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ID PMID Title PublicationDate abstract
20716673 Antibodies to the endoplasmic reticulum-resident chaperones calnexin, BiP and Grp94 in pat 2010 Dec OBJECTIVES: To investigate the presence of autoantibodies against mammalian chaperones of the endoplasmic reticulum (ER) in patients with RA and other immune-mediated diseases. METHODS: Sera from healthy donors, from early RA patients with two follow-up samples, patients with SLE, SSc and IBD were collected and analysed for anti-ER chaperone antibodies. Detection of serum IgG antibodies against immunoglobulin heavy chain binding protein (BiP), glucose-regulated protein 94 (Grp94) and calnexin was carried out using ELISA. The specificity of sera positive for individual ER chaperones was confirmed by immunoblotting. Statistical analysis was performed using Welch's t-test, Mann-Whitney U-test, partial correlation and Pearson's correlation. RESULTS: In patients with RA and SLE, autoantibody titres against BiP, Grp94 and calnexin were significantly higher than those in healthy controls. These autoantibodies were detectable in patients with early RA and titres remained stable for at least 6-12 months. Also several SSc and IBD patients exhibited autoantibodies against these ER chaperones; however, titres and frequencies were lower than in RA or SLE patients. Furthermore, anti-calnexin antibodies correlated significantly with the presence of BiP and Grp94 autoantibodies in patients with RA and SLE. CONCLUSION: Calnexin and Grp94 were identified as novel autoantigens in RA and calnexin in SLE. Since calnexin, Grp94 and BiP are ER-resident proteins of eukaryotic cells, our data suggest that autoantibody generation against ER chaperones is independent of initial exposure to the corresponding bacterial chaperones; rather, ER chaperones may represent genuine autoantigens.
20014086 Haloacetamidine-based inactivators of protein arginine deiminase 4 (PAD4): evidence that g 2010 Jan 25 Dysregulated protein arginine deiminase (PAD) activity, particularly PAD4, has been suggested to play a role in the onset and progression of numerous human diseases, including rheumatoid arthritis (RA). Given the potential role of PAD4 in RA, we set out to develop inhibitors/inactivators that could be used to modulate PAD activity and disease progression. This effort led to the discovery of two mechanism-based inactivators, denoted F- and Cl-amidine, that inactivate PAD4 by the covalent modification of an active-site cysteine that is critical for catalysis. To gain further insights into the mechanism of inactivation by these compounds, the effect of pH on the rates of inactivation was determined. These results, combined with the results of solvent isotope effect and proton inventory studies, strongly suggest that the inactivation of PAD4 by F- and Cl-amidine proceeds by a multistep mechanism that involves the protonation and stabilization of the tetrahedral intermediate formed upon nucleophilic attack by the active-site cysteine, that is, Cys645. Stabilization of this intermediate would help to drive the halide-displacement reaction, which results in the formation of a three-membered sulfonium ring that ultimately collapses to form the inactivated enzyme. This finding-that protonation of the tetrahedral intermediate is important for enzyme inactivation-also suggests that, during catalysis, protonation of the analogous intermediate is required for efficient substrate turnover.
20127485 Th17 cytokines and arthritis. 2010 Mar Th17 cells are implicated in human autoimmune diseases, such as rheumatoid arthritis (RA), although it has not been established whether this persistent destructive arthritis is driven by Th1 and/or Th17 cells. Interleukin-17A (IL-17A) contributes to the pathogenesis of arthritis as has been shown in several experimental arthritis models. Importantly, recent data from first clinical trials with anti-IL-17A antibody treatment in psoriatic arthritis patients and RA patients looks promising. This review summarizes the findings about the role of Th17 cells in arthritis and discusses the impact of the different Th17 cytokines in the pathogenesis of this disease. However, further studies are needed to unravel the interplay between IL-17A and other Th17 cytokines such as IL-17F, IL-22, and IL-21 in the pathoimmunological process of this crippling disease, in particular, whether regulating Th17 cell activity or specific combinations of Th17 cytokines will have additional value compared to neutralizing IL-17A activity alone. Moreover, tumor necrosis factor-positive Th17 cells are discussed as potential dangerous cells in driving persistent arthritis in human early RA.
