Rheumatoid Arthritis: Fitzgerald O

Fitzgerald O, Dougados M. · St Vincent's University Hospital, Elm Park, Dublin 4, Ireland. · Best Pract Res Clin Rheumatol. · Pubmed #16777575 No free full text.

Abstract: Psoriatic arthritis (PsA) is a common, debilitating auto-immune disease with diverse clinical features. In this paper, published evidence is examined, which addresses the issues that (a) PsA exists; and (b) PsA can or cannot be viewed as a distinct rheumatic disease from other spondyloarthritides. Evidence derived from epidemiological, clinical, genetic and immunohistological studies is included. Summarizing the evidence, it is clear that PsA does indeed exist, with the prevalence of rheumatic disease in patients with psoriasis (Ps) higher than would be expected. Certain clinical features also occur more commonly in PsA, although none can differentiate consistently from other arthropathies. Both genetic and immunohistological studies suggest that PsA, both oligo- and polyarticular disease, can be clearly separated from rheumatoid arthritis and that it belongs to the family of spondyloarthritides. The presence of Ps may confer a more severe clinical phenotype with poor radiological outcome. It may be that, with time, a specific genetic marker or diagnostic feature will emerge; additional, more detailed pathogenic studies are required. In the meanwhile, particularly with new treatments being evaluated, it is important to continue to develop specific classification or diagnostic criteria and to define both clinical and laboratory-based outcome measures.

Smith MD, Baeten D, Ulfgren AK, McInnes IB, Fitzgerald O, Bresnihan B, Tak PP, Veale D, Anonymous00013. · Rheumatology Research Unit, Repatriation General Hospital, Adelaide, South Australia. · Ann Rheum Dis. · Pubmed #15975970 links to  free full text

Abstract: 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.

Fitzgerald O. · St Vincent's University Hospital, Dublin, Ireland. · Arthritis Res Ther. · Pubmed #15899064 links to  free full text

Abstract: The clinical features in psoriatic arthritis straddle the divide between rheumatoid arthritis on the one hand and spondyloarthropathy on the other. The paper by Kruithof and colleagues compares synovial immunohistologic features and clearly identifies psoriatic arthritis as being a member of the spondyloarthropathy family.

Foell D, Kane D, Bresnihan B, Vogl T, Nacken W, Sorg C, Fitzgerald O, Roth J. · Department of Pediatrics, University of Münster, Münster, Germany. · Rheumatology (Oxford). · Pubmed #12832707 links to  free full text

Abstract: OBJECTIVES: Infiltration of synovial tissue by neutrophils is crucial in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and seronegative arthritis (SA). Altered vascular function and endothelial activation are important in PsA. S100A12 (EN-RAGE) is secreted by activated granulocytes and binds to the receptor for advanced glycation end products, which induces nuclear factor (NF)-kappaB-dependent activation of endothelium. METHODS: Immunohistochemical studies were performed to detect synovial S100A12 expression. We analysed serum and synovial fluid of 42 patients for S100A12 levels. RESULTS: S100A12 was strongly expressed in inflamed synovial tissue whereas it was nearly undetectable in synovia of controls or patients after successful treatment. Serum levels of S100A12 correlated with disease activity. CONCLUSIONS: Local expression of S100A12 in inflamed tissue suggests a role in synovitis, especially in PsA. High serum concentrations of S100A12 in patients with active arthritis compared with healthy controls or patients in remission point to its usefulness as a serum marker.

Cunnane G, Grehan S, Geoghegan S, McCormack C, Shields D, Whitehead AS, Bresnihan B, Fitzgerald O. · Department of Rheumatology, St. Vincent's University Hospital, Dublin, Ireland. · J Rheumatol. · Pubmed #10648018 No free full text.

