Browse

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

ID PMID Title PublicationDate abstract
27577177 Pomegranate extract alleviates disease activity and some blood biomarkers of inflammation 2017 Jan BACKGROUND/OBJECTIVES: Since the main characteristics of Rheumatoid Arthritis (RA) are joint dysfunction caused by inflammation and serious pain, anti-inflammatory agents may alleviate the clinical symptoms in RA. Pomegranate juice is rich in polyphenolic compounds that possess antioxidant and anti-inflammatory activities. This study aimed to determine the beneficial effects of pomegranate extract (POMx) in RA patients. SUBJECTS/METHODS: A total of 55 RA patients were enrolled and randomly allocated to an intervention group (n=30) or a control group (n=25). The intervention group received 2 capsules of 250 mg POMx and the control group 2 capsules of 250 mg cellulose per day for 8 weeks. At the beginning of the study and after 8 weeks, Health Assessment Questionnaire (HAQ) and Disease Activity Score (DAS) 28 were completed and serum concentrations of C-reactive protein (CRP), matrix metalloproteinases 3 (MMP3), malondialdehyde (MDA), glutathione peroxidase (GPx) and erythrocyte sedimentation rate (ESR) were analyzed using standard methods and compared between the two groups. RESULTS: Compared with the placebo group, POMx supplement significantly reduced the score of DAS28 (P<0.001) which could be related to the decrease in swollen (P<0.001) and tender joints (P=0.001) count, pain intensity (P=0.003) and ESR levels (P= 0.03). POMx consumption also decreased HAQ score (P=0.007) and morning stiffness (P=0.04) and increased GPx concentrations (P<0.001). There were no differences in the change in mean MMP3, CRP and MDA levels between two groups. CONCLUSIONS: POMx alleviates disease activity and improves some blood biomarkers of inflammation and oxidative stress in RA patients.
27373288 [The application of matrix metalloproteinase-3 and 7 joints ultrasonic score in assessment 2016 Jul 1 OBJECTIVE: To evaluate the significance of serum matrix metalloproteinase-3 (MMP-3) and joint ultrasonography in assessing the activity of rheumatoid arthritis (RA) by comparing MMP-3 level and the ultrasonic 7 joints (US7) score in RA patients. METHODS: Serum MMP-3 level and US7 score were measured in 133 RA patients by immune turbidity and Doppler ultrasound. Synchronous 53 healthy subjects were recruited as controls. Clinical data were collected. Erythrocyte sedimentation rate (ESR), serum level of anti-cyclic citrullinated peptide (CCP) antibody, health assessment questionnaire (HAQ) and disease activity score 28 (DAS28) were measured. The level of disease activity is interpreted as remission(DAS28<2.6), low(DAS 28≥2.6-<3.2), moderate(DAS 28≥3.2-<5.1), high(DAS28≥5.1). The discriminating validity of MMP-3 and US7 score in disease was evaluated using receiver operating characteristic (ROC) curve analysis with DAS28 as the reference standard. RESULTS: Compared with that in healthy controls [35.20(25.90, 48.90) μg/L] and remission patients[33.40(22.60, 678.40) μg/L], the MMP-3 level in moderate [105.1(61.70, 172.70) μg/L] and high [363.1(161.50, 475.90) μg/L] groups increased dramatically. US7 score in patients with high disease activity was significantly higher than that in other groups. The level of MMP-3 was significantly correlated with DAS28, HAQ, US7 score, yet did not have correlation with anti-CCP antibody. Serum level of MMP-3 was positively correlated with US7 score(r=0.566, P<0.001). In evaluating the disease activity, US7 score combined with MMP-3 (AUC 0.863 2) was not superior to MMP-3 alone (AUC 0.854 3), but significantly better than single US7 score (AUC 0.764 3, P<0.05). CONCLUSIONS: MMP-3 is an effective and simple index in evaluating RA disease activity. The combination of MMP-3 and US7 score does not further improve the efficacy to evaluate disease activity than MMP-3 alone in patients with RA.
