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ID PMID Title PublicationDate abstract
21867445 Effects of rosuvastatin on subclinical atherosclerosis and arterial stiffness in rheumatoi 2011 Nov OBJECTIVE: To ascertain the effect of rosuvastatin on carotid atherosclerosis and arterial stiffness in patients with rheumatoid arthritis (RA). METHODS: Fifty RA patients were randomized in a double-blind placebo-controlled trial to receive 10 mg rosuvastatin (n = 24) or placebo (n = 26). Patients were followed prospectively every 3 months for 12 months. Intima-media thickness (IMT), augmentation index (AIx), and subendocardial viability ratio (SEVR) were measured at baseline, 6 and 12 months. RESULTS: Rosuvastatin resulted in statistically significant reductions of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and urate levels vs. placebo. However, rosuvastatin had no significant effect on changes in inflammatory markers, including C-reactive protein (CRP) levels [from 2.9 (1.4-11.0) to 3.1 (0.9-13.3) mg/L in the rosuvastatin group compared with from 5.8 (2.6-14.2) to 4.4 (1.2-12.3) mg/L in the placebo group]. Nonetheless, a significant improvement in the Disease Activity Score (DAS) and a reduction in fibrinogen level was observed at 6 and 12 months compared with baseline in the rosuvastatin group. The treatment group exhibited a significant increase in SEVR (from 157 ± 28% to 163 ± 33% in the rosuvastatin group compared with from 143 ± 18% to 143 ± 26% in the placebo group, p = 0.023), but no significant effect was observed in the changes in IMT and AIx. CONCLUSION: Our data suggest that rosuvastatin has a modest anti-inflammatory effect in RA patients with low disease activity in terms of reduction in DAS and fibrinogen level. Rosuvastastin may also improve subendocardial perfusion and lower the urate level.
22516958 Engineering DNA nanoparticles as immunomodulatory reagents that activate regulatory T cell 2012 May 15 Nanoparticles containing DNA complexed with the cationic polymer polyethylenimine are efficient vehicles to transduce DNA into cells and organisms. DNA/polyethylenimine nanoparticles (DNPs) also elicit rapid and systemic release of proinflammatory cytokines that promote antitumor immunity. In this study, we report that DNPs possess previously unrecognized immunomodulatory attributes due to rapid upregulation of IDO enzyme activity in lymphoid tissues of mice. IDO induction in response to DNP treatment caused dendritic cells and regulatory T cells (Tregs) to acquire potent regulatory phenotypes. As expected, DNP treatment stimulated rapid increase in serum levels of IFN type I (IFN-αβ) and II (IFN-γ), which are both potent IDO inducers. IDO-mediated Treg activation was dependent on IFN type I receptor signaling, whereas IFN-γ receptor signaling was not essential for this response. Moreover, systemic IFN-γ release was caused by TLR9-dependent activation of NK cells, whereas TLR9 signaling was not required for IFN-αβ release. Accordingly, DNPs lacking immunostimulatory TLR9 ligands in DNA stimulated IFN-αβ production, induced IDO, and promoted regulatory outcomes, but did not stimulate potentially toxic, systemic release of IFN-γ. DNP treatment to induce IDO and activate Tregs blocked Ag-specific T cell responses elicited in vivo following immunization and suppressed joint pathology in a model of immune-mediated arthritis. Thus, DNPs lacking TLR9 ligands may be safe and effective reagents to protect healthy tissues from immune-mediated destruction in clinical hyperimmune syndromes.
