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ID PMID Title PublicationDate abstract
21123975 A long course of leukocytopenia and splenomegaly with extramedullary hematopoiesis in the 2010 A 70-year-old female with a long history of progressive leukocytopenia and giant splenomegaly is described. She had no clinically manifested rheumatoid arthritis, although she complained of slight arthralgia in the digital joints, wrists and ankles at irregular intervals. Repeated bone marrow aspirations showed no cellular atypism, chromosomal abnormalities, or phenotypical abnormalities. Just before splenectomy, both anti-neutrophil antibody positivity and anti-cyclic citrullinated peptide antibody positivity were shown. Histology of the splenectomized spleen showed follicular hyperplasia with plasmacyte infiltration and extramedullary hematopoeisis. After splenectomy, leukocyte counts returned to normal with normal leukocyte differentials and anti-neutrophil antibodies disappeared. She was almost free of arthralgia one year after splenectomy, although the anti-cyclic citrullinated peptide antibody titers remained high.
20583102 Role of Th17 cells in human autoimmune arthritis. 2010 Oct OBJECTIVE: To delineate the role of Th17 cells in the pathogenesis of autoimmune arthritides. METHODS: Th17 cells were analyzed in well-defined homogeneous cohorts of patients with the prototypical autoimmune arthritides rheumatoid arthritis (RA) and psoriatic arthritis (PsA), grouped according to patients who had very early active RA (n = 36; mean disease duration 2.8 months, Disease Activity Score in 28 joints 5.0) and those who had very early active PsA (n = 20; mean disease duration 2.3 months), none of whom had received treatment with glucocorticoids or disease-modifying antirheumatic drugs, as well as patients with established RA (n = 21; mean disease duration 68 months) who were considered either responders or nonresponders to therapy. Groups of healthy individuals and patients with osteoarthritis (a noninflammatory arthritis) were used as control cohorts. Expression of T lineage-specific transcription factors (RORC, T-bet, GATA-3, and FoxP3) and the response of CD4 T cells to Th17 cell-inducing conditions were analyzed in vitro. RESULTS: The frequencies of Th17 cells and levels of interleukin-17 strongly correlated with systemic disease activity at both the onset and the progression of RA or PsA. The values were reduced to control levels in patients with treatment-controlled disease activity. Th17 cells were enriched in the joints, and increased frequencies of synovial Th17 cells expressed CCR4 and CCR6, indicative of selective migration of Th17 cells to the joints. The intrinsically elevated expression of RORC, accompanied by biased Th17 cell development, and the resistance of Th17 cells to a natural cytokine antagonist in patients with RA and patients with PsA were suggestive of the underlying molecular mechanisms of uncontrolled Th17 activity in these patients. CONCLUSION: Th17 cells play an important role in inflammation in human autoimmune arthritides, both at the onset and in established disease.
18945303 Effect of folic or folinic acid supplementation on methotrexate-associated safety and effi 2009 Mar BACKGROUND: Methotrexate is a folic acid antagonist widely used for the treatment of inflammatory disorders for more than 50 years. Methotrexate is a standard systemic therapy for severe psoriasis and rheumatoid arthritis. Folic acid supplementation has been advocated to limit the toxicity of methotrexate on blood cells, gastrointestinal tract and liver. However, there is still controversy regarding the usefulness of folic acid supplementation. OBJECTIVES: We sought to assess the evidence for the efficacy of folic acid supplementation in patients treated with methotrexate for inflammatory diseases. We also investigated whether folic acid supplementation may decrease the efficacy of methotrexate. METHODS: Cochrane and MEDLINE databases were systematically searched. Randomized controlled trials in patients treated with methotrexate for rheumatoid arthritis or psoriasis with or without arthritis were included. Study selection, assessment of methodological quality, data extraction and analysis were carried out by two independent researchers. We selected double-blind randomized placebo-controlled trials. Analysis was performed for each subgroup of side-effects: gastrointestinal, mucocutaneous, haematological and hepatic. RESULTS: Six randomized controlled trials met the inclusion criteria, with a total sample of 648 patients. There were 257 patients in the placebo group, 198 patients treated with folic acid, and 193 patients treated with folinic acid. The statistical analysis showed a significant reduction of 35.8% of hepatic side-effects induced by methotrexate for patients with supplementation with folic or folinic acid (95% confidence interval -0.467 to -0.248). There was no statistical difference for mucocutaneous and gastrointestinal side-effects although there was a trend in favour of supplementation. The effect of supplementation on haematological side-effects could not be assessed accurately due to a low incidence of these events in the population studied. We were unable to analyse the effect of supplementation on the effectiveness of methotrexate, as markers of activity used in each study were not comparable. CONCLUSIONS: Supplementation with folic acid is an effective measure to reduce hepatic adverse effects associated with methotrexate treatment. There is no difference between folinic acid and folic acid, but the lower cost of the latter promotes its use.
