Or Osteoarthritis Patients Research Articles

Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: Relevance to inflammation in rheumatoid arthritis

To investigate the in vitro effect of activated protein C (APC), a natural anticoagulant and novel antiinflammatory agent, on the regulation of the gelatinases matrix metalloproteinase 2 (MMP-2) and MMP-9. Synovial fibroblasts and peripheral blood monocytes isolated from patients with rheumatoid arthritis (RA) or osteoarthritis (OA) and Mono Mac6 cells were used in this study. After treatment, cells and culture supernatants were collected for zymography, enzyme-linked immunosorbent assay, reverse transcription-polymerase chain reaction, and Western blot analysis. Fibroblasts and monocytes from RA patients produced substantially more MMP-9 than did those from OA patients; however, there was no difference in MMP-2 production. The addition of recombinant APC markedly reduced MMP-9 at the gene and protein levels. In contrast, APC up-regulated and activated MMP-2. Using a blocking antibody to the endothelial protein C receptor (EPCR), we showed that the inhibition of MMP-9 by APC was EPCR-dependent. Furthermore, APC directly suppressed the production of tumor necrosis factor (TNF) and the activation of NF-kappaB and MAP kinase p38, and inhibitors of NF-kappaB or p38 reduced the production of MMP-9, suggesting that APC inhibits MMP-9 by blocking TNF, NF-kappaB, and p38. Thus, APC acts on MMP-9 by binding to EPCRs on the cell surface and, subsequently, inhibiting the intracellular activation of the proinflammatory signaling molecules NF-kappaB and p38. APC appears to be the first physiologic agent to inhibit the production of proinflammatory MMP-9, yet increase antiinflammatory MMP-2 activity. Our results provide the initial evidence that APC may be beneficial in the prevention of inflammation and joint destruction in RA.

Effects of arginine-vasopressin and parathyroid hormone-related protein (1–34) on cell proliferation and production of YKL-40 in cultured chondrocytes from patients with rheumatoid arthritis and osteoarthritis

Both arg-vasopressin (AVP) and parathyroid hormone-related protein (PTHrP) may act as proinflammatory hormones. In addition, they have been suggested to be involved in the pathophysiology of rheumatoid arthritis (RA). We therefore investigated the effects of AVP and PTHrP (1-34) on cell proliferation and secretion of the glycoprotein YKL-40 in human chondrocytes derived from healthy subjects as well as from patients with RA or osteoarthritis (OA). Primary cultures of human chondrocytes were incubated with AVP (1-100 pmol/l) or PTHrP (1-34) (0.1-100 nmol/l). Cell proliferation was measured as [3H]thymidine incorporation. Intracellular cAMP and YKL-40 in cell medium were determined by commercially available kits. AVP and PTHrP (1-34) increased proliferation in chondrocytes derived from healthy donors as well as from RA and OA patients. PTHrP (1-34), but not AVP, increased intracellular levels of cAMP. PTHrP (1-34) did not change the amount of YKL-40 in chondrocytes from healthy subjects or patients with OA. AVP tended to decrease the secretion of YKL-40 from healthy chondrocytes. Both PTHrP (1-34) and AVP increased YKL-40 secretion from RA chondrocytes. In contrast, AVP decreased the secretion of YKL-40 in chondrocytes from patients with OA. AVP and PTHrP (1-34) stimulated proliferation in human chondrocytes derived from healthy subjects as well as from patients with RA or OA. However, the effects of AVP and PTHrP (1-34) on YKL-40 secretion varied depending on the origin of the chondrocytes.

Risk assessment for coronary heart disease in rheumatoid arthritis and osteoarthritis

