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ID PMID Title PublicationDate abstract
19935362 Rheumatoid factor interference in a tacrolimus immunoassay. 2009 Dec Recently, there has been an interest in the use of tacrolimus for the treatment of rheumatoid arthritis (RA). The role of rheumatoid factor (RF) as a cause of immunoassay interferences is well known. This study is the first to investigate the susceptibility of a tacrolimus immunoassay to interference by RF. Tacrolimus apparent concentrations were determined using the antibody conjugated magnetic immunoassay (ACMIA) run on the Dimension RxL Immunoassay System in 100 randomly selected samples previously submitted for routine diagnostic or monitoring of RA in patients not receiving tacrolimus. Fifty of them had an RF concentration exceeding 100 IU/L and 50 had an RF concentration below 20 IU/L. Samples with tacrolimus apparent whole-blood concentrations above 2.3 ng/mL (limit of quantification of the ACMIA assay alleged by the vendor) were considered as potential false positives. No positive tacrolimus result was found among the 50 samples with serum RF < 20 IU/mL. Among the 50 selected samples from patients with RF > 100 IU/mL (RF range 110-2650 IU/mL), 2 were positive for tacrolimus with ACMIA. In both cases, the pretreatment of these samples with an immunoglobulin blocking agent reduced the apparent tacrolimus concentrations to below the limit of detection. This was confirmed using the alternative and reference tacrolimus assays, both of which reported results below their respective limits of detection. The measured human anti-mouse antibodies levels were found to be elevated. These results show that certain patients with positive RF can have false-positive tacrolimus results using the tacrolimus ACMIA-Flex immunoassay on a Dimension RXL analyzer, which was not the case with 2 other techniques. The interference with the tacrolimus ACMIA results was suppressed after preincubation with an immunoglobulin blocking reagent.
19297421 An orally bioavailable synthetic analog of an active dehydroepiandrosterone metabolite red 2009 Jun Dehydroepiandrosterone (DHEA) treatment provides diverse anti-inflammatory benefits in rodent models of diseases, including rheumatoid arthritis (RA), but only limited benefits to patients. In rodents, DHEA is metabolized to (among others) androstene-3beta,7beta,17beta-triol (AET), which retains potent anti-inflammatory activity. 17Alpha-ethynyl-5-androstene-3beta,7beta,17beta-triol (HE3286) is a novel, metabolically stabilized, orally bioavailable derivative of AET. In the DBA mouse model of collagen-induced arthritis (CIA), once-daily oral treatments (gavage) with HE3286 (40 mg/kg), beginning at onset of disease, significantly decreased disease. Benefit was associated with reduction in joint inflammation, erosion, and synovial proliferation as measured by histological analysis and mRNA of proinflammatory cytokines, including tumor necrosis factor-alpha, interleukin (IL)-6, IL-1beta, and IL-23. Significant benefit was also observed in the CIA model even when treatments were delayed until 7 days after the onset of arthritis. Furthermore, dose-dependent benefit was observed in the DBA mouse model of collagen antibody-induced arthritis, as well as reductions in IL-6 and matrix metalloproteinase-3 mRNA levels in joints at the peak of disease and at the end of the study. HE3286, in contrast to dexamethasone, was not immune-suppressive in several classic animal models of immune function. Instead, HE3286 treatment was associated with reduced nuclear factor-kappaB activation and in our previous studies, with increased regulatory T cells. We hypothesize that HE3286 may represent a novel, perhaps first-in-class, anti-inflammatory agent and may more fully translate the benefits of DHEA, heretofore largely limited to rodents, into treatments for human diseases, including autoimmune disorders such as RA.
