Background Although immunological blockade of checkpoint inhibitors (CIs) for cancer therapy is known to be associated with exacerbated inflammation recapitulating many features of autoimmunity1, including synovitis resembling rheumatoid arthritis (RA)2, no reports have investigated cellular infiltrates in synovial tissue (ST) of these patients. Here we provide the first report on ST cell infiltration, in particular PD1 expressing T cells, after a PD1 inhibitor-induced (Nivolumab) immune related adverse event (irAE) and severe synovitis. Objectives To characterise ST cellular infiltration in PD1 inhibitor induced arthritis with particular reference to PD1 positive T cells and compare these changes with active early RA ST. Methods Arthroscopic ST biopsies, parallel synovial fluid (SF) and PBMCs were collected from a DMARD-naïve nivolumab-treated small cell lung cancer (SCLC) patient with severe peripheral inflammatory polyarthritis (negative RF and ACPA; no axial or extra-articular irAE); 3 DMARD-naïve patients with seropositive early RA (<12 months duration; fulfilling 2010 ACR/EULAR criteria) were used as comparators. Serial sections from fresh-frozen ST blocks were stained with H and E, CD3, CD45RO, CD55 and CD68 and semi-quantitatively scored as described3. ST, SF and PBMC cell suspensions were stained with Zombie UV (BioLegend), CD45RO, PD1, CD3, ICOS, CD8, CD4, CD20 (all BD) prior to flow cytometry. Cells were gated on live, singlet, lymphocytes, CD3+ and CD4+ T cells, and CD20+ and CD8+ T cells were excluded from endpoint PD1+, ICOS+ and CD45RO+analysis. Results CD68 +macrophage, CD20+ B cell and CD3+ T cell and CD45RO+memory T cell infiltration in IC-irAE was comparable to RA ST on semi-quantitative scoring, while TNF; staining was markedly elevated in CI-irAE compared to RA (CI-irAE-TNF; 4, RA-TNF; 2). Flow cytometry identified a striking absence of PD1+ ICOS+ CD4+T cells in IC-irAE SCLC in all compartments (CI-irAE: ST; 0.06, SF; 0.01, PBMCs; 0.00) compared to RA (RA: ST mean and SEM; 22.13±3.63: SF; 45.95±1.85: and to a lesser extent in PBMCs; 0.41±0.13: n=3 for each), despite comparable CD4 +T cell frequency in each compartment (frequency of CD3 +cells, CI-irAE: ST; 57.8, SF; 64.7, PBMCs; 38.2, RA: ST; 45.9±15.3, SF; 49.5±11.2, PBMCs; 62.2±13.8, figure 1). Figure 1 PD-1 +ICOS + T cells are absent in CI-irAE. Showing the PD-1 +ICOS + frequency of CD4 +T cells gated on live, singlet, lymphocytes, and CD3+, CD20- and CD8-cells. (RA: ST mean and SEM; 22. 13±3.63: SF; 45.95±1.85 n=3 for each, CI-irAE: ST; 0.06, SF; 0.01, PBMCs; 0.00, n=1 for each). Conclusions While ST infiltration in CI-irAE SCLC recapitulates many features of RA histopathology, PD1 expression principally distinguishes RA from irAE ST T-cell infiltration. Despite abundant CD4 and CD45RO memory T cell infiltration in CI-irAE comparable with RA, we found a conspicuous absence of PD1 positive T-cells. Further research is needed to fully understand the nature of reduced PD1 expression in this setting and the source of elevated TNF, which could shed light on the pathogenesis of CI-irAE and guide CI-irAE management. References [1] van der Vlist, et al. Immune checkpoints and rheumatic diseases: what can cancer immunotherapy teach us?Nat Rev Rheumatol2016. [2] Naidoo, J. et al. Inflammatory Arthritis: A Newly Recognized Adverse Event of Immune Checkpoint Blockade. Oncologist2017. [3] Tak, P. P. et al. Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum. 1997. Disclosure of Interest None declared