Abstract: OBJECTIVE: Acute phase serum amyloid A (A-SAA) has been reported to be more sensitive than C-reactive protein (CRP) as a marker of disease activity. It may function in immune regulation and is linked to the development of secondary amyloidosis. We investigated the profile of A-SAA in early inflammatory arthritis and compared A-SAA with CRP and erythrocyte sedimentation rate (ESR) in relation to diagnosis and disease activity. METHODS: Using a sensitive and specific ELISA, A-SAA was measured in the serum of 140 patients with early arthritis (disease duration 2 weeks to 24 mo, mean 6 mo). CRP was determined using a standard ELISA; ESR and clinical disease activity variables were also recorded. RESULTS: Sixty-four patients had rheumatoid arthritis (RA), 19 psoriatic arthritis (PsA), 28 undifferentiated arthritis (UA), and 29 other forms of arthritis. A-SAA levels correlated with both CRP (r = 0.73, p = 0.0001) and ESR (r = 0.6, p = 0.0001). The magnitude of the A-SAA response was greater than either the CRP or ESR, and very high A-SAA levels were observed in disease as early as 2 weeks. Highest A-SAA concentrations occurred in RA (median 70.3 mg/l, maximum 1542) compared with the other groups (medians, PsA: 33 mg/l; UA: 12.3 mg/l; other arthritis: 11.2 mg/l), with values > 520 mg/l observed exclusively in RA. A-SAA, unlike CRP or ESR, could distinguish patients with a final diagnosis of RA from those who had persistent UA. In RA, A-SAA provided the strongest correlations with clinical measurements of disease activity. Clinical improvement was also best represented by A-SAA, while disease deterioration was associated with a significant increase in A-SAA values, but not CRP or ESR. CONCLUSION: Compared with ESR or CRP, A-SAA correlates best with markers of disease activity, and in patients with recent onset arthritis, very high levels of SAA occur exclusively in RA. As A-SAA is sensitive to change and accurately reflects alterations in disease status, it is the best marker available for the assessment of inflammatory joint disease.

Pearman L, Last J, Fitzgerald O, Veale D, Joyce M, Rainford L, McEntee M, McNulty J, Thomas E, Ryan J, McGee A, Toomey R, D'Helft C, Lowe J, Brennan PC. · UCD School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland. · Br J Radiol. · Pubmed #19153184 No free full text.

Abstract: Rheumatoid arthritis (RA) is the most common form of inflammatory disease, affecting 1-2% of the population. Posteroanterior (PA) and Brewerton projections are well established in radiographic practice for scoring and monitoring RA, but there is little evidence to demonstrate the diagnostic efficacy of these techniques. This work, by varying the positioning of a cadaveric hand, investigates whether an alternative radiographic projection could yield greater diagnostic information than the traditional techniques. Phase I of the study evaluated moving the hand 15 degrees from the anteroposterior position and then in 5 degrees increments in four directions: medial rotation, lateral rotation, flexion of the wrist and extension of the wrist. Phase II of the study took the optimum projections from Phase I and further manipulated these positions in a direction at right angles to the original position. Images were scored based on joint space visualisation in 29 joints. Results demonstrated that significantly higher diagnostic efficacy was evident with 15 degrees lateral rotation of the hand or 15 degrees flexion at the wrist compared to the Brewerton projection. Either projection is recommended, but on the basis of patient comfort, the latter of these novel positions, now known as the UCD projection, was chosen as the optimum procedure to replace the Brewerton projection. The value of using cadavers for the establishment of optimum radiographic procedures is highlighted.

Murphy E, Roux-Lombard P, Rooney T, Fitzgerald O, Dayer JM, Bresnihan B. · Department of Rheumatology, St Vincents University Hospital, Dublin, Ireland. · Clin Rheumatol. · Pubmed #19050823 No free full text.

