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Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
21519861 Exact break point of a 50 kb deletion 8 kb centromeric of the HLA-A locus with HLA-A*24:02 2011 Aug In a structural aberration analysis of patients with arthritis mutilans, a 50 kb deletion near the HLA-A locus with HLA-A*24:02 allele was detected. It was previously reported that HLA-A*24:02 haplotype harbored a large-scale deletion telomeric of the HLA-A gene in healthy individuals. In order to confirm that the deletion are the same in patients with arthritis mutilans and in healthy individuals, and to identify the break point of this deletion, the boundary sequences across the deletion in A*24:02 was amplified by polymerase chain reaction (PCR) as a 3.7 kb genomic fragment and subjected to nucleotide sequence determination. A comparison of these genomic sequences with those of the non-A*24:02 haplotype revealed that the deleted genomic region spanning 50 kb was flanked by 3.7 kb repetitive element-rich segments homologous to each other on both sides in non-A*24. The nucleotide sequences of the PCR products were identical in patients with arthritis mutilans and in healthy individuals, revealing that the deletion linked to A*24:02 is irrelevant to the onset of arthritis mutilans. The deletion was detected in all other A*24 alleles so far examined but not in other HLA-A alleles, except A*23:01. This finding, along with the phylogenic tree of HLA-A alleles and the presence of the 3.7 kb highly homologous segments at the boundary of the deleted genomic region in A*03 and A*32, may suggest that this HLA-A*24:02-linked deletion was generated by homologous recombination within two 3.7 kb homologous segments situated 50 kb apart in the ancestral A*24 haplotype after divergence from the A*03 and A*32 haplotypes.
22752502 The time course of gastric methotrexate intolerance in patients with rheumatoid arthritis 2013 May OBJECTIVES: This study aimed to evaluate the incidence and the time course of methotrexate (MTX)-associated gastric intolerance in patients with rheumatoid arthritis and psoriatic arthritis. METHODS: Four hundred twenty subjects undergoing MTX treatment for rheumatoid arthritis (n = 346) and psoriatic arthritis (n = 74) were retrospectively assessed. The incidence and time course of gastric MTX intolerance resulting in treatment discontinuation were investigated. In addition, the relations between gastric intolerance and patient characteristics, including gender, age, diagnosis, and rheumatoid factor (RF) positivity, were examined. RESULTS: Overall, oral MTX discontinuation rate due to gastric intolerance was 28.6 %. The time to discontinuation for oral MTX was 8.1 ± 11.5 months on average, with more than half of the discontinuations occurring within the first three months of treatment. Discontinuation was not associated with gender, age, diagnosis, or RF positivity. More than half of the patients that switched to a parenteral treatment regimen (52.6 %, 20/38) could tolerate the agent. CONCLUSIONS: Gastric MTX intolerance usually develops within the first year of treatment and presents a major obstacle to long-term treatment retention in patients with rheumatologic disease. However, parenteral MTX appears to be a good alternative for patients intolerant of oral MTX.
21622953 ICSNPathway: identify candidate causal SNPs and pathways from genome-wide association stud 2011 Jul Genome-wide association study (GWAS) is widely utilized to identify genes involved in human complex disease or some other trait. One key challenge for GWAS data interpretation is to identify causal SNPs and provide profound evidence on how they affect the trait. Currently, researches are focusing on identification of candidate causal variants from the most significant SNPs of GWAS, while there is lack of support on biological mechanisms as represented by pathways. Although pathway-based analysis (PBA) has been designed to identify disease-related pathways by analyzing the full list of SNPs from GWAS, it does not emphasize on interpreting causal SNPs. To our knowledge, so far there is no web server available to solve the challenge for GWAS data interpretation within one analytical framework. ICSNPathway is developed to identify candidate causal SNPs and their corresponding candidate causal pathways from GWAS by integrating linkage disequilibrium (LD) analysis, functional SNP annotation and PBA. ICSNPathway provides a feasible solution to bridge the gap between GWAS and disease mechanism study by generating hypothesis of SNP → gene → pathway(s). The ICSNPathway server is freely available at http://icsnpathway.psych.ac.cn/.
