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Biomedical subjects

B Bresnihan

Publications and source records attributed to B Bresnihan.

At least 55 records · Page 3Linked to original sources
PubMed2000

Serum amyloid A in the assessment of early inflammatory arthritis.

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.

Adolescent↗
PubMed1999

Pathogenesis of joint damage in rheumatoid arthritis: evidence of a dominant role for interleukin-I.

Chronic arthritis is characterised by persistent joint inflammation and concomitant joint destruction. Although joint swelling is a major clinical feature, destruction of bone and cartilage may be dissociated from inflammation. It is therefore important to understand fully all elements of the destructive process. Tumour necrosis factor (TNF) and interleukin-I (IL-I) are considered pivotal cytokines in the process of human rheumatoid arthritis (RA), with a claimed cascade of TNF inducing most of the IL-I production. Studies in experimental models have revealed that TNF is indeed a pivotal cytokine in acute joint swelling, yet IL-I beta is the dominant cartilage destructive cytokine and its production may occur independently of TNF alpha. This was found with anti-TNF/IL-I neutralising antibodies and the observations were recently supported by similar findings in arthritis models in TNF and IL-I knock-out mice. In RA, early clinical studies suggested a correlation between levels of IL-I beta and measures of joint damage. In vitro studies have also demonstrated regulatory effects of IL-I beta on both cartilage degradation and cartilage invasion by synoviocytes. A randomised clinical trial has suggested a significant reduction in the rate of joint damage following IL-I beta inhibition by IL-I receptor antagonist. Clinical trials of TNF alpha blockade have demonstrated a marked reduction in the clinical manifestations of inflammation but, to date, an effect on the rate of joint damage awaits confirmation.

Animals↗
PubMed1999

Synovial tissue analysis in rheumatoid arthritis.

In rheumatoid arthritis, synovial tissue is easily accessible for systematic analysis. Blind needle biopsy is a simple and safe procedure, but is restricted to smaller tissue samples. Arthroscopic biopsy is also safe but is more complicated as it allows access to most sites in the joint and provides adequate tissue for extensive laboratory investigations. Synovial tissue analysis has been successfully applied to studies of disease mechanisms, response to treatment and prognosis. The immuno-histological features in synovial tissue have consistently reflected disease status. Synovial tissue analysis has been particularly informative in the study of novel therapeutic agents.

Arthritis, Rheumatoid↗
PubMed1999

Collagenase, cathepsin B and cathepsin L gene expression in the synovial membrane of patients with early inflammatory arthritis.

OBJECTIVE: To examine the expression of the matrix metalloproteinase, MMP-1, and the cysteine proteases, cathepsin B (CB) and cathepsin L (CL), in the synovial membrane (SM) of patients with early inflammatory arthritis. METHODS: Samples of SM were obtained by blind needle biopsy or needle arthroscopy from inflamed knees of 28 patients with early inflammatory arthritis (mean disease duration 10.2 months, range 2 weeks-18 months). Sixteen patients had rheumatoid arthritis (RA), nine psoriatic arthritis and there was one each with ankylosing spondylitis, gout and an undifferentiated arthritis. Comparison was made with tissue from two patients with established erosive RA and three normal synovial tissue samples. In situ hybridization was performed using digoxigenin-labelled RNA probes. RESULTS: MMP-1, CB and CL were expressed in all patients with early arthritis and in established erosive RA, whereas normal synovium showed only scanty expression. The three proteases were prominent in perivascular infiltrates and endothelial cells of early arthritis tissue. MMP-1 was observed primarily in the lining layer, but was also evident in the sublining area. CB and CL were expressed to a lesser extent in the lining layer, and were present mainly in the subintima. The three proteases were not found in lymphoid aggregrates. No differences were observed between the disease categories. CONCLUSIONS: The detection of MMP-1, CB and CL in the synovium shortly after symptom onset implies that the potential for joint destruction exists at a very early stage in the disease. In addition, the perivascular and endothelial cell expression suggests a role for these proteases in mononuclear cell influx to the inflamed synovium and in angiogenesis.

Adult↗
PubMed1999

Quantitative analysis of synovial membrane inflammation: a comparison between automated and conventional microscopic measurements.