Abstract: We investigated the relationship between disease activity, serum biological mediators of joint damage, and periarticular bone loss in inflammatory arthritis. Patients with early inflammatory arthritis were recruited from a dedicated early arthritis clinic. At the time of recruitment, all had clinical evidence of synovitis. Patients were assessed at baseline and at 1-year follow-up. Periarticular and axial bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. Serum levels of matrix metalloproteinase 1 and tissue inhibitor of metalloproteinases 1 (TIMP-1) were measured by enzyme-linked immunosorbent assay. A total 38 patients were included in the study. Twenty had rheumatoid arthritis (RA) and 18 had a seronegative spondylarthropathy (SpA). At baseline, periarticular hand BMD measurements were similar in RA and SpA. At 1 year, the mean periarticular hand BMD was significantly lower in RA (p < 0.05). Significant inverse correlations between both the Ritchie articular index and C-reactive protein levels and the change in periarticular hand BMD at 1 year were observed in RA (r = -0.792, p < 0.001 and r = -0.478, p = 0.045, respectively). Baseline TIMP-1 levels correlated with the change in periarticular hand BMD at 1 year in RA (r = 0.519, p = 0.02). At 1 year, radiographic measures of joint damage were highest in RA. Inverse correlations between the change in periarticular hand BMD and the changes in erosion score (r = -0.90, p = 0.04) were observed in patients demonstrating significant periarticular bone loss. Persistent disease activity was associated with increased periarticular bone loss in the hands in patients with RA, consistent with synovitis-mediated periarticular bone loss. The correlation between baseline TIMP-1 levels and periarticular bone loss over 1 year suggests that TIMP-1 may have utility as a biomarker of periarticular bone loss in early RA.

Gogarty M, Fitzgerald O. · No affiliation provided · Methods Mol Med. · Pubmed #17951651 No free full text.

Abstract: The development in the techniques for obtaining synovial tissue biopsy, especially through arthroscopy, have resulted in greater access to high-quality synovial tissue. The use of immunohistochemistry in arthritis research has greatly furthered our understanding of the varied immunological and biochemical pathways involved in inflammatory arthropathopies such as rheumatoid and psoriatic arthritis. Immunohistochemistry provides a strikingly visual narrative of the essential elements involved in inflammatory arthritis, from the infiltrating inflammatory cells (e.g., T-cells, macrophages, B-cells, and neutrophils), their products (e.g., cytokines, metalloproteinases) and their varied receptor molecules. This chapter describes the standard three-stage immunoperoxidase technique used in our laboratory and widely in the literature. Some problems that may be encountered and how they may be overcome are commented on. Also described is a method for dual-labeled immunofluoresence staining.

Patterson AM, Cartwright A, David G, Fitzgerald O, Bresnihan B, Ashton BA, Middleton J. · Leopold Muller Arthritis Research Centre, Institute for Science and Technology in Medicine, Medical School, Keele University at Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, Shropshire, UK. · Ann Rheum Dis. · Pubmed #17545191 links to  free full text

Abstract: BACKGROUND: Membrane-bound heparan sulphate proteoglycans (HSPGs) act as co-receptors and presenters of cytokines and are involved in cell-matrix and cell-cell adhesion. AIM: To investigate which HSPGs are expressed in knee joint synovia from patients with different forms of arthritis and normal individuals. METHODS: Synovial samples were obtained from patients with early rheumatoid arthritis (n = 8), longstanding rheumatoid arthritis (n = 13), psoriatic arthritis (n = 7), osteoarthritis (n = 6) and normal joints (n = 12). Expression of syndecan-1, -2, -3 and -4 and glypican-1, -3 and -4 was analysed by immunohistochemistry and dual label immunofluorescence. RESULTS: The expression of HSPGs in chronically inflamed synovium exhibited a differential distribution. Syndecan-1 was present in the mononuclear infiltrates of synovia from patients with rheumatoid and psoriatic arthritis where it was expressed by plasma cells. Syndecan-2 was present mainly in blood vessels where it occurred on endothelial cells, pericytes and smooth muscle cells. Syndecan-3 stained intensely in endothelial cells but also occurred in sublining macrophages and the lining layer. Glypican-4 occurred in the lining layer and blood vessels. Increased expression of these HSPGs was apparent in rheumatoid and psoriatic compared to osteoarthritic and normal synovia. Little or no staining for syndecan-4, glypican-1 and glypican-3 was seen in all samples. DISCUSSION: Selected HSPGs, such as syndecan-1, -2 and -3 and glypican-4, could play a part in the pathophysiology of arthritis, such as the migration and retention of leukocytes and angiogenesis in the chronically inflamed synovium.

