Publications by authors named "Gary S Firestein"

183 Publications

Tender and swollen joint counts are poorly associated with disability in chikungunya arthritis compared to rheumatoid arthritis.

Sci Rep 2021 Sep 17;11(1):18578. Epub 2021 Sep 17.

School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.

Chronic rheumatological manifestations similar to those of rheumatoid arthritis (RA) are described after chikungunya virus infection. We aimed to compare the relevance of joint counts and symptoms to clinical outcomes in RA and chronic chikungunya disease. Forty patients with chronic chikungunya arthralgia and 40 patients with RA were enrolled in a cross-sectional study. The association of tenderness and swelling, clinically assessed in 28 joints, and patient evaluations of pain and musculoskeletal stiffness with modified Health Assessment Questionnaire (HAQ) and quality of life (QoL) assessments were investigated. Tender and swollen joint counts, pain and stiffness scores were all associated with the HAQ disability index in RA (all r > 0.55, p ≤ 0.0002), but only stiffness was significantly associated with disability in chikungunya (r = 0.38, p = 0.02). Joint counts, pain and stiffness were also associated with most QoL domains in RA patients. In contrast, in chikungunya disease, tender joint counts were associated only with one QoL domain and swollen joints for none, while pain and stiffness were associated with several domains. Our results confirm the relevance of joint counts in RA, but suggest that in chronic chikungunya disease, joint counts have more limited value. Stiffness and pain score may be more important to quantify chikungunya arthritis impact.
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http://dx.doi.org/10.1038/s41598-021-98164-9DOI Listing
September 2021

Sleep Disturbances are a Significant Predictor of Chikungunya Arthritis Flare Severity.

J Cell Immunol 2021 ;3(3):191-197

School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.

Objective: The primary objective of this research was to explore the link between sleep and flare pain associated with chikungunya virus (CHIKV) infection. The secondary objective was to investigate if cytokines and T regulatory (Treg) cells have an influence on this relationship.

Methods: A cross-sectional study was performed using data collected in Barranquilla, Colombia, which enrolled patients with and without chronic arthritis with a history of chikungunya infection. Flare severity was measured by a version of the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) flare questionnaire adapted for CHIKV arthritis, including metrics for pain, difficulty with physical activity, fatigue, stiffness and difficulty maintaining social activities due to arthritis that contribute to flare severity. In addition, four sleep disturbance items, five inflammatory cytokine levels, four anti-inflammatory cytokine levels, and six Treg levels were measured. Then, multivariable linear regression models were used to test the direct and indirect effects of flare-pain on sleep disturbance, and to determine whether this relationship was mediated by cytokines or Tregs. Finally, the SAS CALIS procedure was used to test path models showing possible causal effects with mediators and confounds.

Results: The analysis showed that sleep disturbance is positively correlated with CHIKV arthritis flare pain, and that it is a significant predictor of flare severity after adjusting for demographic variables, cytokine, and T cell levels. Further, neither T cells nor cytokines mediate the pain/sleep relationship in CHIKV arthritis.

Conclusion: There is a strong association between sleep disturbance and arthritis flare pain and severity; however, this relationship is not mediated by cytokines or T cells. Since this study is unable to determine causation, further research is needed to determine the mechanism underlying the relationship between sleep disturbances and CHIKV arthritis flares.
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http://dx.doi.org/10.33696/immunology.3.098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315573PMC
January 2021

Genetic regulation of nonsense-mediated decay underlies association with risk of severe COVID-19.

medRxiv 2021 Jul 13. Epub 2021 Jul 13.

Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76 variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay of . We suggest that genetically-regulated loss of expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of the risk haplotypes.
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http://dx.doi.org/10.1101/2021.07.09.21260221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288155PMC
July 2021

Building biorepositories in the midst of a pandemic.

J Clin Transl Sci 2021 Feb 5;5(1):e92. Epub 2021 Feb 5.

Clinical & Translational Science Center, Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.

Biospecimen repositories play a vital role in enabling investigation of biologic mechanisms, identification of disease-related biomarkers, advances in diagnostic assays, recognition of microbial evolution, and characterization of new therapeutic targets for intervention. They rely on the complex integration of scientific need, regulatory oversight, quality control in collection, processing and tracking, and linkage to robust phenotype information. The COVID-19 pandemic amplified many of these considerations and illuminated new challenges, all while academic health centers were trying to adapt to unprecedented clinical demands and heightened research constraints not witnessed in over 100 years. The outbreak demanded rapid understanding of SARS-CoV-2 to develop diagnostics and therapeutics, prompting the immediate need for access to high quality, well-characterized COVID-19-associated biospecimens. We surveyed 60 Clinical and Translational Science Award (CTSA) hubs to better understand the strategies and barriers encountered in biobanking before and in response to the COVID-19 pandemic. Feedback revealed a major shift in biorepository model, specimen-acquisition and consent process from a combination of investigator-initiated and institutional protocols to an enterprise-serving strategy. CTSA hubs were well equipped to leverage established capacities and expertise to quickly respond to the scientific needs of this crisis through support of institutional approaches in biorepository management.
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http://dx.doi.org/10.1017/cts.2021.6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134891PMC
February 2021

Lasp1 regulates adherens junction dynamics and fibroblast transformation in destructive arthritis.