23149637 Anti-Ro antibodies in rheumatoid arthritis. 2012 Apr BACKGROUND: Some autoantibodies are associated with peculiar clinical findings. Patients with rheumatoid arthritis (RA) may have anti-Ro antibodies. OBJECTIVE: To study prevalence and clinical associations of anti-Ro antibodies in RA patients. METHODS: We studied 385 patients with RA for anti-Ro by Elisa testing and for clinical profile, functional assessment, DAS-28 4v. (ESR), extra-articular manifestations, thyroid function, autoantibodies and treatment. RESULTS: The prevalence of anti-Ro was 8.31%. There was no significant difference in sex distribution, HAQ, DAS-28 or functional classification in patients with positive anti-Ro (p=ns). Patients with anti-Ro were younger at diagnosis (p=0.02). Analyzing extra-articular disorders we found a greater prevalence of cardiac valvular lesions (p<0.001) in patients with anti-Ro antibodies. No differences were found in other extra-articular manifestations, associated hypothyroidism, amyloidosis, treatment requirements, presence of rheumatoid factor (RF) or anti citrullinated protein antibodies (ACPA). CONCLUSIONS: We conclude that in RA patients with anti-Ro have disease onset at an earlier age. Anti-Ro may be a risk factor for the development of cardiac valvular lesions. There was no association between this antibody and thyroid disease, amyloidosis and treatment needs.
21927902 Chemical synovectomy with sodium morrhuate in the treatment of symptomatic recurrent knee 2012 Oct The aim of this study was to assess the efficacy and safety of intra-articular sodium morrhuate injections in the treatment of recurrent knee joint effusions. Ninety-eight knees of 92 patients (f = 59, m = 33) with knee arthritis of heterogeneous etiology were treated with chemical synovectomy (CSO). Of those, 39 patients suffered from rheumatoid arthritis (RA). The mean follow-up was 29.8 months. Clinical outcome was evaluated by analyzing subjective patient satisfaction, activity level, pain severity on the basis of the Visual Analogue Pain Scale (VAS), Lysholm and Gillquist score, and the Knee Injury and Osteoarthritis Outcome Score (KOOS). Fifty-seven percent of all patients and 67% of patients diagnosed with RA were satisfied with CSO. No significant effects on patient satisfaction by CSO were noted in patients older than 40 years. Overall, VAS, Lysholm and Gillquist score, and KOOS improved significantly at final review. The intra-articular application of sodium morrhuate is an effective and safe measure in the treatment of recurrent symptomatic knee joint effusions in young patients suffering from recurrent knee joint effusions.
22918932 Immune complex-induced inhibition of osteoclastogenesis is mediated via activating but not 2013 Feb OBJECTIVE: To investigate the role of Fcγ receptors (FcγRs) in osteoclastogenesis and osteoclast function. METHODS: Bone destruction was analysed in arthritic knee joints of several FcγR-knockout mouse strains. Unfractionated bone marrow cells were differentiated in vitro towards osteoclasts in the absence or presence of immune complexes (ICs) and stimulated thereafter for 24 h with tumour necrosis factor α (TNFα) or lipopolysaccharide (LPS). In addition, mature osteoclasts were stimulated with ICs. Experiments were analysed for osteoclast formation, bone resorption and the expression of FcγRs and osteoclast markers. RESULTS: Bone destruction was significantly increased in arthritic knee joints of FcγRIIB-deficient mice. All FcγR classes were highly expressed on osteoclast precursors. Expression of the inhibitory FcγRIIB was similar on mature osteoclasts compared to macrophages, whereas activating FcγR levels were significantly lower. IC stimulation of mature osteoclasts did not affect their number or their bone resorptive capacity. ICs significantly inhibited differentiation of unfractionated bone marrow cells towards osteoclasts, bone resorption and expression of osteoclast markers. In the presence of ICs, osteoclastogenesis of FcγRIIB(-/-) precursors and bone resorption remained inhibited. In contrast, ICs could not inhibit osteoclast formation or bone resorption of FcRγ-chain(-/-) precursors. When IC-inhibited osteoclastogenesis was followed by stimulation with TNFα or LPS, the inhibitory effects of ICs were overruled. CONCLUSION: Activating FcγRs mediate IC-induced inhibition of osteoclastogenesis, which might be overruled in the presence of proinflammatory mediators. This suggests that the balance of FcγR-mediated inflammation, through proinflammatory cytokine production, as well as the direct inhibitory effect of ICs on osteoclastogenesis determines the net effect on bone loss.
