Rheumatology Commons^™

Dose-Escalation Of Human Anti-Interferon-Alpha Receptor Monoclonal Antibody Medi-546 In Subjects With Systemic Sclerosis: A Phase 1, Multicenter, Open Label Study, A. Goldberg, T. Geppert, E. Schiopu, T. Frech, V. Hsu, R. W. Simms, S. L. Peng, Y. H. Yao, N. Elgeioushi, S. Yoo, +2 Additional Authors

Journal Articles

Introduction: Type I interferons (IFNs) are implicated in the pathogenesis of systemic sclerosis (SSc). MEDI-546 is an investigational human monoclonal antibody directed against the type I IFN receptor. This Phase 1 study evaluated the safety/tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of single and multiple intravenous doses of MEDI-546 in adults with SSc. Methods: Subjects (>= 18 years) with SSc were enrolled in an open-label, dose-escalation study to receive single (0.1, 0.3, 1.0, 3.0, 10.0, or 20.0 mg/kg), or 4 weekly intravenous doses (0.3, 1.0, or 5.0 mg/kg/week) of MEDI-546. Subjects were followed for 12 weeks. Safety assessments included …

Cell-Bound Complement Activation Products In Systemic Lupus Erythematosus: Comparison With Anti-Double-Stranded Dna And Standard Complement Measurements, C. Putterman, R. Furie, R. Ramsey-Goldman, A. Askanase, J. Buyon, K. Kalunian, W. W. Chatham, E. Massarotti, K. Kirou, T. Dervieux, +10 Additional Authors

Journal Articles

OBJECTIVE: To compare the performance characteristics of cell-bound complement (C4d) activation products (CBCAPS) on erythrocyte (EC4d) and B cells (BC4d) with antibodies to double-stranded DNA (anti-dsDNA) and complement C3 and C4 in systemic lupus erythematosus (SLE). METHODS: The study enrolled 794 subjects consisting of 304 SLE and a control group consisting of 285 patients with other rheumatic diseases and 205 normal individuals. Anti-dsDNA and other autoantibodies were measured using solid-phase immunoassays while EC4d and BC4d were determined using flow cytometry. Complement proteins were determined using immunoturbidimetry. Disease activity in SLE was determined using a non-serological Systemic Lupus Erythematosus Disease Activity …

Platelets Are Required For Enhanced Activation Of The Endothelium And Fibrinogen In A Mouse Thrombosis Model Of Aps, V. Proulle, R. A. Furie, G. Merrill-Skoloff, B. C. Furie, B. Furie

Journal Articles

Antiphospholipid syndrome (APS) is defined by thrombosis, fetal loss, and the presence of antiphospholipid antibodies, including anti-beta 2-glycoprotein-1 autoantibodies (anti-beta 2GP1) that have a direct role in the pathogenesis of thrombosis in vivo. The cellular targets of the anti-beta 2GP1autoantibody/beta 2GP1complex in vivo were studied using a laser-induced thrombosis model of APS in a live mouse and human anti-beta 2GP1 autoantibodies affinity-purified from APS patients. Cell binding of fluorescently labeled beta 2GP1 and anti-beta 2GP1 autoantibodies revealed their colocalization on the platelet thrombus but not the endothelium. Anti-beta 2GP1 autoantibodies enhanced platelet activation, monitored by calcium mobilization, and endothelial activation, …

Randomized, Double-Blind, Placebo-Controlled Trial Of The Efficacy And Safety Of Rilonacept In The Treatment Of Systemic Juvenile Idiopathic Arthritis, N. T. Ilowite, K. Prather, Y. Lokhnygina, L. E. Schanberg, M. Elder, D. Milojevic, J. W. Verbsky, S. J. Spalding, B. S. Gottlieb, C. I. Sandborg, +12 Additional Authors

Journal Articles

OBJECTIVE: To assess the efficacy and safety of rilonacept, an interleukin-1 inhibitor, in a randomized, double-blind, placebo-controlled trial. METHODS: An initial 4-week double-blind placebo phase was incorporated into a 24-week randomized multicenter design, followed by an open-label phase. Seventy-one children who had active arthritis in >/=2 joints were randomized (1:1) to the 2 arms of the study. Patients in the rilonacept arm received rilonacept (loading dose 4.4 mg/kg followed by 2.2 mg/kg weekly, subcutaneously) beginning on day 0. Patients in the placebo arm received placebo for 4 weeks followed by a loading dose of rilonacept at week 4 followed by …

