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ID PMID Title PublicationDate abstract
27472516 Pharmacoeconomic analysis of biological disease modifying antirheumatic drugs in patients 2017 Mar OBJECTIVES: To evaluate the cost-effectiveness of biological disease modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) in a real-world setting in Japan. METHODS: We used a state-transition model and parameters were determined from RA patients registered in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort study on 421 patients who had failed at least one DMARD and started either 1 of 4 bDMARDs (bDMARD group; adalimumab, etanercept, infliximab, and tocilizumab) or methotrexate (control group). bDMARD group was evaluated as two groups: sequence of any 1 of 4 bDMARDs with and without tocilizumab. The incremental cost-effectiveness ratios (ICERs) for bDMARD group were estimated using base-case analysis, probabilistic sensitivity analysis (PSA) and scenario sensitivity analyses. RESULTS: ICERs of bDMARD group with or without tocilizumab were $38,179 and $48,855, respectively. By PSA, these sequences had respective probabilities of 86.8% and 75.1% of falling below the assumed cost-effectiveness threshold of $50,000 in Japan. Scenario sensitivity analyses showed that the best population for initiating bDMARD was RA patients less than 50 years old with Japanese version of HAQ between 1.1 and 1.6 and using tocilizumab as the bDMARD. CONCLUSION: bDMARDs were cost-effective for RA patients based on a real-world setting in Japan.
26422354 A mechanically locked knee joint due to free-floating flake-shaped rice bodies: a case rep 2015 Originating from the synovium, multiple free-floating intra-articular particles, called rice bodies, typically resemble cartilage and have a fibrin structure. While the etiology of rice body formation is unclear, they often occur in rheumatoid arthritis and other seronegative arthropathies; they also occur in tuberculosis, though the incidence is much lower. They are often encountered by rheumatologists or clinical orthopedists. A 33-year-old female who suffered from occasional swelling and pain of her left knee for 3 months was admitted with a mechanically locked knee. Free-floating rice bodies were identified on magnetic resonance imaging (MRI), and arthroscopic intervention was performed for diagnostic and therapeutic purposes. After the removal of all bodies and effusion with mechanical irrigation, an arthroscopic subtotal synovectomy was performed.
26607440 Tailored first-line biologic therapy in patients with rheumatoid arthritis, spondyloarthri 2016 Apr OBJECTIVE: A multidisciplinary expert panel, the Italian board for the TAilored BIOlogic therapy (ITABIO), was constituted to formulate evidence-based decisional statements for the first-line tailored biologic therapy in patient with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA). METHODS: Systematic review of the literature to identify English-language articles on the variables influencing the first-line biologic choice, including the efficacy and safety of the drug, the route of administration, the availability of response predictor biomarkers, the need of monotherapy, the patient socio-economic status, lifestyle, cultural level, personality, fertility and childbearing potential in women, the presence of comorbidities, the host-related risk factors for infection and latent tuberculosis infection (LTBI) reactivation, the cardiovascular (CV) risk, and costs. RESULTS: Some variables, including the patients' preference, the indication for anti-TNF monotherapy in potential childbearing women, and the intravenous route with dose titration in obese subjects resulted valid for all the three rheumatic conditions. Further, evidence of a better cost-effectiveness profile for etanercept (ETN) and biosimilar infliximab (IFX) in RA was found. Any biologic may be employed in absence of choice driving factors in RA. Otherwise, a high infection risk or LTBI positivity drive the choice toward abatacept (ABA), tocilizumab (TCZ), or ETN. TCZ should be the first choice if monotherapy is required. High rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) titers should drive the choice toward TCZ or ABA, while in patients at high CVD risk anti-TNF choice, with preference for ETN, seems appropriate. Presence of anterior uveitis or inflammatory bowel disease drives the choice to monoclonal antibody anti-TNFs (MoAb anti-TNFs). In PsA, ustekinumab (UTK), and to a lesser extent ETN, represents the first choice in patients at high infection and TB risk. Anti-TNFs or UTK choice is guided by skin or articular disease severity, enthesitis, and dactylitis, whereas ETN should be preferred if metabolic syndrome or high CV risk complicate PsA. CONCLUSION: Taking in account of multiple choice driving variables, first-line biologic therapy may be optimized in patients with RA, SpA, and PsA.
