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Abstract Rheumatoid arthritis (RA) is an autoimmune disease involving antigen-specific T and B cells. Here, we perform single-cell RNA and repertoire sequencing on paired synovial tissue and blood samples from 12 seropositive RA patients. We identify clonally expanded CD4 + T cells, including CCL5+ cells and T peripheral helper (Tph) cells, which show a prominent transcriptomic signature of recent activation and effector function. CD8 + T cells show higher oligoclonality than CD4 + T cells, with the largest synovial clones enriched in GZMK+ cells. CD8 + T cells with possibly virus-reactive TCRs are distributed across transcriptomic clusters. In the B cell compartment, NR4A1+ activated B cells, and plasma cells are enriched in the synovium and demonstrate substantial clonal expansion. We identify synovial plasma cells that share BCRs with synovial ABC, memory, and activated B cells. Receptor-ligand analysis predicted IFNG and TNFRSF members as mediators of synovial Tph-B cell interactions. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate the synovium of patients with RA.

Abstract Molecular markers of autoimmunity, such as antibodies to citrullinated protein antigens (ACPA), are detectable prior to inflammatory arthritis (IA) in rheumatoid arthritis (RA) and may define a state that is ‘at-risk’ for future RA. Here we present a cross-sectional comparative analysis among three groups that include ACPA positive individuals without IA (At-Risk), ACPA negative individuals and individuals with early, ACPA positive clinical RA (Early RA). Differential methylation analysis among the groups identifies non-specific dysregulation in peripheral B, memory and naïve T cells in At-Risk participants, with more specific immunological pathway abnormalities in Early RA. Tetramer studies show increased abundance of T cells recognizing citrullinated (cit) epitopes in At-Risk participants, including expansion of T cells reactive to citrullinated cartilage intermediate layer protein I (cit-CILP); these T cells have Th1, Th17, and T stem cell memory-like phenotypes. Antibody-antigen array analyses show that antibodies targeting cit-clusterin, cit-fibrinogen and cit-histone H4 are elevated in At-Risk and Early RA participants, with the highest levels of antibodies detected in those with Early RA. These findings indicate that an ACPA positive at-risk state is associated with multifaceted immune dysregulation that may represent a potential opportunity for targeted intervention.

Fibroblast-like synoviocytes (FLS) are used as a model of rheumatoid arthritis synoviocytes, although cell lines derived from individual patients can have heterogeneous biology. Here the authors use a Taiji computational approach to analyze gene expression, chromatin accessibility and functional differences between individual patient-derived RA FLS lines.

Abstract In seropositive rheumatoid arthritis (RA), the onset of clinically apparent inflammatory arthritis (IA) is typically preceded by a prolonged period of autoimmunity manifest by the presence of circulating autoantibodies that can include antibodies to citrullinated protein antigens (ACPA) and rheumatoid factor. This period before clinical IA can be designated preclinical RA in those individuals who have progressed to a clinical diagnosis of RA, and an “at‐risk” status in those who have not developed IA but exhibit predictive biomarkers of future clinical RA. With the goal of developing RA prevention strategies, studies have characterized immune phenotypes of preclinical RA/at‐risk states. From these studies, a model has emerged wherein mucosal inflammation and dysbiosis may lead first to local autoantibody production, which should normally be transient, but instead is followed by a systemic spread of the autoimmunity as manifested by serum autoantibody elevations, ultimately driving the development of clinically identified joint inflammation. This model can be envisioned as the progression of disease development through serial “checkpoints” that in principle should constrain or resolve autoimmunity; however, instead, the checkpoints “fail” and clinical RA develops. Herein we review the immune processes that are likely to be present at each step and the potential therapeutic strategies that could be envisioned to delay, diminish, halt, or even reverse the progression to clinical RA. Notably, these prevention strategies could utilize existing therapies approved for clinical RA, therapies approved for other diseases that target relevant pathways in the preclinical/at‐risk state, or approaches that target novel pathways.

Objective Traditional nondigital methods of participant recruitment for clinical research studies in rheumatology can be costly and inefficient, particularly for recruitment of underserved populations. We aimed to address this need by evaluating two methods of online recruitment to an observational cohort of individuals at risk for rheumatoid arthritis, namely web and Facebook advertisements. Methods A 3‐month countywide web‐based recruitment campaign was conducted consisting of text and image‐based advertisements. Similar advertisements were subsequently displayed on Facebook, initially in English for 5 months and later in Spanish for an additional 3 months. Individuals who clicked on advertisements were directed to a website landing page containing study information and could contact study personnel to schedule testing for anti‐cyclic citrullinated peptide‐3 (CCP3). The primary outcome measure for each campaign was the click‐through rate. Results During the web campaign, 413,289 advertisement impressions were displayed, resulting in 428 clicks (click‐through rate 0.10%) and only one screened participant. During the English Facebook campaign, 724,815 advertisements were displayed with 6765 clicks (click‐through rate 0.93%) and 43 screened participants, significantly greater than the web campaign (P