27687651 [Correlation of DNase I in serum and synovial fluid with inflammatory activity in patients 2016 Aug 20 OBJECTIVE: To investigate the potential role of deoxyribonuclease I (DNase I) in the pathogenesis of rheumatoid arthritis (RA). METHODS: DNase I activity was measured by radial enzyme-diffusion method in serum samples from 83 RA patients and 60 healthy volunteers and in the synovial fluid (SF) from 27 RA patients and 38 patients with other inflammatory arthritis. SF cfDNA level was measured with Pico Green Kit, and the correlation among DNase I activity, cfDNA level and clinical parameters of RA patients was analyzed. RESULTS: Serum DNase I activity was significantly lower in RA patients than in the healthy control subjects (0.3065∓0.1436 vs 0.4289∓0.1976 U/mL, P<0.001), and was negatively correlated with ESR (r=-0.2862, P=0.0122), CRP (r=-0.2790, P=0.0184) and neutrophil cell counts (r=-0.287, P=0.011). SF DNase I activity was almost negative in patients with RA, ankylosing spondylitis (AS) and gouty arthritis (GA). SF cfDNA level in RA patients was significantly higher than that in patients with osteoarthritis (100.81∓142.98 vs 18.98∓31.40 µg/mL, P=0.002), but similar to that in patients with AS (45.85∓47.67 µg/mL, P=0.428) and GA (162.95∓97.49 µg/mL, P=0.132). In patients with inflammatory arthritis, SF cfDNA level was positively correlated with ESR (r=0.4106, P=0.0116) and CRP (r=0.5747, P=0.0002). CONCLUSION: Impairment of DNase I activity may be responsible for the enhanced NETs generation and plays a role in the pathogenesis of RA.
27084374 The metabolic profile in early rheumatoid arthritis: a high prevalence of metabolic obesit 2017 Jan The aim of the study was to compare the prevalence of metabolic syndrome (MetS) in early RA patients with age-gender-matched population controls focusing on the presence of MetS in different weight categories. The study group consisted of 91 consecutive patients with early RA and 273 age- and gender-matched controls subjects. MetS was diagnosed according to the National Cholesterol Education Program (NCEP-ATP III) criteria. Mean age in both groups was 52 years, and 72.5 % were female. The prevalence of MetS did not differ between the two groups (35.2 % in RA, 34.1 % in control group). Mean systolic blood pressure in the RA group was 137 mmHg, in control group 131 mmHg, P = 0.01, and diastolic blood pressure 85 versus 81 mmHg, respectively (P < 0.01). We found that 20 of 65 (30.8 %) of RA patients compared to 80 of 152 (52.6 %) of the control subjects with elevated blood pressure received antihypertensive treatment (P < 0.01). When comparing subgroups with normal BMI, the odds of having MetS (being metabolically obese) were higher among early RA subjects (OR 5.6, CI 1.3-23.8). Of the individual components of metabolic syndrome, we found increased prevalence of hypertension (OR 2.8, CI 1.3-6.0) and hyperglycemia (OR 2.9, CI 1.0-8.0) in the RA group. Recognition of abnormal metabolic status among normal-weight RA patients who have not yet developed CVD could provide a valuable opportunity for preventative intervention.
26700586 Serum proteomic analysis identifies interleukin 16 as a biomarker for clinical response du 2016 Feb OBJECTIVES: To conduct a comprehensive quantitative proteomics analysis of novel serum protein biomarkers based on synovitis status associated with matrix metalloproteinase-3 (MMP-3) and to determine the clinical significance of these biomarkers in rheumatoid arthritis (RA). METHODS: Patients with untreated RA (n=28), primary Sjogren's syndrome (pSS) (n=30), and healthy controls (HCs) (n=30) were enrolled for the screening assay. A total of 1128 serum proteins were analyzed using the SOMAscan™ assay. Serum levels of MMP-3 and interleukin (IL)-16 were measured using a latex turbidimetric immunoassay and ELISA at baseline and 12weeks after treatment with methotrexate (MTX) for MTX-naïve RA patients (n=28) or with the biologics tocilizumab (TCZ) (n=7), abatacept (ABT) (n=11) or infliximab (n=22) for MTX-inadequate response (IR) RA patients. Correlation analysis was conducted using Spearman's rank correlation method. RESULTS: Proteomics showed that serum IL-16 levels were most positively correlated with those of MMP-3 (ρ=0.51, p<0.01) and were significantly increased in patients with untreated active RA compared to HCs (p<0.01) or those with pSS (p<0.01). IL-16 levels decreased following treatment in both the MTX-naïve and MTX-IR groups. Regarding clinical response, fluctuations in IL-16 levels were positively associated with changes in clinical indicators, particularly the Clinical Disease Activity Index (ρ=0.89, p<0.01) in the TCZ and ABT-treated group. However, no similar correlation was noted in MMP-3 and acute phase reactants in any groups. CONCLUSIONS: IL-16 was a more effective clinical parameter than MMP-3, C-reactive protein, or erythrocyte sedimentation rate in both MTX-naive and MTX-IR RA patients. IL-16 might be a useful biomarker for evaluating clinical response in RA patients.