Nat Commun 2021 06 15;12(1):3624. Epub 2021 Jun 15.

Max Planck Institute for Molecular Genetics, Otto-Warburg-Laboratories, Epigenomics, Ihnestraße 63-73, Berlin, Germany.

The LIM and SH3 domain protein 1 (Lasp1) was originally cloned from metastatic breast cancer and characterised as an adaptor molecule associated with tumourigenesis and cancer cell invasion. However, the regulation of Lasp1 and its function in the aggressive transformation of cells is unclear. Here we use integrative epigenomic profiling of invasive fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and from mouse models of the disease, to identify Lasp1 as an epigenomically co-modified region in chronic inflammatory arthritis and a functionally important binding partner of the Cadherin-11/β-Catenin complex in zipper-like cell-to-cell contacts. In vitro, loss or blocking of Lasp1 alters pathological tissue formation, migratory behaviour and platelet-derived growth factor response of arthritic FLS. In arthritic human TNF transgenic mice, deletion of Lasp1 reduces arthritic joint destruction. Therefore, we show a function of Lasp1 in cellular junction formation and inflammatory tissue remodelling and identify Lasp1 as a potential target for treating inflammatory joint disorders associated with aggressive cellular transformation.
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http://dx.doi.org/10.1038/s41467-021-23706-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206096PMC
June 2021

Development of a Coronavirus Disease 2019 (COVID-19) Application Ontology for the Accrual to Clinical Trials (ACT) network.

JAMIA Open 2021 Apr 19;4(2):ooab036. Epub 2021 Apr 19.

Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Clinical data networks that leverage large volumes of data in electronic health records (EHRs) are significant resources for research on coronavirus disease 2019 (COVID-19). Data harmonization is a key challenge in seamless use of multisite EHRs for COVID-19 research. We developed a COVID-19 application ontology in the national Accrual to Clinical Trials (ACT) network that enables harmonization of data elements that are critical to COVID-19 research. The ontology contains over 50 000 concepts in the domains of diagnosis, procedures, medications, and laboratory tests. In particular, it has computational phenotypes to characterize the course of illness and outcomes, derived terms, and harmonized value sets for severe acute respiratory syndrome coronavirus 2 laboratory tests. The ontology was deployed and validated on the ACT COVID-19 network that consists of 9 academic health centers with data on 14.5M patients. This ontology, which is freely available to the entire research community on GitHub at https://github.com/shyamvis/ACT-COVID-Ontology, will be useful for harmonizing EHRs for COVID-19 research beyond the ACT network.
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http://dx.doi.org/10.1093/jamiaopen/ooab036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083220PMC
April 2021

Scale-up of the Accrual to Clinical Trials (ACT) network across the Clinical and Translational Science Award Consortium: a mixed-methods evaluation of the first 18 months.

J Clin Transl Sci 2020 Jun 30;4(6):515-528. Epub 2020 Jun 30.

Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA, USA.

Introduction: The Clinical and Translational Science Award (CTSA) Program is a Consortium of nearly 60 academic medical research centers across the USA and a natural network for evaluating the spread and uptake of translational research innovation across the Consortium.

Methods: Dissemination of the Accrual to Clinical Trials (ACT) Network, a federated clinical informatics data network for population-based cohort discovery, began January 2018 across the Consortium. Diffusion of innovation theory guided dissemination design and evaluation. Mixed-methods assessed the spread and uptake across the Consortium through July 1, 2019 (n = 48 CTSAs). Methods included prospective time activity tracking (Kaplan-Meier curves), and survey and qualitative interviews.

Results: Within 18 months, nearly 80% of CTSAs had joined the data network and two-thirds of CTSAs achieving technical readiness had initiated launch to local clinical investigators. Over 10,000 ACT Network queries are projected for 2019; and by 2020, nearly all CTSAs will have joined the network. Median time-from-technical-readiness-to-local-launch was 154 days (interquartile range: 87-225 days]. Quality improvement processes reduced time-to-launch by 35.2% (64 days, p = 0.0036). Lessons learned include: (1) conceptualize dissemination as two-stage adoption demonstrating value for both CTSA hub service providers and clinical investigators; (2) include institutional trial into dissemination strategies so CTSA hubs can refine internal workflows and gather local user feedback endorsement; (3) embrace designing-for-dissemination during technology development; and (4) sustain adaptive dissemination and customer relationship management to keep CTSA hubs and users engaged.

Conclusions: Scale-up and spread of the ACT Network provides lessons learned for others disseminating innovation across the CTSA Consortium. The Network is primed for embedded implementation research.
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http://dx.doi.org/10.1017/cts.2020.505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057421PMC
June 2020

Persistent Joint Pain Following Arthropod Virus Infections.

Curr Rheumatol Rep 2021 04 13;23(4):26. Epub 2021 Apr 13.

Department of Medicine, George Washington University, 2150 Pennsylvania Ave Suite 5-416, Washington, DC, 20037, USA.

