[Show abstract][Hide abstract] ABSTRACT: To investigate serum antibody reactivity against a panel of post-translationally modified vimentin peptides (PTMPs) in patients with early inflammatory arthritis.
A panel of PTMPs was developed. Microtitre plates were coated with peptides derived from vimentin that were identical in length and composition except at one amino acid that was changed to introduce one of three post-translational modifications (PTMs)-either a citrullinated, carbamylated or acetylated residue. Sera of 268 treatment-naive patients with early inflammatory arthritis and symptoms ≤3 months' duration were tested. Patients were assigned to one of three outcome categories at 18-month follow-up (rheumatoid arthritis (RA), persistent non-RA arthritis and resolving arthritis).
Antibodies against citrullinated, carbamylated and acetylated vimentin peptides were detected in the sera of patients with early inflammatory arthritis. The proportion of patients seropositive for all antibody types was significantly higher in the RA group than in the other groups. Anti cyclic citrullinated peptide (CCP)-positive patients with RA had higher numbers of peptides recognised and higher levels of antibodies against those peptides, representing a distinct profile compared with the other groups.
We show for the first time that antibodies against acetylated vimentin are present in the sera of patients with early RA and confirm and extend previous observations regarding anticitrullinated and anticarbamylated antibodies.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Annals of the rheumatic diseases 07/2015; 74(Suppl 2). DOI:10.1136/annrheumdis-2014-206785 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background The EULAR Study Group for Risk Factors for Rheumatoid Arthritis (RA) recommends identification of new biomarkers for prediction of RA in early undifferentiated disease. The OMERACT Ultrasound Task Force recently established that US is a reproducible tool for evaluating tenosynovitis (TS) in RA1, which is a common manifestation of early RA. At present, the value of US-defined TS in the prediction of early RA is unknown.
Objectives To explore the ability of US-defined TS to predict early RA compared with clinical and serological variables in an unselected very early arthritis cohort.
Methods 107 patients with clinically apparent synovitis of at least one joint and symptom duration ≤3 months underwent clinical and multiple tendon US assessments and outcome was determined after 18 months by 1987 American College of Rheumatology criteria.
A blinded US assessment determined the presence of grey scale and Power Doppler (PD) TS at 16 tendon regions: bilateral fingers (extensor and flexor compartments), wrists (extensor and flexor compartments), shoulders (biceps tendon), ankles (anterior extensors, peroneals, posterior tibialis) using a Siemens Acuson Antares scanner and 5–13 MHz linear array transducer. Grey scale and PD TS definition was based on the OMERACT Ultrasound Task Force recommendations1 and recorded as binary outcomes. We compared the predictive values of US-defined TS with clinical and serological variables.
Results 43 patients developed RA (VERA), 20 patients developed non-RA persistent disease (NRAP) and 44 patients had resolving disease at follow-up. A total of 1712 tendon regions in 107 patients were included in the analysis. All patient groups had evidence of tenosynovitis in one or more tendon compartments during baseline assessment (VERA 86%, NRAP 75%, resolving 70%). There were significant differences in the distribution of tendon involvement between the three groups including the Extensor Carpi Ulnaris tendon (ECU); [VERA 54%, NRAP 15%, resolving 18%; (p<0.001)].
TS ultrasound variables were superior to clinical variables (early morning stiffness, symmetrical arthritis and hand joint arthritis) in the prediction of early RA.
Conclusions This is the first study to show that US-defined TS is a strong predictor of early RA.
Hand and ECU tendon scanning provides the optimal minimal ultrasound data to predict early RA.
Disclosure of Interest None declared
Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):69.3-70. DOI:10.1136/annrheumdis-2015-eular.1591 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Intra-articular and soft tissue steroid injections are common procedures in Rheumatology and are taking the place of fluoroscopic or CT-guidance injection.
However, little is known about patient views on ultrasound-guided steroid injections and whether observing images during the procedure has a positive or negative impact.
Objectives We conducted a pilot study to quantitatively describe patients' view of US-guided procedures.
Methods 50 survey questionnaires with balanced-likert scales were distributed to Rheumatology patients who underwent an US-guided procedure in the Rheumatology Department at Sandwell and West Birmingham Hospitals NHS Trust between January 2011 and January 2012. All patients were able to view the scanner screen and the procedure and images were explained by the operator. Survey receipt was concluded in April 2012 relating to a post injection period ranging between 4–16 months. Of 50 questionnaires distributed, 30 (60%) were returned and 26 (50%) were completed and included for data analysis.
