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Background/Aims Early diagnosis, tight disease activity control and a treat-to-target approach are now recognised as critical factors that improve the outcome of patients with psoriatic arthritis (PsA). The traditional method used to assess disease activity is clinical examination (CE) by counting the number of tender and swollen joints. Ultrasound (US) has proven its superiority over CE for assessing the presence of synovitis in some studies. We aimed to identify the frequency and location of subclinical synovitis in a cohort of PsA patients with established disease. Methods Patients with established PsA were recruited. All gave informed, written consent and local ethical approval was obtained. All patients had a standard CE including 68/66 tender/swollen joint count. Grayscale (GS) and power doppler (PD) US of a standard set of 44 joints was performed using a GE logiq-P9 machine utilising 6-15-MHz and 8-18-MHz linear transducers. GS and PD were scored on a 0-3 semiquantitative scale for each joint. The presence of US active joints was defined as a GS-score ≥2 and/or PD-score ≥1. Results 78 patients were enrolled; 46/78 were female with a median age = 61 years (range 41-80). Median duration of PsA disease = 31.5 years (range 41-80), 40/78 were on bDMARDs and 27/78 on csDMARDs. The median TJC = 2 (range of 0-6) and mean CRP = 3.2 (SD 3.5). The most common sites for subclinical synovitis were wrists, knees, and metatarsophalangeal joints (see Table 1). 36 patients (46.2%) achieved a clinical state of minimal disease activity (MDA). 11 patients in MDA (30.5%) had a PD-score of > 1, suggesting they did not achieve minimal ultrasound disease activity (MUDA). Conclusion These data demonstrate that a proportion of established PsA patients deemed to have MDA actually have sonographic evidence of active disease. A previous study showed that PD-synovitis in PsA patients in clinical remission was a strong predictor of disease flare. It is unclear if subclinical synovitis in PsA is linked to radiographic progression. Combining CE and sonographic evaluation is an attractive approach to identifying subclinical disease. However, a validated ultrasound composite index, which includes the key joint areas frequently affected in PsA, is needed. Disclosure S. Sundanum: None. H. Darcy: None. P. Gallagher: None. F. Young: None. L. O'Neill: None. D. Veale: None.

Objectives Myeloid cells with a monocyte/macrophage phenotype are present in large numbers in the RA joint, significantly contributing to disease; however, distinct macrophage functions have yet to be elucidated. This study investigates the metabolic activity of infiltrating polarized macrophages and their impact on pro-inflammatory responses in RA. Methods CD14+ monocytes from RA and healthy control (HC) bloods were isolated and examined ex vivo or following differentiation into ‘M1/M2’ macrophages. Inflammatory responses and metabolic analysis ± specific inhibitors were quantified by RT-PCR, western blot, Seahorse XFe technology, phagocytosis assays and transmission electron microscopy along with RNA-sequencing (RNA-seq) transcriptomic analysis. Results Circulating RA monocytes are hyper-inflammatory upon stimulation, with significantly higher expression of key cytokines compared with HC (P Conclusion This study demonstrates a unique inflammatory and metabolic phenotype of RA monocyte-derived macrophages and identifies a key role for NAMPT and STAT3 signalling in regulating this phenotype.

Background: Patient engagement with clinicians results in shared decision making and increased adherence to medication. However, in order for strong patient: clinician partnerships to be achieved, communication barriers need to be identified. Therefore, the aim of this study was to examine the level of understanding of inflammatory arthritis patients and the need for strong patient-partnership in research. Methods: An online anonymous survey was distributed to patients living with inflammatory arthritis which addressed questions about diagnosis, routine tests, medications and how they work, medication adherence, disease flare, heredity, pregnancy, and patient involvement in research. Results: There were 1,873 respondents, 1416 of which had inflammatory arthritis (IA)- rheumatoid arthritis (RA) (65.8%) and psoriatic arthritis (PsA) (34.2%). They were predominantly female (RA 86%, PsA 85 %), aged 55±13 and 50±12 years. Less than 35% of patients had an understanding of diagnostic tests, what was measured and the implication for disease, with 75.5% also concerned about heredity. There was a high level of understanding of how specific medications treat inflammatory arthritis (72.9%). Adherence was also very high (>87%), with the main reasons for stopping medication without the advice of their clinician, ‘feeling better’ and ‘side effects’ however a significant proportion of patients (69.9%) reported a disease-flare following cessation of medication. Patients (31%) were also concerned that inflammatory arthritis reduced their chances of getting pregnant, with only 8% believing arthritis medications were safe to take during pregnancy. Finally, only 9% of patients had ever been asked to participate in a research study. Conclusions: This study demonstrates a need for the development of stronger patient-partnerships with clinicians and researchers in relation to patient education and engagement with research, to create a platform where patients can have meaningful input and involvement in future research studies.

Activation of endothelium and immune cells is fundamental to the initiation of autoimmune diseases such as rheumatoid arthritis (RA), and it results in trans-endothelial cell migration and synovial fibroblast proliferation, leading to joint destruction. In RA, the synovial microvasculature is highly dysregulated, resulting in inefficient oxygen perfusion to the synovium, which, along with the high metabolic demands of activated immune and stromal cells, leads to a profoundly hypoxic microenvironment. In inflamed joints, infiltrating immune cells and synovial resident cells have great requirements for energy and nutrients, and they adapt their metabolic profiles to generate sufficient energy to support their highly activated inflammatory states. This shift in metabolic capacity of synovial cells enables them to produce the essential building blocks to support their proliferation, activation and invasiveness. Furthermore, it results in the accumulation of metabolic intermediates and alteration of redox-sensitive pathways, affecting signalling pathways that further potentiate the inflammatory response. Importantly, the inflamed synovium is a multicellular tissue, with cells differing in their metabolic requirements depending on complex cell-cell interactions, nutrient supply, metabolic intermediates and transcriptional regulation. Therefore, understanding the complex interplay between metabolic and inflammatory pathways in synovial cells in RA will provide insight into the underlying mechanisms of disease pathogenesis.

OBJECTIVE To investigate a role for insulin-resistant pathways in inflammation and therapeutic targeting for disease modification in rheumatoid arthritis (RA). METHODS RA disease activity and cardiovascular risk factors, including insulin resistance and body mass index (BMI), were assessed in an Irish RA cohort. Glucose transporter 1 (GLUT-1) and GLUT-4 activity in RA and osteoarthritis (OA) synovial tissue was examined using immunohistochemistry. Spontaneous release of proinflammatory mediators from ex vivo RA synovial explants and primary synovial fibroblast (SF) cell culture supernatants was quantified by enzyme-linked immunosorbent assay. Phosphorylated AMP-activated protein kinase (p-AMPK) and GLUT-1 protein expression was analyzed by Western blotting. Cellular glycolytic and oxidative phosphorylation was assessed using extracellular flux analysis. RESULTS Insulin resistance was independently associated with both BMI (unstandardized coefficient B 0.113 [95% confidence interval (95% CI) 0.059-0.167]; P < 0.001) (n = 61) and swollen joint count in 28 joints (SJC28) (B 0.114 [95% CI 0.032-0.197]; P = 0.008) (n = 61). Increased GLUT-1 expression in RA synovium (n = 26) versus OA synovium (n = 16) was demonstrated (P = 0.0003), with increased expression in the lining, sublining, and vascular regions. In contrast, decreased GLUT-4 expression in the RA lining layer (n = 21) versus the OA lining layer (n = 8) was observed (P = 0.0358). Decreased GLUT-1 protein expression was observed in parallel with increased p-AMPK protein expression in SFs in the presence of metformin (n = 4). Metformin increased glycolytic activity and decreased oxidative phosphorylation in RASFs (n = 7) (P < 0.05 for both). Metformin or aminoimidazole carboxamide ribonucleotide presence decreased spontaneous production of interleukin-6 (IL-6), IL-8, and monocyte chemotactic protein 1 in RA synovial explants and SFs (n = 5-7). CONCLUSION Insulin resistance is significantly associated with BMI and synovitis in RA, suggesting distinct interplay between glucose availability and inflammation in RA. Furthermore, the effect of metformin on proinflammatory mechanisms suggests a role for AMPK-modifying compounds in the treatment of RA.

ObjectiveMicroRNA (miRNA) are small endogenous regulatory RNA molecules that have emerged as potential therapeutic targets and biomarkers in autoimmunity. Here, we investigated serum miRNA levels in patients with psoriatic arthritis (PsA) and further assessed a serum miRNA signature in therapeutic responder versus nonresponder PsA patients.MethodsSerum samples were collected from healthy controls (HC; n = 20) and PsA patients (n = 31), and clinical demographics were obtained. To examine circulatory miRNA in serum from HC and PsA patients, a focused immunology miRNA panel was analyzed utilizing a miRNA Fireplex assay (FirePlex Bioworks Inc.). MiRNA expression was further assessed in responders versus nonresponders according to the European League Against Rheumatism response criteria.ResultsSix miRNA (miR-221-3p, miR-130a-3p, miR-146a-5p, miR-151-5p, miR-26a-5p, and miR-21-5p) were significantly higher in PsA compared to HC (all P < 0.05), with high specificity and sensitivity determined by receiver-operating characteristic curve analysis. Analysis of responder versus nonresponders demonstrated higher baseline levels of miR-221-3p, miR-130a-3p, miR-146a-5p, miR-151-5p, and miR-26a-5p were associated with therapeutic response.ConclusionThis study identified a 6-serum microRNA signature that could be attractive candidates as noninvasive markers for PsA and may help to elucidate the disease pathogenesis.

