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Research Interests: Immunology, Biology, Cell Adhesion, Cell Biology, Medicine, and 15 moreAngiogenesis, Humans, Monoclonal Antibodies, Mitogen Activated Protein Kinase, Laser Scanning Confocal Microscopy, Live cell Imaging, Colchicine, Monocytes, Low Temperature, Monoclonal Antibody, Enzymatic Activity, Epitopes, Cell Membrane, Cell Aggregation, and binding sites
Lupus nephritis (LN) is a common and severe manifestation of systemic lupus erythematosus (SLE) affecting 50% of SLE patients and leading to end-stage kidney disease (ESKD) in up to 30% of patients with LN.1 Previous studies have reported... more
Lupus nephritis (LN) is a common and severe manifestation of systemic lupus erythematosus (SLE) affecting 50% of SLE patients and leading to end-stage kidney disease (ESKD) in up to 30% of patients with LN.1 Previous studies have reported higher healthcare costs in patients with SLE that develop LN compared to patients without LN.2-5 These studies captured overall treatment costs associated with LN, regardless of disease activity or severity, and were conducted in small patient populations.The aim of this study was to assess the real-world economic implications of achieving low disease activity compared to active disease or ESKD in a large LN population.This study was a retrospective observational analysis of patients with LN within Optum’s health plan identified with ICD9 or ICD10 codes to have LN between January 1, 2015, and December 31, 2019. Patients were ≥18 years of age and had ≥2 months of follow-up data available. Patients were followed until death, loss to follow-up, or Dec...
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doi:10.1182/blood-2005-08-3130
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Background:Voclosporin, a novel calcineurin inhibitor (CNI), has been tested successfully in two pivotal trials in adult patients with lupus nephritis.Previously reported results from the Phase 3 AURORA 1 study and the Phase 2 AURA-LV... more
Background:Voclosporin, a novel calcineurin inhibitor (CNI), has been tested successfully in two pivotal trials in adult patients with lupus nephritis.Previously reported results from the Phase 3 AURORA 1 study and the Phase 2 AURA-LV study showed that compared with mycophenolate mofetil (MMF) and low-dose steroids alone, the addition of voclosporin significantly increased the renal response rate and reduced proteinuria, as measured by urine protein creatinine ratio (UPCR), in patients with lupus nephritis (LN) at approximately one year of treatment (48 weeks in AURA-LV and 52 weeks in AURORA 1).Objectives:Patients that completed one year of treatment in the AURORA 1 study were eligible to enroll into the two-year, blinded, controlled extension study, AURORA 2. Here we report the first interim analysis of the ongoing AURORA 2 study.Methods:Patients completing AURORA 1 were eligible to continue the same randomized treatment of voclosporin (23.7 mg BID) or placebo, in combination with...
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Introduction Le dupilumab (DPL), un anticorps monoclonal entierement humain qui bloque le recepteur commun a IL-4 et IL-13, est approuve aux USA chez les patients (pts) âges de 12 ans et plus atteints de dermatite atopique (DA) moderee a... more
Introduction Le dupilumab (DPL), un anticorps monoclonal entierement humain qui bloque le recepteur commun a IL-4 et IL-13, est approuve aux USA chez les patients (pts) âges de 12 ans et plus atteints de dermatite atopique (DA) moderee a severe insuffisamment controlee par des traitements topiques ou chez qui ces traitements sont deconseilles, au Japon pour les pts adultes atteints de DA insuffisamment controlee par les traitements existants et en Europe pour les pts adultes atteints de DA moderee a severe qui necessitent un traitement systemique. Le delai d’amelioration du prurit est evalue chez des adolescents atteints de DA moderee a severe issus d‘une etude de phase 3 sur le DPL ( NCT03054428 ). Materiel et methodes Les pts (≥ 12 a Resultats Deux cent cinquante et un pts ont ete inclus (1×/2 s n = 82, 1×/4 s n = 84, PBO n = 85). Les valeurs moyennes (ecart-type) au debut de l’etude du score NRS de prurit etaient de 7,5(1,52)/7,5(1,84)/7,7(1,62), pour les groupes 1×/2 s–1×/4 s-P...
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This file contains two supplementary tables. Supplementary Table 1. Reports the treatment patterns of patients with AD stratified by age group. Supplementary Table 2. Reports the treatment patterns of patients with AD stratified by... more
This file contains two supplementary tables. Supplementary Table 1. Reports the treatment patterns of patients with AD stratified by age group. Supplementary Table 2. Reports the treatment patterns of patients with AD stratified by provider type. These tables were not included in the main text because they are larger than A4.
This Figshare page contains a video abstract and summary slide.<strong><br></strong>If you are an author of this publication and would like to provide additional enhanced digital features for your article then please... more
This Figshare page contains a video abstract and summary slide.<strong><br></strong>If you are an author of this publication and would like to provide additional enhanced digital features for your article then please contact adisrapidplus@springer.com.<br> <br> The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as 'peer reviewed' to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.<br&...