OBJECTIVE: The objective of this study was to quantify selected features of chronic synovial tissue inflammation by computerised image analysis and to validate the results by comparison with conventional microscopic measurements. METHODS: Synovial biopsy samples were obtained from the knee joints of patients with chronic arthritis and prepared for immunohistochemical analysis using standard techniques. Following the development of special software, four parameters of chronic synovial inflammation were evaluated: intimal layer thickness, CD3+ cell infiltration, CD8+ cell infiltration and vascularity. Intimal layer thickness was expressed in microns. The intensity of CD3+ and CD8+ cell infiltration was expressed as the percentage area of the tissue section occupied by positively stained cells. Vascularity was expressed as the percentage area occupied by blood vessels. Conventional quantitative microscopic analysis was also undertaken and the results from both methods compared. RESULTS: Seventy eight tissue sections were selected for study. Measurements of intimal layer thickness by both techniques correlated strongly: r = 0.85, p = 0.0006. Measurements of CD8+ cell infiltration, usually widely dispersed, also correlated well: r = 0.64, p = 0.005. Measurements of CD3+ cell infiltration, often densely aggregated, correlated less well: r = 0.55, p = 0.02. Measurements of vascularity demonstrated no statistically significant correlation: r = 0.41, p = 0.07. Proficiency in the use of computerised image analysis was readily acquired. CONCLUSION: Computerised image analysis was successfully applied to the measurement of some features of synovial tissue inflammation. Further software development is required to validate measurement of blood vessels of variable size.

Arthritis↗
PubMed1999

Pathogenesis of joint damage in rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by the appearance of progressive joint damage that may be identified only months after the onset of symptoms. Early cartilage and bone erosion is associated with the accumulation of several cell populations in the synovial membrane (SM) and the formation of a proliferating pannus. The synovial sublining layer contains several cell populations including macrophages, T and B lymphocytes, dendritic cells, and polymorphonuclear leukocytes. The lining layer contains large numbers of macrophages and fibroblast-like synoviocytes. The interface between pannus and cartilage is occupied predominantly by activated macrophage populations and synoviocytes capable of secreting destructive proteases in abundance. We have observed that macrophages aggregate preferentially adjacent to the cartilage-pannus junction (CPJ) and express differentiation phenotypes that are absent from the lining layer macrophages of more remote SM. Moreover, in a prospective study, the number of SM macrophages correlated with the degree of joint damage occurring over one year. Similar results were obtained when SM biopsy samples were analyzed and correlated with clinical and radiological changes occurring over 6 years. Macrophages and synoviocytes at the CPJ express matrix metalloproteinase and cathepsin mRNA from the earliest stage of RA. The mechanisms involved in the secretion of tissue degrading enzymes by macrophages and synoviocytes are undergoing further investigation and preliminary results suggest that different regulation pathways may exist.

Arthritis, Rheumatoid↗
PubMed1999

Imaging in rheumatoid arthritis: results of group discussions.

None of the current scoring methods for radiological damage in rheumatoid arthritis (RA) is ideal. The objective for RA imaging at OMERACT IV was to start discussion about the problems and applicability of the current scoring methods for radiological damage and to start discussion on the challenge of new imaging techniques. The RA imaging module comprised preconference reading material, plenary sessions, small group discussions, and a plenary report of the group sessions, combined with interactive voting. The OMERACT filter guided the discussions. Priorities for further research in imaging studies were: (1) pathologies versus features on radiographs; (2) relation with longterm outcome; and (3) definition of minimum clinically important difference.

Arthritis, Rheumatoid↗
PubMed1999

Predominance of CD8+ T lymphocytes in psoriatic arthritis.