Background: To evaluate the clinical and laboratory factors associated with long-term responses to rituximab therapy in patients with RA. Methods: One hundred fourteen RA patients received intravenous Rituximab between 2003-2016. Prior to treatment, arthroscopy and synovial biopsy was performed on a subgroup of this cohort who had active knee arthritis. Demographic, clinical, and outcome data were collected prospectively and immunohistology was performed on synovial tissue biopsies.Results: In the overall cohort, 89% of patients were seropositive for either RF (rheumatoid factor) or ACPA (anti-citrullinated protein antibodies). At baseline, median disease duration was 13.5 years. Seventy-four percent of patients had received a csDMARD and two thirds had received a bDMARD before rituximab. Rituximab monotherapy was used in 34 patients, while 80 patients received rituximab-csDMARD combination therapy. Twenty-six of the 68 patients in remission (38%) received rituximab monotherapy and 42/68 (62%) received combination therapy with a csDMARD. Twenty-four of 39 (62%) biologic naïve patients achieved remission on treatment with rituximab. Forty-four patients underwent an arthroscopy and synovial biopsy prior to treatment. Synovial tissue lymphoid aggregates (LA) were observed in 21 subjects, of which 17 (81%) showed complete or partial remission in response to treatment with rituximab. The presence of LA was significantly associated with rituximab-induced remission in these patients (p=0.007, OR=7.286 [1.737-30.555]). Conclusion: In this real world series, patients with RA demonstrate long-term, high response rates to rituximab therapy and synovial biopsy B-cell rich lymphoid aggregates are associated with a higher rate of good response.

ObjectivesImmune and stromal cell communication is central in the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), however, the nature of these interactions in the synovial pathology of the two pathotypes can differ. Identifying immune-stromal cell crosstalk at the site of inflammation in RA and PsA is challenging. This study creates the first global transcriptomic analysis of the RA and PsA inflamed joint and investigates immune-stromal cell interactions in the pathogenesis of synovial inflammation.MethodsSingle cell transcriptomic profiling of 178 000 synovial tissue cells from five patients with PsA and four patients with RA, importantly, without prior sorting of immune and stromal cells. This approach enabled the transcriptomic analysis of the intact synovial tissue and identification of immune and stromal cell interactions. State of the art data integration and annotation techniques identified and characterised 18 stromal and 14 immune cell clusters.ResultsGlobal transcriptomic analysis of synovial cell subsets identifies actively proliferating synovial T cells and indicates that due to differential λ and κ immunoglobulin light chain usage, synovial plasma cells are potentially not derived from the local memory B cell pool. Importantly, we report distinct fibroblast and endothelial cell transcriptomes indicating abundant subpopulations in RA and PsA characterised by differential transcription factor usage. Using receptor–ligand interactions and downstream target characterisation, we identify RA-specific synovial T cell-derived transforming growth factor (TGF)-β and macrophage interleukin (IL)-1β synergy in driving the transcriptional profile of FAPα+THY1+invasive synovial fibroblasts, expanded in RA compared with PsA. In vitro characterisation of patient with RA synovial fibroblasts showed metabolic switch to glycolysis, increased adhesion intercellular adhesion molecules 1 expression and IL-6 secretion in response to combined TGF-β and IL-1β treatment. Disrupting specific immune and stromal cell interactions offers novel opportunities for targeted therapeutic intervention in RA and PsA.

Objective To examine the role of synovial CD1c+DCs in patients with Inflammatory Arthritis (IA) with a specific focus on the transcriptional and maturation signatures that govern their function. Methods RNA sequencing was performed on healthy control (HC) peripheral blood (PB), IA PB, and IA synovial fluid (SF) CD1c+DCs. Multiparametric flow-cytometry and SPICE analysis were used to examine site [SF and Synovial Tissue (ST) CD1c+DCs] and disease specific characteristics of CD1c+DCs, while functional assays such as antigen processing, activation, and MMP production were also performed. Results Increased frequency of CD1c+DCs (p

Objective.To compare the association between different remission criteria and physical function in patients with rheumatoid arthritis followed in clinical practice.Methods.Longitudinal data from the METEOR database were used. Seventeen definitions of remission were tested: American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean-based; Simplified/Clinical Disease Activity Index (SDAI/CDAI); and 14 Disease Activity Score (DAS)-based definitions. Health Assessment Questionnaire (HAQ) ≤ 0.5 was defined as good functional status. Associations were investigated using generalized estimating equations. Potential confounders were tested and sensitivity analyses performed.Results.Data from 32,915 patients (157,899 visits) were available. The most stringent definition of remission was the ACR/EULAR Boolean-based definition (1.9%). The proportion of patients with HAQ ≤ 0.5 was higher for the most stringent definitions, although it never reached 100%. However, this also meant that, for the most stringent criteria, many patients in nonremission had HAQ ≤ 0.5. All remission definitions were associated with better function, with the strongest degree of association observed for the SDAI (adjusted OR 3.36, 95% CI 3.01–3.74).Conclusion.The 17 definitions of remission confirmed their validity against physical function in a large international clinical practice setting. Achievement of remission according to any of the indices may be more important than the use of a specific index. A multidimensional approach, targeted at wider goals than disease control, is necessary to help all patients achieve the best possible functional status.

Objectives To investigate the functional role of miR-23a in synovial fibroblasts (SFC) activation in psoriatic arthritis (PsA). Methods Differential expression of the miR-23a-27a-24-2 cluster was identified by real-time quantitative PCR in PsA synovial tissue and peripheral blood mononuclear cells (PBMC) compared to osteoarthritis (OA) and correlated with disease activity. For regulation experiments, PsA synovial fibroblasts (SFC) were cultured with Toll-like receptor (TLR) ligands and pro-inflammatory cytokines. PsA SFC were transfected with a miR-23a inhibitor to assess the functional effect on migration, invasion and expression of pro-inflammatory meditators. The direct interaction between miR-23a and predicted target mRNA, phosphodiesterase 4B (PDE4B), was examined by luciferase reporter gene assay, with the expression and regulation confirmed by RT-PCR and western blot. A PDE4 inhibitor was used to analyse the function of PDE4B signalling in both miR-23a and Poly(I:C)-induced PsA SFC activation. Results Synovial tissue expression of miR-23a was lower in PsA compared to OA and correlated inversely with disease activity and synovitis. TLR activation via Poly(I:C) and LPS, but not Pam3CSK4, significantly decreased miR-23a expression, with no significant effect observed in reponse to stimulation with pro-inflammatory cytokines. Decreased miR-23a expression enhanced PsA SFC migration, invasion and secretion of IL-6, IL-8, MCP-1, RANTES and VEGF. We identified PDE4B as a direct target of miR-23a and demonstrated enhanced mRNA and protein expression of PDE4B in anti-miR-23a transfected PsA SFC. Poly(I:C) and/or miR-23a-induced migration and enhanced cytokine expression was suppressed by the blockade of PDE4 signalling. Conclusions In PsA, dysregulated miR-23a expression contributes to synovial inflammation through enhanced SFC activation, via PDE4B signalling, and identifies a novel anti-inflammatory mechanism of PDE4 blockade.

Giant cell arteritis (GCA) is the most common form of systemic vasculitis. Glucocorticoids are an effective treatment but have significant adverse events and relapses are common. Interleukins 12 (IL-12) and 23 (IL-23) stimulate TWe performed a prospective open label study of ustekinumab in patients with refractory GCA. Ustekinumab 90mg was administered subcutaneously every 12 weeks. The primary outcome was the comparison of the median glucocorticoid dose prior to commencement of ustekinumab and at 52 weeks. Secondary outcomes included physician assessed relapse, acute phase reactants, and imaging assessment of large vessel vasculitis (LVV).Twenty-five GCA patients received ustekinumab. All patients had failed to taper glucocorticoids despite addition of a median of 1 other immunosuppressive agent. At week 52, median (IQR) daily prednisolone dose decreased from 20 (15, 25)mg to 5 (2.5, 5)mg (p0.001). Six patients (24%) stopped prednisolone completely. No patient experienced a relapse of GCA while receiving ustekinumab. Median (IQR) CRP decreased significantly from 12.9 (5.3, 42) to 6 (2.6, 12.5)mg/L (p = 0.006). CT angiography demonstrated improvement of LVV in all patients studied. No unexpected adverse events were observed with ustekinumab.Ustekinumab may be effective for the treatment of GCA and warrants further assessment in a randomized controlled trial.