Background: The risk of coronary heart disease (CHD) is increased in rheumatoid arthritis (RA). The reasons for this remain unknown, but traditional risk factors for CHD identified in the general population may be important contributors.Objective: To assess comparatively the prevalence of traditional CHD risk factors and the absolute 10‐year CHD risk in patients with RA or osteoarthritis (OA) without known cardiovascular co‐morbidity.Methods: Consecutive Caucasian hospital outpatients with RA (n=150) or OA (n=100) aged 40–75 years were assessed for known cardiovascular co‐morbidity, age, sex, smoking status, presence of diabetes mellitus (DM), height, weight, systolic blood pressure (BP), total cholesterol (TC) and HDL cholesterol. Absolute 10‐year CHD risk for each individual was calculated using the Joint British Societies CHD risk calculator.Results: Prevalence and distribution of known cardiovascular co‐morbid conditions were similar in RA (56/150, 37%) and OA (34/100, 34%). The resulting subgroups of patients without known co‐morbidity (RA: n=94; OA: n=66) were not significantly different for age, sex, DM, smoking, systolic BP or TC: HDL cholesterol ratio. There was no significant difference in the absolute 10‐year CHD risk between RA and OA (15.6±11.0 versus 14.8±9.3, p=0.63). However, a significant proportion of patients without known cardiovascular disease in both the RA and OA subgroups had a 10‐year CHD risk above the 15% or 30% risk levels, indicating the need for possible or definite intervention respectively. Over 80% of RA patients had at least 1 CHD risk factor that could be modified.Conclusion: Absolute 10‐year CHD risk was not different between RA and OA patients in this study. Substantial numbers of RA and OA patients have potentially modifiable CHD risk factors present. We suggest that CHD risk should be assessed and modifiable risk factors addressed in the routine rheumatology clinic setting.

Vasoactive intestinal peptide modulates proinflammatory mediator synthesis in osteoarthritic and rheumatoid synovial cells.

Vasoactive intestinal peptide (VIP) has demonstrated beneficial effects in several murine models of immune-mediated inflammation by inhibiting both the inflammatory and the autoimmune components of the disease. We investigate its potential to modulate the release of proinflammatory cytokines and chemokines by human synovial cells from patients with rheumatoid arthritis (RA). Fresh suspensions of synovial tissue cells (STC) or cultured fibroblast-like synoviocytes (FLS) were obtained from patients with RA or osteoarthritis (OA). The effects of VIP on basal or tumour necrosis factor alpha (TNF-alpha)-stimulated production of CCL2 (MCP-1, monocyte chemotactic protein 1), CXCL8 [interleukin (IL)-8], IL-6 and TNF-alpha were studied by specific ELISAs (enzyme-linked immunosorbent assays). The mRNAs for CCL2, CXCL8 and IL-6 in FLS were analysed by real-time reverse transcription-polymerase chain reaction. VIP at 10 nm down-regulated chemokine production by STC and FLS from RA and OA patients. VIP also down-regulated the expression of mRNAs for CCL2, CXCL8 and IL-6. The effects of VIP were more clearly detected in RA samples and after stimulation with TNF-alpha. Our observations confirm that the proposed anti-inflammatory actions of VIP in murine models also apply to human synovial cells ex vivo. Further studies are encouraged to evaluate the use of VIP as a potential therapy for chronic inflammatory joint diseases.

Continuous enhanced expression of Hsc70 but not Hsp70 in rheumatoid arthritis synovial tissue

To investigate the expression of constitutive and inducible members of the Hsp70 protein family in synovial tissue of patients with rheumatoid arthritis (RA) or osteoarthritis (OA). Frozen sections of synovial tissue and isolated synovial adherent cells obtained from 17 RA patients, 5 OA patients, and 1 patient with carpal tunnel syndrome (CTS) were analyzed with specific monoclonal antibodies, by immunohistochemistry, immunocytochemistry, and immunoblotting. Expression of the constitutive chaperone Hsc70 was increased in synovial tissue from 9 of 9 patients with RA, but was faint or undetectable in 3 of 3 samples from patients with OA. In RA samples, cells mainly of the synovial lining stained intensely for Hsc70 as well as for HLA-DR, CD14, and CD68. Also, in vitro-cultured synovial adherent cells from 8 of 9 RA patients overexpressed Hsc70 (specimens from 1 RA patient were used in both the immunochemistry and the in vitro culture studies). On immunoblots of protein extracts, the synovial and HeLa cell molecules appeared identical in size. The inducible chaperone Hsp70 was not detected in samples from any of the same 17 RA patients, except for rare, isolated cells in 3. Samples from 4 of 5 OA patients also were negative for the inducible chaperone Hsp70, and the fifth was very weakly positive. In addition, tissue from 1 patient with CTS was analyzed 10 months before diagnosis of RA. Synovial tissue from this patient showed extreme overexpression of both Hsc70 and Hsp70. In RA, synovial lining cells continuously overexpress Hsc70 but not Hsp70. Hsc70 may be up-regulated due to the high activity of these cells in several respects, including antigen processing and presentation.