26059521 Modelling the cost-effectiveness of combination therapy for early, rapidly progressing rhe 2015 Jun 9 OBJECTIVE: To estimate the cost-effectiveness of adalimumab plus methotrexate (MTX) versus MTX monotherapy in early, aggressive rheumatoid arthritis (RA) when explicitly modelling short-term (reversible) and long-term (irreversible, ie, joint damage) disease activity and physical function. METHODS: A microsimulation model was developed to unify, in a single cost-effectiveness model, measures of reversible and irreversible disease activity and physical function based on data from the PREMIER trial. Short term, reversible disease activity was modelled using DAS28 variables, including swollen joint counts, tender joint counts, C reactive protein concentration and pain. The DAS28 variables were then used in a logistic regression to predict short-term American College of Rheumatology (ACR) responses, which informed treatment continuation and switches. Long term, irreversible, radiographically documented joint damage was modelled using modified Total Sharp Score (mTSS). The model then linked both short-term disease activity and mTSS to the Health Assessment Questionnaire score, which was used to calculate direct and indirect costs, and quality adjusted life-years (QALYs). RESULTS: When both reversible and irreversible effects of therapy were included, combination therapy was estimated to produce 6-month 50% ACR responses in 75% of patients versus 54% in MTX monotherapy. Compared to MTX monotherapy, combination therapy resulted in 2.68 and 3.04 discounted life years and QALYs gained, respectively. Combination therapy also resulted in a net increase in direct costs of £106,207 for a resulting incremental cost/QALY gain of £32,425. When indirect costs were included in the analysis, the ICER (incremental cost-effectiveness ratio) decreased to £27,238. Disregarding irreversible effects increased the incremental cost-effectiveness ratio to £78,809 (when only direct costs were included). CONCLUSIONS: Starting with adalimumab plus MTX combination therapy in early, aggressive RA is cost-effective when irreversible damage is adequately considered.
27815104 Characteristic Magnetic Resonance Imaging Findings in Rheumatoid Arthritis of the Temporom 2017 Apr PURPOSE: The purpose of this study was to determine the characteristic magnetic resonance imaging (MRI) findings indicating bone and soft tissue involvement in patients with rheumatoid arthritis (RA) of the temporomandibular joints (TMJs). PATIENTS AND METHODS: Twenty-one patients with RA and TMJ pain who underwent MRI examination of the TMJs at the authors' hospital from August 2006 to December 2014 were included in this study. Twenty-two patients with normal TMJs who underwent MRI examination at the authors' hospital from November to December 2014 were included as controls. MRI findings were compared between the 2 groups. RESULTS: MRI findings of RA in the TMJ included 1) abnormal disc position (95.2%), 2) abnormal disc morphology (83.3%), 3) joint effusion (30.9%), 4) osseous changes in the mandibular condyle (83.3%), 5) synovial proliferation (pannus; 85.7%), 6) erosion of the articular eminence and glenoid fossa (9.52%), 7) deformity of the articular eminence and glenoid fossa (16.6%), 8) abnormal bone marrow signal in the mandibular condyle (83.3%), and 9) swelling of lymph nodes in the parotid glands (78.5%). The abnormal bone marrow signal and pannus in the mandibular condyle and lymph node swelling in the parotid glands were markedly more common in patients with RA than in controls. CONCLUSIONS: MRI findings of RA of the TMJs were characterized by bone and soft tissue involvement, including abnormal bone marrow signal of the mandibular condyle, pannus, and swelling of lymph nodes in the parotid glands. These characteristic MRI findings could be useful in detecting RA in the TMJ in a clinical situation.
