Background: Patients with RA have an increased prevalence of cardiovascular disease (CVD). This is due to increased traditional risk factors and the effect of chronic inflammation. TNF antagonists are potent suppressors of inflammation and may reduce the risk of CVD. We performed a systematic literature review to determine whether TNF antagonists affect the risk of clinical CVD events in RA. Methods: We searched Medline, Embase, Cochrane database, DARE, HTA and Science Citation Index from 1980-2008. Papers were included if they assessed the relationship between the use of TNF antagonists and clinical CVD outcomes in RA. All articles were assessed for study quality. Results: 1840 abstracts were identified. Two reviewers independently assessed each title and abstract. 20 studies fulfilled the inclusion criteria: 1 RCT, 11 cohorts, 7 case-controls and 1 cross-sectional study(Table to be included in a poster). 7 studies considered all CVD events, 4 demonstrating a significant decreased CVD risk and 3 no change in risk. 7 studies assessed the association of TNF antagonists and MI; 2 demonstrated a significant decreased risk and 5 no difference. The study with the lowest risk of bias, showed a significantly lower risk of MI in TNF responders compared with non-responders. 3 studies considered stroke and TNF antagonists, two demonstrated no change in risk and 1 a reduced risk after 6 months of treatment. 6 studies considered heart failure (HF): 1 demonstrated a significantly increased risk of HF in elderly RA patients, 3 no difference in risk and 2 a significantly decreased risk of HF. In the study with the lowest risk of bias, a non-significant increased risk of HF was considered to be offset by the efficacy of TNF antagonists. Conclusions: For all CVD events there may be a decreased risk associated with use of TNF antagonists. For specific events, e.g. MI and HF the effect is less clear. Atherosclerosis is an inflammatory process, TNF antagonists would be expected to reduce the risk of CVD by decreasing the burden of systemic inflammation. There are several reasons this may not be apparent. Firstly, TNF antagonists may have adverse effects on traditional risk factors (lipids, etc.). Secondly MTX reduces the risk of CVD events, it is commonly used in combination with TNF antagonists and in some of the studies was used by controls. TNF antagonists may therefore have no additional benefit to MTX. In contrast to MTX, TNF antagonists are often used late in the disease when significant irreversible damage has occurred. Finally the effect on CVD may depend on response to treatment as some of the studies demonstrated a lower risk of CVD events in responders compared with non-responders. To determine the true effect of TNF antagonists on CVD risk future studies should publish data on CVD risk factors and clinical events, this is particularly important in studies of early disease when the burden of inflammation has not been realised. Disclosure statement: E.C., Abbott, Allergan, Boehringer, Ingelheim, Chelsa Therapeutica, Eli Lilly, GSK, Jazz Pharmaceuticals, Merrimack Pharmaceutical, MSD, Pfizer, Pierre Fabre Medicament, Roche, Schering Plough, UCB, Celltech and Wyeth - Research grants and honoraria for advisory boards, consultancy and speaker bureaus. C.J.E., Abbott, Roche, wyeth, Schering-Plough and UCB-Pharma - Advisory fees, speaker fees and unrestricted educational grant. A.J.O., Roche, Chugai, Schering-Plough, Abbott, Wyeth, BMS, GSK, MerckSorono and UCB - Support and Consultant. M.Q., Abbott and Schering-Plough - Speaker fees, Abbott, Schering-Plough and UCB - Advisory board, Abbott - Research grants. All other authors have declared no conflicts of interest.
Using physiological, pharmacological, and gene disruption approaches, we demonstrate that proteinase-activated receptor-2 (PAR-2) plays a pivotal role in mediating chronic inflammation. Using an adjuvant monoarthritis model of chronic inflammation, joint swelling was substantially inhibited in PAR-2–deficient mice, being reduced by more than fourfold compared with wild-type mice, with virtually no histological evidence of joint damage. Mice heterozygous for PAR-2 gene disruption showed an intermediate phenotype. PAR-2 expression, normally limited to endothelial cells in small arterioles, was substantially upregulated 2 weeks after induction of inflammation, both in synovium and in other periarticular tissues. PAR-2 agonists showed potent proinflammatory effects as intra-articular injection of ASKH95, a novel synthetic PAR-2 agonist, induced prolonged joint swelling and synovial hyperemia. Given the absence of the chronic inflammatory response in the PAR-2–deficient mice, our findings demonstrate a key role for PAR-2 in mediating chronic inflammation, thereby identifying a novel and important therapeutic target for the management of chronic inflammatory diseases such as rheumatoid arthritis.
