RA Severity Research Articles

Psychiatric disorders in patients with rheumatoid arthritis

IntroductionRheumatoid arthritis (RA) is a systemic inflammatory disease that can lead to significant morbidity and especially to psychiatric disorders. Depression and anxiety are common symptoms in RA patients, and seem to influence disease activity, pain, and treatment response.Objectives The aim of this study was to investigate the prevalence of depression and anxiety and their related factors in RA patients.Methods100 patients diagnosed with rheumatoid arthritis according to ACR1987 or ACR/EULAR criteria 2010 were investigated. Demographic, clinical and laboratorial data were obtained from hospitals records.The RA severity Disease Activity was assessed by the Disease Activity Score (DAS 28). Physical function was assessed by the Health Assessment Questionnaire-Disability Index (HAQ).The Hospital Anxiety and Depression Scale (HAD a/d) was used to evaluate the depression and anxiety symptoms. Patients with results greater than 11 are considered depressed or anxious.ResultsThe group studied included 87% of women and 13% of men. The median age was 55.2 years [27-83]. The median disease duration was 11.7± 8.9 years.The majority of the patients were unemployed, they were housewives in 65% of the cases, retired in 6% and 2 % had taken sick leave.The median ESR was 44 ± 31.6 mm, and the median of CRP level was 26 ± 35.3 mg/l. The median disease activity (DAS 28) was 4.6 ± 1.4. Forty-five % had moderate disease activity (3.2 ≤DAS 28 ≤ 5.1), and 27% of the sample had high disease activity (DAS 28 > 5.1). The mean of the HAQ was 1.1 [0-3].The anxiety and depression questionnaire (HAD a/d) showed means of 10.6 for depression, and 10.25 for anxiety respectively. Depression was presented in 46 % of RA patients. Anxiety was presented in 48 %.There was a correlation of HAD a/d with employment status (p<0.05), and functional disability (HAQ) (p<0.001).There was no significant association of anxiety and depression scales with RA disease activity.ConclusionsChronic inflammation impairs the physiological responses to stress, resulting in depression, anxiety which leads to a worse long-term outcome in RA.Physical disability and social factors, are predictive of psychiatric disorders in RA. This fact must be taken into account when evaluating therapeutic response.Disclosure of InterestNone Declared

Deconvolution of synovial myeloid cell subsets across pathotypes and role of COL3A1+ macrophages in rheumatoid arthritis remission.

Monocyte/macrophage (Mo/Mp) is a critical cell population involved in immune modulation of rheumatoid synovitis (RA) across different pathotypes. This study aims to investigate the contribution of Mo/Mp clusters to RA activity, and the biological function of particular subtypes in RA remission. We integrated single-cell RNA sequencing datasets from 4 published and 1 in-house studies using Liger selected by comparison. We estimated the abundance of Mo/Mp subtypes in bulk RNA-seq data from the 81 patients of the Pathobiology of Early Arthritis Cohort (PEAC) using deconvolution analysis. Correlations between Mo/Mp subtypes and RA clinical metrics were assessed. A particular cell type was identified using multicolor immunofluorescence and flow cytometry in vivo and successfully induced from a cell line in vitro. Potential immune modulation function of it was performed using immunohistochemical staining, adhesion assay, and RT-qPCR. We identified 8 Mo/Mp clusters. As a particular subtype among them, COL3A1+ Mp (CD68+, COL3A1+, ACTA2-) enriched in myeloid pathotype and negatively correlated with RA severity metrics in all pathotypes. Flow cytometry and multicolor immunofluorescence evidenced the enrichment and M2-like phenotype of COL3A1+ Mp in the myeloid pathotype. Further assays suggested that COL3A1+ Mp potentially attenuates RA severity via expressing anti-inflammatory cytokines, enhancing Mp adhesion, and forming a physical barrier at the synovial lining. This study reported unexplored associations between different pathologies and myeloid cell subtypes. We also identified a fibroblast-and-M2-like cluster named COL3A1+ Mp, which potentially contributes to synovial immune homeostasis. Targeting the development of COL3A1+ Mp may hold promise for inducing RA remission.