Purpose Of Review: Persistent joint pain is a common manifestation of arthropod-borne viral infections and can cause long-term disability. We review the epidemiology, pathophysiology, diagnosis, and management of arthritogenic alphavirus infection.

Recent Findings: The global re-emergence of alphaviral outbreaks has led to an increase in virus-induced arthralgia and arthritis. Alphaviruses, including Chikungunya, O'nyong'nyong, Sindbis, Barmah Forest, Ross River, and Mayaro viruses, are associated with acute and/or chronic rheumatic symptoms. Identification of Mxra8 as a viral entry receptor in the alphaviral replication pathway creates opportunities for treatment and prevention. Recent evidence suggesting virus does not persist in synovial fluid during chronic chikungunya infection indicates that immunomodulators may be given safely. The etiology of persistent joint pain after alphavirus infection is still poorly understood. New diagnostic tools along and evidence-based treatment could significantly improve morbidity and long-term disability.
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http://dx.doi.org/10.1007/s11926-021-00987-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042844PMC
April 2021

Development of a COVID-19 Application Ontology for the ACT Network.

medRxiv 2021 Apr 14. Epub 2021 Apr 14.

University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Clinical data networks that leverage large volumes of data in electronic health records (EHRs) are significant resources for research on coronavirus disease 2019 (COVID-19). Data harmonization is a key challenge in seamless use of multisite EHRs for COVID-19 research. We developed a COVID-19 application ontology in the national Accrual to Clinical Trials (ACT) network that enables harmonization of data elements that that are critical to COVID-19 research. The ontology contains over 50,000 concepts in the domains of diagnosis, procedures, medications, and laboratory tests. In particular, it has computational phenotypes to characterize the course of illness and outcomes, derived terms, and harmonized value sets for SARS-CoV-2 laboratory tests. The ontology was deployed and validated on the ACT COVID-19 network that consists of nine academic health centers with data on 14.5M patients. This ontology, which is freely available to the entire research community on GitHub at https://github.com/shyamvis/ACT-COVID-Ontology, will be useful for harmonizing EHRs for COVID-19 research beyond the ACT network.
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http://dx.doi.org/10.1101/2021.03.15.21253596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010766PMC
April 2021

IgG Epitopes Processed and Presented by IgG B Cells Induce Suppression by Human Thymic-Derived Regulatory T Cells.

J Immunol 2021 03 12;206(6):1194-1203. Epub 2021 Feb 12.

Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA 92093;

We described a human regulatory T cell (Treg) population activated by IgG B cells presenting peptides of the heavy C region (Fc) via processing of the surface IgG underlying a model for B cell-Treg cooperation in the human immune regulation. Functionally, Treg inhibited the polarization of naive T cells toward a proinflammatory phenotype in both a cognate and a noncognate fashion. Their fine specificities were similar in healthy donors and patients with rheumatoid arthritis, a systemic autoimmune disease. Four immunodominant Fc peptides bound multiple HLA class II alleles and were recognized by most subjects in the two cohorts. The presentation of Fc peptides that stimulate Treg through the processing of IgG by dendritic cells (DC) occurred in myeloid DC classical DC 1 and classical DC 2. Different routes of Ag processing of the IgG impacted Treg expansion in rheumatoid arthritis patients.
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http://dx.doi.org/10.4049/jimmunol.2001009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939040PMC
March 2021

Distinct DNA Methylation Patterns of Rheumatoid Arthritis Peripheral Blood and Synovial Tissue T Cells.

ACR Open Rheumatol 2021 Mar 5;3(3):127-132. Epub 2021 Feb 5.

University of California, San Diego.

Objective: To study epigenetic patterns in T lymphocytes that accumulate in the rheumatoid arthritis (RA) synovium, we characterized DNA methylation of CD3 T cells in peripheral blood and synovial tissue in patients with RA and osteoarthritis (OA).

Methods: Genomic DNA of CD3 T cells was isolated from patients with RA (n = 8) and OA (n = 5) from blood or the synovium at the time of an arthroplasty using antibodies and magnetic beads. Methylation was measured by using the Illumina Infinium MethylationEPIC Kit. Differentially methylated loci (DML) and differentially methylated genes (DMGs) were identified by using Welch's t-test. Principal component analysis, hierarchical clustering, and pathway analysis were used to determine relationships among groups.

Results: When we compared DNA methylation of CD3 T cells between peripheral blood and synovial tissue within each disease, 4615 and 164 DML were identified in RA and OA samples, respectively, resulting in 832 and 36 DMGs. A principal component analysis showed that methylation differences in T cells were greater on the basis of on location (blood vs synovium) rather than disease (RA vs OA). Differentially modified pathways were significantly enriched between RA blood and synovial T cells, especially in genes related to complement, integrin cell surface interactions, and the P53 pathway. The limited number of DMGs identified between OA blood and synovial T cells did not conform to biologic pathways.