Objective Fibroblast‐like synoviocytes (FLS) play a pivotal role in rheumatoid arthritis (RA) by contributing to synovial inflammation and progressive joint damage. An imprinted epigenetic state is associated with the FLS aggressive phenotype. We identified CASP8 (encoding for caspase‐8) as a differentially marked gene and evaluated its pathogenic role in RA FLSs. Methods RA FLS lines were obtained from synovial tissues at arthroplasty and used at passage 5‐8. Caspase‐8 was silenced using small interfering RNA, and its effect was determined in cell adhesion, migration and invasion assays. Quantitative reverse transcription PCR and western blot were used to assess gene and protein expression, respectively. A caspase‐8 selective inhibitor was used determine the role of enzymatic activity on FLS migration and invasion. Caspase‐8 isoform transcripts and epigenetic marks in FLSs were analyzed in FLS public databases. Crystal structures of caspase‐8B and G were determined. Results Caspase‐8 deficiency in RA FLSs reduced cell adhesion, migration, and invasion independent of its catalytic activity. Epigenetic and transcriptomic analyses of RA FLSs revealed that a specific caspase‐8 isoform, variant G, is the dominant isoform expressed (~80% of total caspase‐8) and induced by PDGF. The crystal structures of caspase‐8 variant G and B were identical except for a unique unstructured 59 amino acid N‐terminal domain in variant G. Selective knockdown of caspase‐8G was solely responsible for the effects of caspase‐8 on calpain activity and cell invasion in FLS. Conclusion Blocking caspase‐8 variant G could decrease cell invasion in diseases like RA without the potential deleterious effects of nonspecific caspase‐8 inhibition.

The ACT Network was funded by NIH to provide investigators from across the Clinical and Translational Science Award (CTSA) Consortium the ability to directly query national federated electronic health record (EHR) data for cohort discovery and feasibility assessment of multi-site studies. NIH refunded the program for expanded research application to become “Evolve to Next-Gen ACT” (ENACT). In parallel, the US Food and Drug Administration has been evaluating the use of real-world data (RWD), including EHR data, as sources of real-world evidence (RWE) for its regulatory decisions involving drug and biological products. Using insights from implementation science, six lessons learned from ACT for developing and sustaining RWD/RWE infrastructures and networks across the CTSA Consortium are presented in order to inform ENACT’s development from the outset. Lessons include intentional institutional relationship management, end-user engagement, beta-testing, and customer-driven adaptation. The ENACT team is also conducting customer discovery interviews with CTSA hub and investigators using Innovation-Corps@NCATS (I-Corps™) methodology for biomedical entrepreneurs to uncover unmet RWD needs. Possible ENACT value proposition hypotheses are presented by stage of research. Developing evidence about methods for sustaining academically derived data infrastructures and support can advance the science of translation and support our nation’s RWD/RWE research capacity.

Abstract Background: Recruitment of study participants is challenging and can incur significant costs. Social media advertising is a promising method for recruiting clinical studies and may improve cost efficiency by targeting populations likely to match a study’s qualifications. Prior systematic reviews of social media as a recruitment tool have been favourable, however, there are no meta-analyses of its cost-effectiveness. Methods: Studies evaluating recruitment costs through social media and non-social media methods were identified on MEDLINE and EMBASE. Articles were screened through a two-step process in accordance with PRISMA guidelines. Cost data were extracted from selected articles and meta-analyzed using the Mantel-Haenszel method. The primary outcome was the relative cost-effectiveness of social media compared to non-social media recruitment, defined as the odds ratio of recruiting a participant per US dollar spent. The secondary outcome was the cost-effectiveness of social media recruitment compared to other online recruitment methods only. Results: In total, 23 studies were included in the meta-analysis. The odds ratio of recruiting a participant through social media advertising compared to non-social media methods per dollar spent was 1.97 [95% CI 1.24–3.00, P = 0.004]. The odds ratio of recruiting a participant through social media compared to other online methods only was 1.66 [95% CI 1.02–2.72, P = 0.04]. Conclusions: Social media advertising may be more cost-effective than other methods of recruitment, however, the magnitude of cost-effectiveness is highly variable between studies. There are limited data on newer social media platforms and on difficult-to-reach populations such as non-English speakers or older individuals.