Bresnihan B, Gerlag DM, Rooney T, Smeets TJ, Wijbrandts CA, Boyle D, Fitzgerald O, Kirkham BW, McInnes IB, Smith M, Ulfgren AK, Veale DJ, Tak PP. · Department of Rheumatology, St. Vincent's University Hospital, and The Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland. · J Rheumatol. · Pubmed #17343309 No free full text.

Abstract: Successive studies from one academic center (Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands) have consistently suggested that synovial tissue expression of sublining macrophages may be a biomarker of clinical response to therapeutic intervention in rheumatoid arthritis (RA) clinical trials. A proof-of-concept, randomized clinical trial was completed at a second academic center (St. Vincent's University Hospital, Dublin, Ireland), and the relationship between the change in disease activity and the change in sublining macrophages in distinct treatment cohorts was determined. The preliminary findings were not conclusive, but appeared to support a role for sublining CD68+ macrophages as a biomarker of clinical response to therapeutic intervention in cohorts of patients with RA.

Matthews C, Fitzgerald O. · Department of Rheumatology, St Vincent's University Hospital, Sublin, Ireland. · Rheumatology (Oxford). · Pubmed #16943373 links to  free full text

This publication has no abstract.

Manzo A, Paoletti S, Carulli M, Blades MC, Barone F, Yanni G, Fitzgerald O, Bresnihan B, Caporali R, Montecucco C, Uguccioni M, Pitzalis C. · Rheumatology Unit, Guy's, King's and St Thomas' School of Medicine, Guy's Campus, London, UK. · Eur J Immunol. · Pubmed #15832291 No free full text.

Abstract: CXCL13 and CCL21 have been functionally implicated in lymphoid tissue organization both in the upstream phases of lymphoid tissue embryogenesis and in ectopic lymphoid neogenesis in transgenic mice. Here, we analyzed the relationship between CXCL13 and CCL21 production and lymphoid tissue organization in rheumatoid synovitis as a model of a naturally occurring ectopic lymphoneogenesis. Through systematic analysis of mRNA and protein expression, we defined the microanatomical relationship between CXCL13 and CCL21 in progressive aggregational and structural phases of synovial inflammatory infiltrate. We provide the first direct in situ evidence that production of CXCL13 and CCL21 (rather than simply protein binding) is associated with inflammatory lymphoid tissue formation and development with the demonstration, in organized aggregates, of a secondary lymphoid organ-like compartmentalization and vascular association. Notably, the presence of CXCL13 and CCL21 (protein and mRNA) was also demonstrated in non-organized clusters and minor aggregational stages, providing evidence that their induction can take place independently and possibly upstream of T-B compartmentalization, CD21(+) follicular dendritic cell network differentiation and germinal center formation. Our data support the concept that, under inflammatory conditions, CXCL13 and CCL21 participate in lymphoid tissue microanatomical organization, attempting to recapitulate, in an aberrant lymphoid neogenetic process, their homeostatic and morphogenetic physiologic functions.

Kane D, Gogarty M, O'leary J, Silva I, Bermingham N, Bresnihan B, Fitzgerald O. · St. Vincent's University Hospital, Dublin, Ireland. · Arthritis Rheum. · Pubmed #15476228 links to  free full text

