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ID PMID Title PublicationDate abstract
24526251 The role of rheumatologists vis-à-vis assessment of traditional cardiovascular risk facto 2014 Jun This study was designed to estimate the burden of care that would be placed on rheumatologists to undertake cardiovascular (CV) risk assessment of traditional CV risk factors in their patients. This cross-sectional study was set in a rheumatology ambulatory clinic of a tertiary care, university hospital. Consecutive rheumatoid arthritis (RA) patients were recruited over 6 weeks and matched 1:1 on age and sex to patients with non-inflammatory problems who presented to the same clinic. CV risk was calculated using the Framingham Risk Score. We recruited 68 RA patients and 64 controls. The distribution of CV risk factors in RA patients and controls was similar. Ten-year Framingham CV risk scores based on traditional risk factors were moderate and similar in RA patients and controls (13.7 and 14.3%, respectively). Nevertheless, the proportion of RA patients with a history of coronary artery disease was more than twice that of controls (13 versus 5%, respectively). Approximately 20% of RA patients and controls did not have a primary care physician. In rheumatology practice, the problem of elevated CV risk due to traditional risk factors is not unique to RA patients. The burden for rheumatologists of undertaking CV risk assessment in their clinic could be considerable. Rheumatologists should manage inflammatory disease and health services should be improved to ensure the optimal management of traditional CV risk factors for all rheumatology patients.
22910140 Adiponectin: a biomarker for rheumatoid arthritis? 2013 Feb Recent achievements in the biology and the function of adipose tissue have regarded white adipose tissue (WAT) as an important endocrine and secretory organ. Releasing a series of multiple-function mediators, WAT is involved in a wide spectrum of diseases, including not only cardiovascular and metabolic complications, such as atherosclerosis and type 2 diabetes, but also inflammatory- and immune-related disorders, such as rheumatoid arthritis (RA) and osteoarthritis (OA). A large number of these mediators, called adipokines, such as tumor necrosis factor alpha (TNF-α), leptin, adiponectin, resistin, chemerin, interleukin-6 (IL-6), visfatin, and so on have been identified and studied widely. Important advances related to these proteins shed new insights into the pathophysiological mechanisms of many complicated diseases, although details of which remain unclear. Adiponectin, one of the most widely investigated adipokine, has been shown to possess both anti- and pro-inflammatory effects. RA is a chronic systemic inflammatory-related autoimmune disease. Accumulated evidence has demonstrated that cytokines and adipokines play an important role in the pathogenesis of RA. In this review, we have summarized the most recent advances in adiponectin research in the context of RA, focusing primarily on its effect on RA-related cells, its regulation on pro-inflammatory cytokines, as well as its validation as a biomarker for RA.
23200852 MeCP2 modulates the canonical Wnt pathway activation by targeting SFRP4 in rheumatoid arth 2013 Mar Rheumatoid arthritis (RA) is an autoimmune disease characterized by the rheumatoid factor and anti-citrullinated peptide antibody (ACPA) against common autoantigens that are widely expressed within and outside the joints. Many factors participate in the pathogenesis of RA, such as cytokine imbalance, Wnt pathway activation, matrix production, and osteoprotegerin on osteoclasts. Fibroblast-like synoviocytes (FLS) activation has an important role in RA pathogenesis. The methyl-CpG-binding protein (MeCP2) which promoted repressed chromatin structure was selectively detected in synovium of diseased articular in rats. Overexpression of this protein results in an up-regulation of global methylation levels and transcriptional suppression of specific genes. There were increased MeCP2 and decreased secreted frizzled-related protein 4 (SFRP4) in synovium as well as the FLS isolated from the synovium of RA rats. Knockdown of MeCP2 using siRNA technique enhanced SFRP4 expression in both mRNA and protein levels in FLS. These results indicated that epigenetic modification was involved in differential expression of SFRP4. To further explore the underlying molecular mechanisms, we hypothesized that the SFRP4 down-regulation in synovium was caused by DNA methylation. Treatment of FLS with DNA methylation inhibitor 5-Aza-2'-deoxycytidine (5-azadC) blocked the cell proliferation and increased the SFRP4 expression. Increased SFRP4 down-regulated the key gene β-catenin, the downstream effectors gene ccnd1 and fibronectin expression in canonical Wnt pathway at the same time. MeCP2 and DNA methylation may provide molecular mechanisms for canonical Wnt pathway activation in RA. Combination of 5-azadC and MeCP2 may be a promising treatment strategy for individuals with RA in which SFRP4 is inactivated.