OBJECTIVE: To characterize the synovial fluid (SF) derived T cell populations in psoriatic arthritis (PsA) and compare with similar populations from rheumatoid arthritis (RA). METHODS: Paired peripheral blood (PB) and SF samples were analyzed by 3 color flow cytometry using monoclonal antibodies to CD3, CD4, CD8, HLA-DR, CD25, CD45RA, and CD45RO. RESULTS: There was a significantly increased CD8+ T cell population in PsA SF compared to RA: PsA mean 61% (range 35-93), RA mean 46% (range 6-72) (p < 0.005). This resulted in a reversal of the CD4:CD8 ratio in PsA SF compared to RA SF (p < 0.001). Patients with oligoarticular PsA had the most pronounced differences in SF derived T cell populations compared to RA (p < 0.0005) but these results were not significantly different from PsA patients with a polyarticular disease pattern. PB PsA T cell populations were not different from controls, in contrast to RA, where the CD4+ T cell population was increased (p < 0.0026), giving an exaggerated PB CD4:CD8 ratio. The majority of PsA SF CD8+ T cells expressed CD45RO, mean 73% (range 58-95), and HLA-DR antigen: mean 72% (range 38-94). Low levels of CD25 were detectable in this population, indicating a nonclassical activation pattern: mean 2% (range 0.3-4.4). CONCLUSION: In PsA, activated (HLA-DR+) and mature (CD45RO+) CD8+ T cells predominate in SE Analysis of this population may uncover clues to pathogenesis in this HLA class I mediated disease.

Adult↗
PubMed1999

Ultrasonography in the diagnosis and management of psoriatic dactylitis.

OBJECTIVE: To determine the ultrasonographic features of dactylitis in psoriatic arthritis (PsA). METHODS: Seventeen patients with PsA presenting with a total of 25 dactylitic fingers and toes underwent ultrasonographic examination of the digits with a 7.5 or 10 MHz transducer. RESULTS: Flexor tenosynovitis was present in 96% (24/25) of dactylitic digits. Articular synovitis was present in 52% (13/25) of dactylitic digits. Subcutaneous soft tissue enlargement was present in all digits. The presence of articular synovitis in a dactylitic finger on ultrasonography correlated with the presence of joint space narrowing and periostitis on plain radiography. CONCLUSION: Dactylitis in PsA is due to both flexor tenosynovitis and articular synovitis. Dactylitis in PsA has an increased incidence of articular synovitis, which was associated with the development of articular damage as assessed by plain radiography.

Adolescent↗
PubMed1999

Expression of myeloid related proteins (MRP) 8 and 14 and the MRP8/14 heterodimer in rheumatoid arthritis synovial membrane.

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.

Adult↗
PubMed1998

Quantitative microscopic analysis of inflammation in rheumatoid arthritis synovial membrane samples selected at arthroscopy compared with samples obtained blindly by needle biopsy.

OBJECTIVE: To evaluate microscopic measures of inflammation in rheumatoid arthritis synovial tissue samples selected at arthroscopy compared with those obtained blindly by needle biopsy from the suprapatellar pouch (SPP) of the same joint. METHODS: Samples were selected at knee arthroscopy from the SPP and the lateral and medial gutters. Immediately following arthroscopy, a biopsy needle was inserted through the same portal into the SPP by a second investigator, and 3 further samples were obtained blindly. Using standard immunohistologic methods, all samples were analyzed by a single investigator without knowledge of the original tissue location and biopsy technique. Following staining with anti-CD3 and anti-CD68 monoclonal antibodies, T lymphocyte and macrophage infiltration were measured by quantitative analysis. RESULTS: Synovial tissues from 14 patients were analyzed. In comparing microscopic measures of inflammation using the 2 procedures, mean scores of lining cell depth and the percentage of CD68+ cells in the lining layer correlated positively (tau = 0.59, P = 0.003 and tau = 0.73, P = 0.0003, respectively). In the sublining layer, CD3+ cell counts also correlated significantly (tau = 0.71, P = 0.0004). Sublining CD68+ cell counts did not correlate. This was explained by the observation that CD68+ cell infiltration in areas adjacent to articular cartilage was significantly greater than in the SPP (P = 0.01), suggesting preferential trafficking to this site by macrophages, but not by T lymphocytes. Macroscopic appearance at arthroscopy did not predict microscopic features. CONCLUSION: Most microscopic measures of inflammation in synovial tissue samples obtained blindly from the SPP were similar to those determined in samples selected at arthroscopy. However, measurements in samples from the SPP may underestimate the intensity of macrophage infiltration in areas more adjacent to cartilage. These observations have important implications for future study of macrophage function in synovial tissue.

