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Biomedical subjects

B Bresnihan

Publications and source records attributed to B Bresnihan.

At least 37 records · Page 2Linked to original sources
PubMed2001

Involvement of the nuclear orphan receptor NURR1 in the regulation of corticotropin-releasing hormone expression and actions in human inflammatory arthritis.

OBJECTIVE: To examine the regulation and mode of action of peripheral corticotropin-releasing hormone (CRH) in human inflammatory arthritis. METHODS: CRH messenger RNA (mRNA) levels were measured in normal and inflamed synovial tissue and in primary synoviocytes prior to and following cytokine stimulation. Primary synoviocytes were transiently transfected with CRH promoter/reporter constructs, and promoter activity in response to cytokines was assessed. Immunohistochemical staining established CRH receptor expression, and Northern blot analysis confirmed that the nuclear transcription factors NUR77 and NURR1 contributed to synovial CRH receptor-mediated signaling. Primary synoviocytes were treated with pro- and antiinflammatory mediators, and the time course of NURR1 and NUR77 modulation was examined. Nuclear extracts were analyzed by electrophoretic mobility shift assay to determine NURR1 binding to the CRH promoter/enhancer. RESULTS: CRH mRNA was up-regulated in the synovial tissue in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and sarcoid arthritis, but not in normal synovium. Inflammatory cytokines, such as interleukin-1beta and tumor necrosis factor alpha, enhanced the transcriptional activity of the human CRH promoter and increased levels of CRH mRNA in primary synoviocytes. Synovial CRH functioned in a paracrine manner to induce NURR1 and NUR77. NURR1 was abundantly expressed in the inflammatory cells of both RA and PsA synovium. NURR1 and NUR77 were differentially regulated, and NURR1 was the major cytokine-regulated member of the NURR subfamily as well as the mediator of cytokine- and CRH-dependent inflammatory responses in synovium. Furthermore, glucocorticoids dramatically suppressed cytokine- and CRH-induced synovial NURR1 mRNA. CONCLUSION: These data demonstrate the involvement of the transcription factor NURR1 in the regulation of CRH expression and activity in human inflammatory arthritis.

Arthritis, Rheumatoid↗
PubMed2001

Synovial tissue protease gene expression and joint erosions in early rheumatoid arthritis.

OBJECTIVE: To relate the expression of proteases in the lining and sublining layers of the synovial membrane to the rate of joint damage during 1 year in patients with early inflammatory arthritis. METHODS: Samples of synovial membrane were obtained by closed-needle biopsy or needle arthroscopy from inflamed knees of 20 patients with early inflammatory polyarthritis (mean disease duration 9.6 months, range 2 weeks to 18 months). Expression of matrix metalloproteinase 1 (MMP-1), cathepsin B (CB), and cathepsin L (CL) was examined using in situ hybridization. Immunohistochemistry was used to identify infiltrating mononuclear cell populations. Radiographs of the hands and feet, performed at presentation and after 1 year, were evaluated for the development of new erosions. RESULTS: Twelve patients had rheumatoid arthritis (RA), 6 had psoriatic arthritis (PsA), 1 had gout, and 1 had an undifferentiated arthritis. Six patients had erosions at presentation. Eleven patients (10 with RA, 1 with PsA) demonstrated at least 1 new erosion after 1 year of followup. MMP-1, CB, and CL messenger RNA (mRNA) were expressed in the synovial membrane of all patients and were present throughout the lining layer, as well as in perivascular cellular infiltrates and endothelial cells in the sublining layer. In the lining layer, the mean percentages of protease mRNA-positive cells per high-power field were higher in those patients who developed new joint erosions than in those without evidence of joint damage. A similar pattern was observed in the sublining layer, where mean numbers of protease mRNA-positive cells were also greater in patients with new joint erosions. There were significant differences between the two groups in MMP-1 mRNA expression in both the lining and sublining layers (P = 0.0007 and P = 0.0027, respectively), as well as in sublining layer CL mRNA expression (P = 0.017), but not in CB mRNA expression. Numbers of lining layer CD68+ cells correlated positively with lining layer MMP-1 mRNA expression (P = 0.043) and with the development of new joint erosions (P = 0.002). CONCLUSION: The detection of MMP-1, CB, and CL in the synovium soon after the onset of symptoms highlights the potential for early joint destruction in patients with RA. High levels of MMP-1 mRNA expression in the lining layer distinguished patients with more rapidly progressive erosive disease. This is the first study to demonstrate features of early synovial pathophysiology that may identify patients at increased risk of developing new joint erosions.