Correlative study of COPD, Rheumatoid Arthritis and Type-II Diabetes Mellitus in South Karnataka Population

Background: Chronic diseases like COPD, RA and DM impair the social and physical activities. Hence their mental status and physical conditions has to be ruled out.Method: 30 COPD, 30 RA, 30 DM, (total 90 patients) were compared with each other and controlled group also. Their base line features, physical activity, ED-5D index after discharged from ICU / hospital since last six months. Mental status was also compared in at three groups and controlled group also with percentage.Results: Higher physical activity was observed in DM patients (20.2 ±1.8) and low level physical activity in COPD (9.4 ± 3.1). ED-5D Index value was least in COPD (0.60 ± 0.20) andhigh index was in DM (0.72 ± 0.26). Mobility problem self care deficiency, pain / discomfort were higher in COPD patient.Conclusion: This comparative of chronic diseases like COPD was compared with RA and DM and severity of disease was observed in COPD which is significantly involved in respiratory distress which creates multiple problems like dyspnoea,anxiety, discomfort need to be treated with more meticulously to avoid morbidity and mortality.

ADSC-derived exosomes inhibit cbl-cathepsin K-dependent osteoclast activation in inflammatory arthritis

Abstract Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes joint inflammation and bone destruction due to increased osteoclast differentiation and activity. Adipose-derived stem cells (ADSCs) are used to treat tissue injury because they are easy to harvest and exhibit immunomodulatory and regenerative capacity. Previous studies demonstrated that ADSC-derived exosomes (ADSC-Exo) protect articular cartilage from damage and exert anti-inflammation effects. Thus, we investigated the underlying mechanisms of ADSC-Exo in regulating osteoclast activation in inflammatory arthritis. RANKL is a TNF-family cytokine that binds to the RANK required for mature osteoclasts. However, whether ADSC-Exo is functionally involved in the inhibition of osteoclast formation via regulating RANK-mediated signaling in these pathological conditions is unclear. Our data revealed that ADSC-Exo ameliorated the RA severity and bone loss in vivo and inhibited osteoclast differentiation, RANK downstream signaling, NFATc1, cathepsin K, and cbl-b. Moreover, ADSC-Exo could significantly suppress the population of RANKL-expressing TH17 cells. In brief, ADSC-Exo protects articular cartilage and bone destruction from damage and ameliorates gait abnormality in CIA rats, which may be related to the inhibition of the RANK-signaling pathway in osteoclasts. As it is relatively feasible to obtain human adipose tissue, ADSC-Exo may be a potential therapy for RA. This study could comprehensively understand the immunomodulatory effects of ADSC-Exo on suppressing osteoclastogenesis. This finding is critical for understanding the bone homeostasis modulated by MSC-Exo and provides biological evidence of ADSC-Exo in inflammatory arthritis. Supported by grants from the Ministry of Science and Technology (111-2321-B-418-002, 111-2314-B-418-004), FEMH (2022-C-042 and 2022-C-123), NYCU-FEMH Cooperation grants (111DN12, 111DN22), NTUH-FEMH Cooperation (111-FTN0012).

A Framework of Faster CRNN and VGG16-Enhanced Region Proposal Network for Detection and Grade Classification of Knee RA

We developed a framework to detect and grade knee RA using digital X-radiation images and used it to demonstrate the ability of deep learning approaches to detect knee RA using a consensus-based decision (CBD) grading system. The study aimed to evaluate the efficiency with which a deep learning approach based on artificial intelligence (AI) can find and determine the severity of knee RA in digital X-radiation images. The study comprised people over 50 years with RA symptoms, such as knee joint pain, stiffness, crepitus, and functional impairments. The digitized X-radiation images of the people were obtained from the BioGPS database repository. We used 3172 digital X-radiation images of the knee joint from an anterior-posterior perspective. The trained Faster-CRNN architecture was used to identify the knee joint space narrowing (JSN) area in digital X-radiation images and extract the features using ResNet-101 with domain adaptation. In addition, we employed another well-trained model (VGG16 with domain adaptation) for knee RA severity classification. Medical experts graded the X-radiation images of the knee joint using a consensus-based decision score. We trained the enhanced-region proposal network (ERPN) using this manually extracted knee area as the test dataset image. An X-radiation image was fed into the final model, and a consensus decision was used to grade the outcome. The presented model correctly identified the marginal knee JSN region with 98.97% of accuracy, with a total knee RA intensity classification accuracy of 99.10%, with a sensitivity of 97.3%, a specificity of 98.2%, a precision of 98.1%, and a dice score of 90.1% compared with other conventional models.