26717357 Interleukin-22 Secreted by NKp44+ Natural Killer Cells Promotes Proliferation of Fibroblas 2015 Dec Although CD3-CD56+NKp44+ natural killer (NKp44+NK) cells have been linked to autoimmune diseases including inflammatory bowel disease, ankylosing spondylitis, and primary Sjogren syndrome, the expansion and role of those cells in patients with rheumatoid arthritis (RA) remain less defined. Here, we investigate the proportion and pathogenesis of NKp44+NK cells in patients with RA. The results show NKp44+NK cells significantly expanded in RA peripheral blood and synovial fluid, which were correlated positively with RA disease activity. They also highly expressed in RA synovial tissues and secreted a high concentration of interleukin-22 (IL-22) in vitro. Further, NKp44+NK cells culture supernatant promoted the proliferation of fibroblast-like synoviocytes (FLS) which was blocked by IL-22 antagonist and AG490. Treated with recombination human IL-22, the proliferation and phosphorylation-STAT3 on RA-FLS increased in a dose-dependent manner and time-dependent manner; the progress of which could be blocked by AG490. The present study clarifies the expansion of NKp44+NK cells in the peripheral blood and synovial fluid of patients with RA, especially in the synovial tissues of RA for the first time. STAT3 is an essential pathway in mediating the effects of IL-22 secreted by NKp44+NK cells on the proliferation of FLS in patients with RA.
25799392 Dysregulated serum IL-23 and SIRT1 activity in peripheral blood mononuclear cells of patie 2015 Sirtuin 1 (Sirt1) is a class III histone deacetylase (HDAC) that modulates gene expression and is involved in the regulation of proinflammatory cytokines. Interleukin-23 (IL-23) is produced by activated macrophages and dendritic cells and could fuel the progression of rheumatoid arthritis (RA). The goal of our study was to evaluate serum IL-23 levels and both Sirt1 activity and expression in peripheral blood mononuclear cells (PBMCs) in patients with RA compared to healthy controls (HC) and to determine the relationship between Sirt1 activity/expression and IL-23 levels. We assessed apoptosis in PBMCs of RA patients and its association with Sirt1 expression and serum IL-23. Serum IL-23 levels were increased in RA patients in comparison with controls. We found a positive correlation between the levels of serum IL-23 and serum IL-6 in RA patients. Decreased cytoplasmic Sirt1 activity was observed in RA patients with severe disease compared to HC. The expression of Sirt1 protein was significantly decreased in PBMCs of RA patients compared to HC using western blotting. Serum IL-23 levels correlated positively with the cytoplasmic Sirt1 activity in RA patients. Apoptosis rate of PBMCs isolated from RA patients was increased compared to HC and correlated negatively with the expression of Sirt1 protein and serum IL-23 levels. Levels of serum IL-23 and Sirt1 activity and expression were disturbed in RA parallel to increased PBMC apoptosis. Our findings might provide the rationale for the development of new therapeutic approaches in RA.
27942004 STAT6 and STAT1 Pathway Activation in Circulating Lymphocytes and Monocytes as Predictor o 2016 OBJECTIVE: To find novel predictors of treatment response to disease-modifying antirheumatic drugs (DMARDs), we studied activation of STAT (signal transducers and activators of transcription) 6 and 1 in circulating leukocytes of patients with rheumatoid arthritis (RA). METHODS: 19 patients with untreated recent-onset RA, 16 patients with chronic RA irresponsive to synthetic DMARDs and 37 healthy volunteers provided blood samples for whole blood flow cytometric determination of intracellular STAT6 and STAT1 phosphorylation, expressed as relative fluorescence units, in response to IL-4 and IFN-γ, respectively. Phosphorylation was restudied and treatment response (according to European League Against Rheumatism) determined after 1-year treatment with synthetic DMARDs in recent-onset RA and with biological DMARD in synthetic DMARD-irresponsive RA. Estimation-based exact logistic regression was used to investigate relation of baseline variables to treatment response. 95% confidence intervals of means were estimated by bias-corrected bootstrapping and the significance between baseline and follow-up values was calculated by permutation test. RESULTS: At baseline, levels of phosphorylated STAT6 (pSTAT6) induced by IL-4 in monocytes were higher in those who achieved good treatment response to synthetic DMARDs than in those who did not among patients with untreated RA (OR 2.74, 95% CI 1.05 to 9.47), and IFN-γ -stimulated lymphocyte pSTAT1 levels were higher in those who achieved good treatment response to a biological drug than in those who did not among patients with chronic RA (OR 3.91, 95% CI 1.12 to 20.68). During follow-up, in recent-onset RA patients with good treatment response to synthetic DMARDS, the lymphocyte pSTAT6 levels decreased (p = 0.011), and, consequently, the ratio of pSTAT1/pSTAT6 in lymphocytes increased (p = 0.042). CONCLUSION: Cytokine-stimulated STAT6 and STAT1 phosphorylation in circulating leukocytes was associated with treatment response to DMARDs in this pilot study. The result, if confirmed in larger studies, may aid in developing personalized medicine in RA.