Serum C-X-C Motif Chemokine 13 Is Elevated In Early And Established Rheumatoid Arthritis And Correlates With Rheumatoid Factor Levels, Jonathan D. Jones, B. Jonell Hamilton, Gregory J. Challener, Artur J. De Brum-Fernandes

Dartmouth Scholarship

We hypothesized that serum levels of C-X-C motif chemokine 13 (CXCL13), a B-cell chemokine, would delineate a subset of rheumatoid arthritis (RA) patients characterized by increased humoral immunity.

Sympathetic Nerve Modulation Of Joint Pathology In Adjuvant-Induced Arthritis, Carlo Anthony Wood

Loma Linda University Electronic Theses, Dissertations & Projects

Background: There is increasing data suggesting a net increase in sympathetic tone plays an important role in rheumatoid arthritis. Several studies have reported altered distribution and density of autonomic nerves in patients with rheumatoid arthritis and animal models for the disease. This provides anatomical evidence that supports a neurally-mediated drive in inflammation and joint destruction. Methods: Adult rats were injected with complete Freund’s adjuvant. At 12 days post immunization, animals were randomly placed into a drug treatment group (SH1293, which interacts with - and ß2-ARs), an adjuvant arthritic group, or a control group. These animals were sacrificed at 14, 21, …

A Prospective Observational Study Of Mycophenolate Mofetil Treatment In Progressive Diffuse Cutaneous Systemic Sclerosis Of Recent Onset., Fabian A. Mendoza, Md, Sarah J. Nagle, Jason B. Lee, Md, Sergio A. Jimenez

Jefferson Institute of Molecular Medicine Papers and Presentations

OBJECTIVE: A prospective observational study of mycophenolate mofetil (MMF) treatment in patients with diffuse progressive cutaneous systemic sclerosis (SSc) of recent onset.

METHODS: Twenty-five previously untreated consecutive patients with recent-onset (< 24 mo) diffuse progressive cutaneous SSc received MMF as the only disease-modifying therapy. Modified Rodnan skin score (mRSS) and affected body surface area (BSA) were compared from initiation of MMF to study end. Pulmonary function tests performed at the same institution before therapy and at study end were available in 15 patients. Histopathology and real-time PCR assessment of fibrosis-related gene expression were performed before and after treatment in skin biopsies from 3 patients.

RESULTS: At 18.2 ± 8.73 months of MMF therapy (median 2000 mg/day) the mRSS decreased from 24.56 ± 8.62 to 14.52 ± 10.9 (p = 0.0004) and the affected BSA from 36% ± 16% to 14% ± 13.3% (p = 0.00001). Pulmonary function tests remained stable from initiation of MMF to the end of the study. Skin histopathology showed a remarkable reduction in accumulation of fibrotic tissue. Real-time PCR …

Ginger And Osteoarthritis, Tessa Therkleson

Research outputs 2012

Ginger has been used for 1000s of years as a food and medicine; it is likely one of the most ancient remedies valued by humans. Ancient Indian and Chinese cultures reportedly used ginger for a wide variety of conditions and modern day research has found it effective as an anti-emetic and anti-inflammatory agent, when taken internally. Random controlled trials using ginger extract have been found effective in relieving symptoms of osteoarthritis. Osteoarthritis is the primary cause of musculoskeletal pain and disability in Western cultures. Current management is primarily through the use of anti-inflammatory and analgesic medication, with cortisone injections and …

Is Etanercept A Safe And Effective Treatment For Ankylosing Spondylitis?, Robyn M. Albert

PCOM Physician Assistant Studies Student Scholarship

Objective: The objective of this selective EBM review is to determine whether or not etanercept is a safe and effective treatment for ankylosing spondylitis (AS).

Study Design: Review of three English language randomized control trials published in 2007, 2008, and 2010.

Data Sources: Two double-blind placebo-controlled randomized controlled trials and one placebo-controlled randomized control trial comparing etanercept to placebo were found using PubMed.