18719928 Outcome of stemmed shoulder hemi-arthroplasty revision. 2009 Jun INTRODUCTION: We report our experience of revision of failed stemmed shoulder hemi-arthroplasty for causes other than infection. MATERIAL/METHOD: Seventeen revisions were followed for a minimum of 2 years. Fifteen cases were revised for symptomatic glenoid erosion. Sixteen were revised to a total shoulder arthroplasty and one to a cuff tear arthropathy head. RESULT: The mean visual analogue pain score following revision surgery was reduced from 6.7 to 3.2 (P = 0.008). However the Constant-Murley and the Association of Shoulder and Elbow Surgeons scores failed to improve significantly. CONCLUSION: We conclude that revision surgery for failed stemmed shoulder hemi-arthroplasty improves pain but not function.
20391501 Risk of revision for infection in primary total hip and knee arthroplasty in patients with 2010 Apr OBJECTIVE: To compare differences in the risk of revision for infection and changes in risk over time and in time from primary surgery to revision for infection after total hip replacement (THR) and total knee replacement (TKR) in rheumatoid arthritis (RA) and osteoarthritis (OA) patients. METHODS: In the Norwegian Arthroplasty Register, 6,629 and 102,157 primary total joint replacements in patients with RA and OA, respectively, were identified from 1987 (1994 for knees) until 2008. Survival analyses with revision due to infection as the end point were performed using Kaplan-Meier methods for constructing survival curves and multiple Cox regression to calculate relative risk (RR) estimates for diagnosis, age, sex, and year of primary surgery. An extended Cox model was used to estimate RR within different followup intervals. RESULTS: RA patients with TKR had a 1.6 times higher risk of revision for infection than OA patients, whereas there was no difference in the THRs. In the THRs, we found a higher risk of revision for infection from 2001 onward, whereas the development for TKRs was the opposite. These time effects affected the RA and OA groups equally. The risk of revision for infection from 6 years postoperatively on was higher in RA patients. CONCLUSION: The overall risk of revision for infection after TKR was higher in RA patients. The risk of late infection leading to revision of the TKR and THR was higher in RA patients than in OA patients. After the year 2000, the RR of revision for infection in RA compared with OA remained unchanged.
20112368 The selective estrogen receptor alpha agonist Org 37663 induces estrogenic effects but lac 2010 Feb OBJECTIVE: Multiple lines of evidence suggest that sex hormones may play a role in the pathogenesis or clinical expression of rheumatoid arthritis (RA). Studies on the effects of exogenous estrogens in RA patients have yielded contradictory results. We undertook this study to determine the effects of the selective estrogen receptor alpha (ERalpha) agonist Org 37663 in patients with RA, in terms of both its estrogenic effects and its ability to ameliorate disease activity. METHODS: A 10-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-finding, proof-of-concept trial was initiated to obtain data on the efficacy and safety of Org 37663 in postmenopausal female patients with RA who were receiving background treatment with either methotrexate or sulfasalazine. Patients were randomized to receive placebo or Org 37663 at doses of 4 mg/day, 15 mg/day, or 50 mg/week. The primary efficacy variable was the Disease Activity Score in 28 joints (DAS28). RESULTS: Org 37663 induced a clear biologic, estrogenic response in several organ systems, including a dose-related increase in levels of sex hormone binding globulin. However, the DAS28 decreased similarly for all treatment groups including placebo, indicating lack of clinical efficacy of Org 37663 in this trial. CONCLUSION: The observed lack of clinical benefit in RA patients treated with an ERalpha agonist, in association with a clear biologic response to the study drug, provides evidence that a biologically relevant ERalpha-mediated estrogenic effect is not associated with a clinically relevant effect on RA symptoms and signs.