26459854 Methotrexate-associated lymphoproliferative disorder presenting as extranodal NK/T-cell ly 2015 Dec Patients having rheumatoid arthritis (RA) treated with methotrexate (MTX) are at an increased risk of developing lymphoproliferative disorder (LPD). Epstein-Barr virus (EBV) sometimes contributes to the development of MTX-associated LPD. Herein, we report the case of a 64-year-old Japanese woman with RA who showed complications of EBV-positive MTX-associated LPD. This case is exceedingly rare in that the LPD was confined to the lungs and its subclassification was extranodal NK/T-cell lymphoma. Only four cases of extranodal NK/T-cell lymphoma in the setting of MTX-associated LPD have ever been reported in the English language literature, only one of which was an extranasal NK/T-cell lymphoma, similar to our case. Extranasal NK/T-cell lymphomas show more aggressive behavior than nasal NK/T-cell lymphomas, possibly reflected by the considerable re-exacerbation of the lesions in only two months after the cessation of MTX in our case. However, the SMILE regimen (steroid, methotrexate, ifosfamide, l-asparaginase, and etoposide) was able to suppress tumor growth in this case.
26476978 Peptide motif analysis predicts alphaviruses as triggers for rheumatoid arthritis. 2015 Dec Rheumatoid arthritis (RA) develops in response to both genetic and environmental factors. The strongest genetic determinant is HLA-DR, where polymorphisms within the P4 and P6 binding pockets confer elevated risk. However, low disease concordance across monozygotic twin pairs underscores the importance of an environmental factor, probably infectious. The goal of this investigation was to predict the microorganism most likely to interact with HLA-DR to trigger RA under the molecular mimicry hypothesis. A set of 185 structural proteins from viruses or intracellular bacteria was scanned for regions of sequence homology with a collagen peptide that binds preferentially to DR4; candidates were then evaluated against a motif required for T cell cross-reactivity. The plausibility of the predicted agent was evaluated by comparison of microbial prevalence patterns to epidemiological characteristics of RA. Peptides from alphavirus capsid proteins provided the closest fit. Variations in the P6 position suggest that the HLA binding preference may vary by species, with Ross River virus, Chikungunya virus, and Mayaro virus peptides binding preferentially to DR4, and peptides from Sindbis/Ockelbo virus showing stronger affinity to DR1. The predicted HLA preference is supported by epidemiological studies of post-infection chronic arthralgia. Parallels between the cytokine profiles of RA and chronic alphavirus infection are discussed.
25918479 Altered immunoregulation in rheumatoid arthritis: the role of regulatory T cells and proin 2015 In recent years several studies investigated the role of T lymphocyte subpopulations in the pathogenesis of rheumatoid arthritis (RA). Pathogenic Th17 cells mediate pannus growth, osteoclastogenesis, and synovial neoangiogenesis; hence they are key players in the development of the disease. On the other hand, regulatory T (Treg) cells are a T cell subset whose peculiar function is to suppress autoreactive lymphocytes. The imbalance between Th17 and Treg cells has been identified as a crucial event in the pathogenesis of RA. In addition, the effects of currently employed RA therapeutic strategies on these lymphocyte subpopulations have been extensively investigated. This review article aims to discuss current knowledge on Treg and Th17 cells in RA and possible implications of their therapeutic targeting in this disorder.
26492962 The economic burden of musculoskeletal disorders on the Italian social security pension sy 2015 Sep 16 The aim of the study is to estimate the pension costs incurred for patients with musculoskeletal disorders (MDs) and specifically with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) in Italy between 2009 and 2012. We analyzed the database of the Italian National Social Security Institute (Istituto Nazionale Previdenza Sociale i.e. INPS) to estimate the total costs of three types of social security benefits granted to patients with MDs, RA and AS: disability benefits (for people with reduced working ability), disability pensions (for people who cannot qualify as workers) and incapacity pensions (for people without working ability). We developed a probabilistic model with a Monte Carlo simulation to estimate the total costs for each type of benefit associated with MDs, RA and AS. We also estimated the productivity loss resulting from RA in 2013. From 2009 to 2012 about 393 thousand treatments were paid for a total of approximately €2.7 billion. The annual number of treatments was on average 98 thousand and cost in total €674 million per year. In particular, the total pension burden was about €99 million for RA and €26 million for AS. The productivity loss for AR in 2013 was equal to €707,425,191 due to 9,174,221 working days lost. Our study is the fi rst to estimate the burden of social security pensions for MDs based on data of both approved claims and benefits paid by the national security system. From 2009 to 2012, in Italy, the highest indirect costs were associated with disability pensions (54% of the total indirect cost), followed by disability benefits (44.1% of cost) and incapacity pensions (1.8% of cost). In conclusion, MDs are chronic and highly debilitating diseases with a strong female predominance and very significant economic and social costs that are set to increase due to the aging of the population.