ObjectivesThis study investigates pathogenic and protective polyfunctional T-cell responses in patient with rheumatoid arthritis (RA), individuals at risk (IAR) and healthy control (HC) synovial-tissue biopsies and identifies the presence of a novel population of pathogenic polyfunctional T-cells that are enriched in the RA joint prior to the development of clinical inflammation.MethodsPathway enrichment analysis of previously obtained RNAseq data of synovial biopsies from RA (n=118), IAR (n=20) and HC (n=44) was performed. Single-cell synovial tissue suspensions from RA (n=10), IAR (n=7) and HC (n=7) and paired peripheral blood mononuclear cells (PBMC) were stimulated in vitro and polyfunctional synovial T-cell subsets examined by flow cytometric analysis, simplified presentation of incredibly complex evaluations (SPICE) and FlowSom clustering. Flow-imaging was utilised to confirm specific T-cell cluster identification. Fluorescent lifetime imaging microscopy (FLIM) was used to visualise metabolic status of sorted T-cell populations.ResultsIncreased plasticity of Tfh cells and CD4 T-cell polyfunctionality with enriched memory Treg cell responses was demonstrated in RA patient synovial tissue. Synovial-tissue RNAseq analysis reveals that enrichment in T-cell activation and differentiation pathways pre-dates the onset of RA. Switch from potentially protective IL-4 and granulocyte macrophage colony stimulating factor (GMCSF) dominated polyfunctional CD4 T-cell responses towards pathogenic polyfunctionality is evident in patient with IAR and RA synovial tissue. Cluster analysis reveals the accumulation of highly polyfunctional CD4+ CD8dim T-cells in IAR and RA but not HC synovial tissue. CD4+ CD8dim T-cells show increased utilisation of oxidative phosphorylation, a characteristic of metabolically primed memory T-cells. Frequency of synovial CD4+ CD8dim T-cells correlates with RA disease activity.ConclusionSwitch from potentially protective to pathogenic T-cell polyfunctionality pre-dates the onset of clinical inflammation and constitutes an opportunity for therapeutic intervention in RA.

ObjectivesPsoriatic arthritis (PsA) is a chronic inflammatory disease associated with psoriasis. Janus Kinase inhibitors (JAKi) have emerged as an encouraging class of drugs for the treatment of PsA. Here, we compare the effect of four JAKi on primary PsA synovial fibroblasts (PsAFLS) activation, metabolic function, and invasive and migratory capacity.MethodsPrimary PsAFLS were isolated and cultured with JAKi (Peficitinib, Filgotinib, Baricitinib and Upadacitinib) in the presence of Oncostatin M (OSM). pSTAT3 expression in response to OSM was quantified by Western Blot analysis. Pro-inflammatory cytokines/chemokines were quantified by ELISA and cell migration by wound-repair scratch assays. Invasive capacity was examined using Matrigel™ invasion chambers and MMP multiplex MSD assays. PsAFLS bioenergetics was assessed using the Seahorse XFe Extracellular Flux Analyzer, which simultaneously quantifies two energetic pathways- glycolysis (ECAR) and oxidative phosphorylation (OCR). In parallel, inflammatory, invasive, and migratory genes were quantified by RT-PCR.ResultsOSM induces pSTAT3 expression in PsAFLS. OSM-induced secretion of MCP-1 and IL-6 was inhibited by all JAKi with Peficitinib, Baricitinib and Upadacitinib showing the greatest effect. In contrast, JAKi had no significant impact on IL-8 expression in response to OSM. PsAFLS cell invasion, migratory capacity and MMP1, 3, and 9 were suppressed following JAKi treatment, with Peficitinib showing the greatest effect. These functional effects were accompanied by a change in the cellular bioenergetic profile of PsAFLS, where JAKi significantly decreased glycolysis and the ECAR/OCR, resulting in a shift to a more quiescent phenotype, with Peficitinib demonstrating the most pronounced effect.ConclusionThis study demonstrates that JAK/STAT signalling mediates the complex interplay between inflammation and cellular metabolism in PsA pathogenesis. This inhibition shows effective suppression of inflammatory mechanisms that drive pathogenic functions of PsAFLS, further supporting the role of JAKi as a therapeutic target for the treatment of PsA.

Background Biologic therapies have greatly improved outcomes in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Yet, our ability to predict long-term remission and persistence or continuation of therapy remains limited. This study explores predictors of remission and persistence of the initial biologic therapy in patients after 12 years. Furthermore, outcomes with adalimumab and etanercept are compared. Patients and methods RA and PsA patients were prospectively recruited from a biologic clinic. Outcomes on commencing therapy, at 1 year and 12 years were reviewed. Demographics, medications, morning stiffness, patient global health score, tender and swollen joint counts, antibody status, CRP and HAQ were collected. Outcomes at 1 year and 12 years are reported and predictors of biologic persistence and EULAR-defined remission (DAS28-CRP Results A total of 403 patients (274 RA and 129 PsA) were analysed. PsA patients were more likely to be male, in full-time employment and have completed higher education. PsA had higher remission rates than RA at both 1 year (60.3% versus 34.5%, p p p p = 0.041). Multivariate analysis showed 1-year continuation [OR 4.28 (1.28–14.38)] and 1-year low-disease activity [OR 3.90 (95% CI 1.05–14.53)] was predictive of a 12-year persistence. Persistence with initial biologic at 12 years [OR 4.98 (95% CI 1.83–13.56)] and male gender [OR 4.48 (95% CI 1.25–16.01)] predicted 12 year remission. Conclusions This is the first study to show better response to biologic therapy in PsA compared to RA at 12 years. Long-term persistence with initial biologic agent was high and was predicted by biologic persistence and low-disease activity at 1 year. Interestingly, PsA patients had higher levels of employment, educational attainment, and long-term remission rates compared to RA patients.

To evaluate the effects of alcohol consumption on disease activity in rheumatoid arthritis. EMBASE, Pubmed, the Cochrane Library, and Web of Science were searched until July 29, 2020. English language studies that reported disease activity outcomes in rheumatoid arthritis were included. Studies were excluded if they were reviews, case reports, had fewer than 20 patients, or reported on prevalence but not disease activity in RA. Forest plots were used to determine pooled mean difference and were generated on RevMan5.3. Linear regression was used to determine correlations between alcohol and antibody status, gender, and smoking status. The search identified 4126 citations of which 14 were included. The pooled mean difference in DAS28 (95% CI) was 0.34 (0.24, 0.44) (p −5) between drinkers and non-drinkers with lower DAS28 in non-drinkers, 0.33 (0.05, 0.62) (p = 0.02) between heavy drinkers and non-drinkers with lower DAS28 in heavy drinkers, and 0.00 (− 0.30, 0.30) (p = 0.98) between low- and high-risk drinkers. The mean difference of HAQ assessments was significantly different between those who drink alcohol compared to those who do not, with drinkers reporting lower HAQ scores (0.3 (0.18, 0.41), p −5). There was no significant correlation between drinking and gender, smoking status, or antibody positivity. Alcohol consumption is associated with lower disease activity and self-reported health assessment in rheumatoid arthritis. However, drinking has no correlation with smoking, gender, or antibody status.

Introduction This study investigates the metabolic activity of circulating monocytes and their impact on pro‐inflammatory responses in RA and explores whether this phenotype is already primed for inflammation before clinical manifestations of disease. Methods Blood was collected and CD14+ monocytes isolated from healthy control donors (HC), individuals at‐risk (IAR) and RA patients. Monocyte frequency in blood and synovial tissue was assessed by flow cytometry. Inflammatory responses and metabolic analysis ± specific inhibitors were quantified by RT‐PCR, Western blot, migration assays, Seahorse‐XFe‐technology, mitotracker assays and transmission electron microscopy. Transcriptomic analysis was performed on HC, IAR and RA synovial tissue. Results CD14+ monocytes from RA patients are hyper‐inflammatory following stimulation, with significantly higher expression of cytokines/chemokines than those from HC. LPS‐induced RA monocyte migratory capacity is consistent with increased monocyte frequency in RA synovial tissue. RA CD14+ monocytes show enhanced mitochondrial respiration, biogenesis and alterations in mitochondrial morphology. Furthermore, RA monocytes display increased levels of key glycolytic enzymes HIF1α, HK2 and PFKFB3 and demonstrate a reliance on glucose consumption, blockade of which abrogates pro‐inflammatory mediator responses. Blockade of STAT3 activation inhibits this forced glycolytic flux resulting in metabolic reprogramming and resolution of inflammation. Interestingly, this highly activated monocytic phenotype is evident in IAR of developing disease, in addition to an enhanced monocyte gene signature observed in synovial tissue from IAR. Conclusion RA CD14+ monocytes are metabolically re‐programmed for sustained induction of pro‐inflammatory responses, with STAT3 identified as a molecular regulator of metabolic dysfunction. This phenotype precedes clinical disease onset and may represent a potential pathway for therapeutic targeting early in disease., In this study, we demonstrated that rheumatoid arthritis CD14+ monocytes are metabolically re‐programmed for sustained induction of pro‐inflammatory responses, an effect that is mediated by STAT3 signalling and precedes clinical disease onset.