Conclusion: The patterns of DNA methylation in RA show location-specific differences related to immune pathways, whereas methylation differences in OA are limited. The RA joint-specific signatures could be due to selective accumulation of T-cell populations or expansion of differentially marked adaptive immune cells. Understanding epigenetic patterns could provide clues to the types of T cells that accumulate in the RA joint and identify potential therapeutic targets.
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http://dx.doi.org/10.1002/acr2.11231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966880PMC
March 2021

Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal.

Sci Adv 2020 Jun 26;6(26):eaba4353. Epub 2020 Jun 26.

Department of Medicine, Altman Clinical and Translational Research Institute, University of California, San Diego, La Jolla, CA 92093, USA.

Fibroblast-like synoviocytes (FLS) are joint-lining cells that promote rheumatoid arthritis (RA) pathology. Current disease-modifying antirheumatic agents (DMARDs) operate through systemic immunosuppression. FLS-targeted approaches could potentially be combined with DMARDs to improve control of RA without increasing immunosuppression. Here, we assessed the potential of immunoglobulin-like domains 1 and 2 (Ig1&2), a decoy protein that activates the receptor tyrosine phosphatase sigma (PTPRS) on FLS, for RA therapy. We report that PTPRS expression is enriched in synovial lining RA FLS and that Ig1&2 reduces migration of RA but not osteoarthritis FLS. Administration of an Fc-fusion Ig1&2 attenuated arthritis in mice without affecting innate or adaptive immunity. Furthermore, PTPRS was down-regulated in FLS by tumor necrosis factor (TNF) via a phosphatidylinositol 3-kinase-mediated pathway, and TNF inhibition enhanced PTPRS expression in arthritic joints. Combination of ineffective doses of TNF inhibitor and Fc-Ig1&2 reversed arthritis in mice, providing an example of synergy between FLS-targeted and immunosuppressive DMARD therapies.
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http://dx.doi.org/10.1126/sciadv.aba4353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319753PMC
June 2020

Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes.

Nat Rev Rheumatol 2020 06 11;16(6):316-333. Epub 2020 May 11.

Division of Rheumatology, Allergy and Immunology, University of California San Diego School of Medicine, San Diego, CA, USA.

Rheumatoid arthritis (RA) is a chronic immune-mediated disease that primarily affects the synovium of diarthrodial joints. During the course of RA, the synovium transforms into a hyperplastic invasive tissue that causes destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS), which form the lining of the joint, are epigenetically imprinted with an aggressive phenotype in RA and have an important role in these pathological processes. In addition to producing the extracellular matrix and joint lubricants, FLS in RA produce pathogenic mediators such as cytokines and proteases that contribute to disease pathogenesis and perpetuation. The development of multi-omics integrative analyses have enabled new ways to dissect the mechanisms that imprint FLS, have helped to identify potential FLS subsets with distinct functions and have identified differences in FLS phenotypes between joints in individual patients. This Review provides an overview of advances in understanding of FLS biology and highlights omics approaches and studies that hold promise for identifying future therapeutic targets.
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http://dx.doi.org/10.1038/s41584-020-0413-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987137PMC
June 2020

In Memoriam: William Phelps Arend, MD, 1937-2020.

Arthritis Rheumatol 2020 06 20;72(6):866-867. Epub 2020 Apr 20.

University of Colorado, Denver, CO.

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http://dx.doi.org/10.1002/art.41258DOI Listing
June 2020

Persistent chikungunya arthritis in Roraima, Brazil.

Clin Rheumatol 2020 Sep 13;39(9):2781-2787. Epub 2020 Mar 13.

Department of Medicine, George Washington University, 2150 Pennsylvania Ave Suite 5-416, Washington, DC, 20037, USA.

Background: The Amazon region of Brazil experienced a large epidemic of East Central South African (ECSA) chikungunya virus (CHIKV) in 2017 and continuous transmission of CHIKV persists. The impact of chronic arthritis caused by ECSA CHIKV is unknown.

Objective: The study aim was to describe the duration, severity, and characteristics of CHIKV arthritis in Roraima, Brazil, in comparison with local controls to further understand the long-term rheumatologic impact of ECSA CHIKV infection.

Methods: We performed a cross-sectional analysis comparing clinical arthritis outcomes among 40 cases with chronic (> 3 months) arthritis attributed to their CHIKV disease (n = 40) with control participants who were exposed to CHIKV but did not develop chronic arthritis (n = 40), rheumatoid arthritis controls (n = 40), and healthy controls lacking CHIKV exposure and arthritis (n = 40).

Findings: Our primary finding is that over 2 years post-infection, patients report moderate arthritis disease severity comparable with rheumatoid arthritis with the most significant impact on decreased quality of life from pain.

Main Conclusions: These findings suggest that chronic arthritis caused by ECSA CHIKV infection has had a moderate impact in the Americas. Key Points • Chikungunya infection is responsible for moderate arthritis disease severity. • The East Central South African (ECSA) strain of CHIKV is a cause of persistent arthritis in Roraima, Brazil.
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http://dx.doi.org/10.1007/s10067-020-05011-9DOI Listing
September 2020

Joint Location-Specific JAK-STAT Signaling in Rheumatoid Arthritis Fibroblast-like Synoviocytes.