19467898 Diagnosis of peripheral psoriatic arthritis: recommendations for clinical practice based o 2009 Oct OBJECTIVE: To propose French recommendations for the clinical, biological and radiological diagnosis of peripheral psoriatic arthritis (PsA) in daily practice based on data from the literature and expert opinion. METHOD: The strategy was the following: the choice of four questions, concerning this topic by the scientific committee according to the Delphi method, forming the basis of the recommendations. The Systematic literature research based on Medline, Cochrane and abstracts from the annual meetings of the French society of rheumatology (SFR), American college of rheumatology (ACR) and European ligue against rheumatism (EULAR). An experts committee of rheumatologists elaborated, validated specifying the strength and the degree of agreement of each recommendation. RESULTS: The questions selected were: (1) What clinical data should be collected to assist in the diagnosis of psoriatic arthritis? (2) What laboratory tests, immunological tests, and genetic tests should be performed to assist in the diagnosis of psoriatic arthritis? (3) What are the radiological investigations useful in the diagnosis of psoriatic arthritis? (4) What classification and/or diagnosis criteria can assist in the diagnosis of psoriatic arthritis? A literature search identified 1627 abstracts and 33 articles were included and analyzed. Four recommendations relative to the diagnosis were drafted and validated by a final vote of the experts committee. CONCLUSION: Recommendations concerning the diagnosis of PsA for daily practice were developed and validated on the basis of data from the literature and expert opinion. They should help to establish the diagnosis of PsA in daily practice.
19689289 TNF-alpha as a therapeutic target in inflammatory diseases, ischemia-reperfusion injury an 2009 Tumor necrosis factor-alpha (TNF-alpha) is a central regulator of inflammation, and TNF-alpha antagonists may be effective in treating inflammatory disorders in which TNF-alpha plays an important pathogenetic role. Recombinant or modified proteins are an emerging class of therapeutic agents. To date, several recombinant or modified proteins which acts as TNF antagonists have been disclosed. In particular, antibodies that bind to and neutralise TNF have been sought as a means to inhibit TNF activity. Inhibition of TNF has proven to be an effective therapy for patients with rheumatoid arthritis and other forms of inflammatory disease including psoriasis, psoriatic arthritis, and ankylosing spondylitis, inflammatory bowel disease. Additionally, the efficacy of preventing septic shock and AIDS has been questioned as a result of recent research. The currently available therapies include a soluble p75 TNF receptor:Fc construct, etanercept, a chimeric monoclonal antibody, infliximab, and a fully human monoclonal antibody, adalimumab. Certolizumab pegol is a novel TNF inhibitor which is an antigen-binding domain of a humanized TNF antibody coupled to polyethylene glycol (PEG) to increase half-life, and thus is Fc-domain-free. In this review, we discuss briefly the present understanding of TNF-alpha-mediated biology and the current therapies in clinical use, and focus on some of the new therapeutic approaches with small-molecule inhibitors. Moreover, we examine recent reports providing important insights into the understanding of efficacy of thalidomide and its analogs, as TNF-alpha activity inhibitories, especially in therapies of several inflammatory diseases within the nervous system.
19771418 Stretch reflexes and joint dynamics in rheumatoid arthritis. 2010 Feb In clinically diagnosed rheumatoid arthritis (RA), studies were conducted to investigate the reflex and passive tissue contribution to measured increases in joint stiffness in the resting upper limb and during constant contractions of an attached muscle. The tonic stretch reflex was induced by a servo-controlled sinusoidal stretch perturbation of the metacarpophalangeal joint of RA patients, and age- and sex-matched controls. The resulting reflexes and mechanical changes in the RA affected joint were explored. Surface electromyographic (EMG) measurements were obtained from first dorsal interosseus muscle. Reflex gain (EMG/joint angle amplitude ratio), phase difference (reflex delay after stretch), coherence square (proportion of EMG variance accounted for by joint angle changes), joint mechanical gain (torque-joint angle amplitude ratio) and mechanical phase difference (torque response delay after stretch) were determined. RA patients showed decreased reflex gain that was partly due to coexistent severe muscle weakness, as determined from maximum voluntary contraction and grip pressure estimates. The decreased reflex gain was most evident at high stretch frequency suggesting a disproportionate loss of the large diameter afferent response and also increased reflex delay in the patients. These changes ensemble suggest significant loss of neural drive to the motor unit population. Patients also showed increased joint stiffness (measured as torque gain) in the contracting muscle, but there was no evidence of reflex activity or increased stiffness at rest. This suggests that the increased joint stiffness in RA was due to changes in the mechanical properties of the active muscle-joint system rather than changes in reflex properties.