22349880 Hepatitis B virus reactivation in rheumatoid arthritis and ankylosing spondylitis patients 2012 Jun Clinical guidelines regarding anti-viral prophylaxis for HBV surface antigen (HBsAg) carriers starting anti-TNFα agents are not yet fully established, even in endemic regions of HBV infection. We retrospectively collected the clinical data of 52 HBsAg carriers with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) that had been administered anti-TNFα treatment at seven medical centers in South Korea. Periodic data of liver function tests and serum HBV DNA were both utilized to assess HBV reactivation. The YMDD motif mutation of HBV DNA polymerase was tested in lamivudine-treated patients with elevated HBV DNA. Three of the 52 patients were excluded from the analysis. Of the 49 analyzed patients, 20 patients received anti-viral prophylaxis (15 lamivudine, five entecavir) with anti-TNFα treatment. The remaining 29 patients were treated with anti-viral agents if needed at the discretion of the clinician and did not receive prophylaxis. Of the 29 patients who did not receive primary prophylaxis, two (6.9%) developed viral reactivation within a year of anti-TNFα treatment. In the prophylaxis group, one patient developed viral reactivation at week 64 of anti-TNFα therapy attributed to YMDD mutation caused by lamivudine. Patients with HBV reactivation all responded well to anti-viral therapy. In summary, anti-viral prophylaxis helped preventing HBV reactivation in HBsAg carriers with RA or AS starting anti-TNFα, yet mutation in the YMDD motif of HBV DNA polymerase could be detrimental to some patients under long-term lamivudine prophylaxis.
22550316 Incomplete response of inflammatory arthritis to TNFα blockade is associated with the Th1 2012 Oct OBJECTIVES: To establish if changes in Th1/Th17 cell populations previously reported in experimental arthritis occur in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor α (TNFα) agents, and whether the therapeutic response to anti-TNFα is compromised in patients and mice because of elevated Th17/IL-17 levels. Finally, to assess the efficacy of combined blockade of anti-TNFα and anti-IL-17 in experimental arthritis. METHODS: A longitudinal study of two independent cohorts (cohort 1, n=24; cohort 2, n=19) of patients with RA treated with anti-TNFα biological agents was carried out to assess their Th17/IL-17 levels before and after the start of anti-TNFα therapy. IL-12/23p40 production was assessed in plasma Peripheral blood lymphocytes (PBLs) and monocytes. Mice with collagen-induced arthritis (CIA) were treated with anti-TNFα alone, anti-IL17 alone or a combination of the two. Efficacy of treatment and response was assessed from changes in Disease Activity Score 28-erythrocyte sedimentation rate scores in patients, and in clinical scores and histological analysis in CIA. RESULTS: Significant increases in circulating Th17 cells were observed in patients after anti-TNFα therapy and this was accompanied by increased production of IL-12/23p40. There was an inverse relationship between baseline Th17 levels and the subsequent response of patients with RA to anti-TNFα therapy. In addition, PBLs from non-responder patients showed evidence of increased IL-17 production. Similarly, in anti-TNFα-treated mice, there was a strong correlation between IL-17 production and clinical score. Finally combined blockade of TNFα and IL-17 in CIA was more effective than monotherapy, particularly with respect to the duration of the therapeutic effect. CONCLUSIONS: These findings, which need to be confirmed in a larger cohort, suggest that a Th17-targeted therapeutic approach may be useful for anti-TNFα non-responder patients or as an adjunct to anti-TNFα therapy, provided that safety concerns can be addressed.