Outcomes Measured: Work instability was measured through the Ankylosing Spondylitis Work Instability Scale (AS-WIS) based on scores of 1-20. Quality of life was measured through the EuroQOL-5D (EQ-5D), which assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. …

Lymphotoxin-Beta Receptor Blockade Reduces Cxcl13 In Lacrimal Glands And Improves Corneal Integrity In The Nod Model Of Sjögren's Syndrome, Roy A. Fava, Susan M. Kennedy, Sheryl G. Wood, Anne I. Bolstad, Jadwiga Bienkowska, Adrian Papandile, John A. Kelly

Dartmouth Scholarship

In Sjögren's syndrome, keratoconjunctivitis sicca (dry eye) is associated with infiltration of lacrimal glands by leukocytes and consequent losses of tear-fluid production and the integrity of the ocular surface. We investigated the effect of blockade of the lymphotoxin-beta receptor (LTBR) pathway on lacrimal-gland pathology in the NOD mouse model of Sjögren's syndrome.

Protein Kinase Cδ And C-Abl Kinase Are Required For Transforming Growth Factor Β Induction Of Endothelial-Mesenchymal Transition In Vitro., Zhaodong Li, Sergio A. Jimenez

Department of Medicine Faculty Papers

OBJECTIVE: The origin of the mesenchymal cells responsible for the intimal fibrosis in systemic sclerosis (SSc) has not been fully identified. The present study was undertaken to investigate whether subendothelial mesenchymal cells may emerge through transdifferentiation of endothelial cells (ECs) into myofibroblasts via endothelial-mesenchymal transition (EndoMT) in vitro and to explore the signaling pathways involved in this process.

METHODS: Primary mouse pulmonary ECs isolated by immunomagnetic methods with sequential anti-CD34 and anti-CD102 antibody selection were cultured in monolayers. Cell morphology and diacetylated low-density lipoprotein uptake assays confirmed their EC characteristics. The induction of EndoMT was assessed by determination of α-smooth …

Is Actemra (Tocilizumab) In Combination With Methotrexate An Effective Treatment For Rheumatoid Arthritis In Patients Who Had An Inadequate Response To Methotrexate Alone?, Jennifer Nagle

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this systematic review is to determine whether or not Actemra (tocilizumab) in combination with methotrexate is an effective treatment for rheumatoid arthritis in patients who had an inadequate response to methotrexate alone. Previous studies have shown other biologic agents and disease modifying antirheumatic drugs (DMARDs) to have some efficacy in treating rheumatoid arthritis. However, tocilizumab is a newly approved FDA drug and therefore, its efficacy in treating RA has yet to be determined.

Role Of Growth Factors In The Pathogenesis Of Tissue Fibrosis In Systemic Sclerosis., Sergio A. Jimenez, Susan V. Castro, Sonsoles Piera-Velazquez

Department of Medicine Faculty Papers

The most severe clinical and pathologic manifestations of systemic sclerosis (SSc) are the result of a fibrotic process characterized by the excessive and often progressive deposition of collagen and other connective tissue macromolecules in skin and numerous internal organs. The mechanisms involved in the initiation and progression of the remarkable fibrotic process in SSc remain largely unknown. Extensive recent studies have indicated that a variety of polypeptide growth factors play a crucial role in this process. The most commonly implicated growth factors include transforming growth factor beta (TGF-β), connective tissue growth factor (CTGF), platelet derived growth factor (PDGF), and vascular …

Most Common Single-Nucleotide Polymorphisms Associated With Rheumatoid Arthritis In Persons Of European Ancestry Confer Risk Of Rheumatoid Arthritis In African Americans, Laura B. Hughes, Richard J. Reynolds, Elizabeth E. Brown, James M. Kelley, Brian Thomson, Doyt L. Conn, Beth L. Jonas, Andrew O. Westfall, Miguel A. Padilla, Leigh F. Callahan

Psychology Faculty Publications

Objective. Large-scale genetic association studies have identified >20 rheumatoid arthritis (RA) risk alleles among individuals of European ancestry. The influence of these risk alleles has not been comprehensively studied in African Americans. We therefore sought to examine whether these validated RA risk alleles are associated with RA risk in an African American population.