20408438 [Incidence of serum rheumatoid factors in elder non-rheumatic individuals]. 2010 Mar With the aging of the Japanese population, an increase in the number of elderly patients with rheumatoid arthritis (RA) has been noted in recent years. Although rheumatoid factor (RF) is found in a high proportion of RA patients, it is also known to be present in non-rheumatoid patients. However, no studies have investigated the rate of RF positivity in elderly non-rheumatoid individuals. In this study, we examined the rate of RF positivity in such individuals and the association between smoking and RF production. The subjects were 25 men (aged 67 to 87 years, with a mean of 74.0) and 24 women (aged 60 to 86 years, with a mean of 70.7). Of these subjects, nine (18.4%), including seven men, were RF-positive. A significant positive correlation was observed between age and RF values (n=49, p<0.05). Of 23 subjects with a smoking habit, eight (34.8%) were RF-positive. In contrast, only one (3.8%) of 26 nonsmokers was RF-positive. This difference in the rate of RF positivity was significant (p<0.01). In addition, a significant positive correlation was noted between the duration of smoking and rate of RF positivity (p<0.05), particularly in men (p<0.01). These results suggest that smoking is closely involved in RF production in the elderly.
19199100 The expression of PADI4 in synovium of rheumatoid arthritis. 2009 Oct PADI4 that catalyzes the conversion of peptidylarginine to citrulline is associated with rheumatoid arthritis in some populations. The current study investigated the expressions of PADI4 in synovial fluid of RA (n = 73), osteoarthritis (OA, n = 96) and ankylosing spondylitis (AS, n = 32) using ELISA and western blotting following immuno-precipitation (n = 6 for each diseases). The study also compared the mRNA level of PADI4 in the synovial membrane of RA with the levels in the samples of OA and AS (n = 6 for each diseases) using real time PCR. ELISA detected a higher level of PADI4 in SF of RA than in samples of OA and AS (P = 0.0001). The level of PADI4 was significantly correlated with the level of rheumatic factor (P = 0.015), but not with anti cyclic citrullinated peptide antibody (anti-CCP) in the RA fluids. Western blotting confirmed the expression of PADI4 in SF of RA. Quantitative PCR measured higher transcription of PADI4 in the synovial membrane of RA than in the samples of OA and AS. The results confirmed increased expression of PADI4 in synovium of RA.
20486929 Tumor necrosis factor alpha converting enzyme: an encouraging target for various inflammat 2010 May Tumor necrosis factor alpha is one of the most common pro-inflammatory cytokines responsible for various inflammatory disorders. It plays an important role in the origin and progression of rheumatoid arthritis and also in other autoimmune disease conditions. Some anti-tumor necrosis factor alpha antibodies like Enbrel, Humira and Remicade have been successfully used in these disease conditions as antagonists of tumor necrosis factor alpha. Inhibition of generation of active form of tumor necrosis factor alpha is a promising therapy for various inflammatory disorders. Therefore, the inhibition of an enzyme (tumor necrosis factor alpha converting enzyme), which is responsible for processing inactive form of tumor necrosis factor alpha into its active soluble form, is an encouraging target. Many tumor necrosis factor alpha converting enzyme inhibitors have been the candidates of clinical trials but none of them have reached in to the market because of their broad spectrum inhibitory activity for other matrix metalloproteases. Selectivity of tumor necrosis factor alpha converting enzyme inhibition over matrix metalloproteases is of utmost importance. If selectivity is achieved successfully, side-effects can be over-ruled and this approach may become a novel therapy for treatment of rheumatoid arthritis and other inflammatory disorders. This cytokine not only plays a pivotal role in inflammatory conditions but also in some cancerous conditions. Thus, successful targeting of tumor necrosis factor alpha converting enzyme may result in multifunctional therapy.