23000565 Association of angiotensin converting enzyme (ACE) gene I/D polymorphism and rheumatoid ar 2012 Dec 10 We sought to determine the frequency of I/D polymorphism genotypes of angiotensin converting enzyme gene in Turkish patients with rheumatoid arthritis. Genomic DNA obtained from 256 individuals (110 patients with rheumatoid arthritis and 146 healthy controls) was used in the study. ACE gene I/D polymorphism genotypes were determined using polymerase chain reaction using I and D allele-specific primers. There was a statistically significant difference between the groups with respect to genotype distribution (p=0.001). A significant difference was found in frequencies of ACE I/D alleles between patients and controls, with RA patients having a higher representation of D and lower representation of I alleles compared to controls (p<0.001). As a result of our study, angiotensin converting enzyme gene I/D polymorphism DD genotype could be a genetic marker in rheumatoid arthritis in the Turkish study population.
21482748 Immune complexome analysis of serum and its application in screening for immune complex an 2011 Jun BACKGROUND: Analysis of circulating immune complexes (CICs) produced during an immune response may be useful in elucidating some aspects of this process. Identification of antigens incorporated into CICs provides information that may be helpful in developing diagnostic and treatment strategies for autoimmune diseases, infection, cancer, and transplantation therapy, and such information might be more relevant than information on free antigens. Because CICs may contain many antigens, comprehensive identification and profiling of such antigens is more effective than immunoblotting detection. METHODS: We developed a novel proteomic strategy (immune complexome analysis) in which immune complexes (ICs) are separated from serum, digested directly with trypsin, and then subjected to nano-liquid chromatography-tandem mass spectrometry for identifying and profiling antigens in CICs. We applied this strategy to the analysis of CICs in 21 rheumatoid arthritis (RA) patients. Serum samples from 13 healthy donors and 8 osteoarthritis patients were used as controls. RESULTS: CICs containing thrombospondin-1 (TSP-1) and platelet factor 4 (PF4) were found in the serum of 81% and 52% of RA patients, respectively, and in none of the controls. CONCLUSIONS: The ICs in the serum of a majority of the RA patients contained TSP-1 or PF4, and these ICs may have potential as alternative biomarkers. Our technique for immune complexome analysis uses routine clinical samples, simple protocols, and widely available equipment. This method may be generally applicable to the study of the relationship between CICs and certain diseases associated with the immune response in animals and humans.
21510862 Decrease in the incidence of total hip arthroplasties in patients with rheumatoid arthriti 2011 Apr 21 INTRODUCTION: One aim of modern pharmacologic treatment in rheumatoid arthritis (RA) is to prevent joint destruction and reduce the need for surgery. Our purpose was to investigate secular trends in the incidence of primary total hip and knee arthroplasties in a well defined sample of patients with RA. METHODS: Prevalent cases with RA in 1997 and incident cases from 1997 to 2007 in a community based register in Malmö, south Sweden, were included. Based on a structured review of the medical records, patients were classified according to the 1987 ACR criteria for RA. This cohort was linked to the Swedish Hip Arthroplasty Register (through December 2006) and the Swedish Knee Arthroplasty Register (through October 2007). Patients with a registered total hip or knee arthroplasty before 1997 or before RA diagnosis were excluded. Incidence rates for the period of introduction of TNF inhibitors (1998 to 2001) were compared to the period when biologics were part of the established treatment for severe RA (2002 to 2006/2007). RESULTS: In the cohort (n = 2,164; 71% women) a primary hip arthroplasty was registered for 115 patients and a primary knee arthroplasty for 82 patients. The incidence of primary total hip arthroplasties decreased from the period 1998 to 2001 (12.6/1,000 person-years (pyr)) to 2002 to 2006 (6.6/1,000 pyr) (rate ratio (RR) 0.52; 95% confidence interval (CI) 0.35 to 0.76). There was a trend towards an increase of primary knee arthroplasties (incidence 4.8/1,000 pyr vs. 6.8/1,000 pyr; RR 1.43; 95% CI 0.89 to 2.31). CONCLUSIONS: Our investigation shows a significant decrease in the incidence of total hip arthroplasties in patients with RA after 2001. Possible explanations include a positive effect on joint damage from more aggressive pharmacological treatment.