19756835 Discontinuation of etanercept in patients with rheumatoid arthritis who were in clinical r 2010 Jan The appearance of tumor necrosis factor blockers changes the treatment goal of rheumatoid arthritis (RA) to include not only the inhibition of bone destruction, but also the induction of remission. We, herein, report two cases with RA that showed a prolonged remission after the discontinuation of etanercept. The two cases were 27 and 38 years of age, and their disease durations were 6 and 14 months, respectively. Their disease activity score 28 (DAS28) before treatment were 4.43 and 5.07, respectively. Case two was resistant to infliximab as determined by previous treatment with this therapy. Both cases showed a dramatic clinical response and discontinued etanercept in the 15th month and the 14th month after the start of treatment, respectively. No exacerbation of arthritis was evident after the discontinuation of etanercept as supported by the maintenance of DAS28 at less than 2.6. Moreover, after the discontinuation of etanercept, radiographic progression was not evident and decreased modified Sharp scores were observed for at least 1 year in both cases. These findings indicate that clinical and radiographic remission is possible in some patients with RA after the discontinuation of etanercept.
20448289 Self-management of rheumatic diseases: state of the art and future perspectives. 2010 Jun Self-management interventions are patient-centred and designed to foster active participation of patients in order to promote well-being and to manage symptoms. Over the past two decades, the role of self-management in chronic diseases has gained momentum. Self-management programmes are now acknowledged as a key element of quality care. New modes of delivery allow greater access to information and are tailored to address patient needs. This systematic review presents data from clinical studies of self-management over the past decade, summarises the evidence for programme effectiveness, and suggests future research directions.
20152040 In vitro and ex vivo effect of hyaluronic acid on erythrocyte flow properties. 2010 Feb 12 BACKGROUND: Hyaluronic acid (HA) is present in many tissues; its presence in serum may be related to certain inflammatory conditions, tissue damage, sepsis, liver malfunction and some malignancies. In the present work, our goal was to investigate the significance of hyaluronic acid effect on erythrocyte flow properties. Therefore we performed in vitro experiments incubating red blood cells (RBCs) with several HA concentrations. Afterwards, in order to corroborate the pathophysiological significance of the results obtained, we replicated the in vitro experiment with ex vivo RBCs from diagnosed rheumatoid arthritis (RA) patients, a serum HA-increasing pathology. METHODS: Erythrocyte deformability (by filtration through nucleopore membranes) and erythrocyte aggregability (EA) were tested on blood from healthy donors additioned with purified HA. EA was measured by transmitted light and analyzed with a mathematical model yielding two parameters, the aggregation rate and the size of the aggregates. Conformational changes of cytoskeleton proteins were estimated by electron paramagnetic resonance spectroscopy (EPR). RESULTS: In vitro, erythrocytes treated with HA showed increased rigidity index (RI) and reduced aggregability, situation strongly related to the rigidization of the membrane cytoskeleton triggered by HA, as shown by EPR results. Also, a significant correlation (r: 0.77, p < 0.00001) was found between RI and serum HA in RA patients. CONCLUSIONS: Our results lead us to postulate the hypothesis that HA interacts with the erythrocyte surface leading to modifications in erythrocyte rheological and flow properties, both ex vivo and in vitro.
19758236 TNF-alpha antagonist survival rate in a cohort of rheumatoid arthritis patients observed u 2009 Sep A cohort of rheumatoid arthritis (RA) patients in the Lombardy Rheumatology Network (LOHREN) registry and receiving anti-TNF therapy was evaluated after 6, 12, 24, and 36 months. Of the 1114 patients in the registry 1064 met the clinical criteria for inclusion with 519 receiving infliximab, 303 adalimumab, and 242 etanercept. The therapeutic survival curve of these patients showed that the likelihood of continuing anti-TNF therapy was 78.8% after 12 months, 65.2% after 24 months, and 52.9% after 36 months, with a risk of dropout similar for inefficacy and adverse events. There were 405 anti-TNF therapy discontinuations (38.1%): 180 (16.9%) due to inefficacy, 194 (18.2%) adverse events, and 31 (2.9%) other reasons. Four deaths (2 septicemia, 1 postinfective cerebritis, 1 heart failure) were considered to be related to anti-TNF therapy. Of the discontinuations, 219 (54.1%) occurred within the first 12 months: 110 due to adverse events, 89 inefficacy, and 20 due to other reasons. After 36 months, the likelihood of survival on etanercept (62.5%) was significantly greater than the likelihood of survival on infliximab (49.1%) or adalimumab (53.6%). A higher risk of therapy discontinuations due to adverse events was associated with increasing age, a corticosteroid > 5 mg/day, a high erythrocyte sedimentation rate (ESR), a higher risk of therapy discontinuations due to inefficacy was associated with the previous use of > or = 4 disease-modifying antirheumatic drugs (DMARDs) and a high ESR. Comorbidities, increasing DAS28 values and co-therapy with methotrexate were associated with a lower risk of discontinuation.