20632150 Comparison of different biologic agents in patients with rheumatoid arthritis after failur 2010 May Switching between different biologic agents for the treatment of rheumatoid arthritis has become a common practice even within similar substance groups. This longitudinal observational study was performed to follow the therapeutic management of patients with rheumatoid arthritis who were switched from one biologic therapy to another. We found no differences between the different biologic agents in regard to drug survival respectively efficacy, neither in the first nor in the second course of therapy. The reason to switch (side effect, lack of efficacy or loss of efficacy) did not influence the following treatment, although a lack of efficacy showed the shortest drug survival in the subsequent therapy. In conclusion, while switching between different biologic substances in rheumatoid arthritis is feasible and reasonable, the choice of substance has to be made on an individual basis.
20533543 Extracellular calreticulin is present in the joints of patients with rheumatoid arthritis 2010 Oct OBJECTIVE: The binding of FasL (CD95L) to its receptor, Fas (CD95), induces apoptosis. Studies have shown that in patients with rheumatoid arthritis (RA), T lymphocytes are resistant to FasL-induced apoptosis in vivo but are susceptible to FasL-induced apoptosis in vitro. Dysfunction in this mechanism may be an important contributor to the pathophysiology of RA. Thus, the present study was undertaken to determine which factors might inhibit FasL-Fas binding in vivo and those that would inhibit apoptosis of T lymphocytes in an in vitro model system. METHODS: Human Jurkat T cells rendered apoptotic by FasL exposure were analyzed by flow cytometry. Necrosis was determined according to measurement of lactate dehydrogenase release. Quantification of calreticulin in plasma and synovial fluid and of calreticulin-FasL binding was performed by enzyme-linked immunosorbent assay. Measurement of nitrite/nitrate in the plasma and synovial fluid was carried out by chemiluminescence assay. RESULTS: Extracellular calreticulin was present at a significantly higher concentration in the plasma (median 10.3 ng/ml, interquartile range [IQR] 14.8 ng/ml) and synovial fluid (median 10.3 ng/ml, IQR 12.0 ng/ml) of RA patients (each P < 0.05) compared with the plasma (median 3.1 ng/ml, IQR 1.3 ng/ml) and synovial fluid (median 2.9 ng/ml, IQR 0.9 ng/ml) of patients with psoriatic arthritis and the plasma of healthy control subjects (median 2.9 ng/ml, IQR 0.9 ng/ml). Calreticulin concentrations in the synovial fluid correlated with the tender and swollen joint counts and the activity scores on the 28-joint Disease Activity Score assessment. Calreticulin also bound directly to FasL. In vitro, calreticulin (2-16 ng/ml) inhibited FasL-induced apoptosis of Jurkat T cells. CONCLUSION: Calreticulin was present at higher concentrations in the plasma and synovial fluid of RA patients. Calreticulin had the capacity to bind directly to FasL and to inhibit FasL-mediated apoptosis of Jurkat T cells, and thus might play a role in inhibiting apoptosis of inflammatory T cells in RA.
20680285 Theory-based analysis of anti-inflammatory effect of infliximab on Crohn's disease and rhe 2012 Jan In Japan, the recommended dosage regimens of infliximab (IFX) for treatment of rheumatoid arthritis (RA) and Crohn's disease (CD) are different. However, the differences have not been analyzed theoretically. In a previous study, we constructed a pharmacokinetic-pharmacodynamic model to investigate the effects of IFX for CD and found it useful to establish a rational dosage regimen of IFX for individual patients with CD. In the present study, we investigated whether the theory-based model could be used for cases of RA and also used it to evaluate the validity of the dosage regimen. The results obtained with our model were in good agreement with observed tender joint count (TJC) ratio data, which was considered to show the validity of our analysis. Thus, we concluded that the model could be used for patients with RA. Furthermore, a second administration of IFX given 2 weeks after the first infusion was important to achieve remission in the early stage of RA. We also compared the estimated pharmacodynamic parameters of RA with those of CD. The elimination rate constant of inflammation in RA was greater than that in CD, suggesting that the recovery from inflammation in RA is faster than that in CD, and indicating a reason for the difference in dosage between RA and CD. In conclusion, use of our model in light of the individual quantitative factor of tumor necrosis factor (TNF)-α allows establishment of IFX dosage regimens for individual patients.