22002013 Synovial infiltration with CD79a-positive B cells, but not other B cell lineage markers, c 2011 Nov OBJECTIVE: The efficacy of B cell depletion in the treatment of patients with rheumatoid arthritis (RA) has revitalized interest in the pathogenic role(s) of B cells in RA. We evaluated the distribution of synovial B lineage cells and their correlation with histologic disease activity and joint destruction in RA. METHODS: Synovial tissue samples were obtained by closed-needle biopsy from 69 Chinese patients with active RA, from 14 patients with osteoarthritis (OA), and from 15 with orthopedic arthropathies (OrthA) as disease controls. Serial tissue sections were stained immunohistochemically for CD79a (pro-B cell to plasma cell), CD20 (B cells), CD38 (plasma cells), CD21 (follicular dendritic cells), CD68 (macrophages), CD3 (T cells), and CD34 (endothelial cells). Densities of positive-staining cells were determined and correlated with histologic disease activity (Krenn 3-component synovitis score) and radiographic joint destruction (Sharp score). RESULTS: Mean sublining CD79a-positive cell density was significantly higher in RA than in OA (p <0.001) or OrthA (p = 0.003). Receiver operating characteristic curve analysis showed that CD79a-positive cell density differentiated RA well from OA [area under the curve (AUC) = 0.79] or OrthA (AUC = 0.75). Spearman's rank order correlation showed significant correlations between sublining CD79a-positive cell density and the synovitis score (r = 0.714, p < 0.001), total Sharp score (r = 0.490, p < 0.001), and the erosion subscore (r = 0.545, p < 0.001), as well as the joint space narrowing subscore (r = 0.468, p = 0.001) in RA. CONCLUSION: Synovial CD79a-positive B cells may be a helpful biomarker for histologic disease activity in RA and may be involved in the pathogenesis of joint destruction in RA.
21478189 Baseline tumour necrosis factor alpha levels predict the necessity for dose escalation of 2011 Jul OBJECTIVES: To investigate the possible role of baseline plasma tumour necrosis factor alpha levels (baseline-TNF) on the clinical response to infliximab in patients with rheumatoid arthritis (RA). METHODS: Patients with RA refractory to methotrexate received 3, 6, or 10 mg/kg of infliximab every 8 weeks, in a randomised, double-blind manner: the RISING study. Clinical response (disease activity score in 28 joints based on C-reactive protein or American College of Rheumatology core set) at week 54 and serum infliximab levels were compared in three patient groups with low, intermediate, or high baseline-TNF (TNF-low, TNF-int, or TNF-high). RESULTS: In TNF-low patients, the clinical response to different doses of infliximab was comparable, whereas TNF-int patients exhibited a dose-dependent trend. In contrast, TNF-high patients (approximately 13% of the total patients) had a clinical response to 10 mg/kg significantly better than the response to 3 and 6 mg/kg of infliximab. In TNF-high patients, the median trough serum levels of infliximab were below the detection limit (<0.1 μg/ml) at 3 and 6 mg/kg but were greater than 2 μg/ml at 10 mg/kg, whereas the levels were approximately 1 μg/ml for each dosage group in TNF-low patients. CONCLUSION: In patients with RA, baseline-TNF is significantly associated with the clinical response to infliximab in patients with a high baseline-TNF. A higher dose of infliximab may be necessary in these patients, whereas lower doses of infliximab are sufficient for those with a low baseline-TNF. Baseline-TNF may be a useful measure for personalising the treatment of RA using infliximab.
21910371 Consumption of pomegranate decreases serum oxidative stress and reduces disease activity i 2011 Aug BACKGROUND: Pomegranate extract (POMx) consumption has been shown to reduce the incidence and severity of collagen-induced arthritis in mice. OBJECTIVES: To investigate whether pomegranate consumption affects disease activity in patients with rheumatoid arthritis (RA), in relation to their serum oxidative status. METHODS: In this pilot 12 week open-labeled study eight patients with active RA consumed POMx (10 ml/day) for 12 weeks. Patients' joint status and serum oxidative status (lipid peroxidation, total thiols group, paraoxonase 1 activity) were evaluated at baseline and at week 12. RESULTS: Six patients completed the study. POMx consumption significantly (P < 0.02) reduced the composite Disease Activity Index (DAS28) by 17%, which could be related mostly to a significant (P < 0.005) reduction in the tender joint count (by 62%). These results were associated with a significant (P < 0.02) reduction in serum oxidative status and a moderate but significant (P < 0.02) increase in serum high density lipoprotein-associated paraoxonase 1 (PON1) activity. The addition of POMx to serum from RA patients reduced free radical-induced lipid peroxidation by up to 25%. CONCLUSIONS: The pomegranate consumption reduced DAS28 in RA patients, and this effect could be related to the antioxidative property of pomegranates. Dietary supplementation with pomegranates may be a useful complementary strategy to attenuate clinical symptoms in RA patients.