26140466 The process of collecting and evaluating evidences for the development of Guidelines for t 2016 OBJECTIVES: To describe the process of collecting and evaluating evidence for treating rheumatoid arthritis (RA) for developing clinical practice guidelines (CPGs) for rheumatologists in Japan. METHODS: The task force comprised rheumatologists, epidemiologists, health economists, and patients. First, the critical outcomes were determined according to a three-round Delphi method, and eight topics with 88 clinical questions (CQs) were formulated. A systematic review of CQs was conducted using the Cochran Database of Systematic Reviews, MEDLINE, and Japana Centra Revvo Medicina (2003-2012). A questionnaire survey and focus group interview were performed to capture the patients' values and preferences. Data from the National Health Insurance drug price list and product information provided by pharmaceutical companies were collected to evaluate drug cost and safety. The GRADE approach was used to describe the evidence quality and determine the strength of recommendations. Recommendations were developed using a modified Delphi method by a multidisciplinary panel including patients. RESULTS: Eight meetings and frequent e-mail communications were conducted to draft a quality assessment of evidence and recommendations. For 88 CQs, recommendation statements were determined. CONCLUSIONS: Using the GRADE approach, new CPGs successfully addressed important clinical issues for treating RA patients. Timely updating of recommendations should be routinely considered.
25370912 Impact of biologic agents with and without concomitant methotrexate and at reduced doses i 2015 May OBJECTIVE: To examine whether concomitant methotrexate (MTX) use is associated with better biologic persistence and whether self-administered anti-tumor necrosis factor (anti-TNF) therapies are used at reduced doses in real-world clinical care settings, not just clinical trials. METHODS: We conducted a retrospective cohort study among rheumatoid arthritis (RA) patients using Medicare claims data from 2006 to 2012. Subjects were new initiators of etanercept, infliximab, adalimumab, abatacept, and tocilizumab with at least 12 months of continuous medical and pharmacy coverage after treatment initiation. We examined the association between concomitant MTX use and persistence on biologic agents using Cox proportional hazards regression, adjusting for demographics and baseline comorbidities. We further identified a subgroup of patients who initiated and were adherent on etanercept or adalimumab for at least 12 months and examined the proportion of patients who subsequently used these therapies at reduced doses continuously for an additional 12, 18, and 24 months. RESULTS: Of 26,510 eligible RA patients, 10,511 initiated biologic monotherapy. Overall, patients who initiated biologic monotherapy were 1.4 (95% confidence interval [95% CI] 1.3-1.5) times more likely to discontinue at 1 year compared to those who initiated combination therapy, and 1.8 (95% CI 1.7-2.0) times more likely if starting infliximab monotherapy. Approximately 10-20% of patients who initiated and adhered to etanercept and adalimumab for ≥12 months subsequently received reduced-dose therapy for an 12 additional months and beyond. CONCLUSION: In real-world practice, concomitant MTX was associated with improved persistence on biologic therapy, especially for infliximab users; reduced-dose injectable anti-TNF therapy was used by a substantial proportion of RA patients.
