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Find video protocols related to scientific articles indexed in Pubmed.
Suppression of rheumatoid arthritis B cells by XmAb5871, an anti-CD19 antibody that coengages B cell antigen receptor complex and Fc? receptor IIb inhibitory receptor.
PUBLISHED: 05-01-2014
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Engagement of Fc? receptor IIb (Fc?RIIb) suppresses B cell activation and represents a promising target for therapy in autoimmunity. The aim of this study was to characterize B cell immunosuppression mediated by the Fc-engineered antibody, XmAb5871, which coengages Fc?RIIb with the B cell antigen receptor (BCR) complex and that is currently in clinical development for the treatment of rheumatoid arthritis (RA). Because rheumatoid factor (RF) might interfere with the binding of XmAb5871 to Fc?RIIb, we correlated RF titers with the potency of XmAb5871.
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Tear cathepsin S as a candidate biomarker for Sjögren's syndrome.
PUBLISHED: 03-13-2014
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The diagnosis of Sjögren's syndrome (SS) in routine practice is largely a clinical one and requires a high index of suspicion by the treating physician. This great dependence on clinical judgment frequently leads to delayed diagnosis or misdiagnosis. Tear protein profiles have been proposed as simple and reliable biomarkers for the diagnosis of SS. Given that cathepsin S activity is increased in the lacrimal glands and tears of NOD mice (a murine model of SS), the aim of this study was to explore the clinical utility of using tear cathepsin S (CTSS) activity as a biomarker for SS.
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Therapeutic targeting of the BAFF/APRIL axis in systemic lupus erythematosus.
Expert Opin. Ther. Targets
PUBLISHED: 02-13-2014
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The B-cell activating factor (BAFF) axis comprises two ligands (BAFF and APRIL) and three receptors (BCMA, TACI, BR3). BAFF is a vital B-cell survival factor and overexpression of BAFF in both mice and humans is associated with systemic lupus erythematosus (SLE). The anti-BAFF monoclonal antibody (mAb), belimumab, was recently approved by the US FDA for the treatment of adult SLE patients, and three additional BAFF antagonists (atacicept, blisibimod, tabalumab) are presently being evaluated in SLE Phase-III trials.
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APRIL mediates peritoneal B-1 cell homeostasis.
Immunol. Lett.
PUBLISHED: 01-20-2014
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BLyS (B lymphocyte stimulator) family cytokines and receptors play key roles in B-2 cell maturation and survival, but their importance for B-1 cells remains less clear. Here we use knockout mice to show that APRIL (A proliferation-inducing ligand), but not BLyS, plays a role in peritoneal B-1 cell maintenance. APRIL likely exerts its effects on peritoneal B-1 cells through binding to HSPG (heparan sulfate proteoglycans) rather than to the TACI (transmembrane activator and cyclophilin ligand interactor) receptor. Finally, we show that peritoneal macrophages express high levels of APRIL message, and are a likely local source of the cytokine in this anatomic locale.
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Local BLyS production by T follicular cells mediates retention of high affinity B cells during affinity maturation.
J. Exp. Med.
PUBLISHED: 12-23-2013
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We have assessed the role of B lymphocyte stimulator (BLyS) and its receptors in the germinal center (GC) reaction and affinity maturation. Despite ample BLyS retention on B cells in follicular (FO) regions, the GC microenvironment lacks substantial BLyS. This reflects IL-21-mediated down-regulation of the BLyS receptor TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) on GC B cells, thus limiting their capacity for BLyS binding and retention. Within the GC, FO helper T cells (TFH cells) provide a local source of BLyS. Whereas T cell-derived BLyS is dispensable for normal GC cellularity and somatic hypermutation, it is required for the efficient selection of high affinity GC B cell clones. These findings suggest that during affinity maturation, high affinity clones rely on TFH-derived BLyS for their persistence.
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Disease Control and Safety of Belimumab Plus Standard Therapy Over 7 Years in Patients with Systemic Lupus Erythematosus.