Adult↗
PubMed2001

Corticotropin-releasing hormone signaling in synovial tissue from patients with early inflammatory arthritis is mediated by the type 1 alpha corticotropin-releasing hormone receptor.

OBJECTIVE: Elevated levels of corticotropin-releasing hormone (CRH) are produced locally in inflamed human synovial tissue, and previous observations indicate a role for CRH in the pathogenesis of inflammatory joint disease. To further elucidate the biologic role of CRH at peripheral sites, we examined the expression of known CRH receptor subtypes in inflamed human synovium and compared the expression patterns in normal synovium. METHODS: Immunohistochemical analysis was used to confirm enhanced expression of specific CRH receptor subtypes in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) synovium. Immunofluorescence double-labeling was used to further characterize CRH receptor-expressing cells. Reverse transcriptase-polymerase chain reaction analysis was performed to examine CRH receptor subtype messenger RNA (mRNA) expression in RA, PsA, and normal synovial tissue. In addition, CRH receptor expression was examined in isolated synovial endothelial cells and synoviocytes. RESULTS: Selective up-regulation of CRH receptors in inflamed synovial tissue indicated that CRH functions locally, in an autocrine/paracrine receptor-mediated manner. Immunoreactive CRH receptor type 1 (CRH-R1) was expressed abundantly on vascular endothelial cells and discrete perivascular cell populations, identified as mast cells. In all samples of inflamed synovium studied, CRH-R1alpha mRNA was detected; however, we were unable to identify CRH-R1beta or any CRH-R2 isoforms in samples from the same cohort of, patients. CRH receptor subtype expression in separated synovial cell populations revealed a pattern of staining similar to that seen in vivo. In contrast, neither CRH receptor subtype was expressed in normal synovial tissue. CONCLUSION: Our findings suggest that CRH signaling, via CRH-R1alpha, may play a role in both the vascular changes and the pathologic mechanisms associated with joint inflammation in human arthritis.

Arthritis, Psoriatic↗
PubMed2001

Early joint erosions and serum levels of matrix metalloproteinase 1, matrix metalloproteinase 3, and tissue inhibitor of metalloproteinases 1 in rheumatoid arthritis.

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.

Adolescent↗
PubMed2001

Psoriasis predicts a poor short-term outcome in patients with spondylarthropathy.

OBJECTIVE: The outcome of patients with recent-onset spondylarthropathy (SpA) is unclear. Therefore, the objective of this study was to prospectively correlate clinical and laboratory features with functional and radiologic outcome in patients with psoriatic SpA (PsS), undifferentiated SpA (uSpA), and Reiter's syndrome/reactive arthritis (ReA). METHODS: Patients presenting to an early arthritis clinic with a spondylarthropathy pattern of peripheral arthritis were selected and prospectively followed. Clinical and laboratory features were recorded at baseline, 12 months, and 24 months. Radiographs of affected joints were taken at presentation and at followup. RESULTS: The cohort consisted of 157 patients: 82 PsS, 59 uSpA, and 16 ReA. Symptom duration at presentation was progressively shorter, and the erythrocyte sedimentation rate/C-reactive protein (ESR/CRP) incrementally higher in ReA, uSpA, and PsS, respectively. There was a higher swollen joint count (SJC) in PsS compared with uSpA. In PsS, strong positive correlations were observed between ESR/CRP and articular indices. Initially, functional impairment was greater in ReA compared with uSpA and PsS but resolved completely in ReA. Clinical remission rates at 2 years were ReA 61% and uSpA 63%, compared with PsS 14%. Remission at 2 years could be predicted in SpA by disease category and presentation SJC. Baseline erosions in PsS (28%) and uSpA (5%) increased to 45% and 25%, respectively, at 2 years. CONCLUSION: These observations suggest a spectrum within the spondylarthropathy subgroups where at presentation the acute phase markers in ReA and uSpA reflect a systemic process, whereas in PsS they reflect articular manifestations. Although the clinical presentations are indistinguishable, PsS has a more aggressive clinical course with a poorer functional and radiologic outcome.

Adult↗
PubMed2001

The safety and efficacy of interleukin-1 receptor antagonist in the treatment of rheumatoid arthritis.