Arthritis, Rheumatoid↗
PubMed1998

Asymptomatic synovitis precedes clinically manifest arthritis.

OBJECTIVE: It has been hypothesized that asymptomatic synovitis may precede clinical manifestations of arthritis in the earliest phase of rheumatoid arthritis (RA). To obtain more insight into this disease phase, we investigated the immunohistologic features of synovial tissue (ST) from the knee joints of rhesus monkeys with induced arthritis and from RA patients with both clinically involved and clinically uninvolved knee joints. METHODS: Serial ST biopsy specimens from the knee joints of 4 rhesus monkeys that had been immunized with type II collagen and ST from 10 RA patients were investigated. Eight patients without inflammatory joint disease served as controls. RESULTS: In ST from immunized monkeys, an influx of macrophages was observed well before the occurrence of arthritis. Signs of inflammation were also demonstrated in ST from clinically uninvolved knee joints of all RA patients evaluated. The ST was characterized in particular by infiltration with macrophages and by the expression of macrophage-derived cytokines. CONCLUSION: The findings support the view that asymptomatic synovitis precedes clinically manifest arthritis in both early and established RA. This implies that the debut of RA already represents a chronic phase of the disease.

Aged↗
PubMed1998

Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist.

OBJECTIVE: To evaluate the efficacy and safety of interleukin-1 receptor antagonist (IL-1Ra) in patients with rheumatoid arthritis (RA). METHODS: Patients with active and severe RA (disease duration <8 years) were recruited into a 24-week, double-blind, randomized, placebo-controlled, multicenter study. Doses of nonsteroidal antiinflammatory drugs and/or oral corticosteroids (< or =10 mg prednisolone daily) remained constant throughout the study. Any disease-modifying antirheumatic drugs that were being administered were discontinued at least 6 weeks prior to enrollment. Patients were randomized to 1 of 4 treatment groups: placebo or a single, self-administered subcutaneous injection of IL-1Ra at a daily dose of 30 mg, 75 mg, or 150 mg. RESULTS: A total of 472 patients were recruited. At enrollment, the mean age, sex ratio, disease duration, and percentage of patients with rheumatoid factor and erosions were similar in the 4 treatment groups. The clinical parameters of disease activity were similar in each treatment group and were consistent with active and severe RA. At 24 weeks, of the patients who received 150 mg/day IL-1Ra, 43% met the American College of Rheumatology criteria for response (the primary efficacy measure), 44% met the Paulus criteria, and statistically significant improvements were seen in the number of swollen joints, number of tender joints, investigator's assessment of disease activity, patient's assessment of disease activity, pain score on a visual analog scale, duration of morning stiffness, Health Assessment Questionnaire score, C-reactive protein level, and erythrocyte sedimentation rate. In addition, the rate of radiologic progression in the patients receiving IL-1Ra was significantly less than in the placebo group at 24 weeks, as evidenced by the Larsen score and the erosive joint count. IL-1Ra was well tolerated and no serious adverse events were observed. An injection-site reaction was the most frequently observed adverse event, and this resulted in a 5% rate of withdrawal from the study among those receiving IL-1Ra at 150 mg/day. CONCLUSION: This study confirmed both the efficacy and the safety of IL-1Ra in a large cohort of patients with active and severe RA. IL-1Ra is the first biologic agent to demonstrate a beneficial effect on the rate of joint erosion.

Adolescent↗
PubMed1998

Interleukin-1 receptor antagonist.

There are three members of the IL-1 gene family: IL-1 alpha, IL-1 beta, and IL-1ra, IL-1 alpha, and IL-1 beta are both antagonist molecules with many proinflammatory effects. IL-1ra is an antagonist molecule that can inhibit the effect of IL-1 alpha and IL-1 beta by specifically blocking the IL-1 receptor on target effector cells. IL-1 alpha and IL-1 beta are considered to be pivotal cytokines in the pathogenesis of many inflammatory diseases. Anti-IL-1 treatment has been shown to cause amelioration of arthritis in animal models and in RA, suggesting that IL-1ra may be an important therapeutic option in the future management of RA.

Arthritis, Rheumatoid↗