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ID PMID Title PublicationDate abstract
19019888 Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, i 2009 Oct OBJECTIVES: To evaluate the safety and efficacy of 5-year, long-term tocilizumab monotherapy for patients with rheumatoid arthritis. METHODS: In an open-label, long-term extension trial following an initial 3-month randomised phase II trial, 143 of the 163 patients who participated in the initial blinded study received tocilizumab monotherapy (8 mg/kg) every 4 weeks. Concomitant therapy with non-steroidal anti-inflammatory drugs and/or oral prednisolone (10 mg daily maximum) was permitted. All patients were evaluated with American College of Rheumatology (ACR) improvement criteria, disease activity score (DAS) in 28 joints, and the European League Against Rheumatism response, as well as for safety issues. RESULTS: 143 patients were enrolled in the open-label, long-term extension trial and 94 (66%) patients had completed 5 years as of March 2007. 32 patients (22%) withdrew from the study due to adverse events and one patient (0.7%) due to unsatisfactory response. 14 patients withdrew because of the patient's request or other reasons. The serious adverse event rate was 27.5 events per 100 patient-years, with 5.7 serious infections per 100 patient-years, based on a total tocilizumab exposure of 612 patient-years. Of the 88 patients receiving corticosteroids at baseline, 78 (88.6%) were able to decrease their corticosteroid dose and 28 (31.8%) discontinued corticosteroids. At 5 years, 79/94 (84.0%), 65/94 (69.1%) and 41/94 (43.6%) of the patients achieved ACR20, ACR50, and ACR70 improvement criteria, respectively. Remission defined as DAS28 less than 2.6 was achieved in 52/94 (55.3%) of the patients. CONCLUSION: In this 5-year extension study, tocilizumab demonstrated sustained long-term efficacy and a generally good safety profile.
17720847 p38 pathway kinases as anti-inflammatory drug targets. 2007 Sep Mitogen-activated protein kinases (MAPK) are intracellular signaling molecules involved in cytokine synthesis. Several classes of mammalian MAPK have been identified, including extracellular signal-regulated kinase, c-jun N-terminal kinase, and p38 MAP kinase. p38alpha is a key MAPK involved in tumor necrosis factor alpha and other cytokine production, as well as enzyme induction (cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloproteinases) and adhesion molecule expression. An understanding of the broad biologic and pathophysiological roles of p38 MAPK family members has grown significantly over the past decade, as has the complexity of the signaling network leading to their activation. Downstream substrates of MAPK include other kinases (e.g., mitogen-activated protein-kinase-activated protein kinase 2) and factors that regulate transcription, nuclear export, and mRNA stability and translation. The high-resolution crystal structure of p38alpha has led to the design of selective inhibitors that have good pharmacological activity. Despite the strong rationale for MAPK inhibitors in human disease, direct proof of concept in the clinic has yet to be demonstrated, with most compounds demonstrating dose-limiting adverse effects. The role of MAPK in inflammation makes them attractive targets for new therapies, and efforts are continuing to identify newer, more selective inhibitors for inflammatory diseases.
18974527 Optical coherence tomography in a patient with chloroquine-induced maculopathy. 2008 Nov We herein report the optical coherence tomography (OCT) findings in a case of chloroquine-induced macular toxicity, which to our knowledge, has so far not been reported. A 53-year-old lady on chloroquine for treatment of rheumatoid arthritis developed decrease in vision 36 months after initiation of the treatment. Clinical examination revealed evidence of retinal pigment epithelial (RPE) disturbances. Humphrey field analyzer (HFA), fundus fluorescein angiography (FFA) and OCT for retinal thickness and volume measurements at the parafoveal region were done. The HFA revealed bilateral superior paracentral scotomas, FFA demonstrated RPE loss and OCT revealed anatomical evidence of loss of ganglion cell layers, causing marked thinning of the macula and parafoveal region. Parafoveal retinal thickness and volume measurements may be early evidence of chloroquine toxicity, and OCT measurements as a part of chloroquine toxicity screening may be useful in early detection of chloroquine maculopathy.
17608234 [Clinic utilization of Guizhi decoction in modern times]. 2007 Apr To discuss the general situation of the clinic utilization of Guizhi decoction in modem times. Look up the literature about the clinic utilization research of guizhi decoction in recent years, then to analyze and coordinate the useful informations. Guizhi decoction is widely used in clinic areas. The range of Guizhi decoction' treatment involves circulation, immunity, procreation, endocrine, digestion, nerve, etc. and covers various clinic illness such as internal medicine, surgery, gynaecology and obstetrics, pediatrics, ophthalmology and otorhinolaryngology, stomatology, etc.