24318979 RAISE - rheumatoid arthritis independent Swiss treatment expectations and outcome: results 2013 QUESTIONS UNDER STUDY: Clinical trials do not necessarily reflect the results obtained in daily clinical practice. By conducting a non-interventional, observational study with biologics in rheumatoid arthritis (RA) patients in Switzerland, we aimed to generate real-world data on reasons for treatment initiation and discontinuation, physicians' expectations for treatment, co-medication, and various treatment outcome parameters. METHODS: Sixty-nine patients with a confirmed diagnosis of RA were included in this non-interventional observational study. Participating physicians used standardised questionnaires to collect data on the use of biologics at three visits over one year. Due to the small sample size of patients receiving biologics other than abatacept, only patients treated with abatacept were considered for analysis. RESULTS: The population receiving intravenously administered abatacept consisted of 56 patients. Of these, 25% received abatacept as a first-line biologic therapy. The retention rate over one year was high (75%) and similar to what has been previously observed in randomised clinical trials. Overall, abatacept was found to be effective in patients irrespective of their baseline disease activity or levels in C-reactive protein and erythrocyte sedimentation rate. Moreover, the use of glucocorticoids was found to be reduced under therapy. There was a tendency for better treatment outcomes and physicians' satisfaction with abatacept the earlier the drug was used in the sequence of biologic therapies. CONCLUSIONS: The present study suggests that abatacept is an effective and well tolerated treatment in RA patients in routine clinical practice, irrespective of disease parameter at baseline.
23318300 Genetic evidence for the involvement of NOTCH4 in rheumatoid arthritis and alopecia areata 2013 Feb To explore the genetic association of single nucleotide polymorphisms (SNPs) in the coding region of the NOTCH4, exon 3 C+1297T and exon 5 A+3063G, in a case-control analysis of 58 rheumatoid arthritis (RA) and 98 alopecia areata (AA) and 100 ethnically matched healthy subjects. NOTCH4 polymorphisms were genotyped by standard PCR followed by restriction digestion. Analysis of C+1297T SNP revealed a significant association of allele C+1297 (p=0.03, OR=1.66, 95%CI 1.04-2.64) and genotype CT (p=0.002, OR=2.82, 95%CI 1.42-5.59) with susceptibility to RA. Analysis of A+3063G SNP revealed a significant association of allele A+3063 (p=0.05, OR=0.59, 95%CI 0.35-1.008) and genotype AA (p=0.002, OR=0.39, 95%CI 0.17-0.87) with RA. Over all analysis between alopecia patients and the studied SNPs failed to show any significant association. Classifying the patients by severity of disease, confined the risk role of CT genotype to the severest form of alopecia universalis (p=0.006, OR=3.82, 95%CI 1.39-3.82) and AG genotype to semiuniversalis alopecia (p=0.004, OR=4.3, 95%CI 1.5-15.3). Present study is the first to report a statistically significant association between RA and NOTCH4 polymorphisms.