20851655 Rheumatoid anemia. 2011 Mar Rheumatoid anemia is a typical example of anemia of chronic disease. It differs from other forms of anemia, such as iron deficiency anemia or iatrogenic anemia. Rheumatoid anemia is normochromic, normocytic or, less often, microcytic, aregenerative, and accompanied with thrombocytosis. Serum transferrin levels are normal or low, transferrin saturation is decreased, serum ferritin levels are normal or high, the soluble transferrin receptor (sTfR) is not increased (a distinguishing feature with iron deficiency anemia), and the sTfR/log ferritin ratio is lower than 1. This review discusses the prevalence and impact of rheumatoid anemia based on a review of the literature. Iron metabolism, absorption, diffusion, storage, and use by the bone marrow are described using published data on transferrin, ferritin, and hepcidin. Hepcidin is now recognized as a key factor in rheumatoid anemia, in conjunction with the cytokine interleukin-6 (IL-6). Hepcidin is a hormone that lowers serum iron levels and regulates iron transport across membranes, preventing iron from exiting the enterocytes, macrophages, and hepatocytes. In addition, hepcidin inhibits intestinal iron absorption and iron release from macrophages and hepatocytes. The action of hepcidin is mediated by binding to the iron exporter ferroportin. Hepcidin expression in the liver is dependent on the protein hemojuvelin. Inflammation leads to increased hepcidin production via IL-6, whereas iron deficiency and factors associated with increased erythropoiesis (hypoxia, bleeding, hemolysis, dyserythropoiesis) suppress the production of hepcidin. Data from oncology studies and the effects of recombinant human IL-6 support a causal link between IL-6 production and the development of anemia in patients with chronic disease. IL-6 diminishes the proportion of nucleated erythroid cells in the bone marrow and lowers the serum iron level, and these abnormalities can be corrected by administering an IL-6 antagonist. IL-6 stimulates hepcidin gene transcription, most notably in the hepatocytes. Studies involving human hepatocyte exposure to a panel of cytokines showed that IL-6, but not TNFα or IL-1, induced the production of hepcidin mRNA. Recent data on hepcidin level variations in patients with rheumatoid arthritis are reviewed. Rheumatoid anemia is best corrected by ensuring optimal control of systemic disease activity. The role for iron supplementation (per os or intravenously) and erythropoietin in the treatment of rheumatoid anemia is discussed. Given the cascade of interactions linking IL-6, hepcidin, and anemia, IL-6 antagonists hold considerable promise for the management of rheumatoid anemia.
20833548 Three-dimensional kinematics during deep-flexion kneeling in mobile-bearing total knee art 2011 Dec We performed an in vivo radiographic analysis of tibiofemoral and polyethylene (PE) insert motions during weight-bearing kneeling beyond 120° of flexion in one high-flexion knee arthroplasty design to determine if kinematics changed over time and if axial rotation occur between the PE insert and the tibial baseplate. Twenty knees implanted with a posterior-stabilized rotating-platform (RP) knee arthroplasty were postoperatively evaluated at 3, 6, and 12 months. The averaged flexion angles were 122°, 129°, and 131° at 3, 6, and 12 months, respectively, showing that the improvement of flexion was achieved up to 6 months. The femoral condyles translated posteriorly from extension to maximum flexion. There was a significant increase in AP translation of femoral lateral condyle in the maximum flexion kneeling between 12 months and the two other intervals (p=0.0003 at 3 months and p=0.016 at 6 months), while no differences in those of medial condyle between all intervals. Almost all rotation occurred at the surface between the tibial baseplate and the PE insert (p=0.0479 at 3 months, p=0.0008 at 6 months, and p=0.0479 at 12 months), almost no rotation occurred at the surface between the PE insert and the femoral component. There were significant increases in the amount of internal rotation angle during full flexion between the tibial component and the PE insert up to 12 months. Knees implanted with this RP knee arthroplasty design show deep-flexion knee kinematics that are consistent with the implant design intent.
19056796 Cordycepin inhibits IL-1beta-induced MMP-1 and MMP-3 expression in rheumatoid arthritis sy 2009 Jan OBJECTIVE: MMP is a key enzyme in the degradation of extracellular matrices, and its expression plays important roles in inflammatory diseases. Cordycepin (3'-deoxyadenosine), a bioactive compound of Cordyceps militaris, has been shown to exhibit many pharmacological activities, such as anti-cancer, anti-inflammatory and anti-infection activities. In this study, we aimed at the inhibitory effect of cordycepin on IL-1beta-induced MMP-1 and MMP-3 expression as well as the molecular basis using RA synovial fibroblasts (RASFs). METHODS: RASFs were isolated from synovial tissue obtained from 12 patients with RA and cultured in monolayer. Expression of MMP-1 and MMP-3 was evaluated using western blotting and real-time PCR. Chemokines were analysed by ELISA. The phosphorylation of mitogen-activated protein kinase was measured by western blotting. Electrophoretic mobility shift assay was performed to evaluate binding activities of DNA to nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). RESULTS: Cordycepin inhibited IL-1beta-induced MMP-1 and MMP-3 expressions in RASFs in a dose-dependent manner. Among various chemokines [such as monocyte chemoattractant protein-1 (MCP-1), GRO-alpha, regulated upon activation, normal T-cell expressed and presumably secreted (RANTES) and epithelial neutrophil activating peptide 78 (ENA-78)], cordycepin specifically blocked IL-1beta-induced ENA-78 production in RASF. Moreover, cordycepin significantly inhibited IL-1beta-induced p38/JNK and AP-1 activation, but not extracellular signal-regulated kinase (ERK) and NF-kappaB activation. CONCLUSIONS: Cordycepin is a potent inhibitor of IL-1beta-induced chemokine production and MMP expression and strongly blocks the p38/JNK/AP-1 signalling pathway in RASFs.