Evaluation of mental functioning of patients with rheumatoid arthritis

IntroductionRheumatoid arthritis (RA) is a chronic inflammatory degenerative disease whose symptoms are mainly joint with significant functional impact, resulting in a restriction of the activities of the patient and increasing the impact on mental well-being.ObjectivesThis study aimed to screen for mental functioning in RA patients, detect anxiety and depression, evaluate self-esteem and study its relation to clinical parameters, as well as disease activity.MethodsSingle-centre cross-sectional study, involving patients with RA using the hospital anxiety and depression scale (HADs). Rosenberg scale was used to evaluate self-esteem. We evaluated the RA severity Disease Activity Severity (DAS 28).ResultsFifty patients were included. The average age was 54 years [24-72]. The mean duration of the disease was 10 years. Thirty-nine patients had immunopositive RA with a mean Rheumatoid Factor level of 189.1 ± 291.3 U/ml and a mean anti-CCP antibody level of 165 ± 225.3 U/ml. At diagnosis, the mean DAS 28 of the patients was 5.1 ± 1.4. Moderately active and highly active RA were predominant with percentages of 40% and 50% respectively. All patients were treated, and 36% received biological treatment.Depression was noted in 42% of the patients with a mean score of 10.1 ± 3.7. Anxiety was noted in 50% of the patients with a mean score of 10.3 ± 4.In this study, we did not find a statistically significant association between disease activity and depression or anxiety scores (p=0.6 and p=0.1 respectively).The mean Rosenberg scale score was 27± 3. Sixty-eight per cent of patients had low self-esteem, twenty-one per cent had moderate self-esteem and eleven per cent very low self-esteem. Disease activity was associated with low self-esteem.ConclusionsRA is a chronic inflammatory disease that has a significant impact on the mental health and quality of life of patients. The detection and treatment of psychiatric disorders such as anxiety, depression and low self-esteem; improve the care of patients with RA.Disclosure of InterestNone Declared

Relation between panoramic mandibular index and disease activity in patients with rheumatoid arthritis

BackgroundDEXA scan could be unavailable at some health centers, and radiologic examination of the mandible and oral cavity is considered more commonly used radiologic test that can predict, diagnose, or even follow-up on any defect in bone mineralization. The aim of this study was to elucidate the ability of panoramic radiograph to detect osteoporosis in rheumatoid arthritis patients and correlate panoramic mandibular index with RA disease activity and severity parameters.ResultsThe sensitivity of panoramic mandibular index for diagnosis of osteoporosis was 96% in group Ι (primary OP) and 70% in group ΙΙ (RA patients). The positive predictive value of PMI was 67% in group Ι and 55% in group ΙΙ. The negative predictive value of PMI was 34% in group Ι and was 46% in group ΙΙ. The cutoff value of PMI for diagnosis of OP was ≤ 0.31 in group Ι and ≤ 0.17 in group ΙΙ. In group I, there were significant correlations between panoramic mandibular index and patient’s ages, weights, T score at L1-4, T score at femoral neck, and T score at forearm while there were insignificant correlations between PMI and patients’ heights. In group ΙΙ, there were significant correlations between PMI, patients’ ages, weights, disease durations, SHARP score, ESR, RF, T score at L1-4, T score at femoral neck, and T score at forearm, while there were insignificant correlations between PMI and patients’ heights, DAS, and CRP.ConclusionsPanoramic radiography could have a potential usability in the diagnosis of osteoporosis in rheumatoid arthritis patients regardless of displaying insignificant correlation with disease activity.

Expression of genes involved in epigenetic modifications in patients with rheumatoid arthritis

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, and evidence revealed that environmental and genetic factors are involved in RA pathogenesis. This study aimed to explore the balance between genes involved in DNA methylation and demethylation in the peripheral blood of patients with RA. MethodsIn this cross-sectional study, ninety RA patients and ninety-two age and sex-matched normal subjects (NS) were enrolled, and RA was confirmed by an expert rheumatologist based on clinical and laboratory data. In addition, the Rheumatoid arthritis severity scale (RASS) and disease activity score (DAS-28) were measured. According to the disease severity, RA patients were categorized into three groups (mild, moderate, and severe). Peripheral blood was collected from subjects, and the expression of ten-eleven translocation methylcytosine dioxygenase 1 (TET1), TET2, and TET3, as well as DNA methyltransferase 1 (DNMT1) genes, were evaluated using real-time polymerase chain reaction (RT-PCR) technique. Serum level of anti-cyclic citrullinated peptide (anti-CCP) antibody was measured by enzyme-linked immunosorbent assay (ELISA) technique. ResultsThis investigation showed that gene expression of TET1 and TET2 was significantly decreased in RA patients compared to NS. Gene expression of DNMT1 and TET3 was also down-regulated in RA patients compared to NS; however, the changes were not statistically significant. Moreover, the correlation matrix test demonstrated no significant association between some demographic and clinical data of RA patients with the expression of studied genes. ConclusionAccording to the findings of this study, the expression of TET1 and TET2 as regulators of inflammatory responses was remarkably reduced in RA patients compared to NS, and disease severity can affect the expression of these genes because the expression of the TET2 is significantly reduced in patients with moderate RA severity and it may lead to increase inflammatory responses and RA development.