19168833 The soluble terminal complement complex (SC5b-9) up-regulates osteoprotegerin expression a 2009 Mar OBJECTIVE: Complement activation products contribute to a large number of inflammatory diseases, including RA. We have investigated whether osteoprotegerin (OPG) may concur with the soluble terminal complement complex (SC5b-9) to the inflammatory cascade characterizing RA. METHODS: Levels of SC5b-9 and OPG in the plasma and SF of patients with active RA were determined by ELISA. The presence of SC5b-9 and OPG in RA synovial lesions was analysed by immunohistochemistry. Cultured endothelial cells were used for in vitro leucocyte/endothelial cell adhesion assays. In addition, endothelial cells were exposed to SC5b-9 in order to evaluate the effects on the production of OPG protein, as well as the activation of the OPG promoter. RESULTS: Patients affected by active RA are characterized by elevated levels of both SC5b-9 and OPG in plasma and/or SF. Of note, we have observed a co-localization of SC5b-9 and OPG in endothelial cells of post-capillary venules of RA synovial lesions. Data on endothelial cell cultures showed that exposure to SC5b-9 induced the up-regulation of OPG expression/release, stimulating the transcriptional activity of the OPG promoter, and synergized with TNF-alpha in up-regulating OPG production. CONCLUSIONS: Our findings demonstrate that SC5b-9 induces OPG production by endothelial cells and we propose that the SC5b-9-mediated up-regulation of OPG may be an important mechanism whereby complement contributes in promoting and/or enhancing the inflammation in RA.
20485705 The safety of infliximab infusions in the community setting. 2010 May BACKGROUND: Tumour necrosis factor-alpha (TNFalpha) has an important role in the pathogenesis of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, ulcerative colitis and psoriasis. Infliximab, a chimeric anti-TNFalpha monoclonal antibody, has been shown to reduce the severity of symptoms or induces remission of active disease. Infusions have generally been limited to the hospital setting due to cost and concerns for patient safety. Studies defining its efficacy and safety have, therefore, originated almost exclusively from hospital settings. OBJECTIVE: To evaluate the safety of infliximab in a community clinic environment, across all types of patients. METHODS: A retrospective chart review of 3161 patients who received a combined 20,976 infusions at a network of community clinics over 16.5 months was conducted. Adverse drug reaction (ADR) information was retrieved and coded for time of onset, severity and outcome. Only ADRs that occurred during or within the first 24 h of the infusion were included. RESULTS: A total of 524 (2.5% of all infusions) acute ADRs in 353 patients (11.2%) were recorded. Most reactions (ie, ADRs) were mild (n=263 [50.2%, 1.3% of all infusions]) or moderate (n=233 [44.5%, 1.1% of all infusions]). Twenty-eight reactions (5.3%, 0.1% of all infusions) were severe. Emergency medical services were called to transport patients to hospital for seven of the severe reactions, of which none required admission. As per pre-established medical directives, adrenaline was administered three times. CONCLUSIONS: Infliximab infusions are safe in the community setting. Severe ADRs were rare. None required active physician intervention; nurses were able to treat all reactions by following standardized medical directives.
19370190 [Severe drug hypersensitivity syndrome due to sulphasalazine in patient with rheumatoid ar 2009 Jan Drug Hypersensitivity Syndrome, also known as Drug Rash with Eosinophilia and Systemic Symptoms is a severe adverse reaction characterized by clinical manifestations including fever, skin eruption, lymphoadenopathy, associated with eosinophilia, leukocytosis and multiple visceral involvement, with 10% of mortality due to development of multiple organ failure. This reaction usually occurs between two and six-eight weeks after the beginning of the treatment and may not resolve with interruption of the suspected drug. Sulfonamides, anticonvulsant, allopurinol are the most frequently involved molecules, but recently cases have been described also with gabapentin and strontium ranelate. In the present report we describe a case of a patient with rheumatoid arthritis who presented severe drug hypersensitivity syndrome, with liver and kidney involvement due to sulphasalazine.