BACKGROUND: Interleukin (IL)-1 has been associated with joint inflammation and damage in rheumatoid arthritis (RA). Endogenous IL-1 receptor antagonist (IL-1Ra) may inhibit IL-1-mediated effects by binding to the IL-1 receptors. OBJECTIVES: These studies were conducted to determine the efficacy and safety of human recombinant IL-1 receptor antagonist (IL-1ra) in blunting the effects of IL-1 in patients with RA. METHODS: Three randomized clinical trials have been completed. First, in a 24-week, double-blind, placebo-controlled study of 472 patients with severe RA, patients were randomly placed into 4 groups: placebo or IL-1ra at 30, 75, or 150 mg/d. In a second study, 309 patients from the placebo-controlled trial enrolled in a 24-week extension study. Patients who had been receiving placebo were randomized into 1 of the 3 treatment groups. Those receiving treatment continued to receive their previous dosages. Finally, in a second double-blind, placebo-controlled study, 419 patients with RA receiving methotrexate at 12.5 to 25 mg/wk for at least 6 months were randomly placed into 1 of 6 groups: placebo or IL-1ra at 0.04, 0.1, 0.4, 1.0, or 2.0 mg/kg/d. RESULTS: In the first study, the primary therapeutic endpoint-an American College of Rheumatology 20% response (ACR20)-was reached by 27% of the placebo group, compared with 43% of the IL-1ra 150-mg/d group. Individual clinical responses, as well as the arrest of joint damage, were also superior in treated patients. In the second trial, 52% of the randomized patients achieved an ACR20. This was maximal (71%) in those receiving the highest treatment dosage. Of patients continuing with the same dosage, 49% maintained an ACR20 at 48 weeks. Radiologic evaluation showed that the reduced rate of cartilage degradation observed in treated patients during the first 24 weeks was maintained, and the rate of joint erosion was slowed even more significantly in the second phase of the study. In the third study, significantly more patients receiving IL-1ra at 1.0 (46%, P =.001) or 2.0 (38%, P =.007) mg/kg/d achieved an ACR20 at week 12 than those receiving placebo (19%). Similar responses were noted at week 24. IL-1ra was generally well tolerated, with injection site reaction the most frequent adverse event. No serious adverse events attributable to IL-1ra treatment were observed. CONCLUSIONS: These studies suggest an important role for IL-1ra as a novel therapeutic agent in the treatment of RA.

Antirheumatic Agents↗
PubMed2001

The effects of treatment with interleukin-1 receptor antagonist on the inflamed synovial membrane in rheumatoid arthritis.

OBJECTIVE: To evaluate the effects of treatment with interleukin-1 receptor antagonist (IL-1Ra) on synovial tissue in rheumatoid arthritis (RA). METHODS: Twelve patients with RA entering a randomized clinical trial of human recombinant IL-1Ra underwent synovial biopsies before and after treatment. Cellular infiltration and adhesion molecule expression were evaluated after immunohistochemical staining. RESULTS: There was a notable reduction in intimal layer macrophages and subintimal macrophages and lymphocytes after treatment with IL-1Ra at 150 mg/day (n=3). Increased cellular infiltration was observed in all patients receiving placebo (n=3); variable changes were observed after IL-1Ra 30 mg/day (n=6). In a limited study of adhesion molecule expression, down-regulation of E-selectin and vascular cell adhesion molecule-1 was observed after treatment with IL-1Ra 150 mg/day, but not after IL-1Ra 30 mg/day or placebo. The apparent arrest of progressive joint damage seen in four patients after treatment with IL-1Ra was associated with reduced intimal layer macrophage accumulation in all patients. CONCLUSION: Treatment of RA with IL-1Ra resulted in reduced mononuclear cell infiltration of synovial membrane, which may represent the in vivo inhibition of biologically relevant IL-1ss-mediated pathogenic effects.

Adolescent↗
PubMed2001

The role of ultrasonography in the diagnosis and management of idiopathic plantar fasciitis.