Background Deep profiling of synovial tissue samples from rheumatoid arthritis (RA) patients may reveal the molecular underpinnings of phases of RA progression and provide new therapeutic targets to intervene earlier in disease pathogenesis. Objectives We sought to identify the molecular pathways expressed in different stages of disease (from seropositive subjects without clinically apparent synovitis to those with established disease) in synovial tissue compared to non-RA controls. Methods Transcriptomics profiling was performed on RNA isolated from synovial tissue biopsies. Normal synovium was collected from subjects with knee pain and without diagnosis of OA or RA (n=28). Arthralgia tissue was collected from ACPA-positive subjects without synovitis (n=10). Early RA tissue was collected from patients recently diagnosed (<1 year) with RA (n=57). Established RA tissue was collected from ACPA-positive subjects with >1 year of disease duration (n=95). Protein expression was confirmed on infiltrating immune cells from synovial biopsy cell suspensions by flow cytometry in separate RA subjects. Results Several pathways previously identified as important for RA pathogenesis (e.g., lymphocyte activation, osteoclast differentiation, NF-kappa B signaling) were enriched in differentially expressed genes in disease synovial biopsies compared to normal tissue samples. Interestingly, several genes known to function in T cell activation as signal 2 co-stimulatory or co-inhibitory molecules were differentially expressed, even in arthralgia and early RA subjects. 66 of 81 known co-stimulatory or co-inhibitory genes profiled were differentially expressed (FDR <5% and absolute fold-change >2) in disease samples from at least one cohort. The genes encoding co-stimulatory proteins that were increased compared to normal included CD28, CD40LG, CD40 and ICOS. Interestingly, some of the genes encoding co-inhibitory proteins were increased (PDCD1/PD-1, CD274/PD-L1, HAVCR2/TIM3, TIGIT, BTLA), whereas others showed decreased expression (C10orf54/VISTA and LAG3) compared to normal controls. We focused on CD28 expression, which is elevated in “pre-RA” arthralgia samples, proposing that anti-CD28 therapeutics could be candidates for RA disease prevention. By flow cytometry we demonstrated that a majority of CD4+ (>90%) and CD8+ (>60%) T cells from RA synovial biopsy cell suspensions (n=4) showed surface expression of CD28. Conclusions We have generated a unique dataset from different phases of RA progression. Our results provide guidance for the selection of co-signaling molecules as therapeutic targets as well as for preventing the progression to RA. In particular, CD28 expression was elevated in synovial tissue biopsies before the development of RA and it was also expressed on the majority of synovial tissue infiltrating CD4+ and CD8+ T cells from RA patients. These observations provide rationale to target CD28 for both RA treatment and disease interception. Disclosure of Interest A. Walsh Shareholder of: Johnson & Johnson, Employee of: Johnson & Johnson, M. Canavan: None declared, Y. Guo Shareholder of: Johnson & Johnson, Employee of: Johnson & Johnson, T. McGarry: None declared, X. Yin Shareholder of: Johnson & Johnson, Employee of: Johnson & Johnson, M. Wechalekar Grant/research support from: Johnson & Johnson, M. Smith Consultant for: Johnson & Johnson, S. Proudman: None declared, C. Orr: None declared, S. Kelly: None declared, C. Pitzalis Grant/research support from: Johnson & Johnson, Consultant for: Abbott, Astellas, MedImmune, BMS, Celgene, Grunenthal, GSK, MSD, Pfizer, Sanofi, Roche, UCB, D. Veale: None declared, U. Fearon: None declared, S. Nagpal Shareholder of: Johnson & Johnson, Employee of: Johnson & Johnson