J. Rheumatol.
PUBLISHED: 11-01-2013
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To evaluate the efficacy/safety of belimumab plus standard therapy in patients (n = 449) with active systemic lupus erythematosus (SLE) treated up to 7 years (n = 177 currently ongoing).
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Future prospects in biologic therapy for systemic lupus erythematosus.
Nat Rev Rheumatol
PUBLISHED: 09-10-2013
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With the approval by the FDA in 2011 of a biologic agent (namely belimumab) for the treatment of systemic lupus erythematosus (SLE), optimism abounds that additional biologic (and nonbiologic) agents will be similarly endorsed. Given the numerous immune-based abnormalities associated with SLE, the potential therapeutic targets for biologic agents and the candidate biologic approaches are also numerous. These approaches include: biologic agents that promote B-cell depletion, B-cell inactivation, or the generation of regulatory B cells; biologic agents that induce T-cell tolerance, block T-cell activation and differentiation, or alter T-cell trafficking; biologic agents that target the B-cell activating factor (BAFF) axis, type I interferons, IL-6 and its receptor, or TNF; and the adoptive transfer of ex vivo-generated regulatory T cells. Owing to the great heterogeneity inherent to SLE, no single approach should be expected to be effective in all patients. As our understanding of the pathogenic mechanisms of SLE continues to expand, additional therapeutic targets and approaches will undoubtedly be identified and should be fully exploited.
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BAFF- and APRIL-dependent maintenance of antibody titers after immunization with T-dependent antigen and CD1d-binding ligand.
J. Immunol.
PUBLISHED: 06-24-2013
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CD1d-restricted invariant NKT (iNKT) cells boost humoral immunity to T-dependent Ags that are coadministered with the CD1d-binding glycolipid Ag ?-galactosylceramide (?-GC). Observations that mice lacking iNKT cells have decaying Ab responses following vaccination have led to the hypothesis that iNKT cells express plasma cell (PC) survival factors that sustain specific Ab titers. Bone marrow chimeric mice in which the entire hematopoietic compartment or iNKT cells selectively lacked BAFF, a proliferation-inducing ligand (APRIL), or both BAFF and APRIL were created and immunized with nitrophenol hapten-conjugated keyhole limpet hemocyanin adsorbed to Imject aluminum hydroxide-containing adjuvant or mixed with ?-GC. In comparison with BAFF- or APRIL-sufficient bone marrow chimeras, absence of hematopoietic compartment- and iNKT-derived BAFF and APRIL was associated with rapidly decaying Ab titers and reduced PC numbers. The iNKT cell-derived BAFF or APRIL assumed a greater role in PC survival when ?-GC was used as the adjuvant for immunization. These results show that iNKT cell-derived BAFF and APRIL each contribute to survival of PCs induced by immunization. This study sheds new light on the mechanisms through which iNKT cells impact humoral immunity and may inform design of vaccines that incorporate glycolipid adjuvants.
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Racial/ethnic differences in the use of biologic disease-modifying antirheumatic drugs among California Medicaid rheumatoid arthritis patients.
Arthritis Care Res (Hoboken)
PUBLISHED: 03-26-2013
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To assess racial/ethnic differences in the use of biologic disease-modifying antirheumatic drugs (DMARDs) among California Medicaid (Medi-Cal) rheumatoid arthritis (RA) patients.
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Development of systemic lupus erythematosus in NZM 2328 mice in the absence of any single BAFF receptor.
Arthritis Rheum.
PUBLISHED: 01-22-2013
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To determine the necessity for any individual BAFF receptor in the development of systemic lupus erythematosus (SLE).
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A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus.
Arthritis Rheum.
PUBLISHED: 12-01-2011
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To assess the efficacy/safety of the B lymphocyte stimulator inhibitor belimumab plus standard therapy compared with placebo plus standard therapy in active systemic lupus erythematosus (SLE).
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Sustained inhibition of progressive joint damage with rituximab plus methotrexate in early active rheumatoid arthritis: 2-year results from the randomised controlled trial IMAGE.
Ann. Rheum. Dis.