OBJECTIVE: To compare ultrasonography with bone scintigraphy in the diagnosis of plantar fasciitis and to compare ultrasound-guided injection with palpation-guided injection in the management of idiopathic plantar fasciitis. METHODS: Twenty-three patients with a clinical diagnosis of idiopathic plantar fasciitis in 28 heels underwent ultrasonography and bone scintigraphy of both heels at baseline. The patients were randomized to ultrasound- or palpation-guided injection of triamcinolone hexacetonide and xylocaine into the plantar fascia. The 100 mm visual analogue scale (VAS) of pain, the heel tenderness index (HTI), and ultrasonography were performed at baseline and follow-up (mean=13.4 weeks). RESULTS: The mean thickness (+/-standard error of the mean) of the plantar fascia, measured by ultrasonography, was 5.7+/-0.3 mm in symptomatic heels as compared with 3.8+/-0.2 mm in asymptomatic heels (P<0.001). Ultrasonography findings correlated with bone scintigraphic findings in the diagnosis of plantar fasciitis (P<0.001). Fourteen heels were randomized to ultrasound-guided injection, 10 heels were randomized to palpation-guided injection and four heels were not injected. Ultrasound- and palpation-guided injection resulted in significant mean improvements in VAS [39.6+/-9.2 (ultrasound) vs 41.5+/-8 (palpation)] and HTI [1.35+/-0.2 (ultrasound) vs 1.3+/-0.4 (palpation)]. There was no significant difference in the response rate following corticosteroid injection by either modality (ultrasound=13/14, palpation=8/10). Following injection, the mean thickness of the plantar fascia decreased from 5.7+/-0.3 mm to 4.65+/-0.4 mm (P<0.01). CONCLUSION: Ultrasonography and bone scintigraphy are equally effective in the diagnosis of plantar fasciitis. Ultrasound-guided injection is effective in the management of plantar fasciitis but is not more effective than palpation-guided injection. Ultrasonography may be used as an objective measure of response to treatment in plantar fasciitis.

Fasciitis↗
PubMed2001

Validated measurement of periarticular bone mineral density at the knee joint by dual energy x ray absorptiometry.

OBJECTIVE: The association of inflammatory arthritis with loss of periarticular bone mineral density (BMD) has been well established. However, changes in bone density cannot be quantified by conventional radiography. This study aimed at developing a new technique for measurement of periarticular bone density at the knee joint by dual energy x ray absorptiometry (DXA) and assessing the precision of this technique for selected areas around the knee. METHODS: To validate this technique for bone density assessment in both patient and control subjects, knee joints from healthy subjects and patients with inflammatory arthritis were selected for study. Posteroanterior (PA) and lateral scans of both knees were acquired with the Hologic 4500 elite bone densitometer. Each scan was repeated three times, with repositioning between scans. Knee scans were obtained with the forearm software and evaluated by subregion analysis. Seven femoral and seven tibial subregions of interest (ROIs) were selected on PA scans. Six ROIs were selected on lateral scans. Precision was determined for each ROI selected. RESULTS: 14 knee joints were studied in each group. Precision, expressed as percentage coefficient of variation (CV%), varied widely between subregions. PA scans were most appropriate for measurement of femoral bone density (CV% = 1.89-2.64%), whereas the best value obtained for ROIs within the tibia was on the lateral scan, where CV% for measurement of the proximal 5 mm was 2.67% in the patient group. CV% for BMD of the patella was excellent at 0.84% in the patient group. CONCLUSION: This new application of DXA can be used to measure periarticular bone density at the knee joint. Regions within the distal femur and patella have been identified as the optimal areas to study

Absorptiometry, Photon↗
PubMed2001

The prospect of treating rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist.

The prospect of introducing a potent novel therapy that specifically targets a pivotal mediator of disease offers new hope to patients with rheumatoid arthritis (RA). There is convincing evidence that interleukin-1 (IL-1) plays a critical role in the pathogenesis of RA. In RA, the inadequate production of IL-1 receptor antagonist (IL-1Ra), the natural inhibitor of IL-1, results in increased IL-1-mediated pathophysiological activity. Unregulated IL-1-mediated effects produce enhanced tissue inflammation and progressive degradation of cartilage and bone matrix. Recombinant IL-1Ra treatment in experimental models of arthritis results in profound suppression of synovial inflammation and joint damage. Recombinant human IL-1Ra (rhu-IL-1Ra) has been evaluated in RA in several randomised clinical trials and was shown to significantly reduce both the clinical manifestations of arthritis and the rate of progressive joint damage. Firstly, in a 6-month placebo-controlled study, 43% of the patients who received the highest dose of rhu-IL-1Ra (150 mg/day) demonstrated a 20% improvement (American College of Rheumatology clinical criteria) compared to 27% of the patients who received placebo. In addition, the patients who received rhu-IL-1Ra demonstrated 46% less joint damage (Larsen scores). Secondly, in a 6-month extension of the placebo-controlled study, the treated patients maintained their clinical improvement and there was further significant reduction in the rate of progressive joint damage. The patients who had originally received placebo demonstrated both clinical and radiological responses that were similar to those observed in the treated patients during the initial phase of the study. Finally, in a combination study with methotrexate (MTX), 42% of patients who received MTX and the optimal dose of rhu-IL-1Ra (1.0 mg/kg/day) demonstrated an ACR 20% clinical response, compared to 23% of those receiving MTX and placebo. rhu-IL-1Ra was well tolerated in all studies and adverse events were uncommon. The most frequently reported adverse event causing withdrawal of treatment was an injection site reaction, occurring in approximately 5% of patients. In conclusion, targeted IL-1 inhibition significantly reduced both the clinical manifestations and the rate of progressive joint damage in patients with RA. These observations suggest that rhu-IL-1Ra has a potential role as a novel therapeutic modality in the future management of RA.