21081667 Peptides presented by HLA-DR molecules in synovia of patients with rheumatoid arthritis or 2011 Mar Disease-associated HLA-DR molecules, which may present autoantigens, constitute the greatest genetic risk factor for rheumatoid arthritis (RA) and antibiotic-refractory Lyme arthritis (LA). The peptides presented by HLA-DR molecules in synovia have not previously been defined. Using tandem mass spectrometry, rigorous database searches, and manual spectral interpretation, we identified 1,427 HLA-DR-presented peptides (220-464 per patient) from the synovia of four patients, two diagnosed with RA and two diagnosed with LA. The peptides were derived from 166 source proteins, including a wide range of intracellular and plasma proteins. A few epitopes were found only in RA or LA patients. However, two patients with different diseases who had the same HLA allele had the largest number of epitopes in common. In one RA patient, peptides were identified as originating from source proteins that have been reported to undergo citrullination under other circumstances, yet neither this post-translational modification nor anti-cyclic citrullinated peptide antibodies were detected. Instead, peptides with the post-translational modification of S-cysteinylation were identified. We conclude that a wide range of proteins enter the HLA-DR pathway of antigen-presenting cells in the patients' synovial tissue, and their HLA-DR genotype, not the disease type, appears to be the primary determinant of their HLA-DR-peptide repertoire. New insights into the naturally presented HLA-DR epitope repertoire in target tissues may allow the identification of pathogenic T cell epitopes, and this could lead to innovative therapeutic interventions.
22045972 Validity of quality of life measurement tools--from generic to disease-specific. 2011 Nov Health-related quality of life (HRQOL) is an important measure of a patient's perception of his/her illness. Over the past 3 decades, numerous instruments have been developed to measure HRQOL in various patient populations, with 2 basic approaches: generic and disease-specific. While generic measures have broad application across different types and severity of diseases, disease-specific measures are designed to assess particular diseases or patient populations. All HRQOL instruments, however, must be valid and have high reliability and responsiveness. Validity ensures that the instrument measures what it is supposed to measure. Reliable instruments are able to reproducibly differentiate between subjects. Responsive evaluative measures are able to detect important changes in HRQOL during a period of time, even if those changes are small. HRQOL measures should also be interpretable, meaning that the differences in scores that correspond to small, moderate, and large HRQOL changes are easily identifiable. This article describes the steps in the development of HRQOL instruments from the conceptual framework to creation and testing. Several examples of generic and disease-specific instruments commonly used to evaluate HRQOL in patients with immune-mediated inflammatory diseases (IMID) are provided.
21965111 Comparative assessment of essential and toxic metals in the blood of rheumatoid arthritis 2012 Apr The present study deals with the comparative evaluation of essential and toxic metals in rheumatoid arthritis and healthy donors. Blood samples collected from rheumatoid arthritis patients and healthy subjects were analysed for selected essential and toxic metals (Ca, Mg, Fe, Zn, Cu, Co, Mn, Cr, Cd and Pb). The samples were digested in nitric acid and perchloric acid mixture, followed by quantification of the metals using atomic absorption spectrometry. Mean levels of Ca, Mg, Fe and Zn were significantly higher in the blood of healthy donors; however, elevated levels of Cd, Co, Cr, Cu and Pb were observed in blood of the patients. The correlation coefficients among the selected metals in the blood of arthritis patients were significantly different compared with the healthy counterparts. Multivariate cluster analysis revealed mutual apportionment of the essential and toxic metals in blood of the patients, whereas, in controls, the essential and toxic metals revealed diverse apportionment. Variations in the metal levels with gender, residence and smoking habits were also evaluated in both donor groups. Relative distribution, correlation and apportionment of the essential and toxic metals in the blood of the patients were significantly different than of controls.