PUBLISHED: 10-19-2011
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In the IMAGEstudy, rituximab plus methotrexate (MTX) inhibited joint damage and improved clinical outcomes at 1 year in MTX-naïve patients with early active rheumatoid arthritis.
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Cytokine disturbances in systemic lupus erythematosus.
Arthritis Res. Ther.
PUBLISHED: 07-06-2011
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The pathogenesis of systemic lupus erythematosus (SLE) is complex, and the resulting disease manifestations are heterogeneous. Cytokine dysregulation is pervasive, and their protein and gene expression profiles may serve as markers of disease activity and severity. Importantly, biologic agents that target specific cytokines may represent novel therapies for SLE. Four cytokines (IL-6, TNF?, IFN?, and BLyS) are being evaluated as therapeutic targets in SLE. The present review will examine the roles of each of these cytokines in murine and human SLE, and will summarize results from clinical trials of agents that target these cytokines.
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BAFF promotes Th17 cells and aggravates experimental autoimmune encephalomyelitis.
PLoS ONE
PUBLISHED: 03-21-2011
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BAFF, in addition to promoting B cell survival and differentiation, may affect T cells. The objective of this study was to determine the effect of BAFF on Th17 cell generation and its ramifications for the Th17 cell-driven disease, EAE.
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B Cell and BAFF dependence of IFN-?-exaggerated disease in systemic lupus erythematosus-prone NZM 2328 mice.
J. Immunol.
PUBLISHED: 03-07-2011
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IFN-? is a potent activator of innate and adaptive immunity, and its administration to preautoimmune (NZB×NZW)F1 mice promotes virulent systemic lupus erythematosus (SLE) disease. Given the known contributions of B cells and BAFF to SLE, we evaluated the ability of IFN-? administration to induce disease in wild-type (WT), B cell-deficient, and BAFF-deficient NZM 2328 mice. Whereas WT mice rapidly developed proliferative glomerulonephritis, marked proteinuria, and increased mortality in response to IFN-? administration, B cell-deficient mice developed neither renal pathology nor clinical disease. Moreover, BAFF-deficient mice, despite developing limited glomerular IgG and C3 deposition, also remained free of histological glomerulonephritis and clinical disease. Strikingly, similar T cell expansion and serum IgG responses were observed in adenovirus (Adv)-IFN-treated WT and BAFF-deficient mice despite their disparate pathological and clinical responses, whereas numbers of activated B cells increased in WT mice but not in BAFF-deficient mice. Nonetheless, B cell, plasma cell, and T cell infiltration of the kidneys in Adv-IFN-treated WT mice was similar to that in WT mice treated with Adv-control. Its ability to promote SLE disease in WT mice notwithstanding, IFN-? administration failed to drive the preferential expansion of CD4(+) memory T cells that occurs during the natural course of disease, and glomerular infiltration of macrophages failed to associate with development of disease. These results collectively suggest that therapeutic targeting in SLE of BAFF and/or B cells in SLE could be successful even in states of IFN-? overexpression. Moreover, our results document important biological differences between IFN-?-driven and spontaneous natural SLE disease.
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Antibody-mediated coengagement of Fc?RIIb and B cell receptor complex suppresses humoral immunity in systemic lupus erythematosus.
J. Immunol.
PUBLISHED: 02-28-2011
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Engagement of the low-affinity Ab receptor Fc?RIIb downregulates B cell activation, and its dysfunction is associated with autoimmunity in mice and humans. We engineered the Fc domain of an anti-human CD19 Ab to bind Fc?RIIb with high affinity, promoting the coengagement of Fc?RIIb with the BCR complex. This Ab (XmAb5871) stimulated phosphorylation of the ITIM of Fc?RIIb and suppressed BCR-induced calcium mobilization, proliferation, and costimulatory molecule expression of human B cells from healthy volunteers and systemic lupus erythematosus (SLE) patients, as well as B cell proliferation induced by LPS, IL-4, or BAFF. XmAb5871 suppressed humoral immunity against tetanus toxoid and reduced serum IgM, IgG, and IgE levels in SCID mice engrafted with SLE or healthy human PBMC. XmAb5871 treatment also increased survival of mice engrafted with PBMC from a unique SLE patient. Unlike anti-CD20 Ab, coengagement of Fc?RIIb and BCR complex did not promote B cell depletion in human PBMC cultures or in mice. Thus, amplification of the Fc?RIIb inhibitory pathway in activated B cells may represent a novel B cell-targeted immunosuppressive therapeutic approach for SLE and other autoimmune diseases that should avoid the complications associated with B cell depletion.