Methods. Twenty-seven candidate single-nucleotide polymorphisms (SNPs) were genotyped in 556 autoantibody-positive African Americans with RA and 791 healthy African American control subjects. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for each SNP were compared with previously published ORs for RA patients of European ancestry. We …

A Functional Difficulty And Functional Pain Instrument For Hip And Knee Osteoarthritis, Alan M. Jette, Christine M. Mcdonough, Pengsheng Ni, Stephen M. Haley

Dartmouth Scholarship

The objectives of this study were to develop a functional outcome instrument for hip and knee osteoarthritis research (OA-FUNCTION-CAT) using item response theory (IRT) and computer adaptive test (CAT) methods and to assess its psychometric performance compared to the current standard in the field.

Development And Validation Of An Index Of Musculoskeletal Functional Limitations, Jeffrey N. Katz, Elizabeth A. Wright, John A. Baron, Elena Losina

Dartmouth Scholarship

While musculoskeletal problems are leading sources of disability, there has been little research on measuring the number of functionally limiting musculoskeletal problems for use as predictor of outcome in studies of chronic disease. This paper reports on the development and preliminary validation of a self administered musculoskeletal functional limitations index.

Retinoid X Receptor And Peroxisome Proliferator-Activated Receptor-Gamma Agonists Cooperate To Inhibit Matrix Metalloproteinase Gene Expression, Peter S. Burrage, Adam C. Schmucker, Yanqing Ren, Michael B. Sporn, Constance E. Brinckerhoff

Dartmouth Scholarship

We recently described the ability of retinoid X receptor (RXR) ligand LG100268 (LG268) to inhibit interleukin-1-beta (IL-1-β)-driven matrix metalloproteinase-1 (MMP-1) and MMP-13 gene expression in SW-1353 chondrosarcoma cells. Other investigators have demonstrated similar effects in chondrocytes treated with rosiglitazone, a ligand for peroxisome proliferator-activated receptor-gamma (PPARγ), for which RXR is an obligate dimerization partner. The goals of this study were to evaluate the inhibition of IL-1--induced expression of MMP-1andMMP-13 by combinatorial treatment with RXR and PPAR  ligands and to investigate the molecular mechanisms of this inhibition.

Decreased Expression Of Caveolin 1 In Patients With Systemic Sclerosis: Crucial Role In The Pathogenesis Of Tissue Fibrosis., Francesco Del Galdo, Federica Sotgia, Cecilia J. De Almeida, Jean-Francois Jasmin, Megan Musick, Michael P. Lisanti, Sergio A. Jimenez

Department of Medicine Faculty Papers

OBJECTIVE: Recent studies have implicated caveolin 1 in the regulation of transforming growth factor beta (TGFbeta) downstream signaling. Given the crucial role of TGFbeta in the pathogenesis of systemic sclerosis (SSc), we sought to determine whether caveolin 1 is also involved in the pathogenesis of tissue fibrosis in SSc. We analyzed the expression of CAV1 in affected SSc tissues, studied the effects of lack of expression of CAV1 in vitro and in vivo, and analyzed the effects of restoration of caveolin 1 function on the fibrotic phenotype of SSc fibroblasts in vitro.

METHODS: CAV1 expression in tissues was analyzed by …

Molecular Ablation Of Transforming Growth Factor Beta Signaling Pathways By Tyrosine Kinase Inhibition: The Coming Of A Promising New Era In The Treatment Of Tissue Fibrosis., Joel Rosenbloom, Sergio A. Jimenez

Department of Medicine Faculty Papers

No abstract provided.

Molecular Ablation Of Tgf-Beta Signaling Pathways By Tyrosine Kinase Inhibition: The Coming Of A Promising New Era In The Treatment Of Tissue Fibrosis, Joel Rosenbloom, Sergio A. Jimenez

Selected Works of Sergio Jiménez, MD, MACR

No abstract provided.