BackgroundMicroRNAs (miRNAs) are small non-coding RNAs which have been implicated as potential biomarkers or therapeutic targets in autoimmune diseases. This study examines circulatory miRNAs in RA patients and further investigates if a serum miRNA signature precedes clinical manifestations of disease in arthralgia or “at-risk individuals”.MethodsSerum was collected from HC subjects (N = 20), RA patients (N = 50), and arthralgia subjects (N = 10), in addition to a subgroup of the RA patients post-methotrexate (MTX) (N = 18). The FirePlex miRNA Immunology-V2 panel was selected for multiplex analysis of 68 miRNAs in each sample. DNA intelligent analysis (DIANA)-mirPath and Ingenuity Pathway Analysis (IPA) software were used to predict pathways targeted by the dysregulated miRNAs.Results8 miRNA (miR-126-3p, let-7d-5p, miR-431-3p, miR-221-3p, miR-24-3p, miR-130a-3p, miR-339-5p, let-7i-5p) were significantly elevated in RA serum compared to HC (all p < 0.01) and 1 miRNA (miR-17-5p) was significantly lower in RA (p < 0.01). High specificity and sensitivity were determined by receiver operating characteristic (ROC) curve analysis. Both miR-339-5p and let-7i-5p were significantly reduced post-MTX (both p < 0.01). MiR-126-3p, let-7d-5p, miR-431-3p, miR-221-3p, miR-24-3p, miR-130a-3p were also significantly elevated in subjects “at risk” of developing RA (all p < 0.05) compared to HC. IPA analysis of this miRNA signature identified downstream targets including key transcription factors NF-κB, STAT-1, STAT-3, cytokines IL-1β, TNF-α, and matrix-metalloproteases all importantly associated with RA pathogenesis.ConclusionThis study identified six miRNAs that are altered in both RA and “at-risk individuals,” which potentially regulate key downstream pathways involved in regulating inflammation. These may have potential as predictive signature for disease onset and early progression.

Synovial tissue is the primary tissue inflamed in rheumatoid arthritis. Initial studies of synovial biopsies were obtained during arthroplasty or using a needle to biopsy the joint percutaneously. Recently, small needle arthroscopy or ultrasonography guided techniques have become more widely available to visualize and reliably obtain synovial biopsies. These techniques have allowed significant progress in the study of rheumatoid arthritis pathogenesis, even at the earliest stages of disease. Currently, research efforts are underway to use synovial biopsies to identify patients and to discover biomarkers that will enable clinicians to predict the course of the disease and perhaps to identify more appropriately the correct therapy for patients with rheumatoid arthritis. In this chapter, we describe the advances in synovial tissue biopsy research and how it has improved our knowledge of rheumatoid arthritis pathogenesis, informed our understanding of possible biomarkers for diagnosis and stratification, and potentially may aid in the prediction of disease outcome and response to treatment.

Objectives To establish, amongst Irish rheumatic musculoskeletal disease (RMD) patients, rates of COVID-19 symptoms and positive tests, DMARD adherence and attitudes to virtual clinics. Methods An online survey assessing COVID-19 status, RMD diagnoses, adherence and information sources was disseminated via the Arthritis Ireland website and social media channels. Results There were 1381 respondents with 74.8% on immunosuppressive medication. Symptoms of COVID-19 were reported by 3.7% of respondents of which 0.46% tested positive, consistent with the general Irish population. The frequency of COVID-19 symptoms was higher for respondents with spondyloarthropathy [odds ratio (OR) 2.06, 95% CI: 1.14, 3.70] and lower in those on immunosuppressive medication (OR 0.48, 95% CI: 0.27, 0.88), and those compliant with health authority (HSE) guidance (OR 0.47, 95% CI: 0.25, 0.89). Adherence to RMD medications was reported in 84.1%, with 57.1% using health authority guidelines for information on medication use. Importantly, adherence rates were higher amongst those who cited guidelines (89.3% vs 79.9%, P Conclusion The rate of COVID-19 positivity in RMD patients was similar to the general population. COVID-19 symptoms were lower amongst respondents on immunosuppressive medication and those adherent to medication guidelines. Respondents were supportive of HSE advice and virtual clinics.

Background Osteoarthritis is the most common cause of disability in people over 65 years old. The readability of of online osteoarthritis information has never been assessed. A 2003 study found the quality of online osteoarthritis information to be poor. This study reviews the quality of online information regarding osteoarthritis in 2018 using three validated scoring systems. Readability is reviewed for the first time, again using three validated tools. Methods The term osteoarthritis was searched across the three most popular English language search engines. The first 25 pages from each search engine were analysed. Duplicate pages, websites featuring paid advertisements, inaccessible pages (behind a pay wall, not available for geographical reasons) and non-text pages were excluded. Readability was measured using Flesch Reading Ease Score (FRES), Flesch-Kincaid Grade Level (FKGL) and Gunning-Fog Index (GFI). Website quality was scored using the the Journal of the American Medical Association (JAMA) benchmark criteria and DISCERN criteria. Presence or absence of HONcode certification, age of content, content producer and author characteristics were noted. Results 37 unique websites were suitable for analysis. Readability varied by assessment tool from 8th to 12th grade level. This compares with the recommended 7- 8th grade level. One (2.7%) website met all four JAMA Criteria. Mean DISCERN quality of information for OA websites was “fair”, comparing favourably with the “poor” grading of a 2003 study. HONCode endorsed websites (43.2%) were of a statistically significantly higher quality. Conclusion Quality of online health information for OA is “fair”. 2.7% of websites met JAMA benchmark criteria for quality. Readability was equal to or more difficult than recommendations. HONcode certification was indicative of higher quality, but not readability. Disclosures K. Murray None. T. Murray None. C. Low None. A. O'Rourke None. D.J. Veale None.

Background Pneumococcal and influenza vaccination rates have been suboptimal in studies of immunosuppressed patients. We aimed to assess barriers to and increase rates of 23-valent pneumococcal polysaccharide vaccine (PPSV23) and influenza vaccination in this group. Methods In 2017, Rheumatology outpatients completed an anonymous questionnaire recording vaccination knowledge, status and barriers. Simultaneously, a low-cost multifaceted quality improvement (QI) intervention was performed. All outpatients on oral steroids, immunosuppressant conventional synthetic disease modifying antirheumatic drugs (csDMARDs) or biologics (bDMARDs) were included in the study. In 2018, post-intervention, the clinic was re-assessed. Demographics, diagnosis, medications, smart phone access and willingness to use this for vaccination reminders were assessed for independent vaccination predictors using binary logistic regression analysis. Results 425 patients were included (72.6% rheumatoid arthritis, 74% women, 45.6% ≥60 years old). From 2017-2018, vaccination rates increased for PPSV23 {41.0% to 47.2% (p = 0.29)} and influenza {61.8% to 62.1% (p = 0.95)}. The most common reason for non-vaccination was lack of awareness. Following the intervention, this decreased for influenza (36.7% to 34.2%) and PPSV23 (82.1% to 76.4%). General Practitioners performed most vaccinations, only 3.6% were delivered in hospital. Significant predictors of PPSV23 vaccination were older age {≥80 years had an OR 41.66 (95% CI 3.69-469.8, P = 0.003), compared to ≤ 39 years}, bDMARD use (OR 2.80, 95% CI 1.24-6.32, P = 0.013) and adequate influenza vaccination (OR 9.01, 95% CI 4.40-18.42, P < 0.001). Up to date PPSV23 vaccination (OR 8.93, 95% CI 4.39-18.17, P < 0.001) predicted influenza vaccination. Conclusion PPSV23 and influenza vaccination rates were suboptimal and increased marginally. Point-of-care vaccination may be more effective. Disclosures K. Murray: None. C. Low: None. F. Young: None. A. O'Rourke: None. I. Callanan: None. E. Feeney: None. D. Veale: None.

Background Rheumatic disease (RD) patients when family planning must consider fertility, disease activity, and management from preconception to lactation. A clear understanding is necessary, especially for those receiving disease-modifying antirheumatic medications. Previous studies have highlighted unmet needs in the care of women with RDs with reproductive healthcare needs. This study describes, to our knowledge, the first published standardised reproductive care pathway for women with RDs and the outcomes of this approach. Methods We developed the care pathway with multidisciplinary input from rheumatologists, rheumatology nurse specialists, obstetricians, midwives, maternal medicine specialists, and pharmacists. We identified patients’ emotional and healthcare needs, ensured access to expert advice, maintenance of good disease control, and positive reproductive outcomes. We prospectively followed the patients and report the results of the service. Results Ninety-eight women with median age (range) of 35 years (19-48) were assessed. The majority had an inflammatory arthritis. Seventy-six babies were born to 62 mothers. There were 12 miscarriages and one perinatal death. Breastfeeding rates at 6 weeks were low (28%). Conclusion We describe the first published evidence-based integrated multidisciplinary reproductive care pathway for women with RDs and the results of this approach. Seventy percent of women successful in trying to conceive delivered a healthy baby, and 90% of patients were ‘very satisfied’ with the service. Disclosures K. Murray: None. L. Moore: None. C. O'Brien: None. A. Clohessy: None. C. Brophy: None. F. McAuliffe: None. D. Veale: None.