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Targeting BLyS in rheumatic disease: the sometimes-bumpy road from bench to bedside.
Curr Opin Rheumatol
PUBLISHED: 02-19-2011
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BLyS family ligands and receptors are key players in the selection and survival of most mature B lymphocytes. The fundamental role of BLyS in transitional B cell selection, coupled with the relative BLyS-independence of memory B cells and plasma cells, suggests that BLyS may be a useful therapeutic target in strategies directed against preimmune B cell pools. Several agents that target BLyS are in clinical trials now, and we summarize recent results here, with a focus on systemic lupus erythematosus (SLE).
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Constitutive overexpression of BAFF in autoimmune-resistant mice drives only some aspects of systemic lupus erythematosus-like autoimmunity.
Arthritis Rheum.
PUBLISHED: 05-28-2010
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To determine whether overexpression of BAFF can promote systemic lupus erythematosus (SLE)-like autoimmunity in mice that are otherwise autoimmune-resistant.
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Systemic lupus erythematosus and its ABCs (APRIL/BLyS complexes).
Arthritis Res. Ther.
PUBLISHED: 04-22-2010
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BLyS and APRIL are closely related members of the TNF ligand superfamily. These cytokines individually may contribute importantly to the development and maintenance of systemic lupus erythematosus (SLE). Dillon and colleagues demonstrate that in contrast to most members of the TNF ligand superfamily, which form only homotrimers, BLyS and APRIL can complex as heterotrimers. These complexes have in vitro biological activity, and circulating levels of BLyS/APRIL heterotrimers are frequently elevated in SLE, but not rheumatoid arthritis, patients. Although the mechanism and regulation of heterotrimer formation, the interconversion (if any) between homotrimers and heterotrimers, and, indeed, the normal physiologic role for such heterotrimers remain unknown, their preferential overexpression in SLE, but not in rheumatoid arthritis, raises the possibility that such heterotrimers may be playing a contributory role in SLE.
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Association of the response to tumor necrosis factor antagonists with plasma type I interferon activity and interferon-beta/alpha ratios in rheumatoid arthritis patients: a post hoc analysis of a predominantly Hispanic cohort.
Arthritis Rheum.
PUBLISHED: 01-30-2010
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Despite the substantial clinical efficacy of tumor necrosis factor alpha (TNFalpha) antagonist therapy in patients with rheumatoid arthritis (RA), some patients respond poorly to such agents. Since an interferon (IFN) signature is variably expressed among RA patients, we investigated whether plasma type I IFN activity might predict the response to TNF antagonist therapy.
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B lymphocyte stimulator expression in pediatric systemic lupus erythematosus and juvenile idiopathic arthritis patients.
Arthritis Rheum.
PUBLISHED: 10-31-2009
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To assess the expression of B lymphocyte stimulator (BLyS) in patients with pediatric systemic lupus erythematosus (SLE) or juvenile idiopathic arthritis (JIA).
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Deficiency of type I IFN receptor in lupus-prone New Zealand mixed 2328 mice decreases dendritic cell numbers and activation and protects from disease.