25595725 Systematic review of the presentation of coagulation factor VIII inhibitors in rheumatic d 2015 Jun OBJECTIVES: To provide a comprehensive review regarding the clinical presentation of acquired factor VIII (FVIII) inhibitors, also known as "acquired hemophilia," in patients with rheumatic diseases. METHODS: A systematic MEDLINE search was conducted to identify English-language articles published from 1993 through January 10, 2012, providing details regarding the clinical presentation, laboratory evaluation, and management of a patient(s) with newly or previously diagnosed autoimmune disease coexistent with an acquired FVIII inhibitor. RESULTS: In total, 49 patients fulfilled the criteria for inclusion in the review; the greatest percentage (24.5%) had systemic lupus erythematosus, followed by rheumatoid arthritis (16%). The majority (78%) presented with spontaneous mucocutaneous or muscular bleeding. Prolonged activated partial thromboplastin time (aPTT) was identified in all of the 45 patients for whom results were provided. Five patients presented with an asymptomatic prolonged aPTT, which was attributed to a lupus anticoagulant in two patients, only one of whom actually had a coexisting lupus anticoagulant. Invasive procedures led to serious bleeding in both of these patients, one of whom died as a result. The majority (59%) of patients experienced complete or partial remission of their inhibitors, most (96%) after systemic eradicative therapy. A total of three (6%) patients died as a direct result of FVIII inhibitors. CONCLUSIONS: Although acquired FVIII inhibitors are rare in patients with autoimmune diseases, prompt diagnosis is essential to avoid extensive bleeding, which could be life threatening. Treatment requires eradication of the factor inhibitors. Rheumatologists must be able to distinguish acquired FVIII inhibitors from lupus anticoagulants.
23670804 Serum macrophage migration inhibitory factor levels are correlated with response to tocili 2014 Mar To examine the relationship between serum cytokine levels and response to tocilizumab in patients with RA. The disease status of 21 RA patients was assessed at baseline and after 12 weeks of tocilizumab treatment, using the clinical disease activity index (CDAI). Clinical response to tocilizumab was defined as an improvement of >50% from the baseline CDAI. Serum cytokine levels were quantified using double-ligand ELISA for TNF-α, IL-6, CCL2, CCL3, CXCL8, CXCL10, CX3CL1, and macrophage migration inhibitory factor (MIF). After 12 weeks of tocilizumab treatment, there was a significant overall reduction in RA disease activity (CDAI), from 22.4 ± 11.3 to 9.2 ± 6.6 (p < 0.0001), across the entire patient group. After 12 weeks of tocilizumab treatment, 14 patients achieved a >50% improvement (the responder group), but there were no significant responses in the other 7 patients (the non-responder group). The erythrocyte sedimentation rate levels, the positive % of anti-cyclic citrullinated protein antibody and patients (%) receiving methotrexate in combination with tocilizumab were significantly higher in the responder group than in the non-responder group. Although serum baseline levels of CCL2 and CXCL8 were higher in the responder group than in the non-responder group, there were no significant changes in these chemokine levels after treatment. The serum MIF levels, but not the levels of other cytokines, in the responder group were significantly decreased after tocilizumab treatment. Our results suggest that tocilizumab differentially regulates serum cytokine profiles in patients with RA, and MIF regulation in patients with active RA may be sensitive to anti-IL-6 therapy.
22833374 Ambient air pollution exposures and risk of rheumatoid arthritis: results from the Swedish 2013 Jun OBJECTIVE: Environmental factors may play a role in the development of rheumatoid arthritis (RA). We examined whether long-term exposures to air pollution were associated with the risk of RA in the Swedish Epidemiological Investigation of Rheumatoid Arthritis Study. METHODS: We studied 1497 incident RA cases and 2536 controls. Local levels of particulate matter (PM10) and gaseous pollutants (sulphur dioxide (SO2) and nitrogen dioxide (NO2)) from traffic and home heating were predicted for all residential addresses. We examined the association of an IQR increase (2 µg/m3 for PM10, 8 µg/m3 for SO2 and 9 µg/m3 for NO2) in each pollutant at different time points before symptom onset and average exposure with the risk of all RA and the risk of the rheumatoid factor and anti-citrullinated protein antibody (ACPA) RA phenotypes. RESULTS: There was no evidence of an increased risk of RA with PM10. Total RA risks were modestly elevated for the gaseous pollutants, but were not statistically significant after adjustment for smoking and education (OR 1.18, 95% CI 0.97 to 1.43 and OR 1.09, 95% CI 0.99 to 1.19 for SO2 and NO2 in the 10th year before onset). Stronger elevated risks were observed for individuals with less than a university education and with the ACPA-negative RA phenotype. CONCLUSIONS: No consistent overall associations between air pollution in the Stockholm area and the risk of RA were observed. However, there was a suggestion of increased risks of RA incidence with increases in NO2 from local traffic and SO2 from home heating sources with stronger associations for the ACPA-negative phenotype.