Background Traditional markers associated with erosive disease in RA do not reliably predict radiographic progression. There are limited data regarding the role of bone biomarkers in erosive disease in early RA treated with conventional DMARDs and no longitudinal data on osteoclast-associated receptor (OSCAR) with therapy. Objectives To determine whether bone biomarkers associated with osteoclast activation (RANKL, OSCAR and Dkk-1) or inhibition (OPG) are associated with erosion progression over 3 years, independent of disease activity in an inception cohort of RA receiving treat-to-target combination DMARD therapy without oral corticosteroids. Methods Dual RF and anti-CCP positive patients with early RA (<1 year; fulfilling ACR 1987 and/or 2010 classification criteria; n=50) received triple therapy (methotrexate, sulfasalazine and hydroxychloroquine) escalated to achieve DAS28 remission. RANKL, OPG and Dkk-1 were analysed by Luminex kits, OSCAR by ELISA at baseline, 6 and 12 months. For radiographic outcomes annual hand and feet radiographs were scored by the van der Heijde modified Sharp (SvH) method. Changes in bone biomarkers and associations with predictor variables were assessed using a linear multi-response random effects model. Relationships between bone biomarkers in the first year and DAS28 remission and radiographic erosion score outcomes over 3 years were analysed using logistic and negative binomial mixed regression respectively. Results Mean (SD) baseline DAS28ESR was 5.55 (1.14), 76% were females, 70% were current/past smokers and mean duration of symptoms prior to diagnosis was 18 (12) weeks. Median (IQR) total SvH score was 2 (7); 24% had erosive disease. With treatment, there was a reduction in DAS28 at 1 year to 3.14 (1.31), significant reduction in RANKL, slight increase in OPG and no significant change in Dkk-1 and OSCAR. DAS28 remission, assessed over 3 years, was less likely to occur both in the presence of detectable RANKL (p=0.01) and/or in the presence of higher average Dkk-1 levels (p=0.007). Baseline erosion scores were higher in the presence of RANKL (p=0.046) and lower OSCAR (p=0.021). There was a trend towards higher erosion scores in the presence of lower OPG levels (p=0.16). Unexpectedly, those with higher mean OPG over the first 12 months had a higher annual increase in erosion scores over 3 years (p=0.018), which may reflect the dynamic processes of bone inflammation. Conclusions Conventional DMARD treatment results in reduction of RANKL, but not OPG, OSCAR or Dkk-1 levels. Higher RANKL levels, lower OSCAR levels and higher mean OPG were associated with erosions. Failure of bone biomarkers to respond to treatment may warrant escalation of therapy to prevent erosion progression. Bone biomarkers may also provide an explanation for the apparent dissociation between disease activity and bone damage in RA. Disclosure of Interest M. D. Wechalekar: None declared, S. Lester: None declared, S. Nagpal Employee of: Johnson & Johnson, S. Cole Employee of: Johnson & Johnson, A. Das Employee of: Johnson & Johnson, P. Hissaria: None declared, T. Crotti: None declared, L. Spargo: None declared, J. Walker: None declared, M. Smith: None declared, S. Proudman: None declared

Background Osteoclast-associated receptor [OSCAR] is expressed by monocyte, endothelial and dendritic cells. OSCAR is a co-stimulation receptor involved in transducing immunoreceptor tyrosine-based activation (ITAM) signals for differentiation from monocytes into active osteoclasts (OCs). Endothelial OSCAR expression may induce monocyte adhesion increasing monocyte extravasation available for osteoclastogenesis in affected joints. Higher expression of OSCAR by endothelial and pre-OCs, as detected by immunohistochemistry, is present in active RA compared with OA and healthy synovial samples (Crotti ART 2012). Inflammation in RA may increase OSCAR expression as supported by increased monocyte (Herman ART 2012) and endothelial cell (Crotti ART 2012) OSCAR expression in response to TNF-alpha in vitro. OSCAR expression in early RA (less than 6 months post diagnosis) and cartilage pannus junction (CPJ) and non-CPJ samples from established RA has not been reported. Objectives To examine OSCAR expression in the synovium of early RA patients at diagnosis and 6 months following treatment. OSCAR was also assessed in the CPJ and non-CPJ tissues of patients with established RA. Methods Samples included synovial biopsies from 15 patients newly diagnosed for RA at 0 and 6 months. CPJ and non-CPJ samples from established RA joints were also assessed (n=14). Serial sections for both cohorts were stained for OSCAR, TRAP (to identify pre-OCs/OCs) and von Willebrand factor (to identify vessels). Positive cells were counted (TRAP) or scored semiquantitatively (OSCAR) in 6x 2mm2 fields. A paired T test was used to detect significance. Results OSCAR was associated with the synovial lining cells and distributed sparsely in association with monocytes in the subsynovial tissue or lymphoid aggregates in both early and established RA. A subset of samples from both cohorts showed a very mild staining associated with the vasculature and lumen. In early RA there was no significant difference in OSCAR expression within lining, sublining and vessels (p=0.217, 0.622, 0.906 respectively) between 0 and 6 months. The expression of OSCAR in the sublining reduced in 10/15 patients by 6 months. Very few TRAP positive cells were detected at either time point. The CPJ and non-CPJ established RA cohort had higher expression of OSCAR than the early cohort. The number of TRAP positive cells was significantly higher in the CPJ versus non-CPJ (p=0.015, mean=88.5 vs 44). Conclusions OSCAR positive cells were observed in all synovial tissues, particularly in the lining, in both early RA and established RA. This has not been previously reported. Expression of OSCAR by sublining cells including OC precursors, possibly dendritic cells, macrophages and endothelial cells is consistent with previous reports. Low numbers of TRAP positive cells may relate to early disease and/or site of biopsy as distant from the actual CPJ due to limitations of arthroscopic technique. In established RA, higher numbers of TRAP and OSCAR positive cells were present in both CPJ and non-CPJ tissues. The reduced sublining OSCAR expression in the majority of patients following treatment suggests modulation of OSCAR by DMARDS and may implicate OSCAR as an inflammation and bone erosion predictive biomarker. Disclosure of Interest None declared