J. Immunol.
PUBLISHED: 10-07-2009
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Type I IFNs are potent regulators of innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus. Here we report that clinical and pathological lupus nephritis and serum anti-nuclear Ab levels are greatly attenuated in New Zealand Mixed (NZM) 2328 mice deficient in type I IFN receptors (IFNAR). To determine whether the inflammatory environment in NZM 2328 mice leads to IFNAR-regulated changes in dendritic cells (DC), the number, activation, and function of DC subsets were compared in 2- and 5-mo-old (clinically healthy) female NZM and NZM-IFNAR(-/-) mice. Numbers of activated CD40(high) plasmacytoid DC (pDC) were significantly increased in renal lymph nodes of 2-mo-old NZM but not NZM-IFNAR(-/-) mice, suggesting an early IFNAR-dependent expansion and activation of pDC at disease sites. Relative to NZM spleens, NZM-IFNAR(-/-) spleens in 5-mo-old mice were significantly decreased in size and contained reduced numbers of conventional DC subsets, but not pDC. Splenic and renal lymph node NZM-IFNAR(-/-) DC analyzed directly ex vivo expressed significantly less CD40, CD86, and PDL1 than did NZM DC. Upon activation with synthetic TLR9 ligands in vitro, splenic NZM-IFNAR(-/-) DC produced less IL-12p40/70 and TNF-alpha than did NZM DC. The limited IFNAR(-/-) DC response to endogenous activating stimuli correlated with reduced numbers of splenic activated memory CD4(+) T cells and CD19(+) B cells in older mice. Thus, IFNAR signaling significantly increases DC numbers, acquisition of Ag presentation competence, and proinflammatory function before onset of clinically apparent lupus disease.
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Novel evidence-based systemic lupus erythematosus responder index.
Arthritis Rheum.
PUBLISHED: 08-29-2009
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To describe a new systemic lupus erythematosus (SLE) responder index (SRI) based on a belimumab phase II SLE trial and demonstrate its potential utility in SLE clinical trials.
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A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus.
Arthritis Rheum.
PUBLISHED: 08-29-2009
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To assess the safety, tolerability, biologic activity, and efficacy of belimumab in combination with standard of care therapy (SOC) in patients with active systemic lupus erythematosus (SLE).
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Urinary TWEAK as a biomarker of lupus nephritis: a multicenter cohort study.
Arthritis Res. Ther.
PUBLISHED: 08-04-2009
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TNF-like weak inducer of apoptosis (TWEAK) has been implicated as a mediator of chronic inflammatory processes via prolonged activation of the NF-kappaB pathway in several tissues, including the kidney. Evidence for the importance of TWEAK in the pathogenesis of lupus nephritis (LN) has been recently introduced. Thus, TWEAK levels may serve as an indication of LN presence and activity.
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Accelerated pathological and clinical nephritis in systemic lupus erythematosus-prone New Zealand Mixed 2328 mice doubly deficient in TNF receptor 1 and TNF receptor 2 via a Th17-associated pathway.
J. Immunol.
PUBLISHED: 02-10-2009
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TNF-alpha has both proinflammatory and immunoregulatory functions. Whereas a protective role for TNF administration in systemic lupus erythematosus (SLE)-prone (New Zealand Black x New Zealand White)F(1) mice has been established, it remains uncertain whether this effect segregates at the individual TNFR. We generated SLE-prone New Zealand Mixed 2328 mice genetically deficient in TNFR1, in TNFR2, or in both receptors. Doubly-deficient mice developed accelerated pathological and clinical nephritis with elevated levels of circulating IgG anti-dsDNA autoantibodies and increased numbers of CD4(+) T lymphocytes, especially activated memory (CD44(high)CD62L(low)) CD4(+) T cells. We show that these cells expressed a Th17 gene profile, were positive for IL-17 intracellular staining by FACS, and produced exogenous IL-17 in culture. In contrast, immunological, pathological, and clinical profiles of mice deficient in either TNFR alone did not differ from those in each other or from those in wild-type controls. Thus, total ablation of TNF-alpha-mediated signaling was highly deleterious to the host in the New Zealand Mixed 2328 SLE model. These observations may have profound ramifications for the use of TNF and TNFR antagonists in human SLE and related autoimmune disorders, as well as demonstrate, for the first time, the association of the Th17 pathway with an animal model of SLE.
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Induced T regulatory cells suppress osteoclastogenesis and bone erosion in collagen-induced arthritis better than natural T regulatory cells.
Ann. Rheum. Dis.
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Although natural regulatory T cells (nTregs) can suppress osteoclastogenesis, the role of TGF-?-induced CD4+Foxp3+ Tregs (iTregs) in osteoclastogenesis remains unknown.