Summary Rheumatoid arthritis (RA) is a chronic autoimmune disease which causes degradation of cartilage and bone. It is well appreciated that the pathogenic hallmark of RA is the mass influx of inflammatory cells into the joint. However, the role that dendritic cells (DC) may play in this inflammatory milieu is still relatively unexplored. Moreover, the contribution this unique synovial microenvironment has on DC maturation is still unknown. Using monocyte-derived DC (MoDC), we established an in-vitro model to recapitulate the synovial microenvironment to explore DC maturation. MoDC treated with conditioned media from ex-vivo synovial tissue biopsy cultures [explant-conditioned media (ECM)] have increased expression of proinflammatory cytokines, chemokines and adhesion molecules. ECM DC have increased expression of CD83 and CC-chemokine receptor (CCR)7 and decreased expression of CCR5 and phagocytic capacity, suggestive of heightened DC maturation. ECM-induced maturation is concomitant with altered cellular bioenergetics, whereby increased expression of glycolytic genes and increased glucose uptake are observed in ECM DC. Collectively, this results in a metabolic shift in DC metabolism in favour of glycolysis. These adaptations are in-part mediated via signal transducer and activator of transcription-3 (STAT-3), as demonstrated by decreased expression of proinflammatory cytokines and glycolytic genes in ECM DC in response to STAT-3 inhibition. Finally, to translate these data to a more in-vivo clinically relevant setting, RNA-seq was performed on RA synovial fluid and peripheral blood. We identified enhanced expression of a number of glycolytic genes in synovial CD1c+ DC compared to CD1c+ DC in circulation. Collectively, our data suggest that the synovial microenvironment in RA contributes to DC maturation and metabolic reprogramming.

Objective To examine the effects of tofacitinib on metabolic activity, mitochondrial function, and proinflammatory mechanisms in rheumatoid arthritis (RA). Methods Ex vivo RA synovial explants and primary RA synovial fibroblasts (RASFs) were cultured with 1 μM tofacitinib. RASF bioenergetics were assessed using an XF24 analyzer, and key metabolic genes were assessed by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Mitochondrial function was assessed using specific cell fluorescent probes and by mitochondrial gene arrays. Mitochondrial mutagenesis was quantified using a mitochondrial random mutation capture assay, and lipid peroxidation was quantified by enzyme-linked immunosorbent assay (ELISA). The effect of tofacitinib on spontaneous release of proinflammatory mediators from RA whole tissue synovial explants was quantified by ELISAs/MSD multiplex assays, and metabolic markers were quantified by RT-PCR. Finally, RASF invasion, matrix degradation, and synovial outgrowths were assessed by transwell invasion/Matrigel outgrowth assays and ELISA. Results Tofacitinib significantly decreased mitochondrial membrane potential, mitochondrial mass, and reactive oxygen species production by RASFs and differentially regulated key mitochondrial genes. Tofacitinib significantly increased oxidative phosphorylation, ATP production, and the maximal respiratory capacity and the respiratory reserve in RASFs, an effect paralleled by a decrease in glycolysis and the genes for the key glycolytic enzymes hexokinase 2 (HK2), glycogen synthase kinase 3α (GSK-3α), lactate dehydrogenase A, and hypoxia-inducible factor 1α. Tofacitinib inhibited the effect of oncostatin M (OSM) on interleukin-6 (IL-6) and monocyte chemotactic protein 1 and reversed the effects of OSM on RASF cellular metabolism. Using RA whole tissue synovial explants, we found that tofacitinib inhibited the key metabolic genes for glucose transporter 1, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, 3'-phosphoinositide-dependent protein kinase 1, HK2, and GSK-3α, the proinflammatory mediators IL-6, IL-8, IL-1β, intercellular adhesion molecule 1, vascular endothelial growth factor, and TIE-2, and RASF outgrowth from synovial explants, RASF invasion, and matrix metalloproteinase 1 activity. Conclusion This study demonstrates that JAK/STAT signaling mediates the complex interplay between inflammation and cellular metabolism in RA pathogenesis.

Inflammatory Arthritis is characterized by synovial proliferation, neovascularization and leukocyte extravasation leading to joint destruction and functional disability. Efficiency of oxygen supply to the synovium is poor due to the highly dysregulated synovial microvasculature. This along with the increased energy demands of activated infiltrating immune cells and inflamed resident cells leads to an hypoxic microenvironment and mitochondrial dysfunction. This favors an increase of reactive oxygen species, leading to oxidative damage which further promotes inflammation. In this adverse microenvironment synovial cells adapt to generate energy and switch their cell metabolism from a resting regulatory state to a highly metabolically active state which allows them to produce essential building blocks to support their proliferation. This metabolic shift results in the accumulation of metabolic intermediates which act as signaling molecules that further dictate the inflammatory response. Understanding the complex interplay between hypoxia-induced signaling pathways, oxidative stress and mitochondrial function will provide better insight into the underlying mechanisms of disease pathogenesis.

We read with interest the research letter by Raychaudhuri et al , which examines the frequencies of cytokine producing CD4+ memory T cells in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) synovial fluid mononuclear cells (SFMC) compared with peripheral blood mononuclear cells (PBMC).1 The authors examined the frequencies of single cytokine-producing T cells, specifically interleukin (IL)-17A+, IL-22+, tumour necrosis factor (TNF)+, interferon gamma (IFNγ)+ or IL-23R+ and report that Th17 cells are enriched in PsA SFMC, while RA is skewed to a Th1-like profile. In our previous publication, Wade et al ,2 we reported the frequencies of both single cytokine-producing and multiple cytokine (polyfunctional)-producing T cells, in addition to the frequencies of Th1, Th17 and exTh17 cells by using the Th17 lineage marker CD161. In our study, however, we reported these findings in synovial tissue biopsies from PsA patients, as opposed to …

Introduction Angiogenesis is an early event in the pathogenesis of both psoriatic arthritis (PsA) and rheumatoid arthritis (RA); however, there are striking differences in blood vessel morphology and activation between the two arthropathies. The aim of this study was to assess if the PsA and RA joint microenvironments differentially regulate endothelial cell function. Methods PsA and RA primary synovial fibroblasts (SFC) were isolated from synovial biopsies, grown to confluence, and supernatants harvested and termed ‘conditioned media’ (CM). Human umbilical vein endothelial cells (HUVEC) were cultured with PsA SFC or RA SFC-CM (20%). HUVEC tube formation, migration, and PBMC adhesion were assessed by matrigel tube formation, wound repair, and PBMC adhesion assays. HUVEC cell surface expression of ICAM, VCAM, and E-Selectin was assessed by flow cytometry. Transcriptome analysis of genes promoting angiogenesis was performed by real-time PCR. Finally, a MSD multiplex angiogenic assay was performed on PsA SFC and RA SFC supernatants. Results Macroscopic synovitis and vascularity were similar in PsA and RA patients; however, significant differences in vascular morphological pattern were recorded with tortuous, elongated vessels observed in PsA compared to straight regular branching vessels observed in RA. Transcriptome analysis showed strong upregulation of the pro-angiogenic signature in HUVEC primed with PsA SFC-CM compared to RA SFC-CM and basal control. In parallel, paired PsA SFC-CM significantly induced HUVEC tube formation compared to that of RA SFC-CM. Furthermore, PsA SFC-CM induced HUVEC migration was paralleled by a significant induction in VEGFA, PFKFB3, ICAM-1, and MMP3 mRNA expression. A significant increase in PBMC adhesion and cell surface expression of VCAM-1, ICAM-1, and E-Selectin expression was also demonstrated in PsA SFC-CM-primed HUVEC compared to RA SFC-CM. Finally, VEGF, TSLP, Flt-1, and Tie-2 expression was elevated in PsA SFC-CM compared to RA SFC-CM, with no significant difference in other pro-angiogenic mediators including MIP-3, bFGF, PIGF, and MCP-1. Conclusion PsA SFC and RA SFC secreted factors differentially regulate endothelial cell function, with soluble mediators in the PsA joint microenvironment inducing a more pro-angiogenic phenotype compared to the RA.

Summary Psoriatic arthritis is a chronic, immune-mediated, inflammatory arthropathy that presents with inflammation of the joints and entheses, including those of the axial skeleton, and is associated with increased mortality from cardiovascular disease. Diagnosis is primarily based on clinical phenotype because of the diversity of the associated features, which can include skin and nail disease, dactylitis, uveitis, and osteitis. Improved understanding of the pathogenesis of psoriatic arthritis has led to the development of effective biologics and small-molecular drugs targeting specific cytokines and signalling pathways, which can prevent disease progression and improve quality of life. However, at least 40% of patients with psoriatic arthritis have only a partial response or fail to respond to such treatments. Cytokine inhibitors, mainly those specific for tumour necrosis factor and, more recently, the interleukin 23–T-helper-17 cell pathway, have been highly successful in the treatment of disease manifestations in several different tissues, although targeting the interleukin 23–T-helper-17 cell pathway might be more effective in psoriasis than in arthritis. However, the precise mechanisms underlying the pathogenesis of psoriatic arthritis—which include genetics, environmental factors, and immune-mediated inflammation—are complex, and the relationship between disease of the joint and that of other domains is poorly understood. Improving our understanding of psoriatic arthritis pathogenesis could help to establish validated biomarkers for diagnosis, predict therapeutic response and remission, develop precision medicines, and predict which patients will respond to which therapy. We discuss advances in pathogenetic translational research that could inform these issues.