21647462 Assessing inflammatory bowel disease-associated antibodies in Caucasian and First Nations 2011 May BACKGROUND: First Nation populations in Canada have a very low incidence of inflammatory bowel disease (IBD). Based on typical infections in this population, it is plausible that the First Nations react differently to microbial antigens with a different antibody response pattern, which may shed some light as to why they experience a low rate of IBD. OBJECTIVE: To compare the positivity rates of antibodies known to be associated with IBD in Canadian First Nations compared with a Canadian Caucasian population. METHODS: Subjects with Crohn's disease, ulcerative colitis (UC), rheumatoid arthritis (RA) (as an immune disease control) and healthy controls without a personal or family history of chronic immune diseases, were enrolled in a cohort study aimed to determine differences between First Nations and Caucasians with IBD or RA. Serum from a random sample of these subjects (n=50 for each of First Nations with RA, First Nations controls, Caucasians with RA, Caucasians with Crohn's disease, Caucasians with UC and Caucasians controls, and as many First Nations with either Crohn's disease or UC as could be enrolled) was analyzed in the laboratory for the following antibodies: perinuclear antineutrophil cytoplasmic antibody (pANCA), and four Crohn's disease-associated antibodies including anti-Saccharomyces cerevisiae, the outer membrane porin C of Escherichia coli, I2 - a fragment of bacterial DNA associated with Pseudomonas fluorescens, and the bacterial flagellin CBir-1. The rates of positive antibody responses and mean titres among positive results were compared. RESULTS: For pANCA, First Nations had a positivity rate of 55% in those with UC, 32% in healthy controls and 48% in those with RA. The pANCA positivity rate was 32% among Caucasians with RA. The rates of the Crohn's disease-associated antibodies for the First Nations and Caucasians were comparable. Among First Nations, up to one in four healthy controls were positive for any one of the Crohn's disease-associated antibodies. First Nations had significantly higher pANCA titres in both the UC and RA groups than Caucasians. DISCUSSION: Although First Nation populations experience a low rate of IBD, they are relatively responsive to this particular antibody panel. CONCLUSIONS: The positivity rates of these antibodies in First Nations, despite the low incidence of IBD in this population, suggest that these antibodies are unlikely to be of pathogenetic significance.
22513145 The assessment of biologic treatment in patients with rheumatoid arthritis using FDG-PET/C 2012 Aug OBJECTIVES: To evaluate whether there is a correlation between the differences in joint uptake of 2-[18F]-fluoro-2-deoxy-d-glucose ((18)F-FDG) and the improvement of clinical findings in RA patients undergoing anti-TNF therapies. METHODS: Twenty-two patients who received anti-TNF therapies, including infliximab for 16 patients and etanercept for 6 patients, were assessed. PET with (18)F-FDG studies and clinical assessments were performed at baseline and 6 months after the initiation of therapy. The maximal standardized uptake value (SUV(max)) was used as a representative value for the assessment of the FDG uptake in the bilateral shoulder, elbow, wrist, hip, knee and ankle joints. Spearman's rank correlation test was applied to assess the correlation between the SUV and the clinical parameters. RESULTS: The ΔSUV (12 joints), the difference in the SUV(max) of the affected 12 joints before and after treatment, was positively correlated with the ΔDAS28 (r = 0.609, P = 0.003), ΔDAS28-CRP (r = 0.656, P = 0.001) and Δtender joint count (TJC) (r = 0.609, P = 0.003). There were also significantly positive correlations between ΔSUV (8 joints); the difference in the SUV(max) of the bilateral shoulder, elbow, wrist and knee joints before and after treatment and the ΔDAS28 (r = 0.642, P = 0.001), ΔDAS28-CRP (r = 0.712, P < 0.001) and ΔTJC (r = 0.608, P = 0.003), respectively. CONCLUSION: The FDG uptake observed in the inflamed RA joints may reflect disease activity. The FDG-PET response was correlated with the clinical response to the biologic treatment of RA.