Abstract: OBJECTIVE: Methotrexate is one of the most commonly used disease-modifying antirheumatic drugs in the management of psoriatic arthritis (PsA). Despite the differences between the inflammation in PsA and rheumatoid arthritis (RA), the effects of methotrexate on the synovium have been described solely in RA. In this study, we sought to determine the effects of methotrexate on the inflammatory infiltrate and on cytokine and metalloproteinase gene expression in the synovium of PsA patients. METHODS: Ten patients with PsA (median duration 18 months) underwent arthroscopy and synovial biopsy of an inflamed knee before and after clinical improvement induced by methotrexate. Immunohistologic analysis was performed using antibodies to CD3, CD4, CD8, CD68, factor VIII, vascular cell adhesion molecule, E-selectin, and intercellular adhesion molecule (ICAM). Matrix metalloproteinase 3 (MMP-3) and tissue inhibitor of metalloproteinases 1 (TIMP-1) messenger RNA (mRNA) were quantified by competitive reverse transcription-polymerase chain reaction (RT-PCR). Interleukin-1alpha (IL-1alpha), IL-1beta, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p35, IL-12p40, IL-15, interferon-gamma (IFNgamma), and tumor necrosis factor alpha (TNFalpha) mRNA expression was quantified by real-time PCR. RESULTS: Patients received a median methotrexate dosage of 13.75 mg/week (range 7.5-15) for a median of 11.5 months (range 7-14 months). The Ritchie Articular Index, swollen joint count, and Disease Activity Score were significantly reduced. There was a decrease in all immunohistologic staining, although this was statistically significant only for CD3, CD4, CD8, CD68, E-selectin, and ICAM. Despite clinical improvement in all patients, there was a residual T cell infiltrate in all synovial biopsy tissues. The synovial lining layer thickness, but not hypervascularity, was significantly reduced. There was also a significant reduction in MMP-3, but not TIMP-1, expression. Before treatment, PsA synovium was characterized by a predominant expression of the proinflammatory cytokines IL-15, IFNgamma, IL-1beta, and TNFalpha and the antiinflammatory cytokine IL-10. Methotrexate reduced synovial IL-1alpha, IL-1beta, IL-8, IL-10, IL-15, IFNgamma, and TNFalpha mRNA expression, but the effect was significant only for IL-8. CONCLUSION: Methotrexate produced a clinical response in PsA by reducing, but not abolishing, the inflammatory infiltrate, adhesion molecule expression, and MMP-3 and proinflammatory cytokine gene expression, particularly IL-8, in the synovium. Methotrexate did not reduce hypervascularity, which is a prominent differentiating feature of PsA synovium.

Kane D, Jensen LE, Grehan S, Whitehead AS, Bresnihan B, Fitzgerald O. · Department of Rheumatology, St. Vincent's University Hospital, Dublin 4, Ireland. · J Rheumatol. · Pubmed #15229943 No free full text.

Abstract: OBJECTIVE: The distinct and different patterns of radiological damage in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) may be a product of the relative balance of proteolytic enzyme and inhibitor gene expression in synovial tissue. This study compared metalloproteinase gene expression in synovium located proximal to the cartilage-pannus junction (CPJ) and distal to the CPJ (non-CPJ) in patients with PsA and RA. METHODS: Synovial biopsies were obtained from CPJ and non-CPJ sites under direct vision at arthroscopy of an inflamed knee in patients with PsA (n = 12) and RA (n = 12) who were not under disease modifying antirheumatic drug treatment. A competitive, quantitative RT-PCR technique was established for synovial RNA using a polycompetitor construct containing mRNA-specific primer sites for collagenase (MMP-1), stromelysin (MMP-3), tissue inhibitor of metalloproteinase-1 (TIMP-1), and GAPDH. cDNA products were separated and quantified by ethidium bromide stained gel electrophoresis and mRNA values were normalized relative to GAPDH expression. RESULTS: MMP-1, MMP-3, and TIMP-1 mRNA were upregulated in RA and PsA synovium with a prodestructive (MMP-1 + MMP-3)/TIMP-1 balance in both diseases. Similar levels of MMP mRNA expression were observed in PsA and RA despite the presence of less radiological erosion in the PsA group. No difference was observed in the degree of upregulation of MMP-1, MMP-3, or TIMP-1 mRNA in paired biopsies from CPJ and non-CPJ sites in either PsA (n = 8) or RA (n = 10). The ratio of TIMP-1 expression in CPJ compared to non-CPJ biopsies was higher in patients with nonerosive disease (10.1 +/- 27.8) than in erosive patients (0.75 +/- 0.27; p = 0.07). CONCLUSION: PsA and RA have similar levels of MMP-1, MMP-3, and TIMP-1 mRNA expression in synovium. There is no evidence of increased metalloproteinase mRNA expression at the CPJ in RA or PsA. The different patterns of radiological progression seen in RA and PsA were not explained by differences in synovial mRNA expression of MMP-1, MMP-3, or TIMP-1.