To assess the association between smoking, anti-cyclic citrullinated peptide (anti-CCP) antibody status, and clinical efficacy of biological therapies in rheumatoid arthritis (RA) patients.This retrospective clinical practice setting study included 1349 RA patients from the METEOR database (aged18 years). We collected data on sociodemographics, smoking status (smoker,10, 10-19, and20 cigarettes/day; ex-smoker; non-smoker), baseline disease activity parameters and anti-CCP, previous disease-modifying anti-rheumatic drugs (DMARDs), biological therapy, combined therapy (steroids and DMARDs), and follow-up disease activity. Clinical efficacy was assessed by European League Against Rheumatism (EULAR) good/moderate response rates for all aggregated biological therapies, based on both smoking and anti-CCP status.The non-smoking RA patients were more often female at biological therapy initiation than the ex-smokers and smokers (91.1% vs 60.4% and 67.9%, respectively, p 0.001), and ex-smokers were older than non-smokers and smokers (mean ± sd 56.5 ± 11.1, 53.5 ± 13.3 and 51.3 ± 11.0 years old, respectively; p 0.001). In total, 845 (62.6%) were non-smokers, 214 (15.9%) ex-smokers, and 290 (21.5%) smokers [daily cigarettes smoked: 148 (11%)11; 61 (4.5%) 11-20; and 81 (6%)20]. Anti CCP-antibody status was similar in both groups. Non-smokers showed higher baseline DAS28 than ex-smokers and smokers (5.0 ± 1.5 vs 4.7 ± 1.4 and 4.7 ± 1.4, respectively; p 0.001) and used more baseline steroids and DMARDs. A higher EULAR response rate was observed in non-smokers than in ex-smokers and smokers (73% vs 65% and 64.1%, respectively; p = 0.004). Drug survival was higher in non-smokers compared to ex-smokers and smokers [57.7 months (46.4-53.8), 38.6 (30.3-46.8), and 50.1 (41.8-58.4); p0.001, respectively].In daily clinical practice, non-smokers respond better than smokers to biological therapy, but this does not result in better drug survival.

Therapeutic targets have been defined for axial and peripheral spondyloarthritis (SpA) in 2012, but the evidence for these recommendations was only of indirect nature. These recommendations were re-evaluated in light of new insights. Based on the results of a systematic literature review and expert opinion, a task force of rheumatologists, dermatologists, patients and a health professional developed an update of the 2012 recommendations. These underwent intensive discussions, on site voting and subsequent anonymous electronic voting on levels of agreement with each item. A set of 5 overarching principles and 11 recommendations were developed and voted on. Some items were present in the previous recommendations, while others were significantly changed or newly formulated. The 2017 task force arrived at a single set of recommendations for axial and peripheral SpA, including psoriatic arthritis (PsA). The most exhaustive discussions related to whether PsA should be assessed using unidimensional composite scores for its different domains or multidimensional scores that comprise multiple domains. This question was not resolved and constitutes an important research agenda. There was broad agreement, now better supported by data than in 2012, that remission/inactive disease and, alternatively, low/minimal disease activity are the principal targets for the treatment of PsA. As instruments to assess the patients on the path to the target, the Ankylosing Spondylitis Disease Activity Score (ASDAS) for axial SpA and the Disease Activity index for PSoriatic Arthritis (DAPSA) and Minimal Disease Activity (MDA) for PsA were recommended, although not supported by all. Shared decision-making between the clinician and the patient was seen as pivotal to the process. The task force defined the treatment target for SpA as remission or low disease activity and developed a large research agenda to further advance the field. orcid-numbers: Machado, Pedro/0000-0002-8411-7972 Inman, Robert/0000-0002-4750-1422 unique-id: ISI:000417778700007 ispartof: Annals Of The Rheumatic Diseases vol:77 issue:1 pages:3-17 ispartof: location:England status: published

There are now high-quality data showing rheumatoid arthritis improves in pregnancy and flares post partum, and that active disease in pregnancy may be associated with adverse fetal outcomes such as low birth weights. However, in psoriatic arthritis (PsA), the data are less clear. Previous studies examining the disease course of PsA, in and around pregnancy, have found conflicting results.1–3 Only one of those studies was prospective and many lack disease activity scores. Much of the data also predate the widespread use of biologic disease-modifying antirheumatic drugs (bDMARDs) in pregnancy and so may not reflect current clinical practice. A recent abstract reviewing a Swedish patient registry reported increased odds of preterm birth, induction of labour and caesarean section in PsA pregnancies compared with population comparators.4 Consecutive female patients with PsA planning pregnancy or were …

Objective Serum anti–citrullinated peptide antibodies (ACPAs) may be present before the development of rheumatoid arthritis (RA) and may be predictive of more severe, erosive disease. This study was undertaken to examine the synovial tissue immunophenotype according to ACPA status in patients with RA, as well as the response to treatment and erosion status. Methods Consecutive RA patients were prospectively recruited and underwent clinical and serologic assessments before and after treatment. Radiologic assessment was performed at the time of clinical follow-up. Synovial tissue was immunostained for specific markers of B cells (CD19), T cells (CD3, CD4, and CD8), macrophages (CD68), and blood vessels (factor VIII). Serum CXCL13 levels were quantified by enzyme-linked immunosorbent assay. Synovial tissue sections were analyzed for immunophenotype according to ACPA status, using a validated semiquantitative scoring method, and also analyzed for the presence of lymphoid aggregates. Response to treatment with nonbiologic or biologic disease-modifying antirheumatic drugs was assessed using the European League Against Rheumatism (EULAR) response criteria. Results In total, 123 subjects (78 ACPA+) were included. Compared to ACPA– RA patients, synovium from ACPA+ RA patients was characterized by significantly higher levels of CD19+ B cells and CD3+ and CD8+ T cells (each P < 0.05), and CD19+ B cell levels were significantly higher in patients who were naive to treatment. The CD19+ B cell infiltrate level was higher in patients with erosions at follow-up (P = 0.0128). Levels of lymphoid aggregates of CD19+ B cells were significantly higher in ACPA+ patients (P < 0.05), and this was associated with increased serum CXCL13 levels. The EULAR response was significantly associated with the level of CD3+ T cell infiltrates (P < 0.05), while CD68+ macrophage and CD8+ T cell levels were predictive of the response to tumor necrosis factor inhibitors (P < 0.05). Conclusion The results of this prospective study demonstrate that the levels of synovial B cell infiltrates and lymphoid aggregates were significantly higher in ACPA+ RA patients, especially those who were naive to treatment. In addition, ACPA+ subjects developed more erosions during progression of the disease and had higher serum levels of CXCL13. The EULAR response to therapy in ACPA+ RA patients was associated with increased levels of T cell and macrophage markers.

Objective Patient-physician discordance in global assessment of disease activity concerns one-third of patients, but what does it reflect? We aimed to assess patient-physician discordance in psoriatic arthritis (PsA) and patient-reported domains of health (physical and psychological) associated with discordance. Methods We analyzed the PsAID (Psoriatic Arthritis Impact of Disease), a cross-sectional, multicenter European study of patients with PsA according to expert opinion. Patient global assessment (PGA) and physician global assessment (PhGA) were rated on a 0–10 numeric rating scale. Discordance was defined as the difference (PGA−PhGA) and as the absolute difference |PGA−PhGA| ≥3 points. Determinants of PGA−PhGA were assessed by a stepwise multivariate linear regression among 12 physical and psychological aspects of impact: pain, skin problems, fatigue, ability to work/leisure, functional incapacity, feeling of discomfort, sleep disturbance, anxiety/fear, coping, embarrassment/shame, social participation, and depressive affects. Results In 460 patients (mean ± SD age 50.6 ± 12.9 years, 52.2% female, mean ± SD disease duration 9.5 ± 9.5 years, mean ± SD Disease Activity Index for Psoriatic Arthritis score 30.8 ± 32.4, and 40.4% undergoing treatment with biologic agents), the mean ± SD PGA was higher than the mean PhGA, with a mean absolute difference of 1.9 ± 1.8 points. Discordance defined by |PGA−PhGA| ≥3 of 10 concerned 134 patients (29.1%), and 115 patients (85.8% of the patients with discordance) had PGA>PhGA. Higher fatigue (β = 0.14), lower self-perceived coping (β = 0.23), and impaired social participation (β = 0.16) were independently associated with a higher difference (PGA−PhGA). Conclusion Discordance concerned 29.1% of these patient/physician dyads, mainly by PGA>PhGA. Factors associated with discordance were psychological rather than physical domains of health. Discordance was more frequent in patients in remission, indicating more work is needed on the patient perspective regarding disease activity.