Mothers’ experiences of wellbeing and coping while living with rheumatoid arthritis: a qualitative study

BackgroundRheumatoid arthritis (RA) can result in difficulties for mothers when undertaking daily care activities and increased psychological distress. However, few studies have examined how women with RA subjectively experience coping and wellbeing as part of their motherhood.MethodsTwenty mothers with a diagnosis of RA and a dependent child (18 years or younger) who were living in Australia took part in a semi-structured interview between June and November 2017. Purposive sampling was undertaken to include participants across degree of current RA severity, number and age of children, and having received a diagnosis before or after a first child to take account of variability across these experiences. A qualitative thematic analysis was conducted on the interview transcripts.ResultsThe following themes were identified: ‘Burden and complexity in the mothering role’, ‘Losing control: Women’s experiences of distress’, and ‘Adjusting and letting go: Women’s experiences of wellbeing’. Experiences of distress, including feelings of failure, were associated with accounts of a loss of control over mothering practices among women, regardless of child age. In contrast, accounts of adjusting mothering practices and relinquishing control were associated with reports of enhanced wellbeing. In addition, some mothers reported greater ease due to increased independence of older children. The absence of social support exacerbated burden and distress in the women’s accounts, while the availability of support alleviated burden and was associated with reports of wellbeing.ConclusionHealth professionals and services can provide support to mothers with RA by addressing feelings of failure, acknowledging strategies of adjustment and letting go, and encouraging access to social support.

The impact of disease severity measures on survival in U.S. veterans with rheumatoid arthritis-associated interstitial lung disease.

To determine whether RA and interstitial lung disease (ILD) severity measures are associated with survival in patients with RA-ILD. We studied US veterans with RA-ILD participating in a multicentre, prospective RA cohort study. RA disease activity (28-joint DAS [DAS28-ESR]) and functional status (multidimensional HAQ [MDHAQ]) were collected longitudinally while pulmonary function tests (forced vital capacity [FVC], diffusing capacity for carbon monoxide) were obtained from medical records. Vital status and cause of death were determined from the National Death Index and administrative data. Predictors of death were assessed using multivariable Cox regression models adjusting for age, sex, smoking status, ILD duration, comorbidity burden and medications. We followed 227 RA-ILD participants (93% male and mean age of 69 years) over 1073 person-years. Median survival after RA-ILD diagnosis was 8.5 years. Respiratory diseases (28%) were the leading cause of death, with ILD accounting for 58% of respiratory deaths. Time-varying DAS28-ESR (adjusted hazard ratio [aHR] 1.21; 95% CI: 1.03, 1.41) and MDHAQ (aHR 1.85; 95% CI: 1.29, 2.65) were separately associated with mortality independent of FVC and other confounders. Modelled together, the presence of either uncontrolled disease activity (moderate/high DAS28-ESR) or FVC impairment (<80% predicted) was significantly associated with mortality risk. Those with a combination of moderate/high disease activity and FVC <80% predicted had the highest risk of death (aHR 4.43; 95% CI: 1.70, 11.55). Both RA and ILD disease severity measures are independent predictors of survival in RA-ILD. These findings demonstrate the prognostic value of monitoring the systemic features of RA-ILD.

7-deacetyl-gedunin suppresses proliferation of Human rheumatoid arthritis synovial fibroblast through activation of Nrf2/ARE signaling