ACR Open Rheumatol 2019 Dec 31;1(10):640-648. Epub 2019 Oct 31.

School of Medicine, Department of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, California.

Objective: Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) derived from hip and knee have distinctive DNA methylation and transcriptome patterns in interleukin (IL)-6 signaling and Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways. To determine the functional effects of these joint-specific signatures, we evaluated how RA hip and knee FLS differ in their response to IL-6.

Methods: Hip or knee RA FLS were obtained after arthroplasty. Previously published datasets on epigenetic landscape of FLS were mined to identify joint-specific IL-6-related epigenomic differences. RNA sequencing was performed on five RA hip and five knee FLS treated with or without IL-6. Differential gene expression was determined using edgeR software. STAT3 phosphorylation was measured using bead assays. Sensitivity to tofacitinib was evaluated by measuring inhibition using quantitative polymerase chain reaction.

Results: Assay for Transposase-Accessible Chromatin sequencing and histone chromatin immunoprecipitation sequencing datasets from RA FLS were analyzed to identify epigenomic differences between hip and knee. Differential chromatin accessibility was associated with ,, and genes. H3K27ac was also differentially marked at other JAK-STAT-related genes, including region. Principal component analysis of RNA sequencing data confirmed segregation between RA hip and knee FLS under basal conditions, that persisted following IL-6 treatment. STAT3 phosphorylation after IL-6 was significantly higher in knee than hip FLS and was highly correlated with JAK1 protein levels. Knee FLS were less sensitive to the JAK inhibitor tofacitinib than hip FLS.

Conclusion: RA hip and knee FLS have distinct transcriptomes, epigenetic marks, and STAT3 activation patterns in the IL-6 pathway. These joint-specific differences might contribute to a differential clinical response in individual joints to targeted therapies such as JAK inhibitors.
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http://dx.doi.org/10.1002/acr2.11093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917316PMC
December 2019

Chronic Joint Pain 3 Years after Chikungunya Virus Infection Largely Characterized by Relapsing-remitting Symptoms.

J Rheumatol 2020 08 1;47(8):1267-1274. Epub 2019 Jul 1.

From George Washington University; George Mason University, Washington, DC; University of California, San Diego, San Diego, California, USA; Allied Research Society LLC; Clinica de La Costa Ltda.; Biomelab; Centro de Reumatología y Ortopedia; Universidad Simón Bolívar, Barranquilla, Atlántico; Universidad El Bosque, Bogotá, Colombia; Evotec ID, Lyon, France.

Objective: To determine the frequency of chronic joint pain and stiffness 3 years after infection with chikungunya virus (CHIKV) in a Latin American cohort.

Methods: A cross-sectional followup of 120 patients from an initial cohort of 500 patients who reported joint pain 2 years after infection from the Atlántico Department, Colombia. Patients were clinically diagnosed as having CHIKV during the 2014-2015 epidemic, and baseline and followup symptoms at 40 months were evaluated in serologically confirmed cases.

Results: Of the initial 500 patients enrolled in the study, 482 had serologically confirmed chikungunya infection. From this group, 123 patients reported joint pain 20 months after infection, and 54% of those patients reported continued joint pain 40 months after infection. Therefore, 1 out of every 8 people who tested serologically positive for CHIKV infection had persistent joint pain 3 years after infection. Participants who followed up in person were predominantly adult (mean ± SD age 51 ± 14 yrs) and female (86%). The most common type of pain reported in these patients at 40 months post-infection was pain with periods of relief and subsequent reoccurrence, and over 75% reported stiffness after immobility, with 39% experiencing morning stiffness.

Conclusion: To our knowledge, this is the first report to describe persistent joint pain and stiffness 40 months after viral infection. The high frequency of chronic disease highlights the need to develop prevention and treatment methods. Further studies should be conducted to understand the similarities between post-chikungunya joint pain and rheumatoid arthritis.
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http://dx.doi.org/10.3899/jrheum.190162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938419PMC
August 2020

Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry.

Nat Immunol 2019 07 6;20(7):928-942. Epub 2019 May 6.

Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)HLA-DRA sublining fibroblasts, IL1B pro-inflammatory monocytes, ITGAXTBX21 autoimmune-associated B cells and PDCD1 peripheral helper T (T) cells and follicular helper T (T) cells. We defined distinct subsets of CD8 T cells characterized by GZMK, GZMB, and GNLY phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1HLA-DRA fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.
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http://dx.doi.org/10.1038/s41590-019-0378-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602051PMC
July 2019

PTPN14 phosphatase and YAP promote TGFβ signalling in rheumatoid synoviocytes.

Ann Rheum Dis 2019 05 26;78(5):600-609. Epub 2019 Feb 26.

Dept. of Medicine, University of California San Diego, La Jolla, California, USA

Objective: We aimed to understand the role of the tyrosine phosphatase PTPN14-which in cancer cells modulates the Hippo pathway by retaining YAP in the cytosol-in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA).