Resume Objectif L’evaluation globale par le patient (EVAgb) est une methode d’evaluation essentielle dans le rhumatisme psoriasique. L’objectif etait d’analyser l’interet de l’evaluation globale par le patient dans le rhumatisme psoriasique en etudiant les associations avec les domaines de sante du questionnaire PsAID (Psoriatic Arthritis Impact of Disease). Methodes Analyse post-hoc d’une etude transversale multicentrique de patients atteints de rhumatisme psoriasique. Les donnees collectees comprenaient l’evaluation globale par le patient, les evaluations globales specifiques d’articulation et de peau par le patient, le questionnaire PsAID couvrant l’impact physique (y compris les manifestations articulaires et cutanees) et l’impact psychologique et social ainsi que d’autres elements de comparaison. Une analyse univariee (correlation de Pearson) et une regression lineaire multivariee ont ete menees pour expliquer l’evaluation globale par le patient et les evaluations globales specifiques d’articulation et de peau par le patient. Resultats Parmi les 223 patients (âge moyen 51,0 [ecart type ± 13,3] ans, duree moyenne de la maladie 9,9 [± 10,1] ans, nombre d’articulations gonflees 4,1 [± 5,1], 84,3 % ayant un psoriasis [pour la plupart moins de 5 % de la surface corporelle]), 50,2 % etaient des femmes. Les valeurs moyennes de l’EVAgb etaient de 4,8 (± 2,7), les valeurs moyennes respectives des evaluations d’articulation et de peau etaient de 5,6 (± 2,5) et de 4,1 (± 3,0). La correlation intra-classe entre l’EVAgb et les evaluations d’articulation et de peau etait respectivement de 0,71 (IC a 95 %, 0,64–0,77) et de 0,52 (IC a 95 %, 0,42–0,60). D’apres l’analyse multivariee, l’EVAgb du patient etait bien expliquee (R2 du modele 0,754) par le « coping » ou capacite a faire face (β = 0,287) ; la douleur (β = 0,240) ; les activites de travail et/ou de loisir (β = 0,141) ; et l’anxiete (β = 0,109). Conclusions L’evaluation globale par le patient dans le rhumatisme psoriasique s’expliquait principalement par les composantes physiques mais egalement psychologiques de la maladie.

Objective To examine the prevalence of α1-antitrypsin deficiency (AATD) in rheumatoid arthritis (RA), and to determine whether AATD is associated with higher levels of rheumatoid factor (RF), antinuclear antibodies (ANAs), and anti–citrullinated peptide autoantibodies (ACPAs). Methods RF, ANAs, and ACPAs were measured by standard immunoturbidimetry, immunofluorescence assay, and enzyme-linked immunosorbent assay, respectively. Characterization of AAT phenotypes was performed by isoelectric focusing and immunofixation. The chi-square test with Yates' correction and the Mann-Whitney U test were used to assess the prevalence of alleles associated with AATD in RA and to compare mean antibody titers, respectively. Results Of 246 patients with RA, 24 who were heterozygous for AATD were identified, with no statistically significant difference in the prevalence of AATD between RA patients and the general population (P = 0.39). A positive association between heterozygosity for AATD and the production of ACPAs was observed (P

The inflammatory CD40–CD40L pathway is implicated in various autoimmune diseases, but the activity status of this pathway in various stages of rheumatoid arthritis (RA) progression is unknown. In this study, we used gene signatures of CD40L stimulation derived from human immature dendritic cells and naive B cells to assess the expression of CD40-downstream genes in synovial tissues from anti-citrullinated protein Ab–positive arthralgia, undifferentiated arthritis (UA), early RA, and established RA cohorts in comparison with healthy donors. Interestingly, the expression of CD40LG and active full-length CD40 was increased in the disease tissues, whereas that of a dominant-negative CD40 isoform was decreased. Gene set variation analysis revealed that CD40L-responsive genes in immature dendritic cells and naive B cells were significantly enriched in synovial tissues from UA, early RA, and established RA patients. Additionally, CD40L-induced naive B cell genes were also significantly enriched in synovial tissues from arthralgia patients. In our efforts to characterize downstream mediators of CD40L signaling, we have identified GPR120 and KDM6B as novel components of the pathway. In conclusion, our data suggest that therapeutic CD40–CD40L blocking agents may prove efficacious not only in early and established RA, but also in inhibiting the progression of the disease from arthralgia or UA to RA.

Pneumococcal and influenza vaccination rates have been suboptimal in studies of immunosuppressed patients. We aimed to assess barriers to and increase rates of 23-valent pneumococcal polysaccharide vaccine (PPSV23) and influenza vaccination in this group. The primary endpoint was a statistically significant increase in adequate PPSV23 and influenza vaccination.In 2017, rheumatology outpatients completed an anonymous questionnaire recording vaccination knowledge, status, and barriers. Simultaneously, a low-cost multifaceted quality improvement (QI) intervention was performed. All outpatients on oral steroids, immunosuppressant conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biologics disease-modifying antirheumatic drugs (bDMARDs) were included in the study. In 2018, post-intervention, the clinic was re-assessed. Demographics, diagnosis, medications, smart phone access, and willingness to use this for vaccination reminders were assessed for independent vaccination predictors using binary logistic regression analysis.Four hundred twenty-five patients were included (72.6% rheumatoid arthritis, 74% women, 45.6% ≥ 60 years old). From 2017 to 2018, PPSV23 vaccination rates changed from 41.0 to 47.2% (P = 0.29) and influenza from 61.8 to 62.1% (P = 0.95). The most common reason for non-vaccination was lack of awareness. Following the intervention, this changed for influenza (36.7 to 34.2%) and PPSV23 (82.1 to 76.4%). General practitioners performed most vaccinations, only 3.6% were delivered in the hospital. Significant predictors of PPSV23 vaccination were older age {≥ 80 years had an OR 41.66 (95% CI 3.69-469.8, P = 0.003), compared with ≤ 39 years}, bDMARD use (OR 2.80, 95% CI 1.24-6.32, P = 0.013), and adequate influenza vaccination (OR 9.01, 95% CI 4.40-18.42, P 0.001). Up-to-date PPSV23 vaccination (OR 8.93, 95% CI 4.39-18.17, P 0.001) predicted influenza vaccination.PPSV23 and influenza vaccination rates were suboptimal. The intervention did not cause a statistically significant change in vaccination rates. Point-of-care vaccination may be more effective.Key Points• Low vaccination rates amongst immunosuppressed inflammatory arthritis outpatients• Less than 5% of vaccinations occurred in hospital• There was no statistically significant difference in the rates of adequate PPSV23 (41.0 to 47.2%) or influenza (61.8 to 62.1%) vaccination following our intervention.

Background Several biologic disease modifying anti-rheumatic drugs (bDMARDs) are currently available, but comparisons among these different drugs in clinical trials are rare and follow-up duration in trials is often limited. A comparison of these bDMARDs in daily practice can provide clinically relevant knowledge on treatment survival of all currently available bDMARDs. Objectives To assess the survival of each and every one of the biological therapies available in patients with rheumatoid arthritis (RA). Methods The METEOR registry is a multinational project that includes data on> 40,000 patients with RA from its diagnosis and prospectively, with proven reliability, in clinical practice. Inclusion criteria: patients> 18 years in biological treatment (bDMARD). Variables under study: disease onset date, bDMARD initiation and discontinuation date, bDMARD type (infliximab, certolizumab, adalimumab, golimumab, etanercept, rituximab, tocilizumab and abatacept), concomitant treatment, line of treatment. Clinical variables: TJC, SJC, ESR, CRP, BMI, patient‘s VAS, and RF and ACPA levels; smoking status. Cox regression analysis that was adjusted for several potential confounders. Results From the 47,263 patients registered in the total METEOR database, 11,132 were eligible for inclusion of the current study. Of these, 9,516 had sufficient data available and were included in the analyses. Included patients (n=9,516) less often smoked than non-included patients (n=1,616), but other baseline characteristics were very similar between groups (data not shonw). Baseline features of all patients were similar. Median time on bDMARD as 1st line treatment for each drug is shown in Table 1, infliximab showed the longest median time on treatment. Using infliximab as ‘reference’ treatment, Table 2 shows abatacept, certolizumab, rituximab and tocilizumab showed higher hazard risk to finish the treatment prematurely, while adalimumab, golimumab or etanercept had similar results than infliximab. Conclusion: after adjusting by several confounders, analysed data showed that most anti-TNF (infliximab, adalimumab, etanercept and golimumab) had a similar hazard to stop treatment in clinical practice. Other than anti-TNF bDMARD showed higher hazard to switch treatment than infliximab. Disclosure of Interests Vicenc Torrente-Segarra Speakers bureau: Roche, GSK, UCB, Thomas Huizinga Consultant for: Merck, UCB, Bristol Myers Squibb, Biotest AG, Pfizer, GSK, Novartis, Roche, Sanofi-Aventis, Abbott, Crescendo Bioscience Inc., Nycomed, Boeringher, Takeda, Zydus, Epirus, Eli Lilly, Karen Solomon-Escoto: None declared, Jose Antonio P. da Silva: None declared, Douglas Veale: None declared, Samar Al Emadi: None declared, Sytske Anne Bergstra Grant/research support from: Bristol-Myers Squibb provided funding for the completion of this study and the development of the abstract.