In rodent models of inflammatory arthritis, bone erosion has been non-invasively assessed by micro-computed tomography (micro-CT). However, non-invasive assessments of paw swelling (oedema) are still based on clinical grading by visual evaluation, or measurements by callipers, not always reliable for the tiny mouse paws. The aim of this work was to demonstrate a novel straightforward 3D micro-CT analysis protocol capable of quantifying not only joint bone erosion, but also soft tissue swelling, from the same scans, in a rodent inflammatory arthritis model. Balb/c mice were divided into two groups: collagen antibody-induced arthritis (CAIA) and CAIA treated with prednisolone, the latter reflecting an established treatment in human rheumatoid arthritis. Clinical paw scores were recorded. On day 10, front paws were assessed by micro-CT and histology. Micro-CT measurements included paw volume (bone and soft tissue together) and bone volume at the radiocarpal joint, and bone volume from the radiocarpal to the metacarpophalangeal joint. Micro-CT analysis revealed significantly lower paw volume (-36%, P < 0.01) and higher bone volume (+17%, P < 0.05) in prednisolone-treated CAIA mice compared with untreated CAIA mice. Paw volume and bone volume assessed by micro-CT correlated significantly with clinical and histological scores (|r| > 0.5, P < 0.01). Untreated CAIA mice showed significantly higher clinical scores, higher inflammation levels histologically, cartilage and bone degradation, and pannus formation, compared with treated mice (P < 0.01). The presented novel micro-CT analysis protocol enables 3D-quantification of paw swelling at the micrometre level, along with the typically assessed bone erosion, using the same images/scans, without altering the scanning procedure or using contrast agents.

Background Rheumatoid arthritis (RA) is a chronic and progressive autoinflammatory disorder characterized by the infiltration of inflammatory cells, including B-cells, T-cells and macrophages, in the synovial membrane ultimately leading to cartilage destruction and bone erosion. Clinical disease activity in RA correlates strongly with macrophage numbers in synovial tissue and expression of macrophage-derived cytokines. Bruton’s tyrosine kinase (Btk) is important not only in B cell activation, but also mediates immune complex-dependent activation of monocytes. Pharmacological inhibition of Btk has been shown to be effective in suppressing pathology in murine models of arthritis Objectives The objective of this study was to determine the potential role of Btk in the pathology of RA. Methods Btk expression was detected by immunohistochemistry and digital image analysis in synovial tissue from 16 RA and 12 PsA patients, naïve to treatment with biologicals. Immunofluorescent double labelling confocal microscopy was performed to identify which cell types express Btk in RA synovial tissue. Validating qRT-PCR and immunoblotting experiments were performed on isolated relevant cell populations. Effects of a specific Btk inhibitor, RN486, on activation-dependent human macrophage IL-6 production (n=8) and RA synovial tissue explant cultures (n=6) were assessed by ELISA. RN486 influence on macrophage expression of genes related to angiogenesis, cellular adhesion, tissue remodelling and innate immune responses was determined using low density qPCR arrays. Results Btk was expressed at equivalent levels in patients with RA and PsA. No relationship was observed between expression levels and patient clinical characteristics (CRP, ESR, DAS28, RF-positivity). In RA, but not PsA, Btk expression was significantly related to numbers of synovial macrophages (R= 0.63, p< 0.01) and T cells (R= 0.79, p< 0.001), but not fibroblast-like synoviocytes (FLS), B cells, plasma cells, or endothelial cells. qPCR and immunoblotting experiments confirmed that Btk was expressed in B cells, monocytes, and macrophages, but not T cells or RA FLS. RN486 (1μM) inhibited macrophage IL-6 production induced by Fc receptor stimulation (40% inhibition, p< 0.01) and anti-CD40 antibodies (50%, p< 0.05), but not TNFα or LPS stimulation. qPCR analysis of human macrophages demonstrated that RN486 inhibited by more than 2-fold 12 of 21 genes induced by IgG, 11 of 52 genes induced by CD40 stimulation, and 6 of 25 genes induced by RA SF in 3 independent experiments. RN486 also inhibited spontaneous IL-6 production by cultured RA synovial explants (65%, p< 0.01). Conclusions Btk is expressed in RA synovial tissue and macrophages would be prominent synovial targets of strategies aimed at inhibiting Btk in RA. Btk activity is needed to drive macrophage activation in response to multiple stimuli relevant to RA, and drives IL-6 production in RA synovial tissue. Pharmacological targeting of Btk may be of therapeutic benefit in the treatment of RA. Disclosure of Interest L. Hartkamp: None Declared, I. van Es: None Declared, J. Fine Shareholder of: Hoffmann-La Roche, Employee of: Hoffmann-La Roche, M. Smith Shareholder of: Hoffmann-La Roche, Employee of: Hoffmann-La Roche, J. Woods Shareholder of: Hoffmann-La Roche, Employee of: Hoffmann-La Roche, S. Narula Shareholder of: Hoffmann-La Roche, Employee of: Hoffmann-La Roche, J. DeMartino Shareholder of: Hoffmann-La Roche, Employee of: Hoffmann-La Roche, P. Tak Consultant for: GlaxoSmithKline, Employee of: GlaxoSmithKline, K. Reedquist Grant/research support from: Hoffmann-La Roche