Results A total of 33 joints/tendon regions were injected in 26 patients [12; hand, 9; wrist, 2; elbow, 3; knee, 5; feet]. All patients felt that observing the US images during the US-guided procedure was helpful. 85% of the patients felt that observing US images during the procedure reduced anxiety with no individuals describing heightened anxiety. 92% of patients felt that observing the US images in real-time helped them to tolerate the procedure better and the same proportion of patients felt seeing the images increased their confidence that the pain source had been identified. 62% of patients felt that observing the US images provides additional information that improves understanding of the procedure.
Amongst those who had a non-guided injection previously (n=19), 68% of patients felt that US-guided injection was more or much more effective compared to traditional injection without US.
Conclusions Observing images during US-guided procedure improves patients' experience and has no negative impact.
This is the first study to describe the benefits of visually demonstrating pathology to patients via ultrasound; further work is required to investigate this in a larger cohort.
Disclosure of Interest None declared
Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):641.2-641. DOI:10.1136/annrheumdis-2015-eular.3566 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Understanding the persistence of biologic treatment in different ethnic groups is important for efficient healthcare delivery. We previously reported that patients with Rheumatoid Arthritis (RA) from South Asian background had high level of side effect concerns about conventional DMARDs (cDMARDs) compared with patients of White British origin. These concerns may have an impact on treatment persistence; however, there is little data on biologic DMARDs (bDMARDs) treatment persistence among different ethnic groups.
Objectives To investigate biologic DMARDs treatment persistence and reasons for switching among patients with RA from South Asian and White British background.
Methods This service evaluation project identified 336 patients with active RA diagnosed by Consultant Rheumatologists at the Sandwell and West Birmingham Hospitals NHS Trust, UK. All patients were commenced on bDMARDs according to NICE guidelines between May 2001 and August 2013.
Frequency of loss of efficacy, number of bDMARDs switches and treatment duration for each bDMARD, were compared between South Asian and White British patients. Loss of efficacy was defined as a drop of DAS-28 score ≤1.2 after at least three months of therapy, or by loss of efficacy in the opinion of the treating physician.
Results The sample included 77 (23%) South Asian and 259 (77%) White British patients with active RA commencing bDMARDs therapy. The frequency of side effects was similar in both groups. Loss of efficacy was more common among South Asian compared with White British patients (65.6% vs. 52.2%; p=0.03). Regarding the number of biologic DMARDs switches, South Asian patients switched bDMARDs more frequently compared to their White British counterparts (South Asian vs White British; one switch: 24.7% vs 21.6%; two switches: 19.5% vs 15.8%; ≥3 switches 13.0% vs 5.8%; p=0.01).
The first biologic drug survival times of infliximab and adalimumab were significantly longer in the White British group compared to the South Asian group (South Asian vs. White British; median time on infliximab: 10 months vs. 26 months; p=0.032, median time on adalimumab; 9 months vs. undefined p=0.006; proportion of South Asian vs. White British group on adalimumab after 60 months; 27.3% vs. 57.4%).
There were no significant differences in the first biologic drug survival times of etanercept and certolizumab between the two groups (White British vs. South Asian median time on etanercept: 50 months vs. 55 months; p=0.593; median time on certolizumab: 25 months vs. 13 months, p=0.860).
There was no significant difference in the DAS28 score between the two groups after three months of biologic therapy [South Asian vs White British, median (IQR); 5.2 (4.2-6.1) vs 4.8 (3.4-6.0)].
Conclusions Our data indicates that there are ethnic differences in the persistence of bDMARDs among patients with RA. This has clinical implications when determining the choice of biologic therapy for patients from different ethnic backgrounds.
Disclosure of Interest K. Kumar: None declared, I. Sahbudin: None declared, A. Filer Grant/research support from: Pfizer, C. D. Buckley: None declared, K. Raza Speakers bureau: K Raza has received honoraria from Pfizer, AbbVie and BMS., R. Stack: None declared, P. Nightingale: None declared, A. Deeming: None declared, D. Situnayake: None declared, P. de Pablo: None declared
Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):483.2-483. DOI:10.1136/annrheumdis-2015-eular.3987 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background A significant component of the pathogenesis of rheumatoid arthritis is driven through inappropriate recruitment of T-cells into the joint. Indeed, targeting T-cell recruitment may moderate the onset, severity and persistence of RA. However, very little is known about the mechanisms by which T-cell migration is regulated during inflammation.