Axford JS, Cunnane G, Fitzgerald O, Bland JM, Bresnihan B, Frears ER. · Academic Unit of Musculoskeletal Disease and Department of Public Health Sciences, St. George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, England, UK. · J Rheumatol. · Pubmed #14719191 No free full text.

Abstract: OBJECTIVE: To determine whether immunoglobulin G (IgG) sugar printing using high density electrophoresis can be a diagnostic and prognostic test to rapidly differentiate early rheumatoid arthritis (ERA), rheumatoid arthritis (RA), and other rheumatic diseases from each other. METHODS: One hundred fifty-three patients with ERA/RA, psoriatic arthritis (PsA), early psoriatic arthritis (EPsA) ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), juvenile idiopathic arthritis (JIA), early undifferentiated seronegative arthritis (UA), and osteoarthritis (OA) were investigated. Samples of their serum IgG were purified, and sugars were released enzymatically and fluorophore-labelled, then subjected to high density electrophoresis, and relative quantities of each sugar were determined by optical density. RESULTS: Sugar prints of 9 sugars were compiled for each of the 9 disease groups. Specific disease-associated sugar changes were determined by comparison with OA. For example, agalactosylated structures were increased in ERA/RA and EPsA/PsA (p = 0.0001-0.004) and digalactosylated structures were decreased in PsA, AS, and JIA (p = 0.0001-0.04). When the disease groups were compared, each disease was characterized by a unique sugar print comprising 7 of the 9 sugars (p = 0.001-0.005); only g0fb and a1f were not associated. ERA/RA differed in the quantities of monogalactosyl and sialylated sugars (p = 0.006-0.007). The presence of agalactosyl sugars enabled correct prediction of RA in 71.2% of individuals, with a specificity of 84.2% and sensitivity of 50.0%. The area under the sensitivity versus specificity curve was 0.7812. CONCLUSION: IgG sugar printing was found to be effective in differentiation of rheumatic diseases and can differentiate ERA and RA from each other and from other rheumatic diseases; and hence may constitute a relatively rapid diagnostic and prognostic test for patients presenting with arthritis.

Minnock P, Fitzgerald O, Bresnihan B. · Rheumatology Rehabilitation, Our Lady's Hospice, Dublin, Ireland. · Arthritis Rheum. · Pubmed #12687514 links to  free full text

Abstract: OBJECTIVE: To examine the relationships between the quality of life (QOL) of women with rheumatoid arthritis (RA) and 1). their perceived levels of social support and 2). their primary caregivers' knowledge of RA and its treatment. METHODS: Women aged 40-60 years with established RA completed validated questionnaires on health status (Arthritis Impact Measurement Scales 2) and satisfaction with the levels of social support from their primary caregiver (Significant Others Scale A). In addition, both the caregivers and patients independently completed questionnaires that were designed to elicit knowledge of RA and its treatment. RESULTS: Fifty-eight patients and their primary caregivers completed the questionnaires. Analysis of the patients' health status demonstrated widespread biopsychosocial impairments. Arthritis pain, identified as the poorest health status dimension, was associated with the lowest levels of satisfaction, and received the highest priority for health status improvement. In contrast, the patients reported highest levels of satisfaction with social support from family and friends. Positive associations between social support variables and a number of QOL measures were observed. Both the caregivers and the patients displayed limited knowledge of RA and its treatment. Associations between the levels of knowledge and the patients' QOL measures were not observed. CONCLUSION: In this study of women with RA and their caregivers, a limited knowledge of disease did not appear to impact QOL measures. However, failure to detect an association between knowledge of disease and QOL may have been influenced by a combination of the relatively small study numbers and insufficient variation in caregivers' knowledge, such that a floor effect existed.