BACKGROUND:The aetiology of rheumatoid arthritis (RA), a prototype immune-mediated inflammatory disorder, is poorly understood. It is currently unknown whether the disease process starts in the synovium, the primary target of RA, or at other sites in the body. OBJECTIVE:To examine, in a prospective study, the presence of synovitis in people with an increased risk of developing RA. METHODS:Thirteen people without evidence of arthritis, who were positive for IgM rheumatoid factor and/or anticitrullinated protein antibodies, were included in the study. To evaluate synovial inflammatory changes, all participants underwent dynamic contrast-enhanced MRI and arthroscopic synovial biopsy sampling of a knee joint at inclusion. Results were compared with knee MRI data and synovial biopsy data of 6 and 10 healthy controls, respectively. RESULTS:MRI findings evaluated by measurement of maximal enhancement, rate of enhancement, synovial volume and enhancement shape curve distribution were similar between the autoantibody-positive subjects and the healthy controls. Consistent with these findings, all but one autoantibody-positive subject showed very low scores for phenotypic markers, adhesion molecules and vascularity, all in the same range as those in normal controls. The one person with higher scores had patellofemoral joint space narrowing. CONCLUSION:Subclinical inflammation of the synovium does not coincide with the appearance of serum autoantibodies during the pre-RA stage. Thus, systemic autoimmunity precedes the development of synovitis, suggesting that a 'second hit' is involved. This study supports the rationale for exploring preventive strategies aimed at interfering with the humoral immune response before synovial inflammation develops.

Poster Presentations / Osteoarthritis and Cartilage 18, Supplement 2 (2010) S45-S256 no such regional difference in type I collagen content in low-grade control specimens (p=0.181).Real-time PCR: COL2A1 expression was not significantly different in regions of damaged and preserved cartilage in AMG (p=0.156),low-grade control (p=0.625) or high-grade control specimens (p=0.813).COL1A1 expression in AMG specimens was significantly greater in the preserved cartilage than damaged cartilage (p=0.031).However, the regional difference in type I collagen expression was not seen in low-grade (p=0.625) or high-grade controls (p=0.219).Conclusions: Type I collagen is abundant in fibro-cartilage but only found in very low levels in mature hyaline cartilage and is not usually found in articular cartilage.Macroscopically normal cartilage in AMG exhibits increased COL1A1 gene expression and a subsequent increase in type I collagen matrix content.Type I collagen is also increased in the equivalent region of knees with early histological features of OA These findings suggest that these cartilage matrix and chondrocyte phenotype changes may be an early feature of OA change in AMG.