19487269 E-selectin, interleukin 18, serum amyloid a, and matrix metalloproteinase 9 are associated 2009 Jul OBJECTIVE: To assess the effect of golimumab (human monoclonal antibody to tumor necrosis factor-alpha) plus methotrexate (MTX) on selected inflammatory biomarkers, and to determine if these effects predict clinical response in rheumatoid arthritis (RA). METHODS: Sera from adults with active RA despite MTX therapy, who received subcutaneous injections of placebo + MTX (MTX alone, n = 34) or golimumab 50 or 100 mg every 2 or 4 weeks + MTX (n = 137), were analyzed for levels of C-reactive protein (CRP), serum amyloid A (SAA), interleukin 18 (IL-18), E-selectin, matrix metalloproteinase 9 (MMP-9), and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1). RESULTS: Golimumab + MTX treatment significantly decreased serum CRP, SAA, IL-18, E-selectin, TIMP-1, and MMP-9 levels (median percent changes of -4.1% to -74.3% across treatment groups) versus MTX alone (-5.8% to 9.7%) when first measured at Week 4; decreases were sustained through Week 16. Larger magnitudes of decrease in all biomarkers were observed for clinical responders versus nonresponders. For golimumab + MTX, regression analyses including all biomarkers and select clinical measures showed that reductions in levels of several markers (SAA, E-selectin, MMP-9) as early as Week 4 correlated significantly with improvement in swollen joint count (SJC) at Week 16, as did reductions in E-selectin with improvement in tender joint count at Week 16. After accounting for the biomarkers, however, treatment group was no longer significant for SJC. CONCLUSION: Significant decreases in several inflammatory biomarkers were associated with golimumab + MTX therapy. Decreases in serum levels of SAA, E-selectin, and MMP-9 at Week 4 may be useful in predicting clinical response at Week 16.
20193633 Vaccines and autoimmune diseases of the adult. 2010 Feb Infectious agents contribute to the environmental factors involved in the development of autoimmune diseases possibly through molecular mimicry mechanisms. Hence, it is feasible that vaccinations may also contribute to the mosaic of autoimmunity. Evidence for the association of vaccinations and the development of these diseases is presented in this review. Infrequently reported post-vaccination autoimmune diseases include systemic lupus erythematosus, rheumatoid arthritis, inflammatory myopathies, multiple sclerosis, Guillain-Barré syndrome, and vasculitis. In addition, we will discuss macrophagic myofasciitis, aluminum containing vaccines, and the recent evidence for autoimmunity following the use of human papillomavirus vaccine.
19814628 Circadian pattern and the effect of standardized physical exercise on procollagen IIA N-pe 2010 Feb BACKGROUND: Variant collagen IIA is re-expressed in diseased cartilage. Low procollagen IIA N-peptide (PIIANP) levels in serum have recently been reported in rheumatoid arthritis (RA). We investigated circadian rhythmicity and effect of physical activity on PIIANP in early and longstanding RA and in healthy subjects. METHODS: Patients with early and longstanding RA and controls were included. Fasting and serial blood samples were collected during 24 h. PIIANP response to physical activity was studied before and serially after standardized exercise. RESULTS AND CONCLUSION: In RA at different stages and healthy individuals, PIIANP exhibited no circadian rhythmicity, and PIIANP in serum was not influenced by physical activity.