McEvoy AN, Bresnihan B, Fitzgerald O, Murphy EP. · Department of Rheumatology, St Vincent's University Hospital, Dublin, Ireland. · Ann N Y Acad Sci. · Pubmed #12114266 No free full text.

Abstract: Modulation of locally produced corticotropin-releasing hormone (CRH) is a component of the cytokine network in human inflammatory arthritis. CRH signaling, through the CRH-receptor subtype R1alpha, may play a role in both vascular changes and pathologic mechanisms associated with joint inflammation. Furthermore, the peripheral actions of CRH may be mediated in part through the NURR subfamily of nuclear orphan receptors. The aim of this study was to establish the signaling mechanisms through which CRH receptor-mediated responses contribute to gene regulation in inflamed synovial vasculature. Immunohistochemical analysis of serial rheumatoid arthritis (RA) tissue sections demonstrates CRH and NURR1 expression in the synovial lining layer, subsynovial lining layer, and the vascular endothelium. The identical pattern of immunolocalization confirms that NURR1 is produced at the same synovial sites shown to produce CRH. The distribution of specific NURR1 staining on the synovial vasculature parallels that observed for CRH-R1 expression. Using primary synovial tissue endothelial cells, we demonstrate that CRH induces specific CREB-1 and ATF-2 binding to the NURR1 promoter. We further provide evidence that CRH signaling can be mimicked by activation of cAMP/PKA/CREB using forskolin in primary human microvascular endothelial cells. These data indicate that the CRH receptor-dependent inflammatory response in synovial tissue endothelium is mediated through the cAMP/CREB signaling pathway.

Cunnane G, Fitzgerald O, Beeton C, Cawston TE, Bresnihan B. · St. Vincent's University Hospital, Dublin, Ireland. · Arthritis Rheum. · Pubmed #11665967 No free full text.

Abstract: OBJECTIVE: To further evaluate the roles of matrix metalloproteinase 1 (MMP-1), MMP-3, and tissue inhibitor of metalloproteinases 1 (TIMP-1) in the pathogenesis of joint inflammation and articular erosions in early inflammatory arthritis. METHODS: Untreated patients with joint symptoms for <2 years were evaluated at presentation and followed up prospectively for 18 months. Swollen joint count and serum levels of C-reactive protein (CRP) were determined every 6 months. Serum levels of MMP-1, MMP-3, and TIMP-1 were measured by double-antibody sandwich enzyme-linked immunosorbent assay at the same time intervals. The number of joint erosions in serial radiographs of the hands and feet was also recorded. Analysis of synovial fluid levels of MMPs and TIMP-1 at presentation was completed in some patients. RESULTS: Of 175 patients evaluated at baseline, 85 had rheumatoid arthritis (RA), 39 had seronegative spondylarthropathy, 38 had undifferentiated arthritis, and 13 had self-limiting arthritis. Of 164 patients with available radiographs of the hands and feet at presentation, 33 (20.1%) had joint erosions. Baseline levels of MMP-1, MMP-3, and TIMP-1 were significantly higher (P = 0.0001, P = 0.013, and P = 0.0001, respectively) and ratios of TIMP-1:MMP-1 and TIMP-1:MMP-3 were significantly lower (P = 0.0001 and P = 0.013, respectively) in RA versus non-RA patients. In RA patients, serum levels of CRP correlated with MMP-3 and TIMP-1 levels, but not with MMP-1 levels. The number of erosions at presentation correlated with baseline levels of both MMP-1 and MMP-3, but not with levels of TIMP-1. One hundred one patients were followed up for the next 18 months. The number of patients with erosions and the number of erosions per patient increased significantly during this period. Area under the curve (AUC) measurements of MMP-1 and TIMP-1 levels, but not of MMP-3 levels, yielded significantly higher values in RA than in non-RA patients. In RA patients, only the AUC level of MMP-3 correlated with the AUC CRP level (r = 0.67, P = 0.0001), while only the AUC level of MMP-1 correlated with the number of new joint erosions (r = 0.28, P = 0.034). CONCLUSION: These data suggest an uncoupling of the pathophysiologic mechanisms associated with joint inflammation and articular erosion. Treatments that inhibit the production and activity of MMP-1 may preferentially limit the formation of new joint erosions and improve the long-term functional outcome of some patients with inflammatory arthritis.