24712864 Structure-based drug design of RN486, a potent and selective Bruton's tyrosine kinase (BTK 2015 Jan 8 Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.
23844402 Patellar tendon properties and lower limb function in rheumatoid arthritis and ankylosing 2013 OBJECTIVE: Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) lead to inflammation in tendons and peritendinous tissues, but effects on biomechanical tendon function are unknown. This study investigated patellar tendon (PT) properties in stable, established RA and AS patients. METHODS: We compared 18 RA patients (13 women, 59.0 ± 2.8 years, mean ± SEM) with 18 age- and sex-matched healthy controls (58.2 ± 3.2 years), and 12 AS patients (4 women, 52.9 ± 3.4 years) with 12 matched controls (54.5 ± 4.7 years). Assessments with electromyography, isokinetic dynamometry, and ultrasound included quadriceps muscle force and cross-sectional area (CSA), PT stiffness, and PT CSA. Additionally, measures of physical function and disease activity were performed. RESULTS: PT stiffness and physical function were lower in RA and AS patients compared to healthy controls, without a significant difference in force production. PT CSA was significantly larger leading to reduction in Young's modulus (YM) in AS, but not in RA. CONCLUSION: The adverse changes in PT properties in RA and AS may contribute to their impaired physical function. AS, but not RA, leads to PT thickening without increasing PT stiffness, suggesting that PT thickening in AS is a disorganised repair process. Longitudinal studies need to investigate the time course of these changes and their response to exercise training.
23392345 Bone graft incorporation after revision hip arthroplasty in patients with rheumatoid arthr 2013 Apr PURPOSE: The aim of the study was to assess bone graft incorporation after revision hip arthroplasty in patients with rheumatoid arthritis (RA). METHODS: We report an acetabular reconstruction using impacted, morselized, frozen, radiation sterilized bone allografts in 71 patients suffering from RA. There were sixty-six women and five men at a mean age of 57.5 years. Reconstruction was performed in 78 revision total hip arthroplasties (THAs) for aseptic loosening of acetabular component. The mean follow-up was five years and four months. In 38 cases, a revision was done with use of reinforcement devices. RESULTS: In four revised hips (10 %) without reinforcement implants, resorption of the allografts was noticed. All Mueller rings and 50 % of unscrews cages (Link, Howmedica) were revised because of aseptic loosening and bone graft resorption. In all of 17 hips with the Burch-Schneider cage, no measurable migration or bone allografts resorption occurred. There were no major general complications. CONCLUSIONS: Acetabular reconstruction with use of morselized, frozen, radiation sterilized bone allografts and the Burch-Schneider cage can be highly successful in managing massive deficiency of acetabular bone stock in revision hip arthroplasty in RA patients.