Modulation Of Tgf-Beta Signaling By Proinflammatory Cytokines In Articular Chondrocytes., Jorge A. Roman-Blas, David G. Stokes, Sergio A. Jimenez

Department of Medicine Faculty Papers

OBJECTIVE: The normal structure and function of articular cartilage are the result of a precisely balanced interaction between anabolic and catabolic processes. The transforming growth factor-beta (TGF-beta) family of growth factors generally exerts an anabolic or repair response; in contrast, proinflammatory cytokines such as interleukin 1 beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) exert a strong catabolic effect. Recent evidence has shown that IL-1beta, and TNF-alpha, and the TGF-beta signaling pathways share an antagonistic relationship. The aim of this study was to determine whether the modulation of the response of articular chondrocytes to TGF-beta by IL-1beta or TNF-alpha signaling pathways …

The Role Of Allograft Inflammatory Factor 1 In Systemic Sclerosis, Francesco Del Galdo, Carol M. Artlett, Sergio A. Jimenez

Selected Works of Sergio Jiménez, MD, MACR

ABSTRACT

Purpose: To review studies which support the hypothesis that allograft inflammatory factor-1 (AIF-1), a protein initially identified in chronically rejected cardiac allografts, may be involved in the pathogenesis of the progressive fibroproliferative vasculopathy which is a hallmark of systemic sclerosis (SSc).

Recent findings: Recent findings demonstrated elevated AIF-1 expression both in SSc affected tissues and peripheral blood mononuclear cells. A detailed immunohistopathologic study examined the tissue and cellular localization of the protein in affected SSc tissues and demonstrated its expression in the endothelium of dermal and pulmonary vessels, in the pulmonary parenchyma, and in relevant inflammatory cells including T …

Description Of Twelve Cases Of Nephrogenic Fibrosing Dermopathy And Review Of The Literature, Fabian A. Mendoza, Carol M. Artlett, Nora Sandorfi, Kevin Latinis, Sonoles Piera-Velazquez, Sergio A. Jimenez

Selected Works of Sergio Jiménez, MD, MACR

ABSTRACT

Objectives: To review the clinical and laboratory features of twelve cases of nephrogenic fibrosing dermopathy (NFD) studied at our institution and of 70 previously described cases in the literature.

Methods: Clinical evaluation and laboratory studies of twelve patients with NFD associated with chronic hemodialysis or peritoneal dialysis for end-stage renal disease and a review of 23 previous publications describing 70 patients with this disease.

Results: Eleven patients undergoing chronic hemodialysis and one patient undergoing chronic peritoneal dialysis for end-stage renal failure developed a severe and progressive cutaneous fibrotic process with woody induration of legs, thighs, hands and forearms, and …

Statins And The Vasculopathy Of Systemic Sclerosis: Potential Therapeutic Agents?, Chris T. Derk, Sergio A. Jimenez

Department of Medicine Faculty Papers

It has been postulated that endothelial cell injury is the initiating event in the pathogenesis of systemic sclerosis, causing attraction, attachment, migration and infiltration of activated T-cells and subsequent production of cytokines and growth factors. As a result of the action of these cytokines and growth factors, chemoattraction of fibroblasts into the vessel wall and transdifferentiation of resident fibroblasts and smooth muscle cells into myofibroblasts occur leading to fibrosis and exaggerated collagen deposition in the vessel wall. To date, the therapeutic options for the vasculopathy of systemic sclerosis have been limited to drugs that cause vasodilation and inhibit platelet aggregation …

Inhibition Of Collagen Gene Expression In Systemic Sclerosis Dermal Fibroblasts By Mithramycin, Nora Sandorfi, Natalia Louneva, Elena Hitraya, Gyorgy Hajnoczky, Biagio Saitta, Sergio A. Jimenez

Selected Works of Sergio Jiménez, MD, MACR

ABSTRACT

Introduction. The antitumor antibiotic mithramycin has also been shown to be a potent and effective inhibitor of fibrosis following glaucoma surgery. This DNA interacting drug displays high affinity binding to GC rich sequences in DNA, including those present in the promoter of the gene encoding the Α1 chain of type I collagen (COL1A1).