18501560 Leptin induces IL-8 expression via leptin receptor, IRS-1, PI3K, Akt cascade and promotion 2008 Aug Leptin, the adipocyte-secreted hormone that centrally regulates weight control, is known to function as an immunomodulatory regulator. We investigated the signaling pathway involved in IL-8 production caused by leptin in both rheumatoid arthritis synovial fibroblasts (RASF) and osteoarthritis synovial fibroblasts (OASF). RASF and OASF expressed the long (OBRl) and short (OBRs) isoforms of the leptin receptor. Leptin caused concentration- and time-dependent increases in IL-8 production. Leptin-mediated IL-8 production was attenuated by OBRl receptor antisense oligonucleotide, JAK2 inhibitor or STAT3 small interference RNA (siRNA). Transfection with insulin receptor substrate (IRS)-1 siRNA or dominant-negative mutant of p85 and Akt or pretreatment with phosphatidylinositol 3-kinase inhibitor (Ly294002 and wortmannin), Akt inhibitor, NF-kappaB inhibitor (PDTC) and NF-kappaB inhibitor peptide also inhibited the potentiating action of leptin. Stimulation of RASF with leptin activated IkappaB kinase alpha/beta (IKK alpha/beta), p65 phosphorylation at Ser(276), p65 translocation from the cytosol to the nucleus, and kappaB-luciferase activity. Moreover, pretreatment with p300 inhibitor (curcumin) also blocked IL-8 expression. The binding of p65 to the NF-kappaB elements, as well as the recruitment of p300 and the enhancement of histone H3 acetylation on the IL-8 promoter was enhanced by leptin, which was inhibited by wortmannin, Akt inhibitor or IRS-1 siRNA. These results suggest that leptin increased IL-8 production in synovial fibroblast via the OBRl/JAK2/STAT3 pathway, as well as the activation of IRS1/PI3K/Akt/NF-kappaB-dependent pathway and the subsequent recruitment of p300.
17951661 Assessment of collagenase activity in cartilage. 2007 Assay of collagenase activity involves the use of radiolabeled collagen. Stimulation of cartilage with proinflammatory cytokines results in the upregulation of collagenases and the subsequent release of degraded collagen fragments. These enzymes can be localized in both osteoarthritic and rheumatoid arthritis cartilage and synovial tissues.
16951473 [Fracture risk assessment tool]. 2006 Sep World Health Organization (WHO) has proposed the use of 10-year absolute risk for fracture (calculated based on incidence and life span) using clinical risk factors as new intervention thresholds. Eight risk factors to be included in the fracture assessment risk tool are age, bone mineral density or body mass index (BMI) when bone density is not available, steroid use, parental history of femoral neck fracture, history of osteoporotic fracture, smoking, excessive alcohol consumption, and rheumatoid arthritis. WHO has proposed that a treatment-intervention threshold be established in accordance with the medical situation in each country.
18482208 Neutralizing IL-21 and IL-15 inhibits pro-inflammatory cytokine production in rheumatoid a 2008 Jul Interleukin IL-21 and IL-15 belong to the common gamma-chain receptor family. IL-15 represents a novel therapeutic target in rheumatoid arthritis (RA), whereas less is known about the role of IL-21 in human inflammatory diseases. We have analysed the effects of blocking IL-21 and IL-15 on spontaneous production of pro-inflammatory cytokines in RA synovial cell cultures. RA synovial membrane cells were cultured in the presence of an IL-21R-Fc chimera or a neutralizing IL-15 antibody and production of tumour necrosis factor (TNF)alpha, IL-6 and IL-1beta was measured by enzyme-linked immunosorbent assay (ELISA). Expression of IL-21 and IL-15 in RA synovium was measured by RT-PCR and ELISA. mRNA for IL-21 and IL-21R was detected in the culture cell lysates. Protein for IL-15 was found at detectable levels in the cell lysates. Both the IL-21R-Fc chimera and anti-IL-15 antibody inhibited cytokine release, although substantially more IL-21R-Fc was needed. IL-21R-Fc at the highest dose (100 microg/ml) significantly reduced TNFalpha production by 50%, IL-6 by 57% and IL-1beta by 81%. Anti-IL-15 antibody (5 microg/ml) significantly inhibited TNFalpha release by 51%, IL-6 by 37% and IL-1beta by 82% in line with previous published observations. The data confirm that IL-15 plays a role in RA and suggests that IL-21 is also involved in driving the pro-inflammatory cytokine response in RA.