23335101 Protein tyrosine phosphatase expression profile of rheumatoid arthritis fibroblast-like sy 2013 May OBJECTIVE: The fibroblast-like synoviocytes (FLS) in the synovial intimal lining of the joint are key mediators of inflammation and joint destruction in rheumatoid arthritis (RA). In RA, these cells aggressively invade the extracellular matrix, producing cartilage-degrading proteases and inflammatory cytokines. The behavior of FLS is controlled by multiple interconnected signal transduction pathways involving reversible phosphorylation of proteins on tyrosine residues. However, little is known about the role of the protein tyrosine phosphatases (PTPs) in FLS function. This study was undertaken to explore the expression of all of the PTP genes (the PTPome) in FLS. METHODS: A comparative screening of the expression of the PTPome in FLS from patients with RA and patients with osteoarthritis (OA) was conducted. The functional effect on RA FLS of SH2 domain-containing phosphatase 2 (SHP-2), a PTP that was up-regulated in RA, was then analyzed by knockdown using cell-permeable antisense oligonucleotides. RESULTS: PTPN11 was overexpressed in RA FLS compared to OA FLS. Knockdown of PTPN11, which encodes SHP-2, reduced the invasion, migration, adhesion, spreading, and survival of RA FLS. Additionally, signaling in response to growth factors and inflammatory cytokines was impaired by SHP-2 knockdown. RA FLS that were deficient in SHP-2 exhibited decreased activation of focal adhesion kinase and mitogen-activated protein kinases. CONCLUSION: These findings indicate that SHP-2 has a novel role in mediating human FLS function and suggest that it promotes the invasiveness and survival of RA FLS. Further investigation may reveal SHP-2 to be a candidate therapeutic target for RA.
24166792 Association of low baseline levels of erythrocyte folate with treatment nonresponse at thr 2013 Nov OBJECTIVE: To investigate whether baseline concentrations of one-carbon metabolism biomarkers are associated with treatment nonresponse and adverse events in rheumatoid arthritis (RA) patients receiving methotrexate (MTX). METHODS: A prospective derivation cohort (n = 285) and validation cohort (n = 102) of RA patients receiving MTX were studied. Concentrations of plasma homocysteine, serum vitamin B12 , serum folate, erythrocyte vitamin B6 , and erythrocyte folate were determined at baseline and after 3 months of treatment. Nonresponse after 3 months was assessed using the Disease Activity Score in 28 joints (DAS28) and the European League Against Rheumatism (EULAR) response criteria. Adverse events at 3 months were assessed using biochemical parameters and health status questionnaires. Analyses were corrected for baseline DAS28, age, sex, MTX dose, comedications, and presence of the methylenetetrahydrofolate reductase 677TT genotype. RESULTS: In the derivation cohort, the mean DAS28 scores at baseline and 3 months were 4.94 and 3.12, respectively, and 78% of patients experienced adverse events. This was similar between the 2 cohorts, despite a lower MTX dose in the validation cohort. Patients with lower levels of erythrocyte folate at baseline had a higher DAS28 at 3 months in both the derivation cohort (β = -0.15, P = 0.037) and the validation cohort (β = -0.20, P = 0.048). In line with these results, lower baseline erythrocyte folate levels were linearly associated with a 3-month DAS28 of >3.2 in both cohorts (derivation cohort, P = 0.049; validation cohort, P = 0.021) and with nonresponse according to the EULAR criteria (derivation cohort, P = 0.066; validation cohort, P = 0.027). None of the other biomarkers (levels at baseline or changes over 3 months) were associated with the DAS28 or treatment nonresponse. Baseline levels of the biomarkers and changes in levels after 3 months were not associated with incidence of adverse events. CONCLUSION: A low baseline concentration of erythrocyte folate is associated with high disease activity and nonresponse at 3 months after the start of MTX treatment and could be used in prediction models for MTX outcome. None of the investigated one-carbon metabolism biomarkers were associated with incidence of adverse events at 3 months.