Objectives Here, we examined the ability of adiponectin, an anti-inflammatory adipose tissue-derived cytokine, and PEPITEM (a novel PEPtide Inhibitor of T-cell Migration) to regulate the migration of T-cells in vitro and in vivo.
Methods Peripheral blood lymphocytes were isolated from healthy controls or from treatment naive patients with a new onset of clinically apparent RA. Lymphocytes were treated in the presence or absence of adiponectin (15μg/ml) or PEPITEM (10ng/ml). Ex vivo, lymphocyte migration across tumour necrosis factor alpha and interferon gamma stimulated endothelial cells was assessed using phase-contrast microscopy. In vivo, lymphocyte migration was assessed in a model of zymosan-driven peritoneal inflammation.
Results We observed that adiponectin inhibited the migration of human lymphocytes across inflamed endothelium in a dose dependent manner. This effect was lost when B-cells were absent, but could be regained by the addition of supernatants from adiponectin-stimulated B-cells. Mass spectrometry identified the adiponectin induced B-cell-derived agent as a small peptide, subsequently named PEPITEM. In vitro, PEPITEM blocks T-cell migration by stimulating endothelial cells to release sphingosine-1-phosphate, a known regulator of T-cell migration. In zymosan-induced peritonitis, T-cell recruitment was significantly increased in B-cell deficient animals compared to wild-type controls, and this was ameliorated by treatment with synthetic PEPITEM. B-cells isolated from patients with early RA expressed lower levels of adiponectin receptors compared to healthy controls and were unable to respond to adiponectin. Consequently, T-cells from patients with early RA were released from the inhibitory effects of adiponectin on transmigration. Excitingly the full effect of adiponectin was rescued in vitro by the therapeutic use of exogenous PEPITEM.
Conclusions We have identified a novel endogenous peptide (PEPITEM) mediated pathway that suppresses T-cell recruitment across inflamed endothelium, which is dysfunctional in patients with early RA. We believe this leads to a loss of PEPITEM-mediated suppression of T-cell migration, resulting in the inappropriate accumulation of T-cells in the rheumatoid joint. Thus, deregulation of the adiponectin-PEPITEM axis during early development and/or progression of disease could directly contribute to pathology in RA. Re-establishing PEPITEM function to “turn off” pathological recruitment of T-cells represents a novel and potentially powerful approach to treating patients with early rheumatoid arthritis.
Acknowledgements HMM and MC contributed equally to this work.
Disclosure of Interest None declared
Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):111.2-111. DOI:10.1136/annrheumdis-2015-eular.3448 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Impairment in the ability of the inflamed synovium to generate cortisol has been proposed to be a factor in the persistence and severity of inflammatory arthritis. In the inflamed synovium, cortisol is generated from cortisone by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. The objective of this study was to determine the role of endogenous glucocorticoid metabolism in the development of persistent inflammatory arthritis.
Urine samples were collected from patients with early arthritis (symptoms ≤12 weeks duration) whose final diagnostic outcomes were established after clinical follow-up and from patients with established rheumatoid arthritis (RA). All patients were free of disease-modifying anti-rheumatic drugs at the time of sample collection. Systemic measures of glucocorticoid metabolism were assessed in the urine samples by gas chromatography/mass spectrometry. Clinical data including CRP and ESR were also collected at baseline.
Systemic measures of 11β-HSD1 activity were significantly higher in patients with early arthritis whose disease went on to persist, and also in the subgroup of patients with persistent disease who developed RA, when compared with patients whose synovitis resolved over time. We observed a significant positive correlation between systemic 11β-HSD1 activity and ESR/CRP in patients with established RA but not in any of the early arthritis patients group.
The present study demonstrates that patients with a new onset of synovitis whose disease subsequently resolved had significantly lower levels of systemic 11β-HSD1 activity when compared with patients whose synovitis developed into RA or other forms of persistent arthritis. Low absolute levels of 11β-HSD1 activity do not therefore appear to be a major contributor to the development of RA and it is possible that a high total body 11β-HSD1 activity during early arthritis may reduce the probability of disease resolution.