23284953 Transport mechanisms and their pathology-induced regulation govern tyrosine kinase inhibit 2012 BACKGROUND: Tyrosine kinase inhibitors (TKIs) are effective in treating malignant disorders and were lately suggested to have an impact on non-malignant diseases. However, in some inflammatory conditions like rheumatoid arthritis (RA) the in vivo effect seemed to be moderate. As most TKIs are taken up actively into cells by cell membrane transporters, this study aimed to evaluate the role of such transporters for the accumulation of the TKI Imatinib mesylates in RA synovial fibroblasts as well as their regulation under inflammatory conditions. METHODOLOGY/PRINCIPAL FINDINGS: The transport and accumulation of Imatinib was investigated in transporter-transfected HEK293 cells and human RA synovial fibroblasts (hRASF). Transporter expression was quantified by qRT-PCR. In transfection experiments, hMATE1 showed the highest apparent affinity for Imatinib among all known Imatinib transporters. Experiments quantifying the Imatinib uptake in the presence of specific transporter inhibitors and after siRNA knockdown of hMATE1 indeed identified hMATE1 to mediate Imatinib transport in hRASF. The anti-proliferative effect of Imatinib on PDGF stimulated hRASF was quantified by cell counting and directly correlated with the uptake activity of hMATE1. Expression of hMATE1 was investigated by Western blot and immuno-fluorescence. Imatinib transport under disease-relevant conditions, such as an altered pH and following stimulation with different cytokines, was also investigated by HPLC. The uptake was significantly reduced by an acidic extracellular pH as well as by the cytokines TNFα, IL-1β and IL-6, which all decreased the expression of hMATE1-mRNA and protein. CONCLUSION/SIGNIFICANCE: The regulation of Imatinib uptake via hMATE1 in hRASF and resulting effects on their proliferation may explain moderate in vivo effects on RA. Moreover, our results suggest that investigating transporter mediated drug processing under normal and pathological conditions is important for developing intracellular acting drugs used in inflammatory diseases.
20820842 Insulin-like growth factor binding protein-related protein 1 is expressed in rheumatoid sy 2011 Feb Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is a secretory protein that shares a structural similarity with IGFBP. Studies have shown that IGFBP-rP1 synergistically increases fibroblast growth with insulin and stimulates angiogenesis in tumor tissues. In this report, we examined the expression and function of IGFBP-rP1 in rheumatoid arthritis (RA). IGFBP-rP1 expression in synovial tissues was examined by reverse transcription-polymerase chain reaction (RT-PCR), real-time PCR, and immunohistochemical analysis. In vitro, IGFBP-rP1 expression was examined in synovial fibroblasts established from rheumatoid synovium (RASFs) by RT-PCR, Western blot, and immunostaining. The effect of IGFBP-rP1 small interfering RNA (siRNA) on RASF proliferation was assessed by alamarBlue assay. IGFBP-rP1 mRNA was detected by RT-PCR in all synovial tissues from RA and OA patients. In immunohistochemical analysis, IGFBP-rP1 was mainly expressed in synovial cells in the lining layers and endothelial cells in the sublining layers of RA synovium. In vitro, constitutive expression of IGFBP-rP1 in RASFs was detected by RT-PCR, Western blot, and immunostaining. Treatment with IGFBP-rP1 siRNA induced a 26% decrease in RASF growth compared to control siRNA. A similar extent of growth-suppressive effect by IGFBP-rP1 siRNA was also observed when RASF proliferation was induced by TNF-α. Collectively, these data suggest that IGFBP-rP1 may regulate synovial fibroblast proliferation in RA.