Background: Appropriate management can reduce the increased perioperative infection risk in RA patients(1). In 2017, American College of Rheumatology (ACR) and the American Association of Hip and Knee Surgeons released Guidelines for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty(1). Atlanto-axial subluxation at induction of general anaesthetic (GA) is another concern. Preoperative C-spine X-rays with flexion-extension views are recommended(2). Objectives: Assess compliance with medication guidelines and C-spine imaging practices for RA patients undergoing arthroplasty under GA. Methods: An anonymous 24 question paper-based survey was distributed at Irish Society of Rheumatology Meeting (September 2017) and Irish Institute of Trauma and Orthopaedic Surgery Curriculum Day (January 2018) examining clinician demographics, imaging and prescribing practices. Results: 33 orthopaedists and 23 rheumatologists responded. The majority (n=46) were trainees and The guideline advocates cDMARD continuation perioperatively(1). Rheumatologists are more likely than orthopaedists to continue cDMARDs (Pearson Chi squared, 0.001). 8 (36%) rheumatologists continue cDMARDs, 6 (27%) stop one week preoperatively and 8 (36%) at two weeks. 1 orthopaedist never stops cDMARDs. 8 (24%) stop at one week preoperatively, 13 (39%) at 2 weeks, 5 (15%) at 4 weeks. 6 (18%) were unsure. The guideline advocates stopping bDMARDs 1 dosing cycle preoperatively and restarting after wound healing. Depending on the agent, 2 to 4 rheumatologists never stop bDMARDs preoperatively. Responses varied by medication half-life. 18 hold etanercept for 8 weeks. 2 orthopaedists never stop bDMARDs preoperatively. Depending on the agent, 14-15 would stop 8 weeks 0-1 times. Regarding patients on glucocorticoids for RA, the guideline advocates continuing current dosing perioperatively. 6 orthopaedists always increase steroids (13 sometimes, 9 never, 5 unsure). 7 never stop (13 sometimes, 6 always, 5 unsure). 12 rheumatologists sometimes increased steroids (8 always, 1 never, 1 not sure, 1 no answer). 14 never stop steroids (8 sometimes, one not sure). In RA patients undergoing GA, 22 orthopaedists always perform C spine imaging prior (10 sometimes, 1 never). 11 rheumatologists always do C spine imaging prior (11 sometimes, 1 never). Orthopaedists are more likely than rheumatologists to always perform spinal imaging preoperatively (P value=0.002, Fisher’s exact test). Conclusion: There is poor compliance with guidelines and variability and uncertainty in prescribing. Orthopaedists often discontinue sDMARDs preoperatively despite guidelines to the contrary. Orthopaedists are more likely than rheumatologists to perform preoperative C spine imaging as per recommendations. References: [1] Goodman SM, Springer B, Guyatt G, Abdel MP, Dasa V, George M, et al. 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons guideline for the perioperative management of antirheumatic medication in patients with rheumatic diseases undergoing elective total hip or total knee arthroplasty. Arthritis care & research. 2017;69(8):1111-24. [2] Wasserman BR, Moskovicich R, Razi AE. Rheumatoid arthritis of the cervical spine. Bull NYU Hosp Joint Dis.2011;69:136-48. Disclosure of Interests: Kieran Murray Grant/research support from: Newman Research Fellowship (Abbvie), Tristan Cassidy: None declared, Abuelmagd Abdalla: None declared, Timothy Murray: None declared, Anna O’Rourke: None declared, Douglas Veale: None declared

Background: The single nucleotide variant rs26232 has been associated with both the susceptibility to, and severity of, rheumatoid arthritis (RA). There is an allele dose response between rs26232 and radiological damage, with the minor, T, allele being protective against disease severity. Rs26232 is situated in the first intron of C5orf30, which is a negative regulator of tissue damage and inflammation in RA. Objectives: The objective of this study is to elucidate the mechanism by which rs26232 may mediate disease severity. We also aimed to determine the genotype-phenotype association of rs26232 in rheumatoid arthritis synovial fibroblasts (RASF). Methods: RASF were derived from knee biopsies of RA patients taken at arthroscopy (n=33). RASFs were used between passages 3-8. Matrigel-coated Boyden transwell chambers were used to measure invasion. Wound healing (scratch assays) were used to measure migration, whereas proliferation was measured via crystal violet staining of fixed RASF. Intracellular cytokine staining and cell surface markers were measured via flow cytometry. Secreted cytokines were measured in the supernatant of RASF using ELISA. Rs26232 genotype was determined by PCR genotyping assay with allelic discrimination analysis. Anticitrullinated protein antibody (ACPA) status was measured for each participant. Quantitative real-time PCR was used to measure gene expression. Mann-Whitney U test was used to compare two independent groups, Kruskal-Wallis test was used to compare groups of greater than two. Results: 49% (n=16) of our RASF cohort where homozygous for the major allele CC, 42% (n=14) were heterozygous CT, 9% (n=3) were TT. Rs26232 is associated with invasion of RASFs with the CC genotype being more invasive than the CT genotype (p=0.021). RASFs with the CC genotype had increased ICAM1 and VEGF cell surface expression compared to CT genotype (p=0.001, p=0.05 respectively). MCP1/CCL2 was decreased in CC compared to CT (p=0.013). No association was found between rs26232 genotype and migration, proliferation, or expression of MMP3, TIMP3, IP10 or MIP1a. rs26232 is located in the first intron of C5orf30. There was no differential expression of total C5orf30 or with any of the 3 individual transcript variants in rs26232 genotype groups. In silico analysis of the region in which rs26232 is located on chromosome 5 identified a DNase Hypersensitivity cluster. Furthermore, mining of the Genotype-Tissue Expression (GTEX) expression quantitative trait loci (eQTL) database revealed a cluster of genes located upstream on chromosome 5 (102,850,000-103,150,000) associated with rs26232. This region upstream from rs26232 contains 4 genes (EIF3KF1, PPIP5K2, PAM and GIN1), of which three are eQTLs of rs26232. In silico analysis revealed that the 3 eQTLs (EIF3KF1, PPiP5K2 and PAM) also contain the active enhancer mark H3K27Ac, whereas GIN1 does not. Conclusion: The CC genotype of rs26232 is associated with both increased invasiveness of RASFs and increased adhesion markers compared to CT genotype. Rs26232 does not mediate its affect via its nearest gene, C5orf30. Rather, in silico analysis predicts rs26232 may function as a distal regulator of EIF3KF1, PPIP5K2 and PAM. Future work will test the hypothesis that rs26232 genotype phenotype association is mediated by EIF3KF1, PPIP5K2 and PAM. Disclosure of Interests: None declared

Background: Disease-related immune dysfunction and medications cause immunosuppression in inflammatory arthritis (IA)(1). EULAR and Centers for Disease Control (CDC) recommend influenza and 23-valent pneumococcal polysaccharide (PPSV23) vaccination. Previous studies show suboptimal coverage. Objectives: To increase influenza (annual) and PPSV23 (5 yearly) vaccination in immunosuppressed IA patients through a multifaceted quality improvement intervention. Methods: Between April and September 2017, IA patients completed an anonymous paper 23 question worksheet recording demographics, medical history, medications, vaccination knowledge, status and barriers. All patients on oral steroids, bDMARDs or immunosuppressant cDMARDs were included. Simultaneously, we introduced staff education sessions, point-of-care paper “Arthritis and Infection Worksheets” and “Vaccination Advice Letters”. In 2018, the clinic was re-assessed. Results: 163 patients met inclusion criteria in 2017 and 262 in 2018. Patients were typical of an IA clinic (74% women, 45.4%≥60 years old, 72.7% had RA, 61.1% on cDMARDs, 53.6% on methotrexate, 46.6% on bDMARDs, 23.1% on cDMARD plus bDMARD). In 2017, 104 (65.4%) knew of the increased infectious risk of IA. In 2018, 168 (65.6%) were aware. Awareness of infection risk with medications increased from 111 (69.8%) to 172 (66.9%). Table 1 shows vaccination rates. PPSV23 rates increased from 41.0% to 47.2% (P value=0.29. Pearson Chi squared), and influenza from 61.8% to 62.1% (P value=0.95, Pearson Chi squared). Vaccination awareness was higher for influenza (Table 2). Most patients were informed of requirements and vaccinated by general practitioners (GPs), with Conclusion: This study shows suboptimal vaccination awareness and uptake. Our interventions increased PPSV23 and influenza vaccination rates. There is debate about who is responsible for vaccinations. Guidelines advocate specialists sharing responsibility with GPs. 57% of rheumatologists considered GPs responsible (2). Perhaps, we should take a more active approach. References [1] Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis & Rheumatism.2002;46(9):2287-93 [2] McCarthy EM, Azeez MA, Fitzpatrick FM, Donnelly S. Knowledge, attitudes, and clinical practice of rheumatologists in vaccination of the at-risk rheumatology patient population. JCR: Journal of Clinical Rheumatology. 2012;18(5):237-41 Disclosure of Interests: Kieran Murray Grant/research support from: Newman Research Fellowship (Abbvie), Francis Young: None declared, Candice Low: None declared, Anna O’Rourke: None declared, Ian Callanan: None declared, Eoin Feeney: None declared, Douglas Veale: None declared

Angiogenesis is the outgrowth of new blood vessels from existing ones and is an early occurrence in inflamed joint tissue. It is governed by a tightly controlled balance of pro- and anti-angiogenic stimuli, which promote or inhibit generation and proliferation of new endothelial cells, vascular morphogenesis, and vessel remodeling. At the beginning, capillary formation is crucial in maintaining the supply of various nutrients as well as oxygen to the inflamed tissue. Local and systemic expression of angiogenic factors may indicate a constant remodeling of synovial vasculature. Redox signaling is closely related to angiogenesis and can alter angiogenic responses of synovial cells. In this review we discuss key issues about the endothelial pathology in inflammatory arthritis followed by a review of angiogenic processes and main angiogenic mediators. We discuss the hypoxia-vascular endothelial growth factor (VEGF)-Ang/Tie2 system and its related therapeutic implications in detail with further review of various mediator protein targets and intracellular regulatory pathway targets with their current and potential future role in preclinical or clinical setting whilst ameliorating inflammation.