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Background and Aims Voclosporin is a novel calcineurin inhibitor with a favorable metabolic profile and a consistent dose-concentration relationship, potentially eliminating the need for therapeutic drug monitoring. We have previously... more
Background and Aims Voclosporin is a novel calcineurin inhibitor with a favorable metabolic profile and a consistent dose-concentration relationship, potentially eliminating the need for therapeutic drug monitoring. We have previously reported the primary endpoint of the Phase 3 AURORA trial showing the addition of voclosporin to mycophenolate mofetil (MMF) and a low-dose glucocorticoid regimen results in significantly higher renal response (RR) rates at one year of treatment compared to MMF and low-dose glucocorticoids alone in patients with lupus nephritis (LN). For the primary endpoint, RR was defined as ≤0.5 mg/mg UPCR with stable renal function in the presence of low-dose glucocorticoids and no use of rescue medication. Several studies have demonstrated that proteinuria represents the best single predictor for long-term renal outcomes.1,2 Given the efficacy of voclosporin in terms of proteinuria reduction, we conducted a sensitivity analysis evaluating RR with additional UPCR t...
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IntroductionAtopic dermatitis (AD) is a chronic inflammatory skin disease often associated with atopic comorbidities and has significant impact on children and their families. There is a lack of robust and longitudinal long-term data on... more
IntroductionAtopic dermatitis (AD) is a chronic inflammatory skin disease often associated with atopic comorbidities and has significant impact on children and their families. There is a lack of robust and longitudinal long-term data on disease characteristics and typical clinical practice with currently available treatments in children with moderate-to-severe AD. Hence, an observational study is needed to evaluate AD characteristics and progression in paediatric patients with moderate-to-severe AD.Methods and analysisPediatric Study in Atopic Dermatitis (PEDISTAD) is a prospective, observational, longitudinal study in paediatric patients with moderate-to-severe AD who are currently receiving systemic or topical treatment and whose disease is not adequately controlled by topical prescription therapies or for whom those therapies are not medically advisable. 1300 children at 100–150 sites in approximately 20 countries worldwide will be enrolled and followed for 5 years. AD therapy is...
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Background An estimated 50% of children in the US are Medicaid-insured. Some of these patients have poor health literacy and limited access to medications and specialty care. These factors affect treatment utilization for pediatric... more
Background An estimated 50% of children in the US are Medicaid-insured. Some of these patients have poor health literacy and limited access to medications and specialty care. These factors affect treatment utilization for pediatric patients with atopic dermatitis (AD), the most common inflammatory skin disease in children. This study assesses and compares treatment patterns and healthcare resource utilization (HCRU) between large cohorts of Medicaid and commercially insured children with AD. Methods Pediatric patients with AD were identified from 2 large US healthcare claims databases (2011–2016). Included patients had continuous health plan eligibility for ≥6 months before and ≥12 months after the first AD diagnosis (index date). Patients with an autoimmune disease diagnosis within 6 months of the index date were excluded. Treatment patterns and all-cause and AD-related HCRU during the observation period were compared between commercially and Medicaid-insured children. Results A mi...
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BACKGROUND Real-world evidence on treatment patterns of pediatric patients with atopic dermatitis (AD) is sparse. OBJECTIVE To assess current treatment patterns in pediatric AD patients. METHODS Retrospective observational analysis of... more
BACKGROUND Real-world evidence on treatment patterns of pediatric patients with atopic dermatitis (AD) is sparse. OBJECTIVE To assess current treatment patterns in pediatric AD patients. METHODS Retrospective observational analysis of commercial insurance and Medicaid administrative claims data (01/2011-12/2016) for pediatric AD patients, stratified by age and provider type. RESULTS Analytic sample comprised 607,258 pediatric AD patients. Median observation period was 30.3 months; 78.6% were prescribed >1 AD medication. 86.7% were prescribed topical corticosteroids (TCS); 5.4% a calcineurin inhibitor. Systemic corticosteroids (SCS) were prescribed for 24.4% patients, of whom 51.8% had no asthma/allergic comorbidities. Of the 46.6% and 16.2% prescribed an antihistamine or montelukast, respectively, 62.0% and 41.3% had no asthma/allergic comorbidities. Systemic immunosuppressants were rarely prescribed (<0.5%). Higher potency TCS and SCS use increased with age. Treatment patterns varied by provider type; specialists were more likely to prescribe higher potency topicals and/or systemics, regardless of age. A minority of patients were treated by/referred to a specialist. LIMITATIONS Identification of AD patients relied on billing diagnoses; disease severity proxied based on treatment. CONCLUSION Results indicate that SCS, despite known risks, and other medications with disproven efficacy in AD are frequently prescribed, suggesting a need for safer and, more effective alternatives.
