment. Primary efficacy endpoint was improvement in the Systemic Lupus Erythematosus Responder Index (SRI) at week 52 (reduction ≥4 points in SELENA-SLEDAI score; no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new B organ domain score; and no worsening [<0.3 increase] in Physician's Global Assessment [PGA] score) versus baseline. Method of analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00424476. Findings: 867 patients were randomly assigned to belimumab 1 mg/kg (n=289) or 10 mg/kg (n=290), or placebo (n=288). 865 were treated and analysed in the belimumab (1 mg/kg, n=288; 10 mg/kg, n=290) and placebo groups (n=287). Significantly higher SRI rates were noted with belimumab 1 mg/kg (148 [51%], odds ratio 1.55 [95% CI 1.10-2.19]; p=0.0129) and 10 mg/kg (167 [58%], 1.83 [1.30-2.59]; p=0.0006) than with placebo (125 [44%]) at week 52. More patients had their SELENA-SLEDAI score reduced by at least 4 points during 52 weeks with belimumab 1 mg/kg (153 [53%], 1.51 [1.07-2.14]; p=0.0189) and 10 mg/kg (169 [58%], 1.71 [1.21-2.41]; p=0.0024) than with placebo (132 [46%]). More patients given belimumab 1 mg/kg (226 [78%], 1.38 [0.93-2.04]; p=0.1064) and 10 mg/kg (236 [81%], 1.62 [1.09-2.42]; p=0.0181) had no new BILAG A or no more than 1 new B flare than did those in the placebo group (210 [73%]). No worsening in PGA score was noted in more patients with belimumab 1 mg/kg (227 [79%], 1.68 [1.15-2.47]; p=0.0078) and 10 mg/kg (231 [80%], 1.74 [1.18-2.55]; p=0.0048) than with placebo (199 [69%]). Rates of adverse events were similar in the groups given belimumab 1 mg/kg and 10 mg/kg, and placebo: serious infection was reported in 22 (8%), 13 (4%), and 17 (6%) patients, respectively, and severe or serious hypersensitivity reactions on an infusion day were reported in two (<1%), two (<1%), and no patients, respectively. No malignant diseases were reported. Interpretation: Belimumab has the potential to be the first targeted biological treatment that is approved specifically for systemic lupus erythematosus, providing a new option for the management of this important prototypic autoimmune disease. Funding: Human Genome Sciences and GlaxoSmithKline. © 2011 Elsevier Ltd.
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.
Jacobi A.M.,University of Munster |
Jacobi A.M.,Feinstein Institute for Medical Research |
Huang W.,Feinstein Institute for Medical Research |
Wang T.,Feinstein Institute for Medical Research |
And 7 more authors.
Arthritis and Rheumatism | Year: 2010
Objective. To understand the effects of long-term BLyS inhibition in human systemic lupus erythematosus (SLE). Methods. Seventeen patients with SLE who were enrolled in a clinical trial of belimumab, a BLyS-specific inhibitor, plus standard of care therapy were studied. Phenotypic analysis of lymphocytes was performed using flow cytometry. Circulating antibody-secreting cells were enumerated using enzyme-linked immunospot assay. Serum was analyzed by enzyme-linked immunosorbent assay using an antibody that recognizes products of the VH4-34 gene. Lymphocyte counts, Ig levels, and anti-double-stranded DNA antibody levels were available as part of the clinical trial analyses. Results. Samples were collected on days 0, 84, 168, 365, and 532 and after day 730. The total number of B cells started to decrease from baseline between days 84 and 168. This was due to a decrease in naive and transitional B cells. CD27+IgD+ memory B cells and plasmablasts decreased only after 532 days, whereas CD27+IgD- memory B cells were not affected, and there were no changes in T cells. Serum IgM levels began to decline between days 84 and 168, but there were no changes in serum levels of IgG, IgG anti-DNA antibodies, or VH4-34 antibodies during the study. SLE patients had more IgM-, IgG-, and autoantibody-producing B cells than did normal controls on day 0. There was only a modest decrease in the frequency of total IgM-producing, but not IgG-producing, cells on days 365 and 532, consistent with the phenotypic and serologic data. Conclusion. Our data confirm the dependence of newly formed B cells on BLyS for survival in humans. In contrast, memory B cells and plasma cells are less susceptible to selective BLyS inhibition. © 2010, American College of Rheumatology.
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..
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.
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.
Fox N.L.,Human Genome science |
Humphreys R.,Human Genome science |
Luster T.A.,Human Genome science |
Klein J.,Human Genome science |
Gallant G.,Human Genome science
Expert Opinion on Biological Therapy | Year: 2010
Importance of the field: Agents that activate the TNF-related apoptosis-inducing ligand death receptors, TRAIL-R1 and TRAIL-R2, have attracted substantial attention and investment as potential anti-cancer therapies. Preclinical studies of TRAIL-R agonists indicate that they may be efficacious in a wide range of tumor types, especially when combined with chemotherapeutic agents. Areas covered in this review: The rationale for clinical development of TRAIL-R agonists is described, including the basis for combining these agents with other agents that modulate the 'checks and balances' of the apoptotic pathways. Accruing data that highlight differences between TRAIL-R1 and TRAIL-R2 that could affect the clinical significance of their specific agonists are described. The clinical experience to date with each of the agonists is summarized. What the reader will gain: The reader will gain an understanding of the rationale for the clinical development of TRAIL-R agonists, as well as the current status of clinical trials of these interesting new agents. Take home message: Ongoing clinical trials will provide important information regarding the future development of TRAIL-R agonists.
Human Genome Science | Date: 2012-08-31
The invention provides methods for separating a polypeptide of interest (such as an antibody) from a virus. In some embodiments, the methods involve eluting the polypeptide of interest from a Protein A resin with an elution buffer have a particular range of conductivity values that minimizes the amount of virus that co-elutes with the polypeptide of interest.