23789797 [Analisis of the budget impact of adalimumab and etanercept in rheumatoid arthritis and sp 2013 May PURPOSE: To assess the economic impact derived from the widening of the administration intervals of adalimumab (ADA) and etanercept (ETN) for the treatment of rheumatoid arthritis (RA) and spondyloarthropathies (SAP) at our working environment. MATERIAL AND METHODS: A budget impact model (BIM) was developed to estimate the economic impact that would have widening the usual administration intervals of ADA, 40 mg every 2 weeks and ETN, 50 mg weekly (scenario A), to ADA, 40 mg every 3 weeks, and ETN, 50 mg every 2 weeks (scenario B) according to the guidelines and recommendations applied to these studies, specifying the target population, the study perspective, the temporal horizon, and analysing the study robustness by a threshold univariate sensitivity analysis. RESULTS: 71 patients were included in the study. The application of the BIM showed yearly savings for ADA and ETN of 19.784 ??and 38.271 ?, respectively. The net cost, that is to say the saving that this would imply within the temporal horizon considered (2 years), was 116.110 ?. The sensitivity analysis showed that the estimated BIM for the study period was very robust since the net result in the different scenarios varied very little, being negative in the new scenarios. CONCLUSIONS: widening the administration intervals of ADA and ETN to every 3 weeks and 2 weeks respectively, would be a strategy that would allow generating savings in the hospital budget close to 116.110 ??for the temporal horizon considered, achieving this way optimization of the treatment with these two drugs.
24728329 Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in pati 2014 Aug OBJECTIVE: To compare the relative bioavailability, safety and tolerability of oral methotrexate (MTX) and subcutaneous (SC) MTX administered via an auto-injector (MTXAI) in patients with rheumatoid arthritis (RA). METHODS: In this randomised, multicenter, open-label, three-way crossover study, patients ≥18 years with adult RA undergoing treatment with MTX for ≥3 months were assigned to receive MTX 10, 15, 20 and 25 mg weekly in a random sequence of three treatments: oral, SC into the abdomen and SC into the thigh. For 24 h after administration of each treatment, blood samples were collected for pharmacokinetic analysis and injection sites were assessed. RESULTS: Forty-seven patients completed the study. Systemic exposure of oral MTX plateaued at doses ≥15 mg/week. In contrast, SC MTX demonstrated a linear increase in systemic exposure that was greater than oral MTX at each dose. No unexpected AEs were noted for either formulation. CONCLUSIONS: Unlike oral MTX, the systemic exposure of SC MTX did not plateau over the doses studied, particularly at doses ≥15 mg/week. In this study, higher systemic MTX exposure was not associated with increases in AEs. Patients with an inadequate clinical response to oral MTX may benefit from higher drug exposure by switching to SC MTX. TRIAL REGISTRATION NUMBER: NCT01618968.
23322460 Symptoms related to tumor necrosis factor receptor 1-associated periodic syndrome, multipl 2013 Mar OBJECTIVE: Tumor necrosis factor (TNF) receptor 1-associated periodic syndrome (TRAPS) is an autoinflammatory disorder caused by autosomal dominantly inherited mutations in the TNF receptor superfamily 1A (TNFRSF1A) gene. The D12E substitution has been described only once to date, in a 4-year-old boy with fever. METHODS: For DNA sequence analysis of the TNFRSF1A gene, genomic DNA was isolated, amplified by PCR, purified, and sequenced. RESULTS: We describe 3 families (8 subjects) with the TNFRSF1A D12E substitution and TRAPS-related symptoms, in 4 cases associated with the autoimmune diseases multiple sclerosis and rheumatoid arthritis. CONCLUSION: The clinical phenotype might be associated with the TNFRSF1A D12E mutation. There is a close pathophysiological relationship between TNF signaling and autoimmune disorders.