19877043 Gadd45beta deficiency in rheumatoid arthritis: enhanced synovitis through JNK signaling. 2009 Nov OBJECTIVE: JNK-mediated cell signaling plays a critical role in matrix metalloproteinase (MMP) expression and joint destruction in rheumatoid arthritis (RA). Gadd45beta, which is an NF-kappaB-regulated gene, was recently identified as an endogenous negative regulator of the JNK pathway, since it could block the upstream kinase MKK-7. This study was carried out to evaluate whether low Gadd45beta expression in RA enhances JNK activation and overproduction of MMPs in RA, and whether Gadd45beta deficiency increases arthritis severity in passive K/BxN murine arthritis. METHODS: Activation of the NF-kappaB and JNK pathways and Gadd45beta expression were analyzed in human synovium and fibroblast-like synoviocytes (FLS) using quantitative polymerase chain reaction, immunoblotting, immunohistochemistry, electrophoretic mobility shift assay, and luciferase reporter constructs. Gadd45beta(-/-) and wild-type mice were evaluated in the K/BxN serum transfer model of inflammatory arthritis, and clinical signs of arthritis, osteoclast formation, and bone erosion were assessed. RESULTS: Expression levels of the Gadd45beta gene and protein were unexpectedly low in human RA synovium despite abundant NF-kappaB activity. Forced Gadd45beta expression in human FLS attenuated tumor necrosis factor-induced signaling through the JNK pathway, reduced the activation of activator protein 1, and decreased the expression of MMP genes. Furthermore, Gadd45beta deficiency exacerbated K/BxN serum-induced arthritis in mice, dramatically increased signaling through the JNK pathway, elevated MMP3 and MMP13 gene expression in the mouse joints, and increased the synovial inflammation and number of osteoclasts. CONCLUSION: Deficient Gadd45beta expression in RA can contribute to activation of JNK, exacerbate clinical arthritis, and augment joint destruction. This process can be mitigated by enhancing Gadd45beta expression or by inhibiting the activity of JNK or its upstream regulator, MKK-7.
20432452 Interleukin-1beta induces ICAM-1 expression enhancing leukocyte adhesion in human rheumato 2010 Aug Interleukin-1beta (IL-1beta) has been shown to induce the expression of adhesion molecules on various cell types and contributes to inflammatory responses. However, the molecular mechanisms by which IL-1beta induced intercellular adhesion molecule (ICAM)-1 expression remain unclear in human rheumatoid arthritis synovial fibroblasts (RASFs). Here, we demonstrated that IL-1beta induces ICAM-1 gene expression via the de novo protein synthesis through transcription and translation, which is attenuated by pretreatment with actinomycin D and cycloheximide, respectively. IL-1beta-induced ICAM-1 expression, extracellular signal-regulated kinase (ERK) and c-Jun-N-terminal kinase (JNK) phosphorylation, AP-1 activation, and nuclear factor-kappaB (NF-kappaB) p65 translocation were attenuated by the inhibitors of MEK1/2 (U0126), JNK (SP600125), AP-1 (tanshinone IIA), and NF-kappaB (helenalin) or transfection with respective short hairpin RNA plasmids. Moreover, IL-1beta-stimulated NF-kappaB p65 translocation was blocked by helenalin, but not by U0126 or SP600125, revealing that MAPKs and NF-kappaB pathways were independent on these responses. IL-1beta-stimulated AP-1 activation was blocked by U0126 or SP600125, revealing that ERK and JNK linked to AP-1 on these responses. IL-1beta-stimulated ICAM-1 gene expression was attenuated by pretreatment with U0126, SP600125, tanshinone IIA, or helenalin, revealed by ICAM-1 promoter assay and real-time RT-PCR analysis. Finally, up-regulation of ICAM-1 enhanced the adhesion of leukocytes to RASFs exposed to IL-1beta. These results suggest that in human RASFs, activation of ERK, JNK, AP-1, and NF-kappaB are essential for IL-1beta-induced ICAM-1 expression and leukocyte adhesion.