22281228 Progressive multifocal leukoencephalopathy in autoimmune diseases. 2012 Jul Progressive multifocal leukoencephalopathy (PML) is a subacute central nervous system infection due to reactivation of the JC virus. Most reported cases occurred in HIV-infected patients (80% of cases), patients with lymphoid malignancies (13%) and transplant recipients taking immunosuppressants (5%). Less often, PML has been described in patients with chronic inflammatory joint diseases associated with autoimmune disorders (lupus, rheumatoid arthritis [RA] and vasculitis) (2%). Magnetic resonance imaging of the brain shows suggestive changes and confirmation of the diagnosis is obtained by performing PCR tests to identify the JC virus in the cerebrospinal fluid or, when necessary, a brain biopsy. No treatments have been proven effective. Most patients experience progressive disease that is fatal within a few months or induces incapacitating neurological impairments. The risk of PML is 0.4/100,000 in patients with RA. In the few case-reports of PML in RA patients, the treatments used included methotrexate (five cases) combined with a biological agent such as infliximab (one case), rituximab (four cases), or leflunomide (two cases including one with concomitant rituximab). PML is an extremely rare but devastating complication. Rituximab therapy is associated with an increased prevalence of PML in RA patients (4/100,000), who should be informed of this risk. In patients with lupus, the risk of PML is higher than in RA (4/100,000) and 40% of cases of PML occur during low-dose glucocorticoid therapy without immunosuppressive therapy.
21618198 Increased sensitivity to apoptosis induced by methotrexate is mediated by JNK. 2011 Sep OBJECTIVE: Low-dose methotrexate (MTX) is an effective therapy for rheumatoid arthritis (RA), yet its mechanism of action is incompletely understood. The aim of this study was to explore the induction of apoptosis by MTX. METHODS: Flow cytometry was performed to assess changes in the levels of intracellular proteins, reactive oxygen species (ROS), and apoptosis. Quantitative polymerase chain reaction was performed to assess changes in the transcript levels of select target genes in response to MTX. RESULTS: MTX did not directly induce apoptosis but rather "primed" cells for markedly increased sensitivity to apoptosis via either mitochondrial or death receptor pathways, by a JNK-dependent mechanism. Increased sensitivity to apoptosis was mediated, at least in part, by MTX-dependent production of ROS, JNK activation, and JNK-dependent induction of genes whose protein products promote apoptosis. Supplementation with tetrahydrobiopterin blocked these MTX-induced effects. Patients with RA who were receiving low-dose MTX therapy expressed elevated levels of the JNK target gene, jun. CONCLUSION: Our results support a model whereby MTX inhibits reduction of dihydrobiopterin to tetrahydrobiopterin, resulting in increased production of ROS, increased JNK activity, and increased sensitivity to apoptosis. The finding of increased jun levels in patients with RA receiving low-dose MTX supports the notion that this pathway is activated by MTX in vivo and may contribute to the efficacy of MTX in inflammatory disease.
22044414 Genetic and genomic predictors of anti-TNF response. 2011 Nov The introduction of anti-TNF therapy has dramatically improved the outlook for patients suffering from a number of inflammatory conditions including rheumatoid arthritis and inflammatory bowel disease. Despite this, a substantial proportion of patients (approximately 30-40%) fail to respond to these potentially toxic and expensive therapies. Treatment response is likely to be multifactorial; however, variation in genes or their expression may identify those most likely to respond. By targeted testing of variants within candidate genes, potential predictors of anti-TNF response have been reported; however, very few markers have replicated consistently between studies. Emerging genome-wide association studies suggest that there may be a number of genes with modest effects on treatment response rather than a few genes of large effect. Other potential serum biomarkers of response have also been explored including cytokines and autoantibodies, with antibodies developing to the anti-TNF drugs themselves being correlated with treatment failure.