BackgroundRheumatoid arthritis (RA) is an chronic autoimmune disease and characterized by high incidence. However, there is no effective therapies for RA. Therefore, it is urgent to discover new drugs for RA treatment. Nuclear factor erythroid 2 (NF-E2)-related factor (Nrf2) can effectively protect against arthritic inflammatory diseases through diverse stages, such as regulating redox balance, detoxification, metabolism and inflammation. Dimethyl fumarate (DMF), targets the Nrf2 pathway, was approved by FDA for the clinical treatment of multiple sclerosis (MS), which is another autoimmune disease. The latest report shown that DMF ameliorates complete Freund's adjuvant-induced arthritis in rats through activation of the Nrf2/HO-1 signaling pathway. Hence, Nrf2 serves as an important target for inflammation interference and oxidative stress of macrophages and RASFs in RA; therefore, it can be adopted as an effective therapeutic approach in the future.Rheumatoid arthritis synovial fibroblasts (RASFs) play crucial roles in the RA pathogenesis. Our results revealed that 7-deacetyl-gedunin (7-d-GDN), derived from fruits of Toona sinensis (A. Juss.) Roem, significantly inhibited RASFs proliferation in dose- and time- dependent manners and inhibited cell viability in MH7A cells, which is a kind of immortal cell line from joints of patients with RA. Additionally, 7-d-GDN remarkably down-regulated MMP-1/3/9/13 in RASFs, IL-6 and IL-33 in MH7A cells. Besides, 7-d-GDN sharply inhibited reactive oxygen species (ROS) in RASFs. Further mechanistic study demonstrated that 7-d-GDN induced heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase quinone 1(NQO1), which all participated in suppressing of oxidative stress. Additionally, 7-d-GDN increased sequestosome 1 (SQSTM1, p62), causing down-regulating Kelch-like ECH-associated protein 1 (Keap1), which resulting in NF-E2-related factor 2 (Nrf2) cytoplasm accumulation and subsequently translocation into nucleus. Collectively, 7-d-GDN exerts the anti-inflammatory effect through regulating anti-oxidative enzymes via p62/ Nrf2/ARE signaling. All suggest that the potential of 7-d-GDN in suppression of inflammation, especially antagonizing RA severity. Our works support for drugs discovery in RA treatment.

Patient Characteristics and Indicators of Treatment Initiation with Repository Corticotropin Injection in Patients with Rheumatoid Arthritis: A Claims Database Analysis.

Repository corticotropin injection (RCI) is indicated as adjunctive, short-term therapy in selected patients with RA. To characterize RCI users and identify predictors of RCI initiation in RA, we compared preindex characteristics, treatment patterns, comorbidities, healthcare resource utilization (HCRU), and costs for patients who had initiated RCI treatment (RCI cohort) versus patients with no RCI claims and ≥ 1 targeted synthetic or biologic disease-modifying antirheumatic drugs (ts/bDMARD) claim (non-RCI ts/bDMARD cohort). We analyzed pharmacy and medical claims data from a large commercial and Medicare supplemental administrative database. Inclusion criteria were age ≥ 18 years, ≥ 1 inpatient or ≥ 2 outpatient claims with RA diagnosis (January 1, 2007–December 31, 2018), and 12-month continuous medical and pharmacy coverage preindex. Results from baseline cohort comparisons informed multiple logistic regression analysis. Compared with the non-RCI ts/bDMARD cohort (n = 162,065), the RCI cohort (n = 350) had a greater proportion of patients with higher Charlson comorbidity index (CCI) scores; higher mean claims-based index of RA severity and CCI scores; greater frequency of almost all comorbidities; higher use of nontraditional DMARDs, glucocorticoids, and opioids; higher all-cause HCRU; and higher medical and total costs. By multivariable analysis, the most significant predictors of RCI initiation were intermittent glucocorticoid use at any dose (odds ratio [OR] 1.67), extended-use glucocorticoids at medium (OR 2.03) and high doses (OR 2.99), nontraditional DMARD use (OR 2.09), anemia (OR 1.39), and renal disease (OR 2.45). Before RCI initiation, patients had more severe RA, higher comorbidity burden, greater use of glucocorticoids and opioids, and higher HCRU compared with non-RCI initiators. The most significant predictors for starting RCI in patients with RA were intermittent use of glucocorticoids at any dose, extended-use high-dose glucocorticoids, use of nontraditional DMARDs, and comorbid anemia and renal disease.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-020-00272-x.

RETRACTED ARTICLE: Does serum B lymphocyte chemoattractant protein13 (CXCL13) level correlate with parameters of disease activity and severity in rheumatoid arthritis? Clinical and musculoskeletal ultrasonographic assessment

BackgroundRheumatoid arthritis (RA) affects about 1–3% of the population making it one of the most popular autoimmune diseases. Chemokines through switching on their receptors exert a climacteric role in RA pathogenesis. The purpose of this cross-sectional study was to quantify the serum levels of serum B lymphocyte chemoattractant protein13 (CXCL13) chemokine in recent onset RA patients and to correlate its levels with clinical, laboratory, and musculoskeletal ultrasonographic parameters (MSUS) of disease activity and severity.ResultsThe mean serum CXCL13 value showed a significant increase in the RA patients (388.86 ± 283.63 pg/ml) than in the controls (62.94 ± 31.62 pg/ml) (P < 0.001). Highly active RA patients had significantly the highest mean of CXCL13 (mean ± SD 819.13 ± 191.05) compared with the moderately active RA patients (mean ± SD 284.95 ± 137.93) (P < 0.001) and the RA patients with low disease activity (mean ± SD 129.5 ± 21.27) (P < 0.001) and its levels were positively related with clinical disease activity and musculoskeletal ultrasonographic severity parameters.ConclusionSerum CXCL13 is correlated with clinical disease activity and MSUS disease severity that encourages its use for monitoring the activity and severity of synovitis in recent onset RA patients. Future studies to detect the effect of disease activity control by medications on CXCL13 levels and the effect of the CXCL13 antagonist on controlling RA disease activity and severity are recommended.