The role of different isoforms of cyclo‐oxygenase (COX) in mediating the acute (0‐6 h) and late (24 h ) phases of inflammation was investigated in the rat knee joint following intra‐articular injection of carrageenan. The hyperaemic response was assessed transcutaneously using laser Doppler imaging (LDI). Samples were taken at corresponding time points for detection of synovial COX‐1, COX‐2 and inducible nitric oxide synthase (iNOS) mRNA, and measurement of urinary prostaglandin (PG) and nitric oxide metabolites (NO x ). A non‐selective COX inhibitor (indomethacin, 15 mg kg −1 i.p. ), a selective COX‐2 inhibitor (SC‐236, 16.8 mg kg −1 i.p. ) or vehicle were administered 1 h prior to carrageenan in the acute phase study. LDI scans were taken hourly for 4 h post‐induction. Inflammatory hyperaemia in the vehicle group was attenuated in the indomethacin‐ ( P < 0.001, two‐way ANOVA) and SC‐236‐treated groups ( P < 0.0001), with no difference between these treatments. At 24 h, i.v. infusion of indomethacin (0.1 mg min −1 ), increased vascular resistance (24 ± 7.1 %; P < 0.05) compared to vehicle infusion, whereas SC‐236 (0.11 mg min −1 ) did not. Resistance changes to indomethacin also differed from SC‐236 ( P < 0.05). Knee joint diameter progressively increased over 24 h ( P < 0.0001, one‐way ANOVA). Urinary PG levels increased by 6 h ( P < 0.05), but returned to baseline by 24 h. COX‐1 mRNA was detectable at all time points; COX‐2 mRNA only at 3 h. Urinary NO x levels increased progressively over 24 h ( P < 0.05), paralleled by induction of iNOS in the 3 and 24 h samples. Prostaglandin production via COX‐2 appears to mediate the development of acute inflammatory hyperaemia, but nitrergic mechanisms may supervene subsequently. COX‐1 but not COX‐2 contributes to the maintenance of basal blood flow in the hyperaemic joint at 24 h.
The proinflammatory properties of angiotensin II have been well described.1 Indeed, the angiotensin 1 receptor (AT1 receptor) is present and upregulated in the synovium of patients with rheumatoid arthritis (RA).2 Two separate studies, have confirmed the therapeutic effect of angiotensin converting enzyme inhibitors (ACEi)3 and angiotensin receptor blockers (ARB)4 on joint inflammation in both mouse and rat. ACEi may differ from ARB as the former tend to be non-specific in their anti-inflammatory effect.
To assess the effect of ACEi and ARB on human C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels, a retrospective analysis was performed …
Objectives The aim of this study was to determine the presence of protease-activated receptor 2 (PAR2) and matriptase proteins and quantify PAR2 and matriptase mRNA expression in the articular cartilage and synovial membrane of cats with and without osteoarthritis (OA). Methods A total of 28 articular cartilage samples from adult cats (14 OA and 14 normal), 10 synovial membranes from adult cats (five OA and five normal) and three cartilage samples from 9-week-old fetal cats were used. The presence of PAR2 and matriptase in the cartilage and synovial membrane of the adult samples was detected by immunohistochemical (IHC) staining, while real-time PCR was used for mRNA expression analyses in all samples. Results PAR2 was detected in all OA and normal articular cartilage and synovial membrane samples but confined to only a few superficial chondrocytes in the normal samples. Matriptase was only detected in OA articular cartilage and synovial membrane samples. PAR2 and matriptase mRNA expression were, however, detected in all cartilage and synovial membrane samples. PAR2 and matriptase mRNA expression levels in OA articular cartilage were five ( P <0.001) and 3.3 ( P <0.001) times higher than that of the healthy group, respectively. There was no significant difference ( P = 0.05) in the OA synovial membrane PAR2 and matriptase mRNA expression compared with the normal samples. Conclusions and relevance Detection of PAR2 and matriptase proteins and gene expression in feline articular tissues is a novel and important finding, and supports the hypothesis that serine proteases are involved in the pathogenesis of feline OA. The consistent presence of PAR2 and matriptase protein in the cytoplasm of OA chondrocytes suggests a possible involvement of proteases in cartilage degradation. Further investigations into the PAR2 and matriptase pathobiology could enhance our understanding of the proteolytic cascades in feline OA, which might lead to the development of novel therapeutic strategies.
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