19404689 Craniovertebral junction lesions: our experience with the transoral surgical approach. 2009 Jun The aim of this study is to review our experience with the transoral surgical management of anterior craniovertebral junction (CVJ) lesions with particular attention to the decision making and to the indication for a consecutive stabilization. During 10 years (1998-2007), 52 consecutive patients presenting exclusively fixed anterior compression at the cervicomedullary junction underwent transoral surgery. Mean age was 55.85 years (range 17-75 years). Encountered lesions were: malformation (32 cases), rheumatoid arthritis (11 cases), tumor (5 cases) or trauma (4 cases). A total of 79% of patients presented with chronic/recurrent headache (cranial and/or high-cervical pain), 73% with varying degrees of quadrip aresis, and 29% with lower cranial nerve deficits. All of the patients but two, with posterior stabilization performed elsewhere, underwent synchronous anterior decompression and posterior occipitocervical fixation. Adjuncts to the transoral approach (Le Fort I with or without splitting of the palate), tailored to the local anatomy and to the extension of the lesions, were performed in seven cases. Follow-up ranged between 4 and 96 months. Of 35 patients with severe preoperative neurological deficits, 33 improved. The remaining 15 patients who presented with mild symptoms, healed throughout the follow-up. Perioperative mortality occurred in two cases and surgical morbidity in eight cases (dural laceration, cerebrospinal fluid leak with meningitis, malocclusion, oral wound dehiscence and occipital wound infection). Delayed instability occurred in one patient because of cranial settling of C2 vertebral body. A successful surgery achieving a stable decompression at the CVJ is an expertise demanding procedure. It requires accurate preoperative evaluation and, appropriate choice of decompression technique and stabilization instruments. Enlarged transoral approaches (despite higher morbidity) are a supportive means in cases of severe basilar invagination, cranial extension of the lesion or limited jaw mobility.
21073693 Effect of adaptive abilities on utilities, direct or mediated by mental health? 2010 Nov 12 BACKGROUND: In cost-utility analyses gain in health can be measured using health state utilities. Health state utilities can be elicited from members of the public or from patients. Utilities given by patients tend to be higher than utilities given by members of the public. This difference is often suggested to be explained by adaptation, but this has not yet been investigated in patients. Here, we investigate if, besides health related quality of life (HRQL), persons' ability to adapt can explain health state utilities. Both the direct effect of persons' adaptive abilities on health state utilities and the indirect effect, where HRQL mediates the effect of ability to adapt, are examined. METHODS: In total 125 patients with Rheumatoid Arthritis were interviewed. Participants gave valuations of their own health on a visual analogue scale (VAS) and time trade-off (TTO). To estimate persons' ability to adapt, patients filled in questionnaires measuring Self-esteem, Mastery, and Optimism. Finally they completed the SF-36 measuring HRQL. Regression analyses were used to investigate the direct and mediated effect of ability to adapt on health state utilities. RESULTS: Persons' ability to adapt did not add considerably to the explanation of health state utilities above HRQL. In the TTO no additional variance was explained by adaptive abilities (Δ R2 = .00, β = .02), in the VAS a minor proportion of the variance was explained by adaptive abilities (Δ R2 = .05, β = .33). The effect of adaptation on health state utilities seems to be mediated by the mental health domain of quality of life. CONCLUSIONS: Patients with stronger adaptive abilities, based on their optimism, mastery and self-esteem, may more easily enhance their mental health after being diagnosed with a chronic illness, which leads to higher health state utilities.