[Show abstract][Hide abstract] ABSTRACT: During an inflammatory response, lymphocyte recruitment into tissue must be tightly controlled because dysregulated trafficking contributes to the pathogenesis of chronic disease. Here we show that during inflammation and in response to adiponectin, B cells tonically inhibit T cell trafficking by secreting a peptide (PEPITEM) proteolytically derived from 14.3.3 zeta delta (14.3.3.ζδ) protein. PEPITEM binds cadherin-15 on endothelial cells, promoting synthesis and release of sphingosine-1 phosphate, which inhibits trafficking of T cells without affecting recruitment of other leukocytes. Expression of adiponectin receptors on B cells and adiponectin-induced PEPITEM secretion wanes with age, implying immune senescence of the pathway. Additionally, these changes are evident in individuals with type 1 diabetes or rheumatoid arthritis, and circulating PEPITEM in patient serum is reduced compared to that of healthy age-matched donors. In both diseases, tonic inhibition of T cell trafficking across inflamed endothelium is lost. Control of patient T cell trafficking is re-established by treatment with exogenous PEPITEM. Moreover, in animal models of peritonitis, hepatic ischemia-reperfusion injury, Salmonella infection, uveitis and Sjögren's syndrome, PEPITEM reduced T cell recruitment into inflamed tissues.
Nature medicine 04/2015; 21(5). DOI:10.1038/nm.3842 · 27.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Synovial fibroblasts in persistent inflammatory arthritis have been suggested to have parallels with cancer growth and wound healing, both of which involve a stereotypical serum response programme. We tested the hypothesis that a serum response programme can be used to classify diseased tissues, and investigated the serum response programme in fibroblasts from multiple anatomical sites and two diseases. To test our hypothesis we utilized a bioinformatics approach to explore a publicly available microarray dataset including rheumatoid arthritis (RA), osteoarthritis (OA) and normal synovial tissue, then extended those findings in a new microarray dataset representing matched synovial, bone marrow and skin fibroblasts cultured from RA and OA patients undergoing arthroplasty. The classical fibroblast serum response programme discretely classified RA, OA and normal synovial tissues. Analysis of low and high serum treated fibroblast microarray data revealed a hierarchy of control, with anatomical site the most powerful classifier followed by response to serum and then disease. In contrast to skin and bone marrow fibroblasts, exposure of synovial fibroblasts to serum led to convergence of RA and OA expression profiles. Pathway analysis revealed three inter-linked gene networks characterising OA synovial fibroblasts: Cell remodelling through insulin-like growth factors, differentiation and angiogenesis through _3 integrin, and regulation of apoptosis through CD44. We have demonstrated that Fibroblast serum response signatures define disease at the tissue level, and that an OA specific, serum dependent repression of genes involved in cell adhesion, extracellular matrix remodelling and apoptosis is a critical discriminator between cultured OA and RA synovial fibroblasts.
PLoS ONE 03/2015; 10(3):e0120917. DOI:10.1371/journal.pone.0120917 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is currently no biochemical test for detection of early-stage osteoarthritis (eOA). Tests for early-stage rheumatoid arthritis (eRA) such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies require refinement to improve clinical utility. We developed robust mass spectrometric methods to quantify citrullinated protein (CP) and free hydroxyproline in body fluids. We detected CP in the plasma of healthy subjects and surprisingly found that CP was increased in both patients with eOA and eRA whereas anti-CCP antibodies were predominantly present in eRA. A 4-class diagnostic algorithm combining plasma/serum CP, anti-CCP antibody and hydroxyproline applied to a cohort gave specific and sensitive detection and discrimination of eOA, eRA, other non-RA inflammatory joint diseases and good skeletal health. This provides a first-in-class plasma/serum-based biochemical assay for diagnosis and type discrimination of early-stage arthritis to facilitate improved treatment and patient outcomes, exploiting citrullinated protein and related differential autoimmunity.
[Show abstract][Hide abstract] ABSTRACT: Rheumatoid arthritis (RA) is a heterogeneous chronic immune-mediated inflammatory disease, associated with significant morbidity and reduced life expectancy. Here, we review recent discoveries; particularly those which have attempted to integrate genome-wide association studies (GWAS) with biological pathways and cell types known to play a role in disease pathology in order to expand our current understanding of the pathogenesis of RA. As the role of stromal cells in the pathogenesis of RA has been reviewed in detail in Current Opinions in Rheumatology, this area will not be covered in this review.
Although our understandings of the pathogenic processes that drive disease in RA remain incomplete, remarkable advances over the past year can be highlighted. GWAS have raised awareness of important new risk loci with genes that either are the targets of approved therapies for RA, or involve pathways for drugs that could be repurposed from other disease indications such as cancer. Furthermore, promising strides have been made in predicting the likelihood of developing RA in those at risk using human leukocyte antigen (HLA), smoking, and autoantibody status prediction models. These findings give a fresh insight into RA pathogenesis and help identify new, or repurpose known therapeutic targets from other disease areas.