22021224 The immunomodulatory effects of Ipomoea carnea in rats vary depending on life stage. 2011 Oct Ipomoea carnea Jacq. ssp. fistulosa (Mart. Ex Choisy; Convolvulaceae; I. carnea) possesses a toxic component: an indolizidine alkaloid swainsonine (SW) that has immunomodulatory effects due to its inhibition of glycoprotein metabolism. It is also known that SW is excreted into both the amniotic fluid and milk of female rats exposed to I. carnea. Thus, the aim of this study was to determine whether SW exposure, either in utero or from the milk of dams treated with I. carnea, modulates offspring immune function into adulthood. In addition, adult (70 days old) and juvenile rats (21 days old) were exposed to I. carnea in order to evaluate several other immune parameters: lymphoid organs relative weight and cellularity, humoral and cellular immune responses. Offspring exposed to I. carnea during lactation developed rheumatoid arthritis (RA) in adulthood after an immunogenic challenge. In addition, both adult and juvenile rats exposed to I. carnea showed discrepancies in several immune parameters, but did not exhibit any decrease in humoral immune response, which was enhanced at both ages. These findings indicate that SW modulates immune function in adult rats exposed to SW during lactation and in juvenile and adult rats exposed to SW as juveniles and adults, respectively.
21809006 Disturbed Th17/Treg balance in patients with rheumatoid arthritis. 2012 Sep Proinflammatory Th17 cells and CD4(+)CD25(+) regulatory T (Treg) cells are two newly identified T lymphocyte subsets, which have opposite effects on autoimmunity and inflammation. To assess the Th17/Treg pattern and cytokine microenvironment in peripheral blood of patients with RA, we included 66 RA patients and 20 healthy volunteers. Of all these subjects, peripheral Th17 and Treg frequencies were analyzed by flow cytometry (FCM) and the plasma levels of interleukin (IL)-17, 23, 6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1 were detected by ELISA. The results demonstrated that RA patients revealed an obvious increase in peripheral Th17 frequencies and levels of Th17-related cytokines (IL-17, IL-23, IL-6, TNF-α) while a significant decrease in Treg frequencies and Treg-related cytokine (TGF-β1) levels when compared with healthy people. Our study indicated that development of RA is associated with peripheral Th17/Treg imbalance and characterized by a proinflammatory cytokine microenvironment, which supports continuing generation of Th17 cells.