ObjectiveChikungunya virus (CHIKV) causes persistent arthritis, and our prior study showed that approximately one third of CHIKV arthritis patients had exacerbated arthritis associated with exercise. The underlying mechanism of exercise-associated chikungunya arthritis flare (EACAF) is unknown, and this analysis aimed to examine the regulatory T-cell immune response related to CHIKV arthritis flares.MethodsIn our study, 124 Colombian patients with a history of CHIKV infection four years prior were enrolled and 113 cases with serologically confirmed CHIKV IgG were used in this analysis. Patient information was gathered via questionnaires, and blood samples were taken to identify total live peripheral blood mononuclear cells, CD4+ cells, T regulatory cells, and their immune markers. We compared outcomes in CHIKV patients with (n = 38) vs. without (n = 75) EACAF using t-tests to assess means and the Fisher’s exact test, chi-squared to evaluate categorical variables, and Kruskal-Wallis tests in the setting of skewed distributions (SAS 9.3).Results33.6% of CHIKV cases reported worsening arthritis with exercise. EACAF patients reported higher global assessments of arthritis disease ranging from 0-100 (71.2 ± 19.7 vs. 59.9 ± 28.0, p=0.03). EACAF patients had lower ratios of T regulatory (Treg)/CD4+ T-cells (1.95 ± 0.73 vs. 2.4 ± 1.29, p = 0.04) and lower percentage of GARP (glycoprotein-A repetitions predominant) expression per Treg (0.13 ± 0.0.33 vs. 0.16 ± 0.24 p= 0.020).ConclusionThese findings suggest relative decreases in GARP expression may indicate a decreased level of immune suppression. Treg populations in patients with CHIKV arthritis may contribute to arthritis flares during exercise, though current research is conflicting.

Abstract 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.

ObjectiveTo improve the fidelity of the cellular transcriptome of disaggregated synovial tissue for applications such as single-cell RNA sequencing (scRNAseq) by modifying the disaggregation technique.MethodsOsteoarthritis (OA) and rheumatoid arthritis (RA) synovia were collected at arthroplasty. RNA was extracted from intact or disaggregated replicate pools of tissue fragments. Disaggregation was performed with either a proprietary protease, Liberase TL (Lib) as a reference method, Liberase TL with an RNA polymerase inhibitor flavopyridol (Flavo), or a cold digestion with subtilisin A (SubA). qPCR on selected markers and RNAseq were used to compare disaggregation methods using the original intact tissue as reference.ResultsDisaggregated cell yield and viability were similar for all three methods with some viability improved (SubA). Candidate gene analysis showed that Lib alone dramatically increased expression of several genes involved in inflammation and immunity compared with intact tissue and was unable to differentiate RA from OA. Both alternative methods reduced the disaggregation induced changes. Unbiased analysis using bulk RNAseq and the 3 protocols confirmed the candidate gene studies and showed that disaggregation-induced changes were largely prevented. The resultant data improved the ability to distinguish RA from OA synovial transcriptomes.ConclusionsDisaggregation of connective tissues such as synovia has complex and selective effects on the transcriptome. We found that disaggregation with an RNA polymerase inhibitor or using a cold enzyme tended to limit induction of some relevant transcripts during tissue processing. The resultant data in the disaggregated transcriptome better represented the in situ transcriptome. The specific method chosen can be tailored to the genes of interest and the hypotheses being tested in order to optimize the fidelity of technique for applications based on cell suspensions such as sorted populations or scRNAseq.

Fibroblast-like synoviocytes are important mediators of joint pathology in rheumatoid arthritis (RA). Here the authors show that Lasp1 is epigenetically regulated and highly expressed by these cells in RA and its deletion can limit joint pathology in a mouse model of inflammatory arthritis.

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.

The content and organization of hyaluronan (HA) in the extracellular matrix (ECM) have been identified as strong indicators of inflammation in joint disease, although the source and role of HA as an effector of inflammation is not clear. In this study, we established co-cultures of activated human CD4 T cells with fibroblast-like synoviocytes (FLS) from osteoarthritis (OA) and rheumatoid arthritis (RA) subjects and examined the role of HA in promoting inflammatory events. Co-cultures of RA FLS with activated CD4 T cells generated an HA-enriched ECM that promoted enhanced monocyte adhesion compared to co-cultures of OA FLS with activated CD4 T cells. In addition, both OA FLS and RA FLS co-cultures with activated CD4 T cells elicited significant increases in the expression of IL1β, TNF, and IL6, with the increase in IL6 expression most prominent in RA co-cultures. Blocking HA synthesis and accumulation with 4-methylumbelliferone reduced expression of IL6, IL1β, and TNF in both OA FLS and RA FLS co-cultures. The increase in HA synthesis in the co-cultures was mimicked by IL6 trans-signaling of FLS in the absence of CD4 T cells. Inhibition of HA synthesis blocked the increase in IL6 by RA FLS mediated by IL6 trans-signaling, suggesting that the HA synthetic pathway may be a key mediator in IL6 expression by FLS. Overall, our study indicates that HA-enriched ECM generated by co-cultures of activated CD4 T cells with FLS from human joints creates a pathogenic microenvironment by promoting adhesion of leukocytes and expression of inflammatory cytokines including IL6.