21068090 The presence or absence of antibodies to infliximab or adalimumab determines the outcome o 2011 Feb OBJECTIVE: The aim of this study was to test the hypothesis that the reason for non-response (caused by immunogenicity or not) to a first tumour necrosis factor (TNF) inhibitor defines whether a second TNF inhibitor will be effective. METHODS: This cohort study consisted of 292 consecutive patients with rheumatoid arthritis (RA), all treated with etanercept. A total of 89 patients (30%) were treated previously with infliximab or adalimumab ('switchers'), and the remaining 203 (70%) were anti-TNF naive. All switchers were divided into two groups: with and without antibodies against the previous biological. Differences in clinical response to etanercept between switchers with and without antibodies and patients who were anti-TNF naive were assessed after 28 weeks of treatment using changes in Disease Activity Score in 28 joints (DAS28). RESULTS: After 28 weeks of treatment, response to etanercept did not differ between patients who were anti-TNF naive and switchers with anti-drug antibodies (ΔDAS28=2.1 ± 1.3 vs ΔDAS28=2.0 ± 1.3; p = 0.743). In contrast, switchers without anti-drug antibodies had a diminished response to etanercept treatment compared to patients who were TNF naive (ΔDAS28 =1.2±1.3 vs ΔDAS28 = 2.1 ± 1.3; p = 0.001) and switchers with antibodies (ΔDAS28 =1.2±1.3 vs ΔDAS28 = 2.0 ± 1.3; p = 0.017). CONCLUSION: Patients with RA with an immunogenic response against a first TNF-blocking agent had a better clinical response to a subsequent TNF blocker compared to patients with RA without anti-drug antibodies. Hence, determining immunogenicity can be helpful in deciding in which patient switching could be beneficial and can be part of a personalised treatment regimen.
20135636 Protease inhibitors: a panacea? 2010 Jul With the increasing evidence of protease involvement in several diseases, novel strategies for drug development involve the use of protease inhibitors (PIs). The local balance between protease inhibitors and proteases is an important determinant of the occurrence and progression of a particular disease. Hence, enzymes and their cognate inhibitors are finding their applications as diagnostic and prognostic markers. PIs are widely implicated for their use in host defense against infection, tissue repair and matrix production, blood coagulation, cancer, and they are, therefore, the current focus as therapeutic alternatives for major diseases such as AIDS and Alzheimer's diseases. This review is a brief summary of the varied role of protein protease inhibitors in controlling the activity of aberrant enzymes in several diseases afflicting mankind today.
19818336 Comparison of chemiluminescence enzyme immunoassay (CLEIA) with ELISA for the determinatio 2010 Jan BACKGROUND: Autoantibodies against cyclic citrullinated peptide (anti-CCP) are sensitive and highly specific markers for rheumatoid arthritis (RA). We evaluated the analytical and diagnostic accuracy of chemiluminescence enzyme immunoassay (CLEIA) for anti-CCP antibodies, and compared it with that of ELISA. METHODS: Ninety-nine RA patients who were diagnosed according to the American College of Rheumatology criteria, 16 patients with osteoarthritis, and 94 healthy subjects were included. Sera were used to assess the precision, functional sensitivity, and linearity of anti-CCP antibody determination by CLEIA and the correlation of anti-CCP antibody values between CLEIA and ELISA. RESULTS: For anti-CCP antibodies by CLEIA, the total CV was 4.0 and 5.3% at 21.17 and 90 U/ml, respectively, and the lower limit of detection was 0.1 U/ml. The correlation of CLEIA (x) with ELISA (y) for anti-CCP was: y=1.08x+4.171, r=0.9178 (p<0.0001). No difference was observed in the sensitivity and specificity between CLEIA and ELISA. CONCLUSIONS: The automated CLEIA processing system for determining anti-CCP antibodies showed a good analytical performance, and suggested that the CLEIA system has a potential to provide clinically useful data within a short time.