25529032 Echocardiographic evaluation of diastolic dysfunction in rheumatoid arthritis - a case-con 2015 Jul OBJECTIVES: To assess left ventricular diastolic dysfunction (LVDD) and its predictors in rheumatoid arthritis (RA). METHODS: This cross-sectional case-control study assessed 100 RA patients and 100 healthy controls for LVDD by M-mode, two-dimensional, colour Doppler echocardiography. RESULTS: RA patients had higher prevalence of LVDD than controls (43% vs. 14%; p < 0.001). LVDD had significant association with duration (p = 0.033), severity of disease activity (p < 0.0001), Steinbrocker stage and functional class (p < 0.0001 each) and non-adherence to treatment (p = 0.047). Peak of late diastolic (A) mitral flow velocity and isovolumic relaxation time (IVRT) were higher (p < 0.05 each), whereas left ventricular ejection fraction, peak of early diastolic (E) mitral flow velocity and E/A ratio were lower (p < 0.05 each) in RA patients than in controls. Deceleration time (DT) was not significantly different in the two groups (p = 0.623). E/A ratio had significant correlation with anti-cyclic citrullinated peptide antibody (ACPA) (r = 0.233, p = 0.019) and age (r = 0.203, p = 0.042). IVRT had significant negative correlation with ACPA (r = -0.196, p = 0.044), while DT had significant correlation with Disease Activity Score with 28-joint (DAS28) counts (r = 0.244, p = 0.014). ACPA was an independent predictor of E/A ratio (p = 0.031). DAS28 was the only independent predictor of LVDD (odds ratio [OR] = 6.01; p = 0.007). CONCLUSIONS: LVDD occurred commonly in RA patients and depended on severity of disease activity.
28350303 Applying Advanced Analytical Approaches to Characterize the Impact of Specific Clinical Ga 2016 Fall INTRODUCTION: The goal of this study was to add a predictive modeling approach to the meta-analysis of continuing medical education curricula to determine whether this technique can be used to better understand clinical decision making. Using the education of rheumatologists on rheumatoid arthritis management as a model, this study demonstrates how the combined methodology has the ability to not only characterize learning gaps but also identify those proficiency areas that have the greatest impact on clinical behavior. METHODS: The meta-analysis included seven curricula with 25 activities. Learners who identified as rheumatologists were evaluated across multiple learning domains, using a uniform methodology to characterize learning gains and gaps. A performance composite variable (called the treatment individualization and optimization score) was then established as a target upon which predictive analytics were conducted. RESULTS: Significant predictors of the target included items related to the knowledge of rheumatologists and confidence concerning 1) treatment guidelines and 2) tests that measure disease activity. In addition, a striking demographic predictor related to geographic practice setting was also identified. DISCUSSION: The results demonstrate the power of advanced analytics to identify key predictors that influence clinical behaviors. Furthermore, the ability to provide an expected magnitude of change if these predictors are addressed has the potential to substantially refine educational priorities to those drivers that, if targeted, will most effectively overcome clinical barriers and lead to the greatest success in achieving treatment goals.
26632183 Pharmacokinetics and Antiinflammatory Effect of a Novel Gel System Containing Ketoprofen S 2015 We previously reported that dermal application using nanoparticles improves skin penetration. In this study, we prepared novel topical formulations containing ketoprofen (KET) solid nanoparticles (KETnano gel ointment) and investigated the antiinflammatory effect of the KET nanoparticle formulations on rheumatoid arthritis using adjuvant-induced arthritis (AA) rats. The KETnano gel ointment was prepared using a bead mill method and additives including methylcellulose and Carbopol 934; the mean particle size of the KET nanoparticles was 83 nm. In the in vitro skin penetration experiment, the penetration rate (Jc) and penetration coefficient through the skin (Kp) values of the KETnano gel ointment were significantly higher than those of gel ointment containing KET microparticles (KETmicro gel ointment; mean particle size 7.7 µm). On the other hand, in the in vivo percutaneous absorption experiment, the apparent absorption rate constant (ka) and the areas under the KET concentration-time curve values in the skin of rats receiving the KETnano gel ointment were significantly higher than those of rats receiving the KETmicro gel ointment, and the amounts of KET in the skin tissues of rats receiving the KETnano gel ointment were also significantly higher than those of rats receiving the KETmicro gel ointment. In addition, the application of the KETnano gel ointment attenuated the enhancement of paw edema of the hind feet of AA rats more than the application of the KETmicro gel ointment. Our findings suggest that a topical drug delivery system using nanoparticles could lead to expansion in the therapeutic use of KET.