Methods: Gene/protein expression levels were measured by quantitative PCR and/or Western blotting. Gene knockdown in RA FLS was achieved using antisense oligonucleotides. The interaction between PTPN14 and YAP was assessed by immunoprecipitation. The cellular localisation of YAP and SMAD3 was examined via immunofluorescence. SMAD reporter studies were carried out in HEK293T cells. The RA FLS/cartilage coimplantation and passive K/BxN models were used to examine the role of YAP in arthritis.

Results: RA FLS displayed overexpression of PTPN14 when compared with FLS from patients with osteoarthritis (OA). PTPN14 knockdown in RA FLS impaired TGFβ-dependent expression of MMP13 and potentiation of TNF signalling. In RA FLS, PTPN14 formed a complex with YAP. Expression of PTPN14 or nuclear YAP-but not of a non-YAP-interacting PTPN14 mutant-enhanced SMAD reporter activity. YAP promoted TGFβ-dependent SMAD3 nuclear localisation in RA FLS. Differences in epigenetic marks within Hippo pathway genes, including YAP, were found between RA FLS and OA FLS. Inhibition of YAP reduced RA FLS pathogenic behaviour and ameliorated arthritis severity.

Conclusion: In RA FLS, PTPN14 and YAP promote nuclear localisation of SMAD3. YAP enhances a range of RA FLS pathogenic behaviours which, together with epigenetic evidence, points to the Hippo pathway as an important regulator of RA FLS behaviour.
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http://dx.doi.org/10.1136/annrheumdis-2018-213799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039277PMC
May 2019

Toreforant, an orally active histamine H-receptor antagonist, in patients with active rheumatoid arthritis despite methotrexate: mechanism of action results from a phase 2, multicenter, randomized, double-blind, placebo-controlled synovial biopsy study.

Inflamm Res 2019 Apr 9;68(4):261-274. Epub 2019 Feb 9.

Immunology Clinical Development, Janssen Research & Development LLC, Spring House, PA, USA.

Objective/design: In a double-blind, placebo-controlled, multiple-dose study, we assessed the molecular mechanism of action of the selective histamine-4-receptor antagonist toreforant.

Patients/treatment: Patients with active rheumatoid arthritis (RA) despite methotrexate were randomized (3:1) to toreforant 30 mg/day (weeks 0-52) or placebo (weeks 0-12) followed by toreforant 30 mg/day (weeks 12-52).

Methods: Primary biomarker analyses comprised 39 different proteins/mRNA transcripts measured in synovial biopsy (n = 39) and/or time-matched serum (n = 15) samples collected at baseline and week 6. Clinical response was assessed using C-reactive protein-based 28-joint disease activity scores. Data were summarized using descriptive statistics.

Results: Among 21 randomized, treated patients (toreforant-16, placebo-5), 18 (toreforant-13, placebo-5) completed the 12-week double-blind period (none completed open-label treatment) prior to the early study termination. Biomarker profiling indicated potential modest effects of toreforant on gene expression of histamine-1-receptor, tumor necrosis factor-alpha, and interleukin-8 in synovium. Potential trends between biomarkers and clinical response were observed with synovial monocyte chemoattractant protein-4 and phosphorylated extracellular-signal-regulated kinases and serum matrix metalloproteinase-3. Minimal synovial gene expression of interleukins-17A and 17F was detected.

Conclusions: While clear biomarker signals associated with toreforant pharmacology in RA patients were not identified, modest associations between biomarkers and clinical response were noted. Synovial expression of interleukins-17A/17F was minimal. Limited sample size warrants cautious interpretation.
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http://dx.doi.org/10.1007/s00011-019-01218-yDOI Listing
April 2019

Accrual to Clinical Trials (ACT): A Clinical and Translational Science Award Consortium Network.

JAMIA Open 2018 Oct 21;1(2):147-152. Epub 2018 Aug 21.

The Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

The Accrual to Clinical Trials (ACT) network is a federated network of sites from the National Clinical and Translational Science Award (CTSA) Consortium that has been created to significantly increase participant accrual to multi-site clinical trials. The ACT network represents an unprecedented collaboration among diverse CTSA sites. The network has created governance and regulatory frameworks and a common data model to harmonize electronic health record (EHR) data, and deployed a set of Informatics for Integrating Biology and the Bedside (i2b2) data repositories that are linked by the Shared Health Research Information Network (SHRINE) platform. It provides investigators the ability to query the network in real time and to obtain aggregate counts of patients who meet clinical trial inclusion and exclusion criteria from sites across the United States. The ACT network infrastructure provides a basis for cohort discovery and for developing new informatics tools to identify and recruit participants for multi-site clinical trials.
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http://dx.doi.org/10.1093/jamiaopen/ooy033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241502PMC
October 2018

Development of a game-based learning tool for applied team science communication in a virtual clinical trial.

J Clin Transl Sci 2018 Jun 13;2(3):169-172. Epub 2018 Sep 13.

Altman Clinical and Translational Research Institute (ACTRI), University of California San Diego, San Diego, CA, USA.