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&NA; The atopic march recognizes the increased occurrence of asthma, allergic rhinitis, or both after atopic dermatitis (AD) onset. Mechanisms for developing atopic comorbidities after AD onset are poorly understood but can involve... more
&NA; The atopic march recognizes the increased occurrence of asthma, allergic rhinitis, or both after atopic dermatitis (AD) onset. Mechanisms for developing atopic comorbidities after AD onset are poorly understood but can involve the impaired cutaneous barrier, which facilitates cutaneous sensitization. The association can also be driven or amplified in susceptible subjects by a systemic TH2‐dominant immune response to cutaneous inflammation. However, these associations might merely involve shared genetic loci and environmental triggers, including microbiome dysregulation, with the temporal sequence reflecting tissue‐specific peak time of occurrence of each disease, suggesting more of a clustering of disorders than a march. Prospective longitudinal cohort studies provide an opportunity to explore the relationships between postdermatitis development of atopic disorders and potential predictive phenotypic, genotypic, and environmental factors. Recent investigations implicate disease severity and persistence, age of onset, parental atopic history, filaggrin (FLG) mutations, polysensitization, and the nonrural environment among risk factors for development of multiple atopic comorbidities in young children with AD. Early intervention studies to repair the epidermal barrier or alter exposure to the microbiome or allergens might elucidate the relative roles of barrier defects, genetic locus alterations, and environmental exposures in the risk and sequence of occurrence of TH2 activation disorders.
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ABSTRACT There has been remarkable progress in our understanding of immunology in the last few decades. Nevertheless, only a very small number of new drugs have made it from the bench to the bedside. Apart from the enormous success of... more
ABSTRACT There has been remarkable progress in our understanding of immunology in the last few decades. Nevertheless, only a very small number of new drugs have made it from the bench to the bedside. Apart from the enormous success of anti-TNF antibodies in the treatment of rheumatoid arthritis and other inflammatory conditions, few other drugs have demonstrated significant efficacy in the clinic. In several cases, clinical failures have followed successes at the bench, which leads one to question the value of in vitro screening assays and animal models of disease as reliable predictors of clinical efficacy. Here I attempt to provide a high level overview of the drug development process, with particular emphasis on some of the reasons behind the difficulties in the identification and validation of new targets, the high attrition rate of new drug candidates, and the true value of animal models in early stages of drug development in Rheumatology. This article is protected by copyright. All rights reserved. © 2015, American College of Rheumatology.
Entry of blood-borne pathogens into the spleen elicits a series of changes in cellular architecture that culminates in the systemic release of protective antibodies. Despite an abundance of work that has characterized these processes, the... more
Entry of blood-borne pathogens into the spleen elicits a series of changes in cellular architecture that culminates in the systemic release of protective antibodies. Despite an abundance of work that has characterized these processes, the regulatory mechanisms that coordinate cell trafficking and antibody production are still poorly understood. Here, marginal zone (MZ) B cells responding to streptococcus in the blood were observed to migrate along splenic nerves, arriving at the red pulp venous sinuses where they become antibody-secreting cells. Electrical stimulation of the vagus nerve, which in turn regulates the splenic nerve, arrested B-cell migration and decreased antibody secretion. Thus, neural circuits regulate the first wave of antibody production following B-cell exposure to blood-borne antigen.
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CD13/aminopeptidase N is a transmembrane peptidase that is induced in the vasculature of solid tumors and is a potent angiogenic regulator. Here, we demonstrate that CD13 controls endothelial cell invasion in response to the serum peptide... more
CD13/aminopeptidase N is a transmembrane peptidase that is induced in the vasculature of solid tumors and is a potent angiogenic regulator. Here, we demonstrate that CD13 controls endothelial cell invasion in response to the serum peptide bradykinin by facilitating signal transduction at the level of the plasma membrane. Inhibition of CD13 abrogates bradykinin B2 receptor internalization, leading to the attenuation of downstream events such as bradykinin-induced activation of Cdc42 and filopodia formation, and thus affects endothelial cell motility. Investigation into mechanisms underlying this block led us to focus on B2R internalization via membrane-dependent mechanisms. Membrane disruption by depletion of cholesterol or trypsinization halts B2R internalization, invasion, and filopodia formation, which can be recovered with addition of cholesterol. However, this functional recovery is severely impaired in the presence of CD13 antagonists, and the distribution of membrane proteins ...