20195397 Description of the efficacy and safety of three new biologics in the treatment of rheumato 2010 Mar English articles on abatacept, golimumab, and tocilizumab in rheumatoid arthritis published between 2002 and 2009 were reviewed systematically. All randomized clinical trials, open-label extensions, meta-analyses, and reviews were examined. There were thirteen articles on abatacept, four on golimumab, and seven on tocilizumab. All three drugs were effective in methotrexate-naïve, methotrexate-incomplete responders, and tumor-necrosis-factor-failure rheumatoid arthritis patients. Of the three, only abatacept has been tested in a head-to-head trial with infliximab, in which it was found to be equivalent to infliximab. Golimumab resulted in a more modest improvement than the others in methotrexate-naïve patients, although no direct comparisons among the three drugs were possible or appropriate. Descriptive analysis of adverse events showed that patients receiving abatacept, golimumab, and tocilizumab were subject to more adverse events than controls overall, as expected. In the abatacept studies, a few cases of tuberculosis, more cardiovascular events and gastrointestinal bleedings and more basal cell carcinoma were seen. Golimumab was associated with more skin rashes and pneumonia, while tocilizumab was associated with increased lipids, more liver-function abnormalities, and neutropenia. These new medications are useful additions to the rheumatologic armamentarium and represent greater convenience (golimumab) or different mechanisms of action (abatacept and tocilizumab) than tumor-necrosis-factor inhibitors for treating rheumatoid arthritis. As expected, some adverse events occur when using these drugs and patients need to be watched carefully.
19788068 Serum biochemical markers in rheumatoid arthritis. 2009 Aug Rheumatoid arthritis (RA) characterized by local and systemic effects of inflammation has a wide range of biochemical markers implicated directly or indirectly to its pathogenesis. In the present study, homocysteine, cortisol, adenosine deaminase (ADA), ferritin, malondialdehyde (MDA) and alpha-tocopherol in serum of RA patients and healthy individuals were estimated to assess if they contribute to the disease process. The markers of disease activity such as erythrocyte sedimentation rate (ESR) and rheumatoid factor (RF) were also measured. The study group included a total of 45 subjects, including 30 RA patients and the rest being healthy individuals. RA group showed a significant increase in the levels of homocysteine, ADA and MDA, and a significant decrease in alpha-tocopherol compared to the healthy individuals. However, cortisol and ferritin levels did not show any significant change. Also, there was no significant correlation between the studied serum markers and markers of disease activity. Our results indicate that these biochemical markers contribute independently to the pathogenesis of RA.
20671022 Meta-analysis of tight control strategies in rheumatoid arthritis: protocolized treatment 2010 Nov OBJECTIVES: Tight control studies including regular assessments of disease activity have shown that this approach has beneficial effects on disease activity, disability and joint damage in treating RA patients. Some of these studies included tight control with protocolized treatment, while others applied tight control without protocolized treatment. The aim of this study was to compare the effects of tight control with usual care and to compare the effects of tight control studies with and without protocolized treatment adjustments. METHODS: A systematic literature search was performed to identify clinical trials in RA that evaluated tight control strategies in comparison with usual care. Two types of study were compared: (i) those using disease activity monitoring with protocolized treatment adjustments, and (ii) those using disease activity monitoring without protocolized treatment adjustments. The databases PubMed and Cochrane were searched from 1995 up to 2009. Primary outcome measure was the mean change in the 28-joint DAS (DAS-28), which was used in a random-effects meta-analysis. RESULTS: Six controlled trials regarding tight control in RA patients were included in the meta-analysis. In all trials, patients treated in the tight control arms had significantly higher DAS-28 responses than patients treated according to usual care [weighted mean difference (WMD) = 0.59, P < 0.001]. Moreover, tight control was significantly more effective (P < 0.001) by means of protocolized treatment adjustments (WMD = 0.97) compared with non-protocolized monitoring of disease activity (WMD = 0.25). CONCLUSION: Tight control in RA resulted in significantly better clinical outcomes than usual care. It is suggested but not proved that tight control with protocolized treatment adjustments is more beneficial than if no such protocol is used.