Factors contributing to possession and use of walking aids among persons with rheumatoid arthritis and osteoarthritis.

To investigate the possession and use of walking aids among patients with rheumatoid arthritis (RA) or osteoarthritis (OA), and to identify factors contributing to possession and actual use of these aids. A random sample of 640 patients with RA or OA was derived from a database of 6,500 registered patients. A total of 410 (64%) patients (223 RA, 187 OA) completed a questionnaire on possession and use of walking aids. Demographics, disease-related characteristics, and information about possession and use were assessed. Logistic regression analyses were used to determine which factors are associated with the possession and use of walking aids. Forty-nine percent of the RA patients and 44% of the OA patients owned a walking aid. Canes, forearm crutches, walkers, and orthopedic footwear were most frequently possessed. In the RA group, age, education, frequency of pain, and disability were associated with possessing a walking aid. In the OA group, age and disability were associated with possession. Approximately 30% of the owners did not use their walking aid. Factors associated with the actual use of an aid included higher age, a high intensity of pain, more disability, decrease in morning stiffness by the aid, and a positive evaluation of the aid. Almost half of patients with RA or OA possess a walking aid. Disability, pain, and age-related impairments seem to determine the need for a walking aid. Nonuse is associated with less need, negative outcome, and negative evaluation of the walking aid.

Arginase levels are increased in patients with rheumatoid arthritis.

Arginase and nitric oxide synthase (NOS) compete for the same substrate, L-arginine. The reciprocal regulation of arginase and NOS in L-arginine-metabolizing pathways has recently been demonstrated. Since NOS is involved in the inflammation of human arthritides, we hypothesized that this reciprocal regulation might also occur within the inflamed synovium. The present study shows that both serum arginase activity and protein levels were significantly higher in patients with rheumatoid arthritis (RA) than in patients with systemic lupus erythematosus (SLE) or osteoarthritis (OA) or in healthy controls. Arginase protein concentrations in supernatants of monocyte cultures from RA patients were also significantly higher than in those from SLE or OA patients or healthy controls. In RA patients, there was a significant correlation between the serum concentrations of arginase protein and rheumatoid factor (r = 0.82, p < 0.0001). These data indicate that increased arginase production is seen in RA patients, but not in other immune-related diseases, suggesting that increased arginase production is unique to, and may play an important role in, the pathogenesis of RA disease.

Tolerability of Multiple Administration of Intramuscular Meloxicam: A Comparison with Intramuscular Piroxicam in Patients with Rheumatoid Arthritis or Osteoarthritis

This multicentre, randomized, open controlled study compared the local and overall tolerability of i.m. meloxicam with i.m. piroxicam in 211 patients with rheumatoid arthritis (RA) (n = 95) or osteoarthritis (OA) (n = 116). Of these, 210 patients were randomized (2:1) to receive meloxicam 15 mg (n = 144) or piroxicam 20 mg (n = 66) for 7 days. Local tolerability of meloxicam was significantly better than piroxicam with respect to occurrence of redness after the first injection (P = 0.03) and global assessment after the first and final injections (P < 0.05). No rise in creatinine phosphokinase levels (a marker of muscle fibre damage) was observed with meloxicam, in contrast to piroxicam (P = 0.0001). The overall tolerability of both treatments was good. Significant differences in favour of meloxicam were observed for global efficacy assessed by the patient in RA (P < 0.05) and for overall pain intensity in OA patients (P = 0.02). In conclusion, i.m. meloxicam is safe and effective for the treatment of acute rheumatic pain and shows some superiority over piroxicam.

The effects of age and gender on the pharmacokinetics of tenidap sodium in patients with rheumatoid arthritis and osteoarthritis.