Inhibiting role of long non-coding RNA LINC01197 in inflammation in rheumatoid arthritis through the microRNA-150/THBS2 axis

PurposeRheumatoid arthritis (RA) is a commonly diagnosed systemic autoimmune disease. Aberrant expression of long non-coding RNAs (lncRNAs) is closely linked to the development of RA. This study was conducted to explore the functions of the lncRNA LINC01197 in RA progression. MethodsDifferentially expressed lncRNAs/microRNAs/mRNAs in patients with RA were analyzed using RNA microarrays. A mouse model with RA was established and RA-fibroblast-like synoviocytes (RA-FLS) were acquired for in vitro experiments. The function of LINC01197 in inflammation and RA progression in mice and its role in the viability of RA-FLS were determined by experiments involving its overexpression or suppression. The sub-cellular localization of LINC01197 was determined and the downstream molecules involved in LINC01197-mediated events were identified. ResultsLINC01197 was poorly expressed in the synovial tissues in the RA model mice. Overexpression of LINC01197 reduced RA severity in mice and inhibited proliferation and inflammatory responses as well as promoted apoptosis in RA-FLS. Online predictions and dual luciferase reporter gene assays suggested that LINC01197 could bind to miR-150 and further regulate THBS2 expression. LINC01197 promoted THBS2 expression through miR-150 sponging and inactivated the TLR4/NF-κB signaling pathway, thus alleviating RA inflammation. ConclusionThe current study suggested that LINC01197 sponged miR-150 to promote THBS2 expression, leading to TLR4/NF-κB inactivation, and ameliorated RA inflammation. These findings may offer new insights into RA treatment.

FRI0576 IDENTIFICATION OF SERUM PROTEIN BIOMARKERS ASSOCIATED WITH RA DISEASE SEVERITY

Background:RA is a systemic autoimmune disease with heterogeneous manifestation. Recent advances in serum proteomics, such as the SomaScan®platform (SomaLogic, Inc., Boulder, USA), allow for a deeper exploration of the protein biomarkers associated with RA and a better understanding of the molecular aetiology of the disease.Objectives:To characterise the differences in baseline serum proteome of patients with RA (enrolled in the Phase IIIb Abatacept vs adaliMumab comParison in bioLogic-naïvERA subjects with background MTX [AMPLE] study)1compared with a healthy population, and to identify serum protein biomarkers associated with disease severity and radiographic progression.Methods:Patients in the AMPLE study had an inadequate response to MTX and were naïve to biologic DMARDs. Protein abundance was assessed in baseline serum samples from 440 AMPLE study patients and 123 healthy individuals with matching demographics using the SomaScan®platform, with 5000+ slow off-rate modified aptamers and up to 8 log of dynamic range.2Differential abundance testing was performed using linear models to identify differences in protein abundance in patients with RA vs healthy individuals. A separate analysis using a linear model was conducted in only the patients with RA to identify the proteins associated with DAS28 (CRP) and TSS. Pathway analyses were performed for proteins significantly (false discovery rate-adjusted p value &lt;0.05) associated with RA and the disease severity measurements to identify over-representation of the molecular pathways.Results:Compared with healthy individuals, &gt;2000 serum proteins were significantly differentially expressed in patients with RA, including many proteins that have been associated with RA (e.g. serum amyloid A [SAA], CRP) and complement. Most of the protein expression differences were of small magnitude (fold change &lt;2). Proteins that were differentially expressed between patients with RA and healthy individuals were enriched in interleukin signalling, neutrophil degranulation, platelet activation/degranulation and extracellular matrix organisation pathways. DAS28 (CRP) was significantly associated with several biomarkers, including SAA, fibrinogen and CRP; in general, proteins associated with DAS28 (CRP) were most strongly enriched in the platelet activation/degranulation pathways (Figure 1), also seen in patients with RA vs healthy individuals. Additionally, many proteins were significantly associated with TSS, including SAA, matrix metalloproteinase-3 and cartilage acidic protein 1. Here, the proteins were most strongly enriched in the extracellular matrix remodelling pathways (Figure 2).Conclusion:Our study revealed that thousands of serum proteins are differentially expressed and several pathways are dysregulated between patients with RA and healthy individuals. Additional pathways were identified that reflect disease severity, including joint damage, distinct from those pathways associated with the disease. The SomaScan®platform provides a unique proteomic tool with a wide dynamic range for the identification of serum protein biomarkers associated with RA and disease severity. Proteomic signatures should be considered in clinical trials to better understand disease pathogenesis and predict risk in response to treatment.