21349387 [Interstitial mycosis fungoid: a rare variant of mycosis fungoids. Two cases]. 2011 Feb Mycosis fungoids can present with various clinical and histological features, with only a few of them being recognized as distinct entities in the current WHO and EORTC classifications. Histologically, mycosis fungoids (MF) usually show a superficial perivascular or band-like lymphocytic infiltrate with epidermotropism. We here report two cases of a rare histological variant of MF, called interstitial in the literature. Our first patient, a 71-year-old male, had a previously diagnosed MF, which clinically evolved towards nodules, showing histologically an interstitial lymphocytic infiltrate without epidermotropism and without large cell transformation. The second patient was a 64-year-old female with widespread plaques and nodules. Histologically, a dense dermal interstitial infiltrate was observed, with foci of epidermotropism, without large cell transformation. At relapse after treatment, she presented with plaques, papules and nodules, histologically showing a slight interstitial lymphocytic infiltrate that resembled granuloma annulare or inflammatory morphea. In both patients, clinical aspect suggested MF and a dominant T-cell clone was found in lesional skin. Nodules in MF are not always the hallmark of large cell transformation, but may correspond to unusual interstitial lesions. Diagnosis of such rare variant may be difficult and requires a good clinical pathological correlation together with the search for foci of epidermotropism on skin biopsy and for a dominant cutaneous T-cell clone.
22955636 Retinal vasculitis in rheumatic diseases: an unseen burden. 2013 Jan Retinal vascular inflammation, a potentially blinding condition (herein: retinal vasculitis (RV)) is commonly associated with a heterogeneous group of diseases characterized by systemic inflammatory cell infiltration and/or necrosis of blood vessel walls. RV may arise as an isolated ocular disorder, as part of systemic vasculitis (Wegener's granulomatosis and Adamantiadis-Behcet Disease), or it can be secondary to an underlying connective tissue disease (systemic lupus erythematosus, sarcoidosis, and rheumatoid arthritis), systemic infection, or malignancy. Depending on the type of RV, it can be a potentially disabling condition, in the short or long term. Early diagnosis is the key to successful treatment and better prognosis. However, early diagnosis can be difficult, because these conditions usually present with nonspecific visual symptoms for a long period before diagnostic manifestations occur. The retina should be examined in warranted patients with verified rheumatic disease, since retinal vasculitis may be asymptomatic at the beginning (peripheral retinal disease). RV can be detected clinically (often accompanied by uveitis, scleritis, or macular edema) or revealed on fluorescein fundus angiography, even if minimal signs of retinal vessel inflammation are present. RV may also represent one of the possible extra-articular manifestations of the rheumatic disease. Rheumatologists should be familiar with the ocular manifestations of these disorders, since they may not only be sight-threatening, but more importantly, could be the presenting or even the very first manifestations of active, potentially lethal systemic disease in a patient with nonspecific rheumatologic presentation.
22942404 The efficacy of biologic agents in patients with rheumatoid arthritis and an inadequate re 2012 Dec OBJECTIVE: To assess the relative efficacy of subsequent biologic therapies in patients with RA who have had an inadequate response to prior therapy with a TNF-α inhibitor. METHODS: A systematic review was conducted using the MEDLINE, Embase and Cochrane Library databases and abstract lists from the European League Against Rheumatism, American College of Rheumatology and British Society of Rheumatology congresses. Searches covered the period from May 2009 (August 2009 for MEDLINE) to January 2011. Therapies considered were abatacept, adalimumab, etanercept, infliximab and rituximab, used at European licensed standard dose regimens. RESULTS: Four full publications and 41 congress abstracts met the criteria for inclusion. Significant improvements in RA signs and symptoms were reported for TNF inhibitors (individual agents or groups of agents, depending on the study) and for abatacept and rituximab. Rituximab was also associated with significantly improved radiographic outcomes. No head-to-head randomized controlled trials directly comparing different agents were published during the search period. Comparative data from registries and other observational studies suggest that rituximab is at least as effective as an alternative TNF inhibitor, and in some studies significantly more effective, in TNF inadequate responders. CONCLUSIONS: RA patients with an inadequate response to one or more TNF inhibitors derive significant clinical benefit from subsequent therapy with an alternative TNF inhibitor or with rituximab or abatacept. Prospective randomized controlled trials are needed to help physicians in the best choice of further therapy for their patients.