AIM:To ascertain the mortality risk and investigate clinical and serological factors influencing survival of patients listed on the South Australian Scleroderma Register (SASR).METHODS:The SASR is a population-based register, which was commenced in 1993 and has actively sought to recruit all scleroderma patients diagnosed in SA over a 15-year period. Clinical and serological details have been accessed from questionnaires or from clinical and laboratory files. Standardized mortality ratio (SMR) was calculated and survival analyses performed on all living and deceased patients listed on this SASR (n = 786).RESULTS:Patients with scleroderma had increased mortality compared with the general SA population (SMR 1.46 (95% confidence interval (CI) 1.28-1.69)). Factors that adversely altered survival included older age at onset, male gender, diffuse skin involvement, presence of scleroderma renal crisis, pulmonary fibrosis, pulmonary arterial hypertension, cancer and anti-topoisomerase (Scl-70) and anti-U1 RNP antibodies, while a trend was observed with increased nailfold capillary dropout. Mean age of death for patients with limited scleroderma was 74.1 years (95% CI 72.5-75.7), diffuse scleroderma 62.9 years (95% CI 59.4-66.4) and overlap disease 57.8 years (95% CI 48.7-66.9). Survival improved over the 15-year study period.CONCLUSIONS:Scleroderma substantially reduces life expectancy. Survival is influenced by age at onset, gender, diffuse involvement of skin fibrosis, visceral involvement, development of cancer, extent of microvascular capillary damage and by the presence of scleroderma-associated antibodies, Scl-70 and RNP. Scleroderma renal crisis continues to carry high mortality. Survival improved over the 15-year study period.

Objective: To demonstrate the efficacy of intra-articular infliximab in a patient with a persistent monarthritis who had previously had two arthroscopic synovectomies with limited success, and to determine the effect of intra-articular infliximab on synovial membrane pathologyMethod: Arthroscopic synovial biopsy specimens were collected before and after treatment with intra-articular infliximab. The synovial tissue was stained for a range of inflammatory cell subsets, cell adhesion molecules and cytokines using immunohistochemical techniques and quantified using digital image analysis and a semiquantitative scoring method.Results: Clinical improvement in the knee synovitis was seen after the first two intra-articular infliximab treatments, with a sustained clinical remission lasting for more than 12 months after the third treatment. Significant changes in cellular infiltration and expression of cytokines and cell adhesion molecules occurred as a result of treatment with intra-articular infliximab, with a reduction in some but not all cells in the inflammatory infiltrate, as well as a reduction in the expression of cell adhesion molecules (intercellular adhesion molecule-1 and vascular adhesion molecule-1) and production of cytokines (interleukin 1 beta and tumour necrosis factor alpha).Conclusion: Intra-articular infliximab administration is a viable treatment for a persistent monarthritis resistant to other treatment options and can successfully modulate the inflammatory milieu within the synovial membrane.

OBJECTIVES:To characterise the phenotype of the putative dendritic cells strongly expressing Jak3 and STAT4, which have been previously identified in the synovial tissue of patients with active rheumatoid arthritis (RA). METHODS:Synovial biopsy specimens were obtained at arthroscopy from 30 patients with active RA (42 synovial biopsies). Immunohistological analysis was performed using monoclonal antibodies to detect dendritic cell subsets, including activation markers and cytokines relevant to dendritic cell function. Co-localisation of cell surface markers and cytokines was assessed primarily using sequential sections, with results confirmed by dual immunohistochemistry and immunofluorescence with confocal microscopy. RESULTS:The dendritic cells identified in RA synovial tissue that strongly express Jak3 also strongly express STAT4 and STAT 6 and are correlated with the presence of serum rheumatoid factor. These cells are not confined to a single dendritic cell subset, with cells having phenotypes consistent with both myeloid- and plasmacytoid-type dendritic cells. The activation status of these dendritic cells suggests that they are maturing or mature dendritic cells. These dendritic cells produce IL12 as well as interferon alpha and gamma. CONCLUSIONS:The close correlation of these dendritic cells with the presence of serum rheumatoid factor, a prognostic factor for worse disease outcome, and the strong expression by these cells of components of the Jak/STAT transcription factor pathway suggest a potential therapeutic target for the treatment of RA.