24608404 Risk of hospitalised infection in rheumatoid arthritis patients receiving biologics follow 2015 Jun BACKGROUND: The risk of subsequent infections in rheumatoid arthritis (RA) patients who receive biologic therapy after a serious infection is unclear. OBJECTIVE: To compare the subsequent risk of hospitalised infections associated with specific biologic agents among RA patients previously hospitalised for infection while receiving anti-tumour necrosis factor (anti-TNF) therapy. METHODS: Using 2006-2010 Medicare data for 100% of beneficiaries with RA enrolled in Medicare, we identified patients hospitalised with an infection while on anti-TNF agents. Follow-up began 61 days after hospital discharge and ended at the earliest of: next infection, loss of Medicare coverage or 18 months after start of follow-up. We calculated the incidence rate of subsequent hospitalised infection for each biologic and used Cox regression to control for potential confounders. RESULTS: 10 794 eligible hospitalised infections among 10183 unique RA patients who contributed at least 1 day of biologic exposure during follow-up. We identified 7807 person-years of exposure to selected biologics--333 abatacept, 133 rituximab and 7341 anti-TNFs (1797 etanercept, 1405 adalimumab, 4139 infliximab)--and 2666 associated infections. Mean age across biologic exposure cohorts was 64-69 years. The crude incidence rate of subsequent hospitalised infection ranged from 27.1 to 34.6 per 100 person-years. After multivariable adjustment, abatacept (HR: 0.80, 95% CI 0.64 to 0.99) and etanercept (HR: 0.83, 95% CI 0.72 to 0.96) users had significantly lower risks of subsequent infection compared to infliximab users. CONCLUSIONS: Among RA patients who experienced a hospitalised infection while on anti-TNF therapy, abatacept and etanercept were associated with the lowest risk of subsequent infection compared to other biologic therapies.
23897050 Role of ADAM-17, p38 MAPK, cathepsins, and the proteasome pathway in the synthesis and she 2013 Nov OBJECTIVE: To evaluate the mechanism of fractalkine (FKN)/CX3 CL1 synthesis and shedding in rheumatoid arthritis synovial fibroblasts (RASFs) and in rat adjuvant-induced arthritis (AIA). METHODS: The effect of tumor necrosis factor α (TNFα) and/or interferon-γ (IFNγ) on FKN synthesis and shedding in human RASFs was determined over time by immunostaining, quantitative reverse transcription-polymerase chain reaction, and Western blotting. The role of protease enzymes and signaling pathways was evaluated using chemical inhibitors and small interfering RNA (siRNA). The activity of 20S proteasome in the lysates and the DNA binding of NF-κB/p65 in the nuclear fractions were evaluated. The in vivo relevance of these findings was examined in rat AIA. RESULTS: In RASFs, stimulation with the combination of TNFα and IFNγ induced cellular expression of FKN within 24 hours. Activation of ADAM-17, but not ADAM-10, partly mediated the proteolytic shedding and release of soluble FKN (sFKN) following TNFα/IFNγ stimulation for 24-72 hours. Compared with control siRNA, ADAM-17 siRNA markedly inhibited TNFα/IFNγ-induced sFKN production (by ∼33%). TNFα/IFNγ-induced sFKN release was markedly suppressed by inhibitors of ADAM-17, p38 MAPK, proteasome, or cathepsin inhibitor but not by inhibitors of caspase 3 or calpain. TNFα/IFNγ-induced proteasome activity also correlated with rapid degradation of IκBα and p38 MAPK phosphorylation. In vivo findings showed increased FKN expression in the joints of rats with AIA, which correlated with increased expression of ADAM-17 and phospho-p38 MAPK. CONCLUSION: Our results provide new understanding of the role of ADAM-17, p38 MAPK, cathepsins, and the proteasome pathway in FKN expression and shedding. Regulating these pathways may suppress FKN-mediated inflammation and tissue destruction.