1. This open-label study was conducted to evaluate the effects of age and gender on the pharmacokinetics of tenidap sodium in patients with either rheumatoid arthritis (RA) or osteoarthritis (OA). 2. A total of 145 male and female patients, 80 with RA (aged 22-91 years) and 65 with OA (aged 45-83 years) each received a single dose of 120 mg tenidap sodium. Pharmacokinetic parameters were estimated from individual tenidap plasma concentration-time curves determined up to 120 h post-dose. Tenidap plasma protein binding was determined in the youngest and oldest age groups for both RA and OA patients. 3. In RA patients, age and gender did not significantly affect the disposition of tenidap or the percentage of unbound tenidap in plasma. Only for tmax were statistically significant effects in the analysis of covariance observed and these were attributed to very high tmax values in two female patients. Likewise, in patients with OA, age and gender did not significantly affect the pharmacokinetics of tenidap, although patients with larger body weights had lower Cmax values. 4. Pharmacokinetic parameters were not significantly different between RA and OA patients, except for t1/2, where two outlier RA patients had low values that caused the mean value to be significantly lower in RA (24 h) than in OA (26 h) patients. Pharmacokinetic parameters for pooled values from RA and OA patients were as follows: t1/2 = 25 h, AUC = 538.4 micrograms ml-1 h, Cmax = 21.9 micrograms ml-1, tmax = 3.2 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytokine inter-relationships and their association with disease activity in arthritis.

In order to investigate the relationships between cytokine production and arthritic disease we have determined the concentrations of immunoreactive interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, tumour necrosis factor-alpha (TNF-alpha), interferon-alpha (IFN-alpha), IFN-gamma, and soluble IL-2-receptor (sIL-2R), as well as bioactive IL-1 and IL-6, in synovial fluids (SF) and plasma of patients with a variety of arthritides. Careful assay revealed only minimal concentrations of IL-1, particularly its biologically active form, in SF. No IL-1 was detectable in the plasma of patients that had IL-1 in their SF. Concentrations of both immunoreactive IL-1 beta and TNF-alpha in SF of rheumatoid arthritis (RA) patients were significantly higher than those in SF from patients with other inflammatory arthritides or osteoarthritis (OA). IL-6 and sIL-2R concentrations in both SF and plasma were higher in RA patients than in OA patients, and were significantly correlated. Approximately half of the SF from patients with all arthropathies contained detectable IFN-alpha, whilst IFN-Y was present in less than 10%. There were significant associations between IL-6, sIL-2R, IL-1 beta, TNF-alpha and IFN-alpha. The concentration of these cytokines, where detectable, was also related to leukocyte counts in the SF, as well as to parameters assessing local and systemic disease activity. Although IL-6 was the cytokine most clearly related to other cytokines, and to parameters assessing disease activity, the relationship between general articular disease activity and IL-6 was only evident in patients with arthropathies other than rheumatoid arthritis.

Large-scale open trials with etodolac (Lodine®) in France: An assessment of safety

Two large-scale open-label studies were performed in France to confirm the efficacy and safety of etodolac (Lodine), a new non-steroidal anti-inflammatory drug (NSAID). Study I, a 6-week study performed by 974 rheumatologists, involved 4947 patients who had rheumatoid arthritis (RA), ankylosing spondylitis (AS), or osteoarthritis (OA). Both efficacy and safety were assessed. Study II, a postmarketing safety study performed by approximately 9000 general practitioners, involved 51,355 patients who had rheumatic conditions requiring therapy with NSAIDs. The daily dose of etodolac ranged from 200 to 600 mg/day in these studies, depending on the protocol and patient response. By the end of study I (visit 3), spontaneous pain improved by 33% for patients with RA, by 42% for patients with AS, and by 50% for OA patients. A total of 1276 adverse reactions (AR) were reported during the study, and fewer than half of these were related to study treatment. Only 6 severe reactions were reported; three of these were considered unrelated to study treatment, including 2 deaths. In study II, 10.1% of patients reported 6236 ARs and 9.0% of patients dropped out because of AR. Twenty-one of the ARs reported in study II were judged severe, and all of these patients recovered completely. The overall opinion of safety was assessed as very good or good by 89% of patients. In both studies (greater than 55,000 patients), 11% of patients reported an AR, and severe reactions were rare. These results confirmed the very acceptable risk/benefit ratio of etodolac and rank this drug high for efficacy and safety among the NSAIDs recently introduced in France.