19542367 Prostaglandin E2 differentially modulates proinflammatory/prodestructive effects of TNF-al 2009 Jul 15 The present study investigated the influence of PGE(2), E prostanoid (EP) receptors, and their signaling pathways on matrix metalloproteinase (MMP)-1 and IL-6 expression in synovial fibroblasts (SFs) from rheumatoid arthritis (RA) patients. RASFs expressed all four EP receptors, with selective induction of EP2 by TNF-alpha. TNF-alpha time-dependently increased intracellular cAMP/protein kinase A signaling (maximum, 6-12 h) and PGE(2) secretion (maximum, 24 h). PGE(2) and the EP2 agonists butaprost or ONO-AE1-259 ((16)-9-deoxy-9beta-chloro-15-deoxy-16-hydroxy-17,17-trimethylene-19,20-didehydro PGE(1)), in turn, induced a rapid, time-dependent (maximum, 15-30 min) increase of cAMP. Additionally, cyclooxygenase-2 inhibition by NS-398 (N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide) reduced the TNF-alpha-induced increase in IL-6 mRNA/protein, which was restored by stimulation with PGE(2) or EP2, EP3, and EP4 agonists. In contrast, TNF-alpha-induced MMP-1 secretion was not influenced by NS-398 and diminished by PGE(2) via EP2. Finally, 3-isobutyl-1-methylxanthine enhanced the effects of PGE(2) on MMP-1, but not on IL-6 mRNA. In conclusion, PGE(2) differentially affects TNF-alpha-induced mRNA expression of proinflammatory IL-6 and prodestructive MMP-1 regarding the usage of EP receptors and the dependency on cAMP. Although specific blockade of EP2 receptors is considered a promising therapeutic strategy in RA, opposite regulation of proinflammatory IL-6 and prodestructive MMP-1 by PGE(2) via EP2 may require more complex approaches to successfully inhibit the cyclooxygenase-1/2 cAMP axis.
19326165 Rosai-Dorfman disease with factor XII deficiency. 2009 Jun A 17-year-old female patient presented with chronic symmetrical oligoarthritis of both knees and ankles, xerostomia, xerophthalmia, multiple bilateral lymphadenopathies in the cervical region, and bilateral parotid enlargement with the histological finding of chronic sialoadenitis. She had been already given methotrexate, chloroquine, and corticosteroids with the diagnosis of rheumatoid arthritis (RA) before referral to our outpatient clinic. Because her complaints and the lumps did not remit and she could be classified as neither RA nor primary Sjögren's syndrome (SS) according to 1987 ACR RA criteria or European preliminary criteria for SS, lymph node biopsy was repeated and revealed the diagnosis of Rosai-Dorfman disease (RDD) with the histological findings of histiocytes, phagocyting lymphocytes in enlarged sinuses, and mature plasma cells infiltrating the pulpa. All the medications were stopped after the pathological diagnosis of RDD and consulting with the Division of Hematology. She was reevaluated with magnetic resonance imaging, which showed dense infiltrative areas around knee and ankle joints, and computed tomography that showed a soft tissue mass surrounding the descending aorta and upper part of the abdominal aorta. Activated partial thromboplastin time was found to be prolonged in prebiopsy examinations, and factor XII deficiency was detected after detailed hematological evaluation. The symptoms of joint involvement were relieved with nonsteroidal antiinflammatory drugs. She has been followed-up without medication without obvious clinical or laboratory change. We herein report a patient with RDD mimicking RA and SS. We consider that RDD should be kept in mind especially in patients with resistant symptoms to conventional therapies, younger disease onset, and predominant parotid and lymph node enlargement.
19743942 Cost-utility of celecoxib use in different treatment strategies for osteoarthritis and rhe 2009 Sep OBJECTIVE: To assess the cost-utility of celecoxib in three treatment strategies for arthritis in Quebec, considering both upper gastrointestinal (GI) and cardiovascular (CV) events. METHODS: A Markov analytic framework was used to model patients with osteoarthritis and rheumatoid arthritis at low/average and high risk of GI and CV toxicity over 5 years with monthly cycles. Treatment strategies were modelled in line with Canadian clinical practice. In first-line treatment, patients started on celecoxib; second-line, patients started on a non-selective non-steroidal anti-inflammatory drug (NSAID) and switched to celecoxib after a first GI event; third-line, patients started on a non-selective NSAID, added a proton pump inhibitor (PPI) after a first GI event, and switched to celecoxib after a second GI event (while maintaining the PPI). Model inputs were determined through comprehensive literature searches (MEDLINE and EMBASE) from 1995 to 2006. Included studies evaluated GI (dyspepsia, uncomplicated and complicated ulcers, death) and CV (myocardial infarction, stroke, death) events. Drug and procedure costs were derived from Canadian published sources (Can$2005). RESULTS: Total costs per patient for celecoxib first-, second-, and third-line treatment were Can$4,790, $3,390, and $3,466, and total quality-adjusted life-years (QALY) were 3.251, 3.231, and 3.230, respectively. In all risk categories, celecoxib second-line was less costly and as effective as celecoxib third-line, producing savings to the healthcare system. Although celecoxib first-line generated incremental expenditures versus celecoxib second-line, it was also more effective. The resulting cost-utility ratio for the high-risk population was Can$54,696/QALY. Based on this analytical approach, a treatment strategy where celecoxib is used before the combination of a non-selective NSAID plus a PPI possesses cost advantages for the Quebec provincial drug programme. One-way sensitivity analysis (varying GI and CV event rates, utilities, and cost) generally showed second-line treatment with celecoxib as the dominant strategy compared with third-line treatment with celecoxib. CONCLUSION: Although effectiveness of second- and third-line celecoxib use is similar, total cost is lower for second-line. These results suggest that the use of celecoxib before the combination of a non-selective NSAID plus a PPI is relatively cost-effective in the treatment of arthritis pain and support the full benefit listing of celecoxib in Quebec's drug programme.