20091667 Golimumab for rheumatoid arthritis. 2010 Jan 20 BACKGROUND: Golimumab is a humanized inhibitor of Tumor necrosis factor-alpha, recently approved by the Food and Drug Administration (FDA) for the treatment of Rheumatoid arthritis (RA). OBJECTIVES: The objective of this systematic review was to compare the efficacy and safety of golimumab (alone or in combination with DMARDs or biologics) to placebo (alone or in combination with DMARDs or biologics) in randomized or quasi-randomized clinical trials in adults with RA. SEARCH STRATEGY: An expert librarian searched six databases for any clinical trials of golimumab in RA, including the Cochrane Central Register of Controlled Trials (CENTRAL), OVID MEDLINE, CINAHL, EMBASE, Science Citation Index (Web of Science) and Current Controlled Trials databases. SELECTION CRITERIA: Studies were included if they used golimumab in adults with RA, were randomized or quasi-randomized and provided clinical outcomes. DATA COLLECTION AND ANALYSIS: Two review authors (JS, SN) independently reviewed all titles and abstracts, selected appropriate studies for full review and reviewed the full-text articles for the final selection of included studies. For each study, they independently abstracted study characteristics, safety and efficacy data and performed risk of bias assessment. Disagreements were resolved by consensus. For continuous measures, we calculated mean differences or standardized mean differences and for categorical measures, relative risks. 95% confidence intervals were calculated. MAIN RESULTS: Four RCTs with 1,231 patients treated with golimumab and 483 patients treated with placebo were included. Of these, 436 were treated with the FDA-approved dose of golimumab 50 mg every four weeks. Compared to patients treated with placebo+methotrexate, patients treated with the FDA-approved dose of golimumab+methotrexate were 2.6 times more likely to reach ACR50 (95% confidence interval (CI) 1.3 to 4.9; P=0.005 and NNT= 5, 95% confidence interval 2 to 20), no more likely to have any adverse event (relative risk 1.1, 95% Cl 0.9 to 1.2; P=0.44), and 0.5 times as likely to have overall withdrawals (95% Cl 0.3 to 0.8; P=0.005). Golimumab-treated patients were significantly more likely to achieve remission, low disease activity and improvement in functional ability compared to placebo (all statistically significant). No significant differences were noted between golimumab and placebo regarding serious adverse events, infections, serious infections, lung infections, tuberculosis, cancer, withdrawals due to adverse events and inefficacy and deaths. No radiographic data were reported. AUTHORS' CONCLUSIONS: With an overall high grade of evidence, at the FDA-approved dose, golimumab is significantly more efficacious than placebo in treatment of patients with active RA , when used in combination with methotrexate. The short-term safety profile, based on short-term RCTs, is reasonable with no differences in total adverse events, serious infections, cancer, tuberculosis or deaths. Long-term surveillance studies are needed for safety assessment.
21341505 [Non-enzymatic glycation of proteins: from diabetes to cancer]. 2010 Mar Incubation of proteins with glucose leads to their non-enzymatic glycation and formation of Amadori products known as an early glycation product. Oxidative cleavage of Amadori products is considered as a major route to advanced glycation endproducts (AGEs) formation in vivo. Nonenzymatic glycation of proteins or Maillard reaction is increased in diabetes mellitus due to hyperglycemia and leads to several complications such as blindness, heart disease, nerve damage and kidney failure. Accumulation of the early and advanced glycation products in plasma and tissues of diabetic patients and causes production of autoantibodies against corresponding products. The advanced glycation products are also associated with other diseases like cancer. This review summarizes current knowledge of these stage specific glycated products as common and early diagnostic biomarkers for the associated diseases and the complications with the aim of a novel therapeutic target for the diseases.
21355379 Certolizumab pegol and rheumatoid arthritis. Just another TNF alpha antagonist, no therape 2010 Dec No comparison with other TNF alpha antagonists; possible bleeding risk.
19714599 Does the weather really matter? A cohort study of influences of weather and solar conditio 2009 Sep 15 OBJECTIVE: To explore how reported joint pain in patients with rheumatoid arthritis (RA) relates to weather and solar variables. METHODS: A prospective cohort study was conducted in Norway on 36 patients with stable RA. Daily reports of pain in the morning on a visual analog scale for 84 consecutive days were correlated (using time-series methodology) with records of atmospheric and solar variables for the same days. RESULTS: Pain was significantly associated with 3 or more external variables in 6 (17%) of the patients, with 1 or 2 external variables in 16 (44%) of the patients, and no associations were observed in 14 (39%) of the patients. The multivariate model explained between 19% and 64% of the variance in pain (R(2)) in the patients with associations to at least 3 weather/solar variables. The patients differed in the variables they responded to and in which direction, except for consistent negative associations between pain and ultraviolet light dose, and between pain and solar radio flux/sunspot count. The associations were mostly with same-day weather, but also lagged up to 3 days. We were not able to fit a statistically significant model at the group level. CONCLUSION: Weather sensitivity seems to be a continuum and a highly individual phenomenon in patients with RA. In the present sample, pain was significantly associated with 3 or more weather variables in 1 out of 6 patients, for whom the magnitude of weather sensitivity might significantly influence pain reporting in clinical care and research.