Objective. To evaluate the effects of mithramycin on the production of type I collagen in fibroblast cultures from patients with systemic sclerosis. Methods. Confluent cultures of dermal fibroblasts from patients with recent onset of the diffuse form of systemic sclerosis were treated with varius concentrations of …

Patient Characteristics And Clinical Management Of Patients With Shoulder Pain In U.S. Primary Care Settings: Secondary Data Analysis Of The National Ambulatory Medical Care Survey, James L. Wofford, Richard J. Mansfield, Raquel S. Watkins

Dartmouth Scholarship

Although shoulder pain is a commonly encountered problem in primary care, there are few studies examining its presenting characteristics and clinical management in this setting. We performed secondary data analysis of 692 office visits for shoulder pain collected through the National Ambulatory Medical Care Survey (Survey years 1993–2000). Information on demographic characteristics, history and place of injury, and clinical management (physician order of imaging, physiotherapy, and steroid intraarticular injection) were examined.

B-Myb Acts As A Repressor Of Human Col1a1 Collagen Gene Expression By Interacting With Sp1 And Cbf Factors In Scleroderma Fibroblasts, Lucia Cicchillitti, Sergio A. Jimenez, Arturo Sala, Biaggio Saitta

Selected Works of Sergio Jiménez, MD, MACR

We investigated the role of B-Myb, a cell-cycle-regulated transcription factor, in the expression of the alpha1 (I) pro-collagen gene (COL1A1) in scleroderma fibroblasts. Scleroderma or SSc (systemic sclerosis) is a fibrotic disease characterized by excessive production of extracellular matrix components, especially type I collagen. Northern-blot analysis showed an inverse relationship between COL1A1 mRNA expression and that of B-Myb during exponential cell growth and during quiescence in human SSc fibroblasts. Overexpression of B-Myb in SSc fibroblasts was correlated with decreased COL1A1 mRNA expression. Transient transfections localized the down-regulatory effect of B-Myb to a region containing the proximal 174 bp of the …

Transcriptional Inhibition Of Type I Collagen Gene Expression In Scleroderma Fibroblasts By The Antineoplastic Drug Ecteinascidin 743., Natalia Louneva, Biagio Saitta, David J Herrick, Sergio A. Jimenez

Department of Medicine Faculty Papers

We previously showed that COL1A1 expression is up-regulated at the transcriptional level in systemic sclerosis (SSc) fibroblasts and that the CCAAT-binding factor (CBF) is involved in this increased expression. Ecteinascidin 743 (ET-743) is a chemotherapeutic agent that binds with sequence specificity to the minor groove of DNA and inhibits CBF-mediated transcriptional activation of numerous genes. Therefore, we examined the effects of ET-743 on the increased COL1A1 expression in SSc fibroblasts. The drug caused a potent and dose-dependent inhibition of type I collagen biosynthesis, which reached 70-90% at 700 pM without affecting cell viability. The same drug concentration caused 60-80% reduction …

Are Antinuclear Antibodies And Rheumatiod Factor Positivity More Prevalent In Apparently Healthy Smokers Compared To Ex-Smokers And Never Smokers?, Susan Nyanzi

Loma Linda University Electronic Theses, Dissertations & Projects

Context: There is now consistent evidence from population and epidemiological studies that cigarette smoking is an independent risk factor for Rheumatoid Arthritis (RA), via Rheumatoid Factor (RF) production (Deighton, 1997; Saag, 1997; Silman, 1996; Uhlig, 1999; Wolfe, 2000). Antinuclear Antibodies (ANA) are another collection of autoantibodies that are being associated with smoking and RA initiation. To our knowledge, no studies have examined the effects of smoking on both ANA and RF simultaneously in healthy subjects.

Objectives: To determine whether cigarette smoking has an effect on ANA and RF positivity in healthy blood donors.

Design, Setting, Participants: This was a cross-sectional, …

Systemic Sclerosis: Current Views Of Its Pathogenesis., Chris T. Derk, Sergio A. Jimenez

Department of Medicine Faculty Papers

Systemic sclerosis (SSc) is an autoimmune disorder of unknown etiology characterized by severe and often progressive cutaneous and visceral fibrosis, pronounced alterations in the microvasculature, and numerous cellular and humoral immune abnormalities. Clinically, SSc is very heterogeneous, encompassing a spectrum ranging from mild limited forms of skin sclerosis with minimal internal organ involvement to severe skin and multiple internal organ fibrosis. Mortality and morbidity in SSc are very high and are directly related to the extent of the fibrotic and microvascular alterations. A better understanding of the pathogenesis of this incurable disorder will help to better target and design effective …