20178127 Synovial tissue heterogeneity in rheumatoid arthritis in relation to disease activity and 2010 Jun OBJECTIVE: To investigate the clinical relevance of synovial tissue subtypes in rheumatoid arthritis (RA) and to search for peripheral blood (PB) markers that may serve as biomarkers for tissue subtypes. METHODS: Gene expression analysis using complementary DNA microarrays was applied on paired synovial tissue biopsy and PB samples obtained from 17 RA patients. Molecular tissue subtypes were correlated with histologic parameters (CD3, CD22, CD38, CD68, CD163, tumor necrosis factor alpha, intercellular adhesion molecule 1, vascular cell adhesion molecule, and E-selectin), disease characteristics, and PB markers. PANTHER classification was used for pathway analysis. RESULTS: Genomic subtyping of high- and low-inflammation rheumatoid synovial tissues based on gene expression profiles exactly matched immunohistochemical classification. The patients with the high-inflammation tissue type had higher Disease Activity Scores in 28 joints, higher C-reactive protein levels, higher erythrocyte sedimentation rates, increased numbers of platelets, and shorter disease durations. Comparative analysis of PB gene expression profiles yielded no statistically significant differences between the 2 tissue groups at the single-gene expression level. PANTHER pathway analysis revealed a significant association of increased protein biosynthesis with high-inflammation tissue. CONCLUSION: High-inflammation tissue is associated with more severe disease and shorter disease duration. While pathway-level analysis revealed that coordinate differential expression of genes involved in protein synthesis in PB is associated with high-inflammation tissue types, differential tissue pathology was not reflected in the PB by differential expression of single genes.
20208419 Hyaluronan inhibits prostaglandin E2 production via CD44 in U937 human macrophages. 2010 Mar Prostaglandin E(2) (PGE(2)) is one of the key mediators of inflammation in affected joints of rheumatoid arthritis (RA). Intra-articular injection of high molecular weight hyaluronan (HA) into RA knee joints relieves arthritic pain. Although HA has been shown to inhibit PGE(2) production in cytokine-stimulated synovial fibroblasts, it remains unclear how HA suppresses PGE(2) production in activated cells. Furthermore, HA effect on macrophages has rarely been investigated in spite of their contribution to RA joint pathology. This study was aimed to investigate the inhibitory mechanism of HA on lipopolysaccharide (LPS)-stimulated PGE(2) production in U937 human macrophages. Stimulation of U937 macrophages with LPS enhanced PGE(2) production in association with increased protein levels of cyclooxygenase-2 (COX-2). Pretreatment with HA of 2,700 kDa resulted in suppression of the LPS-mediated induction of COX-2, leading to a decrease in PGE(2) production. Likewise, the LPS-stimulated PGE(2) production was inhibited by the pretreatment with a specific COX2 inhibitor, NS-398, or a specific inhibitor of nuclear factor (NF)-kappaB, BAY11-7085. HA also decreased the degree of phosphorylation and nuclear translocation of NF-kappaB enhanced by LPS. Fluorescence cytochemistry demonstrated that HA bound to CD44, the principal HA receptor, on U937 macrophages. Anti-CD44 antibody reversed the inhibitory effects of HA on the LPS-mediated increase in PGE(2) production, COX-2 induction, and activation of NF-kappaB. These results indicate that HA suppresses the LPS-stimulated PGE(2) production via CD44 through down-regulation of NF-kappaB. Administration of HA into RA joints may decrease PGE(2) production by activated macrophages, which could result in improvement of arthritic pain.