20533271 [Association study on single nucleotide polymorphisms in HTRA1 gene and rheumatoid arthrit 2010 Jun OBJECTIVE: To study the association between the single nucleotide polymorphisms (SNPs) in the high-temperature requirement A-1 (HTRA1) gene and rheumatoid arthritis (RA) in Chinese Han population. METHODS: Five SNPs in the HTRA1 gene (rs2014307, rs2248799, rs2300433, rs714816 and rs2268356) were genotyped by ABI Snapshot method in Han Chinese cohort composed of 344 patients with RA and 288 healthy controls. The serum rheumatoid factor (RF) and C-reactive protein (CRP) of the patients were determined by endpoint nephelometry method. RESULTS: Genotypes of all the five SNPs in the HTRA1 gene were not significantly different between the RA patients and controls (P> 0.05). Haplotypes generated by these five SNPs did not show significantly difference between the two groups either (P> 0.05). Serum RF levels in the RA patients had no significant difference among the genotypes for four SNPs (rs2014307, rs2248799, rs714816, and rs2268356) in the HTRA1 gene, while RF levels in the RA patients with genotypes AA+AG of the rs2300433 locus were significantly higher than that in genotype GG carriers (P< 0.05). Serum CRP levels in the RA patients had no significant difference among the genotypes for all the five SNPs. CONCLUSION: Author's results suggested that although the five SNPs in the HTRA1 gene were not associated with RA in Chinese Han population, RF levels in the RA patients with genotypes AA and AG in the rs2300433 locus were significantly higher than the GG carriers. The HTRA1 role in RF regulation needs to be further investigated.
19141573 Validation of a simple activity participation measure for rheumatoid arthritis clinical tr 2009 Feb OBJECTIVE: To examine the validity, reliability and sensitivity to change of the Activity Participation Questionnaire (APaQ), a simple measure of activity participation for patients with RA. METHODS: The questionnaire contained two items: (i) number of days in the past month of being unable to perform one's usual activities because of RA; and (ii) a score measuring how often one's usual activities could be completed. The APaQ was administered to 1043 RA patients in two clinical trials of abatacept. Construct validity was evaluated by examining changes from baseline in activity scores by clinical response measured by the European League Against Rheumatism (EULAR) and ACR criteria and minimal disease activity (MDA) state and by correlations with patient-reported outcome measures of physical function, disease activity, pain and fatigue at study end-point. Internal consistency, test-retest reliability and sensitivity to change were assessed. RESULTS: Both activity participation items were significantly associated with levels of EULAR and ACR response and the achievement of MDA state (P < 0.0005 for all comparisons). Moderate correlations with patient-reported outcomes were consistently found (correlations 0.5-0.6). Cronbach's alpha was 0.7 indicating good internal consistency, the intraclass correlation coefficient of 0.6 suggesting acceptable test-retest reliability. Sensitivity to change was demonstrated by the treatment differences and the standardized response mean (0.39 and 0.30) for the two activity items. CONCLUSION: The APaQ is a simple, reliable and valid measure of patient activity, which is sensitive to change, suggesting its suitability for use in clinical trials.
20971923 Suppression of TNF-α and IL-1 signaling identifies a mechanism of homeostatic regulation 2010 Dec 1 IL-27 is a pleiotropic cytokine with both activating and inhibitory functions on innate and acquired immunity. IL-27 is expressed at sites of inflammation in cytokine-driven autoimmune/inflammatory diseases, such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, and sarcoidosis. However, its role in modulating disease pathogenesis is still unknown. In this study, we found that IL-27 production is induced by TNF-α in human macrophages (MΦ) and investigated the effects of IL-27 on the responses of primary human MΦ to the endogenous inflammatory cytokines TNF-α and IL-1. In striking contrast to IL-27-mediated augmentation of TLR-induced cytokine production, we found that IL-27 suppressed MΦ responses to TNF-α and IL-1β, thus identifying an anti-inflammatory function of IL-27. IL-27 blocked the proximal steps of TNF-α signaling by downregulating cell-surface expression of the signaling receptors p55 and p75. The mechanism of inhibition of IL-1 signaling was downregulation of the ligand-binding IL-1RI concomitant with increased expression of the receptor antagonist IL-1Ra and the decoy receptor IL-1RII. These findings provide a mechanism for suppressive effects of IL-27 on innate immune cells and suggest that IL-27 regulates inflammation by limiting activation of MΦ by inflammatory cytokines while preserving initial steps in host defense by augmenting responses to microbial products.