22586176 Childhood socioeconomic factors and perinatal characteristics influence development of rhe 2013 Mar BACKGROUND: Rheumatoid arthritis (RA) has been associated with lower socioeconomic status (SES), but the reasons for this are not known. OBJECTIVE: To examine childhood SES measures, SES trajectory and other perinatal factors in relation to RA. METHODS: The sample included 50 884 women, aged 35-74 (84% non-Hispanic white) enrolled 2004-9 in a US national cohort study. In baseline questionnaires, cases (N=424, 0.8%) reported RA diagnosis after age 16, ever use of disease-modifying antirheumatic drugs or steroids for RA and ≥6 weeks bilateral joint swelling. Childhood SES measures are presented as OR and 95% CI adjusted for age and race/ethnicity. Analyses of perinatal factors also adjusted for childhood SES, and joint effects of childhood and adult SES and smoking exposures were evaluated. RESULTS: Patients with RA reported lower childhood household education (<12 years vs college degree; OR=1.7; 95% CI 1.1 to 2.5), food insecurity (OR=1.5, 95% CI 1.1 to 2.0) and young maternal age (<20 vs 20-34 years; OR=1.7, 95% CI 1.2 to 2.5), with a trend (p<0.0001) for increasing number of adverse factors (OR=3.0; 95% CI 1.3 to 7.0; 4 vs 0 factors) compared with non-cases. Low birth weight (<2500 g) [corrected] and preconception paternal smoking were independently associated with RA. Together, lower childhood SES and adult education (
22516039 A randomized, double-blind, parallel, single-site pilot trial to compare two different sta 2012 May BACKGROUND: Methotrexate (MTX) is a cornerstone in the treatment of rheumatoid arthritis. Despite its widespread use, expert opinions differ about the optimal MTX starting dosage to achieve rapid onset of action while averting increased occurrence of adverse effects. Plasma concentrations have not been assessed in previous studies that monitored clinical efficacy. OBJECTIVE: This study was performed to compare the pharmacokinetic parameters and clinical response of a standard (15 mg) and an accelerated (25 mg) dosing regimen, each administered orally once a week. METHODS: This randomized, controlled, double-blind, parallel, single-site study included 19 MTX-naïve patients older than 18 years with rheumatoid arthritis. Patients participated for 16 weeks. Disease activity was assessed using the Disease Activity Score in 28 joints (DAS-28) as the primary outcome parameter. Plasma MTX concentrations were measured using HPLC at weeks 1, 5, 10, and 16. Tolerability was assessed via routine blood analysis (hematology and clinical chemistry) and a patient questionnaire to monitor adverse events. Reported or observed adverse events were recorded along with information about their severity and causal relationship to the study medication. RESULTS: Nineteen white patients (13 women and 6 men; mean age, 56 years; and mean weight, 74 kg) participated. At study entry, mean (SD) DAS-28-4v (erythrocyte sedimentation rate) was 4.73 (1.02). Health Assessment Questionnaire scores were 1.45 (0.85); for C-reactive protein, 11.45 (10.04) mg/dL; for alkaline phosphatase, 73.58 (19.91) U/L; for aspartate aminotransferase, 23.32 (7.13) U/L; and for creatinine, 0.87 (0.22) mg/dL. Although pharmacokinetic parameters such as AUC and C(max) were significantly higher after the accelerated dosing regimen, clinical activity scores (DAS-28) and inflammation parameters (C-reactive protein) did not indicate a significant benefit of an accelerated starting regimen. Considering toxicity, no elevation in liver function enzymes and no decrease in renal function were observed using the accelerated dosing (statistical significance set at P ≤ 0.05). No serious adverse events were noted. All observed adverse events were classified as study related. Overall, adverse events were noted in 58% of patients. Comparison of the two doses revealed that 60% of patients receiving the standard dosing regimen and 56% of patients receiving the accelerated dosing regimen reported adverse events, the most frequent being gastrointestinal. These events were generally self-limiting. CONCLUSIONS: Differences in clinical response between these two small selected patient groups who received an initial oral dose of either 15 or 25 mg MTX per week did not reach the level of statistical significance. The overall incidence of adverse effects, all classified as study related, was 58%, with 60% of patients receiving the standard dosage and 56% of patients receiving the accelerated dosing regimen reporting adverse effects. However, because of the small sample size, this study was not powered to detect differences in the incidence of adverse events between the two dosing groups. ClinicalTrials.gov identifier: NCT00695188.