Educational tools for application of team science competencies in clinical research are needed. Our interdisciplinary group developed and evaluated acceptability of a virtual world game-based learning tool simulating a multisite clinical trial; performance hinges on effective intrateam communication. Initial implementation with clinical research trainees (n=40) indicates high satisfaction and perceived relevance to team science and research career goals. Game-based learning may play an important role in team science training.
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http://dx.doi.org/10.1017/cts.2018.8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199551PMC
June 2018

The Cytokine Profile in Acute Chikungunya Infection is Predictive of Chronic Arthritis 20 Months Post Infection.

Diseases 2018 Oct 20;6(4). Epub 2018 Oct 20.

Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University, Washington, DC 20037, USA.

The cytokine profile during acute chikungunya infection that predicts future chronic arthritis has not yet been investigated. We conducted a nested case-control study comparing serum cytokine concentrations during acute chikungunya infection in cases ( = 121) that reported the presence of chronic joint pain versus age- and gender-matched controls ( = 121) who reported recovery at 20 months post infection. We observed that a robust cytokine response during acute infection was correlated with a decreased incidence of chronic joint pain and that low TNFα, IL-13, IL-2, and IL-4 during acute infection was predictive of chronic joint pain. These data suggest that a robust cytokine response is necessary for viral clearance and cytokines that are related to immune tolerance during acute infection may be protective for chronic arthritis pathogenesis.
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http://dx.doi.org/10.3390/diseases6040095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313749PMC
October 2018

PATHOGENESIS OF RHEUMATOID ARTHRITIS: THE INTERSECTION OF GENETICS AND EPIGENETICS.

Authors:
Gary S Firestein

Trans Am Clin Climatol Assoc 2018 ;129:171-182

LA JOLLA, CALIFORNIA.

Rheumatoid arthritis is a synovial inflammatory disease marked by joint infiltration by immune cells and damage to the extracellular matrix. Although genetics plays a critical role in heritability and its pathogenesis, the relative lack of disease concordance in identical twins suggests that noncoding influences can affect risk and severity. Environmental stress, which can be reflected in the genome as altered epigenetic marks, also contributes to gene regulation and contributes to disease mechanisms. Studies on DNA methylation suggest that synovial cells, most notably fibroblast-like synoviocytes, are imprinted in rheumatoid arthritis with epigenetic marks and subsequently assume an aggressive phenotype. Even more interesting, the synoviocyte marks are not only disease specific but can vary depending on the joint of origin. Understanding the epigenetic landscape using unbiased methods can potentially identify nonobvious pathways and genes that that are responsible for synovial inflammation as well as the diversity of responses to targeted agents. The information can also be leveraged to identify novel therapeutic approaches.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116585PMC
December 2018

Systems approach to assessing and improving local human research Institutional Review Board performance.

J Clin Transl Sci 2018 Apr 8;2(2):103-109. Epub 2018 Aug 8.

University of California at San Diego, San Diego, CA, USA.

Objective: To quantifying the interdependency within the regulatory environment governing human subject research, including Institutional Review Boards (IRBs), federally mandated Medicare coverage analysis and contract negotiations.

Methods: Over 8000 IRB, coverage analysis and contract applications initiated between 2013 and 2016 were analyzed using traditional and machine learning analytics for a quality improvement effort to improve the time required to authorize the start of human research studies.

Results: Staffing ratios, study characteristics such as the number of arms, source of funding and number and type of ancillary reviews significantly influenced the timelines. Using key variables, a predictive algorithm identified outliers for a workflow distinct from the standard process. Improved communication between regulatory units, integration of common functions, and education outreach improved the regulatory approval process.

Conclusions: Understanding and improving the interdependencies between IRB, coverage analysis and contract negotiation offices requires a systems approach and might benefit from predictive analytics.
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http://dx.doi.org/10.1017/cts.2018.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6799096PMC
April 2018

Hexokinase 2 as a novel selective metabolic target for rheumatoid arthritis.

Ann Rheum Dis 2018 11 30;77(11):1636-1643. Epub 2018 Jul 30.

Department of Medicine, University of California San Diego, San Diego, California, USA.

Objectives: Recent studies indicate that glucose metabolism is altered in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). Hexokinases (HKs) catalyse the first step in glucose metabolism, and HK2 constitutes the principal HK inducible isoform. We hypothesise that HK2 contributes to the synovial lining hypertrophy and plays a critical role in bone and cartilage damage.

Methods: HK1 and HK2 expression were determined in RA and osteoarthritis (OA) synovial tissue by immunohistochemistry. RA FLS were transfected with either HK1 or HK2 siRNA, or infected with either adenovirus (ad)-GFP, ad-HK1 or ad-HK2. FLS migration and invasion were assessed. To study the role of HK2 in vivo, 10 particles of ad-HK2 or ad-GFP were injected into the knee of wild-type mice. K/BxN serum transfer arthritis was induced in HK2 mice harbouring Col1a1-Cre (HK2), to delete HK2 in non-haematopoietic cells.