P218 Interrogation of transcriptome data in RA for identifying disease susceptibility loci and predictors of treatment response

Abstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting approximately 1% of the Caucasian population worldwide causing significant morbidity. The genetics of disease pathogenesis remains poorly understood despite recent advances in high throughput genotyping and sequencing. Biological agents (e.g. TNF inhibitors, TNFi) have significantly impacted on disease management, however 30-40% of RA patients do not respond to this therapy. The aim of this study was to use transcriptome sequencing (RNA sequencing) data from human neutrophils to identify variants in RA that may underpin disease pathogenesis and predict response to biologic therapy. Methods RNA sequencing (RNA-seq) data from peripheral blood neutrophils isolated pre-TNFi treatment was analysed from 27 RA patients and 6 healthy controls. 21 RA patients subsequently responded to TNFi therapy (change in DAS28 &amp;gt;1.2). RNA-seq reads were mapped to the human genome (hg19) using TopHat2 and annotated using Cufflinks. Data was combined, calibrated and filtered using the Genome Analysis Tool Kit (GATK) to create a file of identified variants. These variants were subsequently interrogated using the VCFtools program package. Quality control parameters were applied in accordance with guidance and available literature, excluding variants that were: PHRED &amp;lt; 30, Minimum read depth &amp;lt; 4 and a loci sequencing success rate &amp;lt; 80%, with SNP clusters and indels also removed. Tajima D was used as a statistic for identifying regions of interest within the RNA-seq data. Identified variants were annotated and interrogated using the UCSC bioinformatics platform and pathway analysis of identified genes predicted through Ingenuity Pathway Analysis (IPA). Results GATK analysis identified 536,668 variants, which were refined to 5230 variants following application of QC parameters as specified with over 99% of variants excluded. RA patients had a mean Tajima-D score of 0.51 vs -0.19 in the controls (p &amp;lt; 0.0001) and furthermore had significantly more regions of transcriptome with extreme positive Tajima-D values (p &amp;lt; 0.0001). Bioinformatics analysis identified the variants with high Tajima-D scores to be within a number of biologically relevant loci, including NCF1, which has been associated with autoimmune diseases including SLE and is predictor of RA severity in rat models. IPA revealed that a number of the highest scoring variants were within loci that were linked via a gene network regulated by activation of Fcgamma receptors (FCGR1A/B/C, FCGR2A/B, FCGR3B) and p38 MAPK. Conclusion This study suggests that interrogation of transcriptome data has a role in elucidating the components underpinning RA pathogenesis, identifying a number of interesting loci that may contribute towards its missing heritability. However, such preliminary data will require validation through direct sequencing of variants and investigation in independent data sets as well sub-group analysis of treatment response to biological therapy. Disclosures R. Smith None. N. Goodson None. R.J. Moots None. H.L. Wright None.

Is Rheumatoid Arthritis a Risk Factor for Fractures: A Systematic Review of Observational Studies.

The primary objective was to assess the risk of fractures in adults with RA compared with controls from the general population. The review also assessed an increased risk of fractures in RA patients when accounting for steroid use, RA disease severity or functional impairment. Citations were screened from MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and CINAHL. Included citations were written in English, including adult patients at least 18 years of age and compared fracture incidence or prevalence between RA patients and a control group. Case-control, cohort and cross-sectional studies were included. There were a total of 3451 citations; after application of the inclusion criteria, 17 studies were selected. In 14 of the 17 studies, there was an increase in the risk of fracture in RA patients compared to controls. In studies that evaluated for glucocorticoid use, four of 13 demonstrated an increased risk of fracture with glucocorticoid use, however, only two of these four studies specifically assessed glucocorticoid use amongst patients with RA. In studies that analyzed RA severity or functional impairment, two of seven demonstrated disease severity or impairment as a risk factor for fracture. There was marked study heterogeneity in terms of patient and fracture characteristics, which was a limitation of the analysis that impeded the ability to make direct comparisons. The risk of fracture in RA patients is elevated when compared to the general population, although the etiology of the increased risk remains to be elucidated.