Background: The aim of this study was to estimate the effect of rheumatoid arthritis (RA) on the personal income of a cohort of individuals with RA in Australia.Methods: A cross-sectional study of a sample of 497 working age people with RA in Adelaide, South Australia was carried out.Results: The average personal income of an individual with RA in our cohort in 2003-2004 was $A22 400 compared with the Australian mean annual income of $A38 000. When standardized, the income of our cohort was 66% that of the average income of the Australian population. Overall one-third of the RA cohort relied principally on the social security system for their income and more than 75% of the cohort estimated they had lost greater than $A10 000 per annum in personal income as a result of their disease. Individuals with RA who were not working had annual incomes on average of more than $A20 000 less than those who continued to work.Conclusion: The personal income loss associated with RA in Australia is of enormous significance. It reduces a large population of individuals to relative financial poverty and potentially limits their access to a range of services including private health services.

Aim:  To determine the diagnostic utility of qualitative nailfold capillaroscopy (NC) in a clinical setting. Methods:  One hundred and sixty-seven patients, generally with Raynaud's phenomena of uncertain significance, were referred to an experienced operator for NC. NC was performed using low power wide field microscopy. Nailfold capillary arcades, number, calibre and presence of microbleeds were assessed on the third fourth and fifth nailfolds in each patient. Patients’ final diagnoses were determined by case note review following a mean of 6.6 years post-initial NC. Results:  Nailfold capillaroscopy was considered abnormal in 86/167 patients (51%), suspicious in eight, technically unsatisfactory in two and normal in the remainder. In those 86 patients with abnormal findings the follow-up diagnosis revealed scleroderma in 79, dermatomyositis in four and antisynthetase myositis in three. Three patients with suspicious findings also developed scleroderma. Of those 71 patients with initial normal NC only four were found to have developed scleroderma at follow-up. For a diagnosis of scleroderma NC demonstrated a sensitivity of 95%, a specificity of 91%, a positive predictive value of 92% and a negative predictive value of 94%. Nailfold capillary microbleeds were also frequently observed in patients with scleroderma, but were less specific than capillary morphological changes. Conclusion:  Qualitative NC performed by an experienced operator is considered to have high diagnostic utility in the early assessment of patients with Raynaud's phenomena, and when abnormal, is highly suggestive of scleroderma, dermatomyositis or antisynthetase myositis.

Background: Modulation of Jak-STAT signalling may provide an effective therapeutic strategy in inflammatory arthritis. Objective: To document Jak-STAT expression in a cohort of patients with active rheumatoid arthritis (RA), spondyloarthritis (SpA), and osteoarthritis (OA) and compare these subsets with normal synovial tissue. Methods: Synovial tissue biopsy specimens from patients with RA, OA, and SpA and histologically normal tissue (n = 10 in each arthritis group) were examined for the presence of Jak3, STAT1, STAT4, and STAT6 expression using immunohistochemistry. Phenotyping was performed using immunohistochemistry and immunofluorescence. Clinical and serological characteristics of patients with RA expressing Jak3-STAT4 were assessed. Results: STAT1, STAT4, and Jak3 protein expression was generally increased in inflammatory arthritis. In contrast, STAT6 expression was relatively heterogeneous. A subpopulation of CD1a positive dendritic cells unique to seropositive patients with RA was detected. These cells showed intense protein expression for Jak3, STAT4, and STAT6. Conclusion: CD1a positive dendritic cells intensely express Jak3, STAT4, and STAT6 in seropositive RA tissue and may be an alternative marker for dendritic cells in their early stages of activation as well as providing a tool for identifying RA at the level of the synovium. Jak3 inhibition may be a potential therapeutic target to prevent dendritic cell maturation in RA. STAT1 expression is increased in inflammatory arthritis, suggesting that its pro-apoptotic and anti-inflammatory effects cannot effectively counteract inflammation. STAT6 expression is heterogeneous in synovium, suggesting a possible homoeostatic role in addition to any anti-inflammatory effects.