19111632 Flavonol-rich RVHxR from Rhus verniciflua Stokes and its major compound fisetin inhibits i 2009 Mar Rheumatoid arthritis (RA) is an aggressive inflammatory disease in which cytokines/chemokines are thought to recruit leukocytes and induce angiogenesis. The aim of this study is to investigate the effect of flavonol-rich residual layer of hexane fraction from Rhus verniciflua Stokes (RVHxR) and its major compound fisetin on inflammatory cytokine/chemokine production and angiogenic factor in IL-1beta-stimulated RA fibroblast-like synovial cells (FLS) and inflammatory in vivo models. Flavonol-rich RVHxR and its major compound fisetin significantly inhibited IL-1beta-induced FLS proliferation in a dose-dependent manner. Flavonol-rich RVHxR and fisetin significantly decreased IL-1beta-induced inflammatory cytokines (TNF-alpha, interleukin (IL)-6)/chemokines (IL-8, monocyte chemoattractant protein (MCP)-1), and vascular endothelial growth factor (VEGF) of RA FLS. Flavonol-rich RVHxR dose dependently diminished the phophorylation of extracellular signal regulated kinase (ERK) and phospho-Jun NH((2))-terminal kinase (JNK), and its down regulation induced by RVHxR at nontoxic concentrations, while activated the phosphorylation of p38 MAPK in IL-1beta-stimulated RA FLS. The p38 specific inhibitor SB203580 cotreatment with RVHxR effectively increased the expression of VEGF and blocked the phosphorylation of p38 MAPK in IL-1beta-stimulated RA FLS, confirming a critical role of p38 MAPK pathway in angiogenesis inhibition. In experimental inflammation-related models, flavonol-rich RVHxR and fisetin have shown significant anti-inflammatory activities on vascular permeability, leukocyte migration and cellular immunity. Also, flavonol-rich RVHxR and fisetin treatments significantly reduced the incidence and severity of collagen-induced arthritis model. These results suggest that RVHxR and its major compound fisetin have shown potent suppressive effects on some inflammatory cytokines/chemokines and angiogenic factor in IL-1beta-stimulated RA FLS and inflammatory in vivo models. We believe that flavonol-rich RVHxR is a potential therapeutic agent in the treatment of inflammatory and angiogenesis related diseases.
19478038 Missed opportunities in the treatment of elderly patients with rheumatoid arthritis. 2009 Aug OBJECTIVE: To investigate whether there is a difference in waiting time between indication and start of anti-TNF-alpha therapy in younger and older RA patients. METHODS: The study was carried out in the Nijmegen inception cohort of early RA. All patients meeting indications for anti-TNF-alpha therapy according to the Dutch reimbursement criteria were included in the analysis. Time from indication to start of anti-TNF-alpha therapy or censoring was calculated in all patients. Multivariable Cox regression analysis was used to investigate the influence of age at indication on the time to commencement of anti-TNF-alpha treatment. Hazard ratios were calculated for groups in age quartiles. The model was corrected for 28-joint disease activity score (DAS28), disease duration, gender, the Charlson comorbidity index and episodes of serious illnesses between indication and anti-TNF-alpha therapy or censoring. RESULTS: From the 487 eligible patients, 215 patients started anti-TNF-alpha treatment during their follow-up (44%). Age significantly influenced the time to receiving anti-TNF-alpha after first indication, adjusting for confounders (HR = 0.975/year, P < 0.001). The same analysis using age quartiles showed that the younger age groups had a higher chance of receiving anti-TNF-alpha treatment within an equal period of time than older patients [HR 2.67 (95% CI 1.64, 4.35); 2.30 (1.43, 3.71); 1.79 (1.14, 2.81) with increasing age; the eldest group as reference]. The eldest patients had significantly higher DAS28 values prior to anti-TNF-alpha treatment than younger patients. CONCLUSION: Elderly RA patients were less likely to receive anti-TNF-alpha treatment within an equal period of time compared with younger patients, taking disease activity, disease duration and comorbidities into account.