Abstract 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.

The COVID-19 global pandemic required the rapid development of vaccines with a quick start up of phase 1–3 studies with large enrollment targets. The University of California San Diego was identified as a site for the phase 3 trial of the mRNA-1273-SARS-CoV-2 vaccine. There were many challenges with scaling up a large-scale clinical trial in such a short time. This report describes the processes and procedures that were implemented to successfully complete the enrollment target in under 10 weeks. This required the team to identify existing tools that could rapidly be accessed to develop a database, scheduling system, effective communication, document management, staff time tracking/efficiency, subject scheduling/tracking, project management, and accrual/study performance. The outcome of these efforts resulted in rapid enrollment and study completion in a short time. The lessons learned from this experience can be used by other clinical trial sites faced with similar challenges.

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 CCL2 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 IL‐6, IL‐6R, and JAK1 genes. H3K27ac was also differentially marked at other JAK‐STAT–related genes, including STAT3‐STAT5A 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.

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.

Abstract 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.

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.

Fibroblast-like synoviocytes (FLS) in the intimal layer of the synovium can become invasive and destroy cartilage in patients with rheumatoid arthritis (RA). Here the authors integrate a variety of epigenomic data to map the epigenome of FLS in RA and identify potential therapeutic targets.

ObjectiveTo quantifying the interdependency within the regulatory environment governing human subject research, including Institutional Review Boards (IRBs), federally mandated Medicare coverage analysis and contract negotiations.MethodsOver 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.ResultsStaffing 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.ConclusionsUnderstanding and improving the interdependencies between IRB, coverage analysis and contract negotiation offices requires a systems approach and might benefit from predictive analytics.

Proliferation of synoviocytes contributes to joint damage in rheumatoid arthritis. Here the authors show that targeting of these cells by a vector, consisting of a baculovirus conjugated to an adenovirus carrying the pro-apoptotic gene PUMA, has therapeutic efficacy in a rat arthritis model.

Introduction The time required to obtain Institutional Review Board (IRB) approval is a frequent subject of efforts to reduce unnecessary delays in initiating clinical trials. This study was conducted by and for IRB directors to better understand factors affecting approval times as a first step in developing a quality improvement framework. Methods 807 IRB-approved clinical trials from 5 University of California campuses were analyzed to identify operational and clinical trial characteristics influencing IRB approval times. Results High workloads, low staff ratios, limited training, and the number and types of ancillary reviews resulted in longer approval times. Biosafety reviews and the need for billing coverage analysis were ancillary reviews that contributed to the longest delays. Federally funded and multisite clinical trials had shorter approval times. Variability in between individual committees at each institution reviewing phase 3 multisite clinical trials also contributed to delays for some protocols. Accreditation was not associated with shorter approval times. Conclusions Reducing unnecessary delays in obtaining IRB approval will require a quality improvement framework that considers operational and study characteristics as well as the larger institutional regulatory environment.

Abstract Histamine H4 receptor (H4R) has immune-modulatory and chemotaxic effects in various immune cells. This study aimed to determine the osteoclastogenic role of H4R in rheumatoid arthritis (RA). The concentration of histamine in synovial fluid (SF) and sera in patients with RA was measured using ELISA. After RA SF and peripheral blood (PB) CD14+ monocytes were treated with histamine, IL-17, IL-21 and IL-22, and a H4R antagonist (JNJ7777120), the gene expression H4R and RANKL was determined by real-time PCR. Osteoclastogenesis was assessed by counting TRAP–positive multinucleated cells in PB CD14+ monocytes cultured with histamine, Th17 cytokines and JNJ7777120. SF and serum concentration of histamine was higher in RA, compared with osteoarthritis and healthy controls. The expression of H4R was increased in PB monocytes in RA patients. Histamine, IL-6, IL-17, IL-21 and IL-22 induced the expression of H4R in monocytes. Histamine, IL-17, and IL-22 stimulated RANKL expression in RA monocytes and JNJ7777120 reduced the RANKL expression. Histamine and Th17 cytokines induced the osteoclast differentiation from monocytes and JNJ7777120 decreased the osteoclastogenesis. H4R mediates RANKL expression and osteoclast differentiation induced by histamine and Th17 cytokines. The blockage of H4R could be a new therapeutic modality for prevention of bone destruction in RA.

Rheumatoid arthritis is an inflammatory disease that selectively affects different joints. Here the authors show that gene expression and DNA methylation patterns of fibroblast-like synoviocytes differ between hip and knee joints in patients with RA, thus providing epigenetic and transcriptomic evidence for this anatomic selectivity of inflammation.

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 (n = 121) that reported the presence of chronic joint pain versus age- and gender-matched controls (n = 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.