17012439 Dose escalation of the anti-TNF-alpha agents in patients with rheumatoid arthritis. A syst 2007 Mar OBJECTIVE: To estimate the proportion of rheumatoid arthritis (RA) patients on anti-tumour necrosis factor (anti-TNF) who require dose escalation. METHODS: Systematic review of the scientific literature. Infliximab, etanercept and adalimumab studies in RA were considered. Primary outcome was the proportion of patients requiring dose escalation. American College Rheumatology (ACR) and Disease activity score (DAS) responses post-escalation were assessed when available. RESULTS: From 1801 references, 16 studies with 8510 patients were included. Of all the infliximab patients, 53.7% underwent dose escalation. Fourty-four per cent of the infliximab patients experienced dose increase and 8.3%, frequency increase. The ACR20 response to dose escalation ranged from 27 to 36% and DAS28 improved from 5.2 to 4.5 in one study and from 4.1 to 3.7 in another. Of the etanercept patients, 17.5% experienced a dose increase but changes on the mean dose were not statistically significant. CONCLUSIONS: Dose escalation is common in patients treated with infliximab, and less frequent with etanercept. In a proportion of patients, the dose escalation seems effective. The design and evidence level of the available studies limit the strength of the conclusions.
16633924 The role of c-Src kinase in the regulation of osteoclast function. 2006 The targeted disruption of c-Src impairs osteoclast bone resorbing activity, causing osteopetrosis. Although it has been reported that restoring only the c-Src adaptor function at least partly rescues the skeletal phenotypes, the importance of c-Src kinase activity remains controversial. We here highlight the contributions of the Src adaptor and kinase activities in cytoskeletal organization and osteoclast function using adenovirus vectors containing various mutants of Src or Pyk2. In addition, we describe the importance of c-Src in mitochondria, where it phosphorylates cytochrome c oxidase (Cox). Src-induced Cox activity is also required for bone resorbing activity of osteoclasts that require high levels of ATP. Thus, c-Src kinase activity not only on the plasma membrane but also within mitochondria is essential for the regulation of osteoclastic bone resorption.
18220799 Emerging indications for statins: a pluripotent family of agents with several potential ap 2007 Statins are pluripotent agents exhibiting multiple non-lipid-lowering actions. Besides their established role in the management of hypercholesterolemia, statins may also have beneficial actions in other pathological conditions, namely: a) osteoporosis and osteoporosis-related bone fractures, b) cancer, c) solid organ transplantation, d) cerebrovascular events (transient ischemic attack and stroke episodes), e) various neurological disorders, such as Alzheimer's disease, Parkinson's disease and multiple sclerosis, f) cardiac arrhythmias and heart failure, g) renal diseases, h) rheumatoid arthritis, i) autoimmune diseases, j) sepsis, and k) allergic asthma. We reviewed the literature searching for studies that support or oppose the use of statins in each proposed indication. In some of these emerging indications, a role for statin treatment is more firmly set; for others, current evidence is more controversial. Future trials may reveal more convincing evidence that will make statin use necessary in the therapeutic management of several diseases.
17114192 Reduced telomere length in rheumatoid arthritis is independent of disease activity and dur 2007 Apr BACKGROUND: Rheumatoid arthritis (RA) is associated with reduced lifespan and shortened telomere length in lymphocytes, but the mechanism underlying this is unclear. Telomere loss in white blood cells (WBC) is accelerated by oxidative stress and inflammation in vitro. It was postulated that the accelerated WBC telomere shortening in RA occurs as a result of exposure to chronic inflammation. OBJECTIVES: To measure telomere terminal restriction fragment (TRF) length in a large cohort of RA cases and healthy controls, to explore associations of TRF length with features of disease and with RA-associated HLA-DRB1 alleles. METHODS: WBC and TRF length were measured by Southern blot in DNA from 176 hospital-based RA cases satisfying the 1987 American College of Rheumatology criteria and from 1151 controls. TRF length was compared between cases and controls, and the effects of disease duration, severity and HLA-DRB1 alleles encoding the shared epitope (SE) were assessed. RESULTS: Age- and sex-adjusted TRF length was significantly shorter in RA cases compared with controls (p<0.001). There was no association between age- and sex-adjusted TRF length and disease duration, C reactive protein or Larsen score. The presence of one or more SE-encoding alleles was associated with reduced adjusted TRF length in RA cases (SE positive vs SE negative cases, p=0.038), but not in controls. CONCLUSION: The reduced TRF length in a large group of patients with RA compared with controls has been shown. The reduction is apparently independent of disease duration and markers of disease severity, but is influenced by HLA-DRB1 genotype.