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Bruton&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;a... more
Bruton&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s tyrosine kinase (BTK) plays a critical role in B cell development and function. We recently described a selective BTK inhibitor, RN486, that blocks B cell receptor (BCR) and Fcγ receptor signaling and is efficacious in animal models of arthritis. The aim of this study was to examine the potential efficacy of BTK in systemic lupus erythematosus (SLE), using an NZB × NZW mouse model of spontaneous SLE. Mice received RN486 or its vehicle (administered in chow) at a final concentration of 30 mg/kg for 8 weeks, starting at 32 weeks of age. The administration of RN486 completely stopped disease progression, as determined by histologic and functional analyses of glomerular nephritis. The efficacy was associated with striking inhibition of B cell activation, as demonstrated by a significant reduction in CD69 expression in response to BCR crosslinking. RN486 markedly reduced the secretion of IgG anti-double-stranded DNA (anti-dsDNA) secretion, as determined by enzyme-linked immunosorbent and enzyme-linked immunospot assays. Flow cytometric analysis demonstrated depletion of CD138(high) B220(low) plasma cells in the spleen. RN486 inhibited secretion of IgG anti-dsDNA but not IgM anti-dsDNA, suggesting that pharmacologic blockade of BTK resembles the reported transgenic expression of low levels of endogenous BTK in B cells. In addition, RN486 may also impact the effector function of autoantibodies, as evidenced by a significant reduction in immune complex-mediated activation of human monocytes in vitro and down-regulation of the expression of macrophage-related and interferon-inducible genes in both the kidneys and spleens of treated mice. Collectively, our data suggest that BTK inhibitors may simultaneously target autoantibody-producing and effector cells in SLE, thus constituting a promising therapeutic alternative for this disease.
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Introduction Les adolescents atteints de DA moderee a severe font etat d’une deterioration de leur qualite de vie principalement liee au prurit et aux troubles du sommeil. Le dupilumab (DPL) est approuve aux Etats-Unis pour les patients... more
Introduction Les adolescents atteints de DA moderee a severe font etat d’une deterioration de leur qualite de vie principalement liee au prurit et aux troubles du sommeil. Le dupilumab (DPL) est approuve aux Etats-Unis pour les patients âges de 12 ans et plus atteints de DA moderee a severe insuffisamment controlee par des traitements topiques soumis a prescription ou chez qui ces traitements sont deconseilles ; au Japon pour les patients adultes atteints de DA insuffisamment controlee par les traitements existants et en Europe pour les patients âges de 18 ans et plus, atteints de DA moderee a severe qui necessite un traitement systemique. Nous analysons l’effet du DPL vs placebo (PBO) sur trois mesures du sommeil chez des adolescents atteints de DA modere a severe recrutes dans une etude de phase 3 randomisee, en double aveugle, controlee par PBO ( NCT03054428 ). Materiel et methodes Les patients (≥ 12 a Resultats Deux cent cinquante et un patients etaient randomises. Les donnees ...
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Abstract: Aminopeptidase N (E.C. 3.4.11.2) is a membrane-bound metalloproteinase expressed in many tissues. Although its cytoplasmic portion has only eight amino acids, cross-linking of CD13 by monoclonal antibodies (mAb) has been shown... more
Abstract: Aminopeptidase N (E.C. 3.4.11.2) is a membrane-bound metalloproteinase expressed in many tissues. Although its cytoplasmic portion has only eight amino acids, cross-linking of CD13 by monoclonal antibodies (mAb) has been shown to trigger intracellular signaling. A functional associ-ation between CD13 and receptors for immuno-globulin G (FcRs) has been proposed. In this work, we evaluated possible functional interactions between CD13 and FcRs in human peripheral blood monocytes and in U-937 promonocytic cells. Our results show that during FcR-mediated phagocytosis, CD13 redistributes to the phagocytic cup and is internalized into the phagosomes. More-over, modified erythrocytes that interact with the monocytic cell membrane through FcRI and CD13 are ingested simultaneously, more efficiently than those that interact through the FcRI only. Also, co-cross-linking of CD13 with FcRI by spe-cific mAbs increases the level and duration of Syk phosphorylation induced by FcRI cross-l...
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Leukocyte membrane receptors for the Fc portion of Igs (FcRs) link antigen recognition by antibodies to effector functions involved in immune phenomena, from pathogen elimination to autoimmunity. Moreover, they also signal for the... more
Leukocyte membrane receptors for the Fc portion of Igs (FcRs) link antigen recognition by antibodies to effector functions involved in immune phenomena, from pathogen elimination to autoimmunity. Moreover, they also signal for the synthesis and secretion of cytokines and chemokines, thus having a role in immune homeostasis. Even though the structural and functional similarities between FcRs and the clonotypic antigen receptors of lymphocytes (the T-cell receptor and B-cell receptor) are well established, participation of regulatory membrane molecules in leukocyte activation by FcRs has rarely been considered. Here, we summarize evidence demonstrating that FcR-mediated signaling could be modulated by other membrane molecules (signal regulators), and propose that comprehension of this phenomenon is essential for understanding the functions of FcRs, knowledge of which could then be used for therapeutic interventions.