21645266 P2X7 receptor gene polymorphism analysis in rheumatoid arthritis. 2011 Oct The P2X7 receptor, a member of the P2X family of nucleotide-gated channels, is predominantly expressed by monocytic cells. The activation of this receptor has been associated with downstream-signalling cascades, resulting in the release of a number of inflammatory mediators. There are more than 815 single nucleotide polymorphisms (SNPs) that have been described in the human P2X7R gene, but only few have been functionally characterized. The main aim of this study is to determine whether P2X7R gene polymorphisms confer susceptibility to rheumatoid arthritis (RA). A total of 125 patients with RA and 158 healthy volunteers were enrolled in this study. DNA fragment was PCR amplified and sequenced on the AB 3130 Genetic Analyzer. No significant difference in allele frequencies of 489 C→T, 1096 C→G and 1513 A→C polymorphisms, among sporadic cases of RA and healthy controls was found. However, the 1513A/C genotype was significantly associated with the presence of rheumatoid factor and anti-MCV autoantibody in RA patients. Interestingly, the genotype frequency of 1068 A/A was 0.19 in the RA group and 0.09 in control group (P = 0.025). Consequently, this polymorphism (AA) is two folds greater in the RA group compared to controls. Moreover, this polymorphism was significantly associated with mean concentration of C-reactive protein in RA patients. In contrast, 946G→A and 1729 T→A were not detected in both groups. As a result, these two polymorphisms are uncommon in Omani Arab population. Polymorphism at position 1068 and 1513 in the P2X7R gene might contribute to the pathogenesis of RA. Moreover, the loss-of-function SNP at position 1096 C→G or the gain-of-function SNP at position 489 C→T of the P2X7 gene does not appear to be a susceptibility gene locus for the development of RA. Further studies are required to confirm this finding.
22108001 Detection of autoantibodies to citrullinated BiP in rheumatoid arthritis patients and pro- 2011 INTRODUCTION: Anti-citrullinated protein/peptide antibodies (ACPAs) are highly specific to rheumatoid arthritis (RA) patients and are thought to have a close relationship with the pathogenesis of arthritis. Several proteins, including fibrinogen, vimentin, and alpha-enolase, were reported as ACPA-target antigens, and their importance in RA pathogenesis was widely proposed. We identified citrullinated immunoglobulin binding protein (citBiP) as another ACPA target in RA patients and examined its pro-inflammatory role in arthritis. METHODS: We measured the levels of anti-citBiP, anti-BiP, and anti-cyclic citrullinated peptide (CCP) antibodies in the serum of RA patients (n = 100), systemic lupus erythematosus (SLE) patients (n = 60), and healthy controls (n = 30) using ELISA and immunoblotting. Epitope mapping was performed using 27 citBiP-derived peptides. In the mouse study, after DBA/1J mice were immunized with BiP or citBiP, serum titers of ACPAs were measured by ELISA and immunohistochemistry. The development of collagen-induced arthritis (CIA) was observed in BiP- or citBiP-pre-immunized mice. RESULTS: The serum levels of anti-BiP and anti-citBiP antibodies were significantly increased in RA patients, although only anti-BiP antibodies were slightly increased in SLE patients. Interestingly, anti-citBiP antibody levels were higher than anti-BiP antibody levels in 72% of RA patients, whereas no significant increase in anti-citBiP antibody levels was detected in SLE patients and healthy controls. The serum levels of anti-CCP antibodies were correlated with those of anti-citBiP antibodies in RA patients (R2 = 0.41). Several citrulline residues of citBiP were determined to be major epitopes of anti-citBiP antibodies, one of which showed cross-reactivity with CCP. Immunization of DBA/1J mice with citBiP induced several kinds of ACPAs, including anti-CCP and anti-citrullinated fibrinogen antibodies. Pre-immunization with citBiP exacerbated CIA, and anti-CCP antibody levels were increased in citBiP-pre-immunized CIA mice. CONCLUSIONS: CitBiP is a newly described ACPA target that may play a pro-inflammatory role in arthritis.