25593229 High degree of nonadherence to disease-modifying antirheumatic drugs in patients with rheu 2015 Mar OBJECTIVE: To test medication adherence using the Compliance-Questionnaire-Rheumatology (CQR). METHODS: Invitation letter and CQR were sent to 240 patients with rheumatoid arthritis. Followup CQR was sent 3 months later. Adherence was evaluated using CQR 80% cutoff scores. RESULTS: Seventy-eight patients who were being treated with disease-modifying antirheumatic drugs provided full information on the CQR at both points in time. Eleven patients (14.1%) were classified as adherent based on taking compliance (TC), with only 3 patients (3.8%) adherent in regard to correct dosing (CD) [followup: 13 (16.7%) and 3 (3.8%) for TC and CD, respectively]. Nonadherence was not related to disease activity or side effects. CONCLUSION: We demonstrated low adherence, suggesting differences between doctors' records and patients' practice of antirheumatic drug therapy.
25477167 Upconversion nanoprobes for efficiently in vitro imaging reactive oxygen species and in  2015 Jan Over-generation of reactive oxygen species (ROS) is closely associated with the biological processes of rheumatoid arthritis (RA). Thus, efficient monitoring ROS in inflammatory joints would be essential for better understanding the pathogenesis and optimizing therapeutic interventions. Herein, we designed a ratiometric nanoprobe utilizing upconversion nanoparticles (UCNPs) conjugated with chromophore labeled hyaluronic acid (HA) for high sensitively sensing ROS in the aqueous solution, bioimaging ROS in inflammatory mimic cells and diagnosing RA in vivo. In this approach, the conjugation of HA conferred UCNPs not only water solubility but also biocompatibility and ROS recognizing properties. Particularly, the HA backbone cleavage and detachment of chromophore labeled HA fragments from UCNPs induced by ROS inhibited the luminescent energy transfer (LRET) and allowed rational metric upconversion luminescence (UCL) emission as the detection signal. Importantly, the upconversion nanoprobe showed high effectiveness for early assessing the treatment response of arthritic animals to an antiarthritic drug-methotrexate (MTX).
27616146 The prolactin receptor is expressed in rheumatoid arthritis and psoriatic arthritis synovi 2016 Dec OBJECTIVES: Prolactin (PRL) is a lactation-inducing hormone with immunomodulatory properties and is found at elevated levels in the serum of patients with RA and other rheumatic diseases. The PRL receptor (PRLR) has been shown to be expressed by macrophages in atherosclerotic plaques. The aim of this study was to examine PRLR expression by synovial macrophages and its role in the regulation of macrophage activation. METHODS: Serum monomeric 23 kDa PRL levels were measured in 119 RA patients using a fluoroimmunometric assay. PRLR expression was assessed in synovial tissue of 91 RA, 15 PsA and 8 OA patients by immunohistochemistry and digital image analysis. Double IF was used to identify PRLR-expressing cells. The effects of PRL on monocyte-derived macrophage gene expression were examined by quantitative real-time PCR and ELISA. RESULTS: Serum PRL levels were similar in female and male RA patients. Median (interquartile range) PRLR expression was significantly higher (P < 0.05) in RA and PsA synovial tissue compared with OA. PRLR colocalized with synovial CD68(+) macrophages and von Willebrand factor(+) endothelial cells. In vitro, PRLR was prominently expressed in IFN-γ-and IL-10-polarized macrophages compared with other polarizing conditions. PRL by itself had negligible effects on macrophage gene expression, but cooperated with CD40L and TNF to increase expression of pro-inflammatory genes including IL-6, IL-8 and IL-12β. CONCLUSIONS: Synovial PRLR expression is enhanced in patients with inflammatory arthritis compared with OA, and PRL cooperates with other pro-inflammatory stimuli to activate macrophages. These results identify PRL and PRLR as potential new therapeutic targets in inflammatory arthritis.
27678042 Calycosin suppresses expression of pro-inflammatory cytokines via the activation of p62/Nr 2016 Nov The activation of synovial fibroblasts (SFs) and the subsequent production and expression of pro-inflammatory cytokines play a crucial role in the pathogenesis and progression of rheumatoid arthritis (RA). In the current study, rheumatoid arthritis synovial fibroblasts (RASFs) isolated from the joint of the patients were used to evaluate the suppressive effects of calycosin (CAL), a compound derived from the Chinese medicinal herb Radix Astragali, on the expression of pro-inflammatory cytokines in RASFs. The results demonstrated that increased mRNA expression levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-25 (IL-25), interleukin-33(IL-33) were significantly inhibited by CAL. Furthermore, the compound obviously suppressed IL-6 and IL-33 secretion. The key inflammatory mediator, cyclooxygenase-2 (COX-2) was significantly attenuated by CAL. A mechanistic study showed that the antioxidant enzymes heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase quinone 1(NQO1) and Nrf2 of RASFs were markedly activated by CAL. Furthermore, CAL potentiated the accumulation of sequestosome 1 (SQSTM1, p62) and the degradation of Kelch-like ECH-associated protein 1 (Keap1), thereby inducing Nrf2 translocation from the cytoplasm to the nucleus. Thus, CAL suppresses the expression of pro-inflammatory cytokines via p62/Nrf2-linked HO-1 induction in RASFs, which suggests that the compound should be further investigated as a candidate anti-inflammatory and anti-arthritic agent.