The findings discussed in this review underscore the progress made to date and the need for future studies, investigating disease mechanisms in RA, with particular interest in at-risk RA gene loci, their function in immune and stromal cells within the synovium, and how they interact with environmental factors to initiate and perpetuate disease.
Current Opinion in Rheumatology 03/2015; 27(3). DOI:10.1097/BOR.0000000000000174 · 4.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: For our understanding of the pathogenesis of rheumatoid arthritis (RA), it is important to elucidate the mechanisms underlying early stages of synovitis. Here, synovial cytokine production was investigated in patients with very early arthritis.
Synovial biopsies were obtained from patients with at least one clinically swollen joint within 12 weeks of symptom onset. At an 18-month follow-up visit, patients who went on to develop RA, or whose arthritis spontaneously resolved, were identified. Biopsies were also obtained from patients with RA with longer symptom duration (>12 weeks) and individuals with no clinically apparent inflammation. Synovial mRNA expression of 117 cytokines was quantified using PCR techniques and analysed using standard and novel methods of data analysis. Synovial tissue sections were stained for CXCL4, CXCL7, CD41, CD68 and von Willebrand factor.
A machine learning approach identified expression of mRNA for CXCL4 and CXCL7 as potentially important in the classification of early RA versus resolving arthritis. mRNA levels for these chemokines were significantly elevated in patients with early RA compared with uninflamed controls. Significantly increased CXCL4 and CXCL7 protein expression was observed in patients with early RA compared with those with resolving arthritis or longer established disease. CXCL4 and CXCL7 co-localised with blood vessels, platelets and CD68(+) macrophages. Extravascular CXCL7 expression was significantly higher in patients with very early RA compared with longer duration RA or resolving arthritis CONCLUSIONS: Taken together, these observations suggest a transient increase in synovial CXCL4 and CXCL7 levels in early RA.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Annals of the Rheumatic Diseases 03/2015; DOI:10.1136/annrheumdis-2014-206921 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives To explore how social interactions at the onset of rheumatoid arthritis (RA) influence help-seeking behaviour from the perspectives of those with RA and their significant others (family and friends). Methods Nineteen semi-structured qualitative interviews were undertaken with people recently diagnosed with RA and their significant others. Interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis. Results Significant others' initial appraisals of symptoms led them to provide practical support with daily activities rather than advice to seek help. People with RA described difficulties in communicating the severity of their symptoms and often attempted to hide their symptoms from others. Significant others also reacted negatively, expressing disbelief and dismissing symptoms. On occasion, early symptoms were even described as the catalyst for the breakdown of relationships. On reflection, significant others expressed guilt about their initial reactions and wished that they had recognized the need for intervention earlier. When symptoms had advanced and were more obvious, significant others often strongly advised that help should be sought and, in some cases, physically escorted the patient to their medical appointment. In many instances, people with RA described significant others as the catalyst for eventually seeking help. Conclusions Significant others play an important role in influencing help-seeking behaviour; this has implications for theoretical models of help-seeking and the development of help-seeking interventions. A negative consequence of social interactions resulted from a lack of understanding and knowledge about RA among significant others, highlighting the need for greater public awareness about the early symptoms of RA.
British Journal of Health Psychology 02/2015; 20(3). DOI:10.1111/bjhp.12134 · 2.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and objectives We have recently identified a subset of pro-inflammatory memory B cells in RA synovial fluid and tissue, characterised by the expression of Fc receptor-like 4 (FcRL4). These cells produce RANKL, and express high levels of TNFα mRNA, indicating a destructive, pro-inflammatory role. Their immunophenoptype suggest that they are activated B cells; however, they show no signs of differentiation towards plasmablasts, suggesting that their functional role does not involve antibody production. The aim of this project was to investigate the characteristics of their immunoglobulin genes and determine whether their B cell receptors recognise autoantigens.
Methods Single FcRL4-positive and -negative B cells were sorted from synovial tissue (n = 2) and synovial fluid (n = 5) of patients with active RA. Their Ig variable region genes were sequenced and subsequently expressed to generate recombinant monoclonal antibodies. Antigen specificities of the generated monoclonal antibodies were determined by ELISA.