22660799 Use of the 28-joint count yields significantly higher concordance between different examin 2012 Jul OBJECTIVE: Joint counts are the key outcome measure in rheumatoid arthritis (RA). There is a great variability between different assessors of the same patient; this variability can be reduced by standardized training. The training effect is far less pronounced for the 66/68-joint count compared to the 28-joint count. We evaluated the reason for the higher interrater disagreement in the 66/68 compared to the 28-joint count. METHODS: Participants in joint examination seminars evaluated a patient with RA before and after training in the European League Against Rheumatism technique. Joints were rated positive or negative for tenderness and swelling. The number of positive joints and the variability between examiners before and after the training were compared. Concordance was calculated for every single joint using the Fleiss-Kappa test. RESULTS: In total, 256 health professionals were instructed in the 66/68-joint count and 84 in the 28-joint count. The disagreement between examiners was higher for swelling than for tenderness. After the training, there was a significant reduction of interrater variability, which was more pronounced in the 28 than in the 66/68-joint count. Comparisons between joint counts revealed that the joints of the feet were more likely to be rated negative, yet interrater disagreement was still high. CONCLUSION: Standardization of joint examination significantly reduces variability between assessors. The better performance of the 28-joint count is due to the lower number of joints examined, especially the foot joints, which remain difficult to assess reliably even after training.
22614743 The interferon signature and STAT1 expression in rheumatoid arthritis synovial fluid macro 2012 Oct OBJECTIVE: Type I interferons (IFNs) have emerged as potential activators of the IFN signature and elevated STAT-1 expression in rheumatoid arthritis (RA) synovium, but mechanisms that induce synovial IFN expression are unknown. Recently, tumor necrosis factor α (TNFα) was shown to induce a delayed IFN response in macrophages. We undertook this study to test whether TNFα, classically thought to activate inflammatory NF-κB target genes in RA, also contributes to the "IFN signature" in RA synovial macrophages. METHODS: Synovial fluid (SF) macrophages purified from 24 patients with RA and 18 patients with spondylarthritides (SpA) were lysed immediately after isolation or were cultured ex vivo in the absence or presence of blockade of endogenous type I IFN or TNFα. Expression of IFN-inducible target genes was measured by quantitative reverse transcription-polymerase chain reaction, and expression of their corresponding proteins was measured by enzyme-linked immunosorbent assay. RESULTS: Expression of an IFN signature and STAT1 in RA synovial macrophages was suppressed when type I IFNs or TNFα were blocked, whereas TNFα blockade did not affect expression of IFN response genes or STAT1 in SpA synovial macrophages. RA SF suppressed the IFN signature in RA synovial macrophages and in TNFα-, IFNα-, and IFNβ-stimulated control macrophages. Type I IFNs suppressed expression of IL8 and MMP9 in RA synovial macrophages and in TNFα-stimulated control macrophages. CONCLUSION: Our findings identify a new function of TNFα in RA synovitis by implicating TNFα as a major inducer of the RA synovial IFN response. The results suggest that the expression of IFN response genes in RA synovium is regulated by interplay between TNFα and opposing homeostatic factors expressed in the synovial microenvironment.