Results: HK2 is particular of RA histopathology (9/9 RA; 1/8 OA) and colocalises with FLS markers. Silencing HK2 in RA FLS resulted in a less invasive and migratory phenotype. Consistently, overexpression of HK2 resulted in an increased ability to migrate and invade. It also increased extracellular lactate production. Intra-articular injection of ad-HK2 in normal knees dramatically increased synovial lining thickness, FLS activation and proliferation. HK2 was highly expressed in the synovial lining after K/BxN serum transfer arthritis. HK2 mice significantly showed decreased arthritis severity, bone and cartilage damage.

Conclusion: HK2 is specifically expressed in RA synovial lining and regulates FLS aggressive functions. HK2 might be an attractive selective metabolic target safer than global glycolysis for RA treatment.
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http://dx.doi.org/10.1136/annrheumdis-2018-213103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328432PMC
November 2018

Reply.

Arthritis Rheumatol 2018 11 27;70(11):1891-1892. Epub 2018 Aug 27.

University of California, San Diego.

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http://dx.doi.org/10.1002/art.40663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203595PMC
November 2018

Reply.

Arthritis Rheumatol 2018 11 27;70(11):1893. Epub 2018 Aug 27.

University of California, San Diego.

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http://dx.doi.org/10.1002/art.40664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203644PMC
November 2018

Methods for high-dimensional analysis of cells dissociated from cryopreserved synovial tissue

Arthritis Res Ther 2018 07 11;20(1):139. Epub 2018 Jul 11.

Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.

Background: Detailed molecular analyses of cells from rheumatoid arthritis (RA) synovium hold promise in identifying cellular phenotypes that drive tissue pathology and joint damage. The Accelerating Medicines Partnership RA/SLE Network aims to deconstruct autoimmune pathology by examining cells within target tissues through multiple high-dimensional assays. Robust standardized protocols need to be developed before cellular phenotypes at a single cell level can be effectively compared across patient samples.

Methods: Multiple clinical sites collected cryopreserved synovial tissue fragments from arthroplasty and synovial biopsy in a 10% DMSO solution. Mechanical and enzymatic dissociation parameters were optimized for viable cell extraction and surface protein preservation for cell sorting and mass cytometry, as well as for reproducibility in RNA sequencing (RNA-seq). Cryopreserved synovial samples were collectively analyzed at a central processing site by a custom-designed and validated 35-marker mass cytometry panel. In parallel, each sample was flow sorted into fibroblast, T-cell, B-cell, and macrophage suspensions for bulk population RNA-seq and plate-based single-cell CEL-Seq2 RNA-seq.

Results: Upon dissociation, cryopreserved synovial tissue fragments yielded a high frequency of viable cells, comparable to samples undergoing immediate processing. Optimization of synovial tissue dissociation across six clinical collection sites with ~ 30 arthroplasty and ~ 20 biopsy samples yielded a consensus digestion protocol using 100 μg/ml of Liberase™ TL enzyme preparation. This protocol yielded immune and stromal cell lineages with preserved surface markers and minimized variability across replicate RNA-seq transcriptomes. Mass cytometry analysis of cells from cryopreserved synovium distinguished diverse fibroblast phenotypes, distinct populations of memory B cells and antibody-secreting cells, and multiple CD4 and CD8 T-cell activation states. Bulk RNA-seq of sorted cell populations demonstrated robust separation of synovial lymphocytes, fibroblasts, and macrophages. Single-cell RNA-seq produced transcriptomes of over 1000 genes/cell, including transcripts encoding characteristic lineage markers identified.

Conclusions: We have established a robust protocol to acquire viable cells from cryopreserved synovial tissue with intact transcriptomes and cell surface phenotypes. A centralized pipeline to generate multiple high-dimensional analyses of synovial tissue samples collected across a collaborative network was developed. Integrated analysis of such datasets from large patient cohorts may help define molecular heterogeneity within RA pathology and identify new therapeutic targets and biomarkers.
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http://dx.doi.org/10.1186/s13075-018-1631-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042350PMC
July 2018

Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes.

Nat Commun 2018 05 15;9(1):1921. Epub 2018 May 15.

Division of Rheumatology, Allergy and Immunology, 9500 Gilman Drive, UCSD School of Medicine, La Jolla, CA, 92093, USA.

Epigenetics contributes to the pathogenesis of immune-mediated diseases like rheumatoid arthritis (RA). Here we show the first comprehensive epigenomic characterization of RA fibroblast-like synoviocytes (FLS), including histone modifications (H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K27me3, and H3K9me3), open chromatin, RNA expression and whole-genome DNA methylation. To address complex multidimensional relationship and reveal epigenetic regulation of RA, we perform integrative analyses using a novel unbiased method to identify genomic regions with similar profiles. Epigenomically similar regions exist in RA cells and are associated with active enhancers and promoters and specific transcription factor binding motifs. Differentially marked genes are enriched for immunological and unexpected pathways, with "Huntington's Disease Signaling" identified as particularly prominent. We validate the relevance of this pathway to RA by showing that Huntingtin-interacting protein-1 regulates FLS invasion into matrix. This work establishes a high-resolution epigenomic landscape of RA and demonstrates the potential for integrative analyses to identify unanticipated therapeutic targets.
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http://dx.doi.org/10.1038/s41467-018-04310-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953939PMC
May 2018
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