17156952 Liposomes for phospholipase A2 triggered siRNA release: preparation and in vitro test. 2007 Mar 1 Small interfering RNA (siRNA) is potent and highly specific for gene silencing. However, for therapeutic applications, delivery systems are required to protect siRNA from degradation, to enhance cellular uptake and for site-specific delivery. We used a double emulsion technique to encapsulate siRNA into stealth liposomes (SL) to increase entrapment efficiency compared to passive encapsulation. SL are designed for localized, active release of siRNA by secretory phosholipase A(2) (sPLA(2)). sPLA(2) acts as a site-specific enzymatic trigger that actively degrades the liposomal carrier in inflamed tissue releasing entrapped drug. Relatively good encapsulation efficiencies compared to passive encapsulation were demonstrated (7-9%) and SL size was appropriate for i.v. administration (60-90 nm). siRNA targeting enhanced green fluorescent protein (EGFP) entrapped in SL did not silence gene expression of HeLa-cells stably expressing EGFP. However, preliminary flow cytometry and confocal microscopy data showed that the SL siRNA formulation increased uptake of siRNA into vesicular compartments of HeLa-cells in a concentration-dependent manner that could be augmented by exogenuos sPLA(2). We hypothesize that the SL can be used to target siRNA to inflammed tissue for silencing of cytokine expression in rheumatoid arthritis.
18534386 Comparison of the Insall-Burstein II and NexGen legacy total knee arthroplasty systems wit 2008 Sep This study retrospectively contrasts 2 cohorts of consecutive patients ""(N = 202) after primary total knee arthroplasty with respect to the types and numbers of patella and extensor mechanism complications. Our results demonstrated an overall decrease of patellofemoral complications associated with the NexGen Legacy PS system (Zimmer Inc, Warsaw, Ind). Patella fractures decreased from 6 to 0 (P = .013), avascular necrosis from 9 to 0 (P = .0002), and lateral retinacular release trended down from 24 to 14. The Insall-Burstein II (Zimmer Inc, Warsaw, Ind) has a significantly higher incidence of patella fractures, avascular necrosis, and the lateral retinacular release. We feel that the alteration and adjustment of the patellofemoral dimension in the NexGen Legacy design to a more anatomical, extended design of the femoral component and patella modifications led to a decrease in the incidence of complications.
16371420 Identification of gene expression signatures in autoimmune disease without the influence o 2006 Feb 1 Even though autoimmune diseases are heterogeneous, believed to result from the interaction between genetic and environmental components, patients with these disorders exhibit reproducible patterns of gene expression in their peripheral blood mononuclear cells. A portion of this gene expression profile is a property of familial resemblance rather than autoimmune disease. Here, we wanted to identify the portion of this gene expression profile that is independent of familial resemblance and determine whether it is a product of disease duration, disease onset or other factors. By employing supervised clustering algorithms, we identified 100 genes whose expression profiles are shared in individuals with various autoimmune diseases but are not shared by unaffected family members of individuals with autoimmune disease or by controls. Individuals with early disease (1 year after onset) and established disease (10 years after onset) exhibit a near-identical expression pattern, suggesting that this unique profile is a product of disease onset rather than disease duration.
17075711 [New developments in joint ultrasonography]. 2006 Dec Musculoskeletal ultrasonography has become an established imaging technique in rheumatology. The ability of ultrasonography to visualize soft tissue changes provides a possibility for differentiating between exudative and proliferative synovial tissue changes. Superficial cartilage and bone lesions can be detected earlier by ultrasonography than by conventional radiography. The application of Doppler and power Doppler ultrasonography is helpful for the detection of early inflammation. Current studies with ultrasound contrast media demonstrate its benefit in the differentiation of inflammatory processes. Musculoskeletal ultrasonography is helpful in the diagnosis of early arthritis, especially in patients with inconspicuous conventional radiography or suspicious clinical findings. It is a convenient method for follow-up analysis, and therefore has an impact on the monitoring of therapy. It is patient-friendly and is an important tool for the diagnostic work-up of arthritis.