Youssef P, Roth J, Frosch M, Costello P, Fitzgerald O, Sorg C, Bresnihan B. · Department of Rheumatology, St Vincent's University Hospital, Dublin, Ireland. · J Rheumatol. · Pubmed #10606357 No free full text.

Abstract: OBJECTIVE: Myeloid related proteins (MRP) 8 and 14 and the heterodimer MRP8/14 are myeloid differentiation markers present on infiltrating tissue macrophages in inflammation but not on resident tissue macrophages. We determined the pattern of expression of MRP8, MRP14, and the MRP8/14 heterodimer (27E10 antigen) in rheumatoid arthritis (RA) synovial membrane (SM). METHODS: SM samples were obtained from patients with RA at joint replacement surgery or at arthroscopy and patients without joint disease (healthy subjects) and immunostained for MRP8, MRP14, 27E10 antigen (MRP8/14 heterodimer), and CD68. Positive cell staining was measured by quantitative analysis. RESULTS: SM from 8 patients with RA, including 7 who had paired samples from both adjacent to the cartilage-pannus junction (CPJ) and an area remote from the CPJ, and 2 healthy controls were analyzed. In RA, CD68+ cells accumulated in greater numbers adjacent to the CPJ than remote from the CPJ [mean +/- standard error of the mean (SEM) 488+/-103 and 286+/-76 cells/mm2, respectively; p = 0.01]. SM lining layer (LL) MRP8, MRP14, and 27E10 staining was observed predominantly adjacent to the CPJ and only in patients with active disease. Minimal or absent LL MRP staining was observed in non-CPJ sections. Synovial sublining layer (SL) MRP8, MRP14, and 27E10 staining was also observed only in patients with active disease, but in contrast to the LL, SL staining was observed predominantly in sections remote from the CPJ. CONCLUSION: MRP antigens, representing activation markers on SM macrophages, were observed predominantly in the LL of sections adjacent to the CPJ samples. These original observations suggest altered activation and differentiation of lining layer macrophages at the site of maximal cartilage destruction in RA.

Gladman DD, Mease PJ, Healy P, Helliwell PS, Fitzgerald O, Cauli A, Lubrano E, Krueger GG, van der Heijde D, Veale DJ, Kavanaugh A, Nash P, Ritchlin C, Taylor W, Strand V. · The University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada. · J Rheumatol. · Pubmed #17477479 No free full text.

Abstract: Psoriatic arthritis (PsA), an inflammatory arthritis associated with psoriasis usually seronegative for rheumatoid factor, has emerged as a more common and severe disease than previously appreciated. The disease is multifaceted. Thus the assessment of PsA requires attention to peripheral joint involvement, axial disease, dactylitis, and enthesitis, as well as the skin manifestations. In addition, the assessment of patient reported features such as patient assessment of disease activity, pain, fatigue, quality of life, and the new concept of participation are important. The assessment of damage and the assessment of tissue histology are also important outcome measures. This article summarizes these features of PsA as well as current knowledge on the instruments available for the assessment of these domains.

Doran M, Wordsworth P, Bresnihan B, Fitzgerald O. · No affiliation provided · J Rheumatol. · Pubmed #11327280 links to  free full text

This publication has no abstract.