Results In total, we have cloned and sequenced B cell receptors from 332 individual B-cells (171 from FcRL4+ and 160 from FcRL4- cells). Ig gene sequence analysis demonstrated that the Ig repertoire was highly diverse with no major differences in the IGH and IGK or IGL gene segment usage or IGH CDR3 features between FcRL4+ and FcRL4- memory B cells. The prevalence of mutations, suggesting somatic hypermutation and selection in germinal centres, was equivalent in the FcRL4+ and FcRL4- populations. From the sequenced clones we have generated recombinant monoclonal antibodies from both FcRL4+ (n = 29) and FcRL4– B cells (n = 26) and have determined their specificity for citrullinated candidate autoantigens. A similar proportion of recombinant antibodies derived from the FcRL4+ and FcRL4- B cell populations (23% and 24% respectively) reacted with citrullinated antigens (including α-enolase, fibrinogen, vimentin and histones)
Conclusion We conclude that memory B cells from both the FcRL4+ and FcRL4- populations are post-germinal centre hypermutated B cell subsets with similar Ig gene features. Their antigen specificity suggests that these functionally distinct B subpopulations both emerge from the autoantigen driven immune response in the inflamed joint.
Annals of the Rheumatic Diseases 02/2015; 74(Suppl 1):A11-A11. DOI:10.1136/annrheumdis-2015-207259.26 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives Fibroblasts have been shown to actively regulate the inflammatory infiltrate that accumulates within synovial joints. On way they achieve their effects in part by conversing with neighbouring vascular endothelial cells imparting a stromal “address code” that regulates leukocyte recruitment. Here we compared the ability of synovial fibroblasts from resolving arthritis and very early RA to communicate with vascular endothelial cells (EC).
Methods Fibroblasts were isolated from synovial biopsies taken from treatment naive patients with a new onset of clinically apparent arthritis and symptom duration of ≤12weeks, who at follow-up had either a resolving arthritis or RA (VeRA). Endothelial cell-fibroblast co-cultures were formed using porous filters for 24 h prior to a further 24 h stimulation with tumour necrosis factor alpha and interferon gamma. Microarray analysis was performed on mRNA extracted from endothelial cells and evaluated using Ingenuity Pathway Analysis.
Results Resolving and VeRA fibroblasts differentially modified the transcriptional profile of EC. There were 52 differentially expressed genes (76 probe sets) between the two conditions, with 21 genes expressed higher in EC from VeRA co-cultures compared to resolving co-cultures. These related to 18 ingenuity canonical pathways associated with cell signalling (e.g. Wnt and NKFB pathways), cellular differentiation, and metabolism (e.g. lipid and amino acid).
Conclusions Fibroblasts from acutely resolving and early persistent arthritis are distinct. Differences in the way in which fibroblasts communicate with endothelial cells could be involved in the pathogenesis and perpetuation of the inflammatory response in the earliest clinically apparent phases of RA.
Annals of the Rheumatic Diseases 02/2015; 74(Suppl 1):A57-A57. DOI:10.1136/annrheumdis-2015-207259.132 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Treating patients with rheumatoid arthritis (RA) within 3 months of symptom onset leads to significantly improved clinical outcomes. However, many people with RA symptoms wait a long time before seeking medical attention. To develop effective health interventions to encourage people to seek help early, it is important to understand what the general public knows about RA, how they would react to the symptoms of RA, and what might delay help-seeking.
Qualitative interviews were conducted with 38 members of the general public (32 women) without any form of inflammatory arthritis about their perceptions of RA symptoms and decisions to seek help were they to experience such symptoms. The interviews were audio-recorded, transcribed verbatim, and analyzed using thematic analysis.
A number of barriers and drivers to help-seeking were identified and grouped into 5 themes: perceived causes of symptoms; factors related to presentation, location, and experience of symptoms; perceived effect of symptoms on daily life; self-management of symptoms; and general practitioner-related drivers and barriers.
To our knowledge, our study is the first to investigate barriers to and drivers of help-seeking in response to the onset of RA symptoms in individuals without a diagnosis of RA. It has revealed a number of additional factors (e.g., the importance of the location of the symptoms) besides those previously identified in retrospective studies of patients with RA. Together with the data from previous research, these findings will help inform future health interventions aimed at increasing knowledge of RA and encouraging help-seeking.
The Journal of Rheumatology 02/2015; 42(4). DOI:10.3899/jrheum.140913 · 3.19 Impact Factor