21932657 [Periodontal therapy for rheumatoid arthritis: a systematic review]. 2011 Aug OBJECTIVE: To assess the effect and safety of periodontal therapy in relieving the symptoms and clinical signs of rheumatoid arthritis (RA). METHODS: The electronic search was conducted in Medline (OVID, 1950-2010 Sep), EMBASE (1984-2010 Sep), CENTRAL (2010, Issue 3), CBM (1978-2010 Sep) and the Chinese journals on stomatology were hand-searched. Clinical randomized controlled trials as well as clinical controlled trials were selected regarding the targeted issue. Two investigators evaluated the reporting quality and risk of bias of those included trials in accordance with CONSORT statement and Cochrane risk of bias assessment tools, and collected data of included studies in duplicate. Revman 5.0.23 was applied for Meta-analysis. RESULTS: Four trials met the inclusion criteria and a total of 150 patients were enrolled in the trials, one had low risk of bias and others had moderate risk of bias. Meta-analysis showed that pure periodontal therapy could not decrease disease activity score in 28 joints (DAS28) (P=0.06), and there was no statistically significant difference between periodontal therapy with anti-tumor necrosis factor-alpha (TNF-alpha) medication and pure anti-TNF-alpha medication (P=0.24). But the subgroup analysis showed that a significantly decreased DAS28 was achieved by periodontal therapy (P=0.03), and the interventions provided a remarkable effect on alleviating clinical signs and erythrocyte sedimentation rate of RA (P<0.05). Results of the symptoms relief differed from the studies. No adverse events were reported. CONCLUSION: The evidence available currently indicates that periodontal therapy may play a positive role in remitting the clinical signs and periodontal status of RA except the relief of the symptoms.
21061259 Genome-wide association study of genetic predictors of anti-tumor necrosis factor treatmen 2011 Mar OBJECTIVE: Anti-tumor necrosis factor (anti-TNF) agents are successful therapies in rheumatoid arthritis (RA); however, inadequate response occurs in 30-40% of patients treated. Knowledge of the genetic factors that influence response may facilitate personalized therapy. The purpose of this study was to identify genetic predictors of response to anti-TNF therapy in RA and to validate our findings in independent cohorts. METHODS: Data from genome-wide association (GWA) studies were available from the Wellcome Trust Case Control Consortium for 566 anti-TNF-treated RA patients. Multivariate linear regression analysis of changes in the Disease Activity Score in 28 joints at 6 months was conducted at each single-nucleotide polymorphism (SNP) using an additive model. Associated markers (P < 10(-3) ) were genotyped in 2 independent replication cohorts (n = 379 and n = 341), and a combined analysis was performed. RESULTS: Of 171 successfully genotyped markers demonstrating association with treatment response in the GWA data, 7 were corroborated in the combined analysis. The strongest effect was at rs17301249, mapping to the EYA4 gene on chromosome 6: the minor allele conferred improved response to treatment (coefficient -0.27, P = 5.67(-05) ). The minor allele of rs1532269, mapping to the PDZD2 gene, was associated with a reduced treatment response (coefficient 0.20, P = 7.37(-04) ). The remaining associated SNPs mapped to intergenic regions on chromosomes 1, 4, 11, and 12. CONCLUSION: Using a genome-wide strategy, we have identified and validated the association of 7 genetic loci with response to anti-TNF treatment in RA. Additional confirmation of these findings in further cohorts will be required.
22652781 IL-6, IL-17 and STAT3: a holy trinity in auto-immunity? 2012 Jun 1 Interleukin-6 (IL-6) is a pleiotropic cytokine involved in the regulation of the cross talk between haematopoietic/immune cells and stromal cells, including the onset and resolution of inflammation, responses to infection, tissue remodelling and cancer. It is produced, among others, by fibroblasts, endothelial cells, macrophages and lymphocytes. IL-6 can interact with both membrane-bound and soluble forms of its ligand-binding receptor, the IL-6Ralpha, triggering signalling via dimerization of gp130, the signalling subunit of the IL-6 receptor complex. This leads to the activation of the JAK/STAT pathway and mainly culminates in the activation of the STAT3 transcription factor. Both IL-6 and STAT3 have recently emerged as main regulators of the differentiation and function of Th17 cells, via a positive feedback loop enhancing expression and/or activation of IL-6 itself, IL-17 and STAT3. Dysregulated IL-6 production and signalling are associated with chronic inflammatory diseases, auto-immunity and cancer, and are the object of intense translational research as promising therapeutic targets.