Arthritis, Rheumatoid↗
PubMed2001

Treating early rheumatoid arthritis in the younger patient.

Early diagnosis and intervention may provide the greatest hope for reducing the disability associated with rheumatoid arthritis (RA). In patients with early RA, accurate diagnosis can be delayed by limited access to a specialist service, slow evolution of the clinical features, and lack of definitive diagnostic criteria. However, acute phase reactants, serologic features including presence of rheumatoid factor, and immunohistologic analysis of synovial tissue can provide the basis for differentiating RA from other forms of arthritis. Factors associated with poorer prognosis in patients with early RA are female sex, larger number of joints involved, elevated levels of acute phase reactants, presence of rheumatoid factor, and radiologic evidence of joint damage. Special treatment considerations in younger persons with RA include issues related to conception, pregnancy, and lactation. Methotrexate, hydroxychloroquine, sulfasalazine, and low dose corticosteroids are usually the mainstays of treatment for younger patients with RA. Recommendations for taking these drugs while considering conception vary with their effect on fertility and on the developing embryo. Sulfasalazine, for example, can be taken during pregnancy but caution is advised for breastfeeding mothers. Leflunomide must be discontinued for 2 years before attempting conception; this time can be shortened if the patient opts for drug washout.

Adult↗
PubMed2000

Acute-phase serum amyloid A production by rheumatoid arthritis synovial tissue.

Acute-phase serum amyloid A (A-SAA) is a major component of the acute-phase response. A sustained acute-phase response in rheumatoid arthritis (RA) is associated with increased joint damage. A-SAA mRNA expression was confirmed in all samples obtained from patients with RA, but not in normal synovium. A-SAA mRNA expression was also demonstrated in cultured RA synoviocytes. A-SAA protein was identified in the supernatants of primary synoviocyte cultures, and its expression colocalized with sites of macrophage accumulation and with some vascular endothelial cells. It is concluded that A-SAA is produced by inflamed RA synovial tissue. The known association between the acute-phase response and progressive joint damage may be the direct result of synovial A-SAA-induced effects on cartilage degradation.

Acute Disease↗
PubMed2000

A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larsen scores.

OBJECTIVE: To evaluate radiographic progression and the relationship of radiologic scores obtained by the Genant and Larsen methods in a clinical trial of recombinant human interleukin-1 receptor antagonist (IL-1Ra). METHODS: Patients with rheumatoid arthritis (RA) were randomized into 4 groups: placebo (n = 121) or IL-1Ra at a daily dosage of 30 mg (n = 119), 75 mg (n = 116), or 150 mg (n = 116). Hand radiographs obtained at baseline, 24 weeks, and 48 weeks were scored using both methods. RESULTS: At 24 weeks, by the Genant method, there was significant reduction in the score for progression of joint space narrowing (JSN) and the total score (a combination of erosion and JSN) in all treatment groups. Least-squares mean changes in the Genant erosion score from baseline to 24 weeks were significantly reduced after treatment with IL-1Ra at 30 mg/day and for all IL-1Ra treatment groups combined. The changes corresponded to a reduction of 38% in erosion, 58% in JSN, and 47% in total score. Patients treated with IL-1Ra at 75 mg/day had a significant reduction in the Larsen erosive joint count (LEJC), and all IL-1RA-treated groups combined showed a 45% reduction. Correlations (r) between the Genant total and Larsen scores were 0.84 at baseline, 0.83 at week 24, and 0.83 at week 48 (P < 0.0001); correlations between the Genant erosion score and the LEJC were 0.83 (P < 0.0001) at all visits; correlations between the Genant total and the Larsen scores were 0.32 and 0.49 (P < 0.0001) for progression from baseline to week 24 and from baseline to week 48, respectively; correlations between the Genant erosion score and the LEJC were 0.36 and 0.41 (P < 0.0001) for progression to weeks 24 and 48, respectively. CONCLUSION: IL-1Ra reduced radiologic progression of RA. Scores by the 2 methods correlated strongly for each individual time point, but much less strongly for assessments of disease progression.

Adult↗