Prevalence and associated factors of subclinical atherosclerosis in rheumatoid arthritis at the university hospital of Kinshasa

BackgroundRheumatoid arthritis (RA) is associated with a 5 to 10 years reduction in life expectancy due to premature atherosclerosis. This reduction is the consequence of traditional cardiovascular risk factors (TCRF) as well as systemic inflammation. The aim of the present study was to describe the prevalence and factors associated with subclinical atherosclerosis in RA at the University Hospital of Kinshasa (UHK).MethodsPatients with a diagnosis of RA based on the 2010 ACR/EULAR criteria were included in this cross-sectional study from 1 June 2014 to 31 May 2015 at the UHK. RA disease activity was measured using the DAS28-ESR. Active RA was defined by a DAS 28 > 2.6. Severe RA was defined by the presence of extra-articular manifestation, joint erosions on X-rays or HAQ ≥0.5. An assessment of subclinical atherosclerosis was performed by the measurement of the carotid intima-media thickness (cIMT) using two-dimensional ultrasonography. Subclinical atherosclerosis was defined by a cIMT ≥0.9 mm. A diagnosis of atheroma plaque was retained when the cIMT was ≥1.5 mm. The association between subclinical atherosclerosis and potential risk factors was modeled using logistic regression analysis.ResultsWe recruited 75 patients. The average age was 51.8 ± 14.6 years, with a sex ratio F/M of 4. The prevalence of subclinical atherosclerosis was 32%. In logistic regression being a woman of ≥55 years old (aOR 10.6, 95% CI [2.087–53.82], p = 0.028), DAS28-ESR > 2.6 (aOR 3.5,95% CI [1.55–10.38], p = 0.044), severe RA (aOR 32.6,95% CI [1.761–60.37],p = 0.035), high blood pressure (aOR 22.4,95% CI [5.04–99.41], p = 0.005) and obesity (aOR 32.3, 95% CI [2.606–40.73], p = 0.026) emerged as factors associated with subclinical atherosclerosis.ConclusionSubclinical atherosclerosis is common in RA patients attending the UHK. It appears to be associated with RA disease activity and severity apart from traditional cardiovascular risk factors. These results suggest that early management of subclinical atherosclerosis targeting remaining RA disease activity and cardiovascular risk factors could slow down progression to clinical cardiovascular disease.

Lipid management in rheumatoid arthritis: a position paper of the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology.

Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity, partly due to alterations in lipoprotein quantity, quality and cell cholesterol trafficking. Although cardiovascular disease significantly contributes to mortality excess in RA, cardiovascular prevention has been largely insufficient. Because of limited evidence, optimal strategies for lipid management (LM) in RA have not been determined yet, and recommendations are largely based on expert opinions. In this position paper, we describe abnormalities in lipid metabolism and introduce a new algorithm for estimation of cardiovascular risk (CVR) and LM in RA. The algorithm stratifies patients according to RA-related factors impacting CVR (such as RA activity and severity and medication). We propose strategies for monitoring of lipid parameters and treatment of dyslipidaemia in RA (including lifestyle, statins and other lipid-modifying therapies, and disease modifying antirheumatic drugs). These opinion-based recommendations are meant to facilitate LM in RA until more evidence is available.

Disease progression in relation to pre-onset parity among women with rheumatoid arthritis

ObjectiveRheumatoid arthritis (RA) often ameliorates during pregnancy and flares postpartum, but the relationship of pregnancy and childbirth to RA prognosis is unclear. We examined RA severity for association with parity prior to RA onset and asked whether time from birth (latency) and/or the mother's HLA genotype influenced results. MethodsA cohort study was conducted of 222 women previously identified in a prospective study of newly diagnosed RA, who returned for follow-up evaluation a median of 8 years later. Stratified analyses using Mantel-Haenszel methods were conducted to evaluate 5 RA severity measures based on hand and wrist radiographs, physical exams, and Health Assessment Questionnaires for association with parity. ResultsOverall, we observed little evidence of altered risk of progression to severe RA in relation to pre-onset parity, adjusting for RA onset age and time to follow-up. Stratifying parous women who had only live births by latency (<15 years/15+ years) showed no difference in risk of severe RA compared to nulligravid women. Live birth deliveries were significantly protective for women with 0 but not for those with 1 or 2 copies of the RA risk-associated HLA-DRB1 shared epitope sequence for erosion score (RR 0.26 95% CI 0.09–0.89) and joint count (RR 0.28 95% CI 0.09–0.87). ConclusionWe observed little evidence of difference in severe RA by pre-onset parity overall. However, among women not predisposed to RA by possessing the risk-associated HLA genotype, parous women who had only live births had lower risk of progression to severe RA as measured by erosion score and joint count.