24757150 CTLA-4Ig-induced T cell anergy promotes Wnt-10b production and bone formation in a mouse m 2014 Apr OBJECTIVE: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by severe joint erosion and systemic osteoporosis. Chronic T cell activation is a hallmark of RA, and agents that target the CD28 receptor on T cells, which is required for T cell activation, are being increasingly used as therapies for RA and other inflammatory diseases. Lymphocytes play complex roles in the regulation of the skeleton, and although activated T cells and B cells secrete cytokines that promote skeletal decline, under physiologic conditions lymphocytes also have key protective roles in the stabilization of skeletal mass. Consequently, disruption of T cell costimulation may have unforeseen consequences for physiologic bone turnover. This study was undertaken to investigate the impact of pharmacologic CD28 T cell costimulation blockade on physiologic bone turnover and structure. METHODS: C57BL6 mice were treated with CTLA-4Ig, a pharmacologic CD28 antagonist or with irrelevant control antibody (Ig), and serum biochemical markers of bone turnover were quantified by enzyme-linked immunosorbent assay. Bone mineral density and indices of bone structure were further measured by dual x-ray absorptiometry and micro-computed tomography, respectively, and static and dynamic indices of bone formation were quantified using bone histomorphometry. RESULTS: Pharmacologic disruption of CD28 T cell costimulation in mice significantly increased bone mass and enhanced indices of bone structure, a consequence of enhanced bone formation, concurrent with enhanced secretion of the bone anabolic factor Wnt-10b by T cells. CONCLUSION: Inhibition of CD28 costimulation by CTLA-4Ig promotes T cell Wnt-10b production and bone formation and may represent a novel anabolic strategy for increasing bone mass in osteoporotic conditions.
24239487 The relationship between an intramedullary high signal intensity and the clinical outcom 2014 Jun 1 BACKGROUND CONTEXT: In patients affected by cervical spondylotic myelopathy (CSM), numerous authors have reported the existence of a relationship among the intramedullary high signal intensity in T2-weighted MRIs, preoperative neurologic severity, and neurologic recovery after surgery; however, to our knowledge, there have been no previous reports that have described its relationship in patients with atlanto-axial subluxation (AAS) owing to rheumatoid arthritis (RA). PURPOSE: The purpose of this study was to clarify the characteristics of patients with AAS owing to RA showing intramedullary high signal intensity in T2-weighted MRIs, and to assess the relationship with the neurologic severity and neurologic recovery after surgery. STUDY DESIGN: This was a retrospective cohort study. PATIENTS SAMPLE: Fifty consecutive patients (37 females and 13 males) with AAS treated by surgery were reviewed. OUTCOME MEASURES: The outcome was determined 1 year after surgery. METHODS: According to preoperative T2-weighted MRIs, the patients were classified into two groups as follows: An NC group not showing any signal intensity change on sagittal images, and an SI group showing signal intensity changes with narrowing of the spinal cord. In all patients, we investigated the atlanto-dental distance (ADD) and the space available for the spinal cord (SAC) at the neutral position and the maximal flexion position in lateral cervical radiographs before surgery. We also observed MRIs 1 year after surgery in the SI group. We evaluated the severity of neurologic symptoms before and 1 year after surgery in all patients. RESULTS: Preoperative T2-weighted MRIs demonstrated NC in 38 cases and SI in 12 cases. The preoperative average ADD at the neutral position in the NC and SI groups was 6.4 and 10.2 mm, respectively (p<.01). The preoperative ADD at the maximal flexion position in the two groups were 10.8 and 13.8 mm, respectively (p<.01). The preoperative average SAC at the neutral position in the NC and SI groups were 17.6 and 13.8 mm, respectively (p<.01). The SAC at the maximal flexion position in the two groups were 14.3 and 10.8 mm, respectively (p<.01). The SI group included significantly more Ranawat grade III cases showing severe neurologic deficits compared to the NC group (p<.01). However, there were no differences between the two groups regarding the number of patients with Ranawat grade III status after surgery (p>.65). On MRIs 1 year after surgery, the regression or disappearance of the signal intensity change in T2-weighted images was demonstrated in four and seven cases, respectively. CONCLUSIONS: Preoperative ISHI in T2-weighted MRIs in RA-induced AAS patients was demonstrated in patients showing an enlargement of the ADD and a narrowing of the SAC. This affected the preoperative neurologic severity, but not the postoperative severity, which was in contrast to CSM patients. Furthermore, the regression or disappearance of ISHI was demonstrated in all of the cases after surgery. It is therefore speculated that RA AAS patients may have both dynamic instability and stenosis.