17214582 NF-kappaB and rheumatic diseases. 2006 Dec NF-kappaB is an inducible transcription factor that is controlled by the signal activation cascades. NF-kappaB controls a number of genes involved in immuno-inflammatory responses, cell cycle progression, inhibition of apoptosis, and cell adhesion, thus promoting chronic inflammatory responses. In fact, NF-kappaB is constitutively activated in some rheumatic conditions such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Interestingly, a number of anti-RA compounds have been shown to exhibit anti-NF-kappaB activities. In addition, NF-kappaB activation has been linked to carcinogenesis and its constitutive activation has been demonstrated in some cancers and leukemias. These findings have substantiated the long-standing proposal of the link among chronic inflammation, autoimmunity, and carcinogenesis by molecular terms. In this review, I have attempted to overview the pathologic involvement of NF-kappaB in rheumatic diseases and discuss the feasibility of a therapeutic strategy with NF-kappaB and its signaling cascade as novel molecular targets.
16793005 A novel BLyS antagonist peptide designed based on the 3-D complex structure of BCMA and BL 2006 Aug 11 B lymphocyte stimulator (BLyS) is a member of tumor necrosis factor (TNF) family. Because of its roles in autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren syndrome (SS), BLyS antagonists have been tested to treat SLE- and RA-like symptoms in mice and obtained optimistic results. So far, reported BLyS antagonists were mostly decoyed BLyS receptors or anti-BLyS antibodies. In this study, a novel BLyS antagonist peptide, PT, was designed based on the modeling 3-D complex structure of BCMA and BLyS. The interaction mode of PT with BLyS was analyzed theoretically. The results of competitive ELISA demonstrated that PT could inhibit the binding of BCMA-Fc and anti-BLyS antibody to BLyS in vitro. In addition, PT could partly block the proliferating activity of BLyS on mice splenocytes. The BLyS antagonizing activity of PT was significant (p<0.05). This study highlights the possibility of using BLyS antagonist peptide to neutralize BLyS activity. Further optimization of PT with computer-guided molecular design method to enhance its biopotency may be useful in developing new BLyS antagonists to treat BLyS-related autoimmune diseases.
17181926 Synovial expression of vasoactive intestinal peptide in polymyalgia rheumatica. 2006 Sep OBJECTIVE: Polymyalgia rheumatica (PMR) is an inflammatory disease that typically affects elderly people. Its clinical hallmark is the severity of pain in the shoulder and pelvic girdle. Mild to moderate synovitis and/or bursitis of the joints involved has been described. Neuropeptides are involved in nociception and modulation of inflammatory reaction. To evaluate whether neuropeptides have a role in PMR pathophysiology, we studied the expression of substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and somatostatin (SOM) in shoulder synovial tissues of PMR patients. METHODS: Synovial expression of neuropeptides was investigated by immunohistochemical analysis, in two groups of PMR patients: the first one at the onset of disease and the second one after corticosteroid treatment, and in other joint diseases, rheumatoid arthritis (RA) and osteoarthritis (OA). RESULTS: The only significant expression of VIP was found in PMR and, to a lesser extent, in RA synovial tissue. In PMR, we observed VIP immunostaining both in the lining layer and in the sublining area. In patients on corticosteroid treatment VIP lining layer expression was not significantly different while VIP positive cells in the sublining area were almost absent. CONCLUSION: Local VIP production in PMR synovial tissue might contribute to the typical musculoskeletal discomfort and it may have a role in the immunomodulation of synovial inflammation.
17691996 Efficacy of the newest COX-2 selective inhibitors in rheumatic disease. 2007 Non-steroidal antiinflammatory drugs (NSAIDs) are standard treatment for the pain and inflammation associated with arthritis. Traditional NSAIDs and cyclooxygenase-2 (COX-2) selective inhibitors exhibit comparable efficacy, with different safety profiles. Traditional NSAIDs are associated with an increased risk of serious gastrointestinal (GI) adverse events versus COX-2 selective inhibitors, and chronic use frequently necessitates adjunctive therapy with gastroprotective agents. COX-2 selective inhibitors are often used in preference to avoid these GI adverse events. Recent studies have raised the concern that COX-2 selective inhibitors and traditional NSAIDs appear to be associated with a higher incidence of thrombotic cardiovascular events versus placebo. The key in prescribing these agents is for the physician to take a proactive approach to patient management and evaluation of GI and cardiovascular risk factors. This review examines the role of the newest COX-2 selective inhibitors, etoricoxib and lumiracoxib, in treating rheumatic disease.