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Incremental expenditure of biologic disease modifying antirheumatic treatment using instrumental variables in panel data.
Health Econ
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In health care, decision makers are generally interested in simultaneous comparisons among multiple treatments or interventions available as treatment choices in real-world clinical setting. The lack of random assignment to treatment in real-world clinical settings leads to selection-bias issues when evaluating the marginal benefits of treatment. The application of instrumental variables (IV) estimation to mitigate selection bias has traditionally been limited to comparing only two treatments/interventions concurrently. Using the case of biologic treatment in rheumatoid arthritis, we describe a generalized method of moments (GMM)-based panel data IV (IV-GMM) framework, to simultaneously estimate multiple treatment effects in the presence of time-varying selection bias and time-invariant heterogeneity. To satisfy the order and rank conditions for identification with multiple endogeneity, we propose lagged values of each treatment as excluded instruments. We evaluate the validity of the IV estimation assumptions on instrument relevance and exogeneity. Results indicate that the IV-GMM model offers enhanced control over selection bias and heterogeneity, and more importantly the panel data framework can provide valid excluded instruments that satisfy the order and rank conditions for identification when dealing with multiple endogenous variables. The approach outlined in this article has broad application for comparative effectiveness and health technology assessment involving multiple treatments/interventions using real-world nonexperimental data.
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Effect of belimumab on vaccine antigen antibodies to influenza, pneumococcal, and tetanus vaccines in patients with systemic lupus erythematosus in the BLISS-76 trial.
J. Rheumatol.
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In patients with systemic lupus erythematosus (SLE), evidence suggests that most vaccines (except live-virus vaccines) are safe, although antibody response may be reduced. This substudy from the phase III, randomized, double-blind, placebo-controlled BLISS-76 trial evaluated the effects of belimumab on preexisting antibody levels against pneumococcal, tetanus, and influenza antigens in patients with SLE.
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Biologic differences between various inhibitors of the BLyS/BAFF pathway: should we expect differences between belimumab and other inhibitors in development?
Curr Rheumatol Rep
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For the first time in more than 50 years, the US Food and Drug Administration has approved a drug specifically for the treatment of systemic lupus erythematosus (SLE). This drug, belimumab, is a monoclonal antibody that neutralizes the B-cell survival factor, B-lymphocyte stimulator (BLyS). Although belimumab has demonstrated a very favorable safety profile, many SLE patients have failed to clinically improve from belimumab therapy. Three additional BLyS antagonists (atacicept, blisibimod, tabalumab) are currently undergoing clinical testing. These antagonists subtly differ from belimumab in their biologic targets, and each is administered through a route (subcutaneous) that differs from the route through which belimumab is currently delivered (intravenous). Whether these differences will have meaningful consequences for efficacy and safety remains to be determined.
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Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus.
Arthritis Rheum.
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To assess the effects of the B lymphocyte stimulator (BLyS)-specific inhibitor belimumab on immunologic biomarkers, including B cell and T cell populations, and maintenance of antibody titers to prior vaccines in autoantibody-positive systemic lupus erythematosus (SLE) patients.
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The discovery and development of belimumab: the anti-BLyS-lupus connection.
Nat. Biotechnol.
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For the first time in more than 50 years, the US Food and Drug Administration has approved a drug specifically for the treatment of systemic lupus erythematosus (SLE). This drug, belimumab (Benlysta), is a human monoclonal antibody that neutralizes the B-cell survival factor, B-lymphocyte stimulator (BLyS). The approval of belimumab combined a pioneering approach to genomics-based gene discovery, an astute appreciation of translational medicine, a disciplined clinical strategy, a willingness to take calculated risks, a devoted cadre of patients and physicians and a healthy dose of serendipity. Collectively, these efforts have provided a model for the development of a new generation of drugs to treat the broad manifestations of SLE. However, as a substantial percentage of SLE patients do not respond to belimumab, further research is needed to better characterize the pathogenetic mechanisms of SLE, identify additional therapeutic targets, and develop effective and nontoxic novel agents against these targets.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.