BACKGROUND:Modulation of Jak-STAT signalling may provide an effective therapeutic strategy in inflammatory arthritis (IA). OBJECTIVE:To examine the effect of successful disease-modifying antirheumatic drug (DMARD) treatment on the expression of Jak-STAT in a cohort of patients with active rheumatoid arthritis. METHODS:Synovial tissue biopsy specimens from 16 patients with active rheumatoid arthritis, taken before and after initiation of DMARD treatment, were examined for the presence of janus kinase (Jak)3, signal transducer and activator of transcription (STAT)1, STAT4 and STAT6 expression using immunohistochemistry. RESULTS:Successful treatment with DMARDs results in reduction in STAT1 expression in the lining, and STAT1 and STAT6 in the sublining of rheumatoid arthritis synovial tissue. Although the overall expression of STAT4 and Jak3 was not significantly altered by DMARD treatment, there was a significant reduction in the expression of the STAT4 and Jak3 bright cells, thought to be an activated dendritic cell subpopulation. CONCLUSION:Results show that Jak3, STAT1, STAT4 expression and STAT6 sublining expression decrease in response to successful treatment of rheumatoid arthritis with standard DMARDs. Therefore, altering the expression of these pathways may represent an alternative treatment option, either through promoting up-regulation of inhibitory pathways, or suppressing inflammatory paths.

The aim of this study was to determine the incidence, prevalence, survival and selective demographic characteristics of scleroderma occurring in South Australia over the 10-year period 1993-2002. Analysis of the database of the South Australian Scleroderma Register: a population-based register established in 1993. Patients with scleroderma resident in South Australia (n = 353 at 2002) were ascertained from multiple sources and clinical and demographic data were obtained from mailed questionnaire and from review of computerized hospital databases, case notes or referring letters. Time-space cluster analysis was carried out according to the Knox method. Control data were obtained from the Australian Bureau of Statistics census. The mean prevalence was 21.4 per 10(5) (95% confidence interval 20.2-22.6) and the mean cumulative incidence of 1.5 per 10(5) (95% confidence interval 1.32-1.73) with no significant change in incidence over the study period (P = 0.13). Cumulative survival improved over the study period, with patients with diffuse disease having significantly reduced survival (as compared with limited disease, P < 0.001). The proportion with diffuse disease ( approximately 22%) remained steady. There was a small but significant predisposition in patients with a continental European birthplace (P < 0.001). A family history of scleroderma was noted in 1.6% with lambda1 (familial risk) of 14.3 (95% confidence interval 5.9-34.5). However, a family history of systemic autoimmunity (especially rheumatoid arthritis) was more common (6%). No socioeconomic stratification, temporal clustering nor spatio-temporal clustering was observed either at time of initial symptom or at 10 years before disease onset. Scleroderma occurs relatively infrequently in South Australia with no significant change in incidence observed over the 10-year study period. However, cumulative survival has improved. Identified risk factors include family history of scleroderma (risk approximately 14-fold), female sex (risk approximately 5-fold) and European birthplace (risk approximately 2.5-fold); however, the majority of the disease variance appears unexplained. A stochastic explanation based on genetic instability is favoured to explain this paradox.

Changes in cellular infiltrate and expression of cytokines, chemokines, and cell adhesion molecules as a result of therapeutic interventions in rheumatoid arthritis can be demonstrated in the synovial membrane. However, before synovial tissue analysis can be used as an outcome measure in such studies, standardisation of the site and method of synovial tissue acquisition, methods of tissue processing, and appropriate methods of detection and measurement of cell lineage specific markers and relevant biological proteins is needed.

AIMS:To investigate the histological, ultrastructural and immunohistochemical features of the vascular lining of dermal telangiectasia, a characteristic clinical finding in scleroderma.METHODS:Standard histological, electron microscopic and immunohistological techniques were used to examine dermal telangiectasias in five patients with limited scleroderma, the most common scleroderma variant in Caucasian populations.RESULTS:The telangiectasias were dilated postcapillary venules located in the papillary and superficial reticular dermis. The vessel walls consisted of non-fenestrated endothelial cells surrounded by a variable number of pericytes and smooth muscle cells. There were no unique ultrastructural features. Thickened collagen fibres in the reticular or deep dermis were seen in all but one patient, although in variable and generally minimal quantities. Surrounding infiltrating inflammatory cells were scarce. No enhanced endothelial staining was obtained with antibodies directed against endoglin, endothelin, E-selectin and ICAM-1 suggesting a resting or inactivated state.CONCLUSION:The immunohistological and ultrastructural features of the lining endothelium of established telangiectasias in long-standing, limited scleroderma appear benign. It would be of interest to examine telangiectasias in the early phase of their formation. Alternatively, other explanations need to be explored in understanding the aetiopathogenesis of telangiectasia in scleroderma.