27682808 Incidence and predictors of cardiovascular events in a cohort of patients with rheumatoid 2016 Jul INTRODUCTION: An excess in cardiovascular (CV) morbidity and mortality has been recognized in Rheumatoid Arthritis (RA) patients when compared to the general population. Given the paucity of prospective data, our aim was to estimate the incidence of CV events and the contribution of traditional CVD risk factors and RA-related parameters to future events. METHODS: Incident fatal and non-fatal CV events (hospitalizations due to unstable angina, myocardial infarction, coronary artery revascularization procedures, stroke, or CV death) were assessed in a prospective cohort of RA women followed since 2007 and without CV events at cohort entry. The presence of traditional CV risk factors, disease characteristics, medication, carotid ultrasound, and biomarkers of inflammation and endothelial activation were evaluated at baseline. Univariate Cox proportional hazard models were used to identify risk factors for CV events. RESULTS: Among 106 women followed over 565 patient-years we identified 4 CV events (1 fatal stroke, 2 myocardial infarction and 1 unstable angina), which contributed to an incidence rate of 7 per 1000 person-years (95%CI 2.0- 13.9). Patients who developed CV events were older, but the distribution of other traditional CV risk factors was otherwise similar in both groups. Also, corticosteroid dosage and proportion of patients with carotid atherosclerotic plaques was higher in those with CV events. Erythrocyte sedimentation rate (ESR) (HR 1.036; 95%CI 1.005-1.067) and soluble intercellular adhesion molecule-1 (sICAM-1) serum levels (HR 1.002; 95%CI 1.000-1.003) significantly contributed to CV events. These results remained significant after adjusting for patients' age. CONCLUSION: We found an incidence of cardiovascular events in women with RA of 7 per 1000 patent-years. This value is similar to that found in other Portuguese cohort of RA patients1 and much higher than the incidence reported for the general Portuguese population. Markers of inflammation and endothelial activation contributed significantly to CV events, but the limited number of events prevents further analysis.
27802921 Impact of Charlson indices and comorbid conditions on complication risk in bilateral simul 2016 Dec BACKGROUND: The purpose of this study was to evaluate the influence of Charlson indices and comorbid conditions on the risk of perioperative complications in bilateral simultaneous total knee arthroplasty (BSTKA). METHODS: In our retrospective analysis, 556 patients including 133 males and 423 females (mean age 65.8years), who had undergone bilateral simultaneous total knee arthroplasty between 2011 and 2014 were included. Risk factors (Charlson comorbidity index (CCI), age-adjusted Charlson comorbidity index (ACCI), and comorbid illnesses) and perioperative complications were noted, and subsequently, statistical tests were applied. RESULTS: There was significant association between Charlson indices and most of the complications (P<0.05) with high-risk ACCI groups (a score>5) bearing maximum odds for cumulative major complication (OR 4.165, P<0.001, 95% CI 1.874 to 9.256). In addition, hypertension, non-ischemic cardiac illness, and moderate to severe chronic kidney disease proved be to be determinants for major complications (P=0.031, P=0.041, and P=0.014, respectively). We also found significant associations between organ-specific illnesses and complications such as cardiac, pulmonary, neurological and renal complications (P<0.05). CONCLUSIONS: Both CCI and ACCI are predictors of post-operative complications with ACCI being the better predictive determinant. Hence, these predictors should be used for risk stratification prior to patient selection for BSTKA. The influence of hypertension, non-ischemic cardiac illness and moderate to severe chronic kidney disease should also be considered during patient selection. Moreover, optimum organ function at the time of surgery should be a priority to avoid these complications.