19054823 Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy wit 2009 Jul OBJECTIVE: To evaluate the efficacy and toxicity of methotrexate (MTX) monotherapy compared with MTX combination with non-biological disease-modifying antirheumatic drugs (DMARDs) in adults with rheumatoid arthritis. METHOD: A systematic review of randomised trials comparing MTX alone and in combination with other non-biological DMARDs was carried out. Trials were identified in Medline, EMBASE, the Cochrane Library and ACR/EULAR meeting abstracts. Primary outcomes were withdrawals for adverse events or lack of efficacy. RESULTS: A total of 19 trials (2025 patients) from 6938 citations were grouped by the type of patients randomised. Trials in DMARD naive patients showed no significant advantage of the MTX combination versus monotherapy; withdrawals for lack of efficacy or toxicity were similar in both groups (relative risk (RR) = 1.16; 95% CI 0.70 to 1.93). Trials in MTX or non-MTX DMARD inadequate responder patients also showed no difference in withdrawal rates between the MTX combo versus mono groups (RR = 0.86; 95% CI 0.49 to 1.51 and RR = 0.75; 95% CI 0.41 to 1.35), but in one study the specific combination of MTX with sulfasalazine and hydroxychloroquine showed a better efficacy/toxicity ratio than MTX alone with RR = 0.3 (95% CI 0.14 to 0.65). Adding leflunomide to MTX non-responders improved efficacy but increased the risk of gastrointestinal side effects and liver toxicity. Withdrawals for toxicity were most significant with ciclosporin and azathioprine combinations. CONCLUSION: In DMARD naive patients the balance of efficacy/toxicity favours MTX monotherapy. In DMARD inadequate responders the evidence is inconclusive. Trials are needed that compare currently used MTX doses and combination therapies.
19050823 Serum levels of tissue inhibitor of metalloproteinase-1 and periarticular bone loss in ear 2009 Mar We investigated the relationship between disease activity, serum biological mediators of joint damage, and periarticular bone loss in inflammatory arthritis. Patients with early inflammatory arthritis were recruited from a dedicated early arthritis clinic. At the time of recruitment, all had clinical evidence of synovitis. Patients were assessed at baseline and at 1-year follow-up. Periarticular and axial bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. Serum levels of matrix metalloproteinase 1 and tissue inhibitor of metalloproteinases 1 (TIMP-1) were measured by enzyme-linked immunosorbent assay. A total 38 patients were included in the study. Twenty had rheumatoid arthritis (RA) and 18 had a seronegative spondylarthropathy (SpA). At baseline, periarticular hand BMD measurements were similar in RA and SpA. At 1 year, the mean periarticular hand BMD was significantly lower in RA (p < 0.05). Significant inverse correlations between both the Ritchie articular index and C-reactive protein levels and the change in periarticular hand BMD at 1 year were observed in RA (r = -0.792, p < 0.001 and r = -0.478, p = 0.045, respectively). Baseline TIMP-1 levels correlated with the change in periarticular hand BMD at 1 year in RA (r = 0.519, p = 0.02). At 1 year, radiographic measures of joint damage were highest in RA. Inverse correlations between the change in periarticular hand BMD and the changes in erosion score (r = -0.90, p = 0.04) were observed in patients demonstrating significant periarticular bone loss. Persistent disease activity was associated with increased periarticular bone loss in the hands in patients with RA, consistent with synovitis-mediated periarticular bone loss. The correlation between baseline TIMP-1 levels and periarticular bone loss over 1 year suggests that TIMP-1 may have utility as a biomarker of periarticular bone loss in early RA.
20714812 An antibody against RANKL for the treatment of osteoporosis, inflammatory and malignant bo 2010 Sep Over the years, the importance of receptor activator of nuclear factor κB ligand (RANKL) in bone physiology and pathophysiology has been thoroughly documented. Denosumab, also known as AMG 162, is a fully human monoclonal antibody against RANKL which is being studied in the treatment of metabolic, inflammatory, and malignant bone diseases. The purpose of this review is to analyze the potential role of denosumab in osteoporosis, rheumatoid arthritis, bone metastases and multiple myeloma.