27832150 One-Year Tuberculosis Risk in Rheumatoid Arthritis Patients Starting Their First Tumor Nec 2016 OBJECTIVE: To investigate the risk of tuberculosis (TB) among rheumatoid arthritis (RA) patients within 1 year after initiation of tumor necrosis factor inhibitor (TNFi) therapy from 2008 to 2012. METHODS: We used the 2003-2013 Taiwanese National Health Insurance Research Database to identify RA patients who started any RA-related medical therapy from 2008 to 2012. Those who initiated etanercept or adalimumab therapy during 2008-2012 were selected as the TNFi group and those who never received biologic disease-modifying anti-rheumatic drug therapy were identified as the comparison group after excluding the patients who had a history of TB or human immunodeficiency virus infection/acquired immune deficiency syndrome. We used propensity score matching (1:6) for age, sex, and the year of the drug index date to re-select the TNFi group and the non-TNFi controls. After adjusting for potential confounders, hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to examine the 1-year TB risk in the TNFi group compared with the non-TNFi controls. Subgroup analyses according to the year of treatment initiation and specific TNFi therapy were conducted to assess the trend of 1-year TB risk in TNFi users from 2008 to 2012. RESULTS: This study identified 5,349 TNFi-treated RA patients and 32,064 matched non-TNFi-treated controls. The 1-year incidence rates of TB were 1,513 per 105 years among the TNFi group and 235 per 105 years among the non-TNFi controls (incidence rate ratio, 6.44; 95% CI, 4.69-8.33). After adjusting for age, gender, disease duration, comoridities, history of TB, and concomitant medications, TNFi users had an increased 1-year TB risk (HR, 7.19; 95% CI, 4.18-12.34) compared with the non-TNFi-treated controls. The 1-year TB risk in TNFi users increased from 2008 to 2011 and deceased in 2012 when the Food and Drug Administration in Taiwan announced the Risk Management Plan for patients scheduled to receive TNFi therapy. CONCLUSION: This study showed that the 1-year TB risk in RA patients starting TNFi therapy was significantly higher than that in non-TNFi controls in Taiwan from 2008 to 2012.
26546586 Increased pretreatment serum IFN-β/α ratio predicts non-response to tumour necrosis fact 2016 Oct OBJECTIVE: Studies suggest that circulating type I interferon (IFN) may predict response to biological agents in rheumatoid arthritis (RA). Prediction of response prior to initiating therapy would represent a major advancement. METHODS: We studied sera from a test set of 32 patients with RA from the Auto-immune Biomarkers Collaborative Network Consortium and a validation set of 92 patients with RA from the Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository registry. The test set included those with good response or no response to tumour necrosis factor (TNF) inhibitors at 14 weeks by European League Against Rheumatism criteria. The validation set included subjects with good, moderate or no response at 12 weeks. Total serum type I IFN activity, IFN-α and IFN-β activity were measured using a functional reporter cell assay. RESULTS: In the test set, an increased ratio of IFN-β to IFN-α (IFN-β/α activity ratio) in pretreatment serum associated with lack of response to TNF inhibition (p=0.013). Anti-cyclic citrullinated peptide antibody titre and class of TNF inhibitor did not influence this relationship. A receiver-operator curve supported a ratio of 1.3 as the optimal cut-off. In the validation set, subjects with an IFN-β/α activity ratio >1.3 were significantly more likely to have non-response than good response (OR=6.67, p=0.018). The test had 77% specificity and 45% sensitivity for prediction of non-response compared with moderate or good response. Meta-analysis of test and validation sets confirmed strong predictive capacity of IFN-β/α activity ratio (p=0.005). CONCLUSIONS: Increased pretreatment serum IFN-β/α ratio strongly associated with non-response to TNF inhibition. This study supports further investigation of serum type I IFN in predicting outcome of TNF inhibition in RA.
26110994 The Additive Inflammatory In Vivo and In Vitro Effects of IL-7 and TSLP in Arthritis Under 2015 INTRODUCTION: The cytokines interleukin (IL)-7 and thymic stromal lymphopoietin (TSLP) signal through the IL-7R subunit and play proinflammatory roles in experimental arthritis and rheumatoid arthritis (RA). We evaluated the effect of inhibition of IL-7R- and TSLPR-signalling as well as simultaneous inhibition of IL-7R- and TSLPR-signalling in murine experimental arthritis. In addition, the effects of IL-7 and TSLP in human RA dendritic cell (DC)/T-cell co-cultures were studied. METHODS: Arthritis was induced with proteoglycan in wildtype mice (WT) and in mice deficient for the TSLP receptor subunit (TSLPR-/-). Both mice genotypes were treated with anti-IL-7R or phosphate buffered saline. Arthritis severity was assessed and local and circulating cytokines were measured. Autologous CD1c-positive DCs and CD4 T-cells were isolated from peripheral blood of RA patients and were co-cultured in the presence of IL-7, TSLP or both and proliferation and cytokine production were assessed. RESULTS: Arthritis severity and immunopathology were decreased in WT mice treated with anti-IL-7R, in TSLPR-/- mice, and the most robustly in TSLPR-/- mice treated with anti-IL-7R. This was associated with strongly decreased levels of IL-17, IL-6 and CD40L. In human DC/T-cell co-cultures, TSLP and IL-7 additively increased T-cell proliferation and production of Th17-associated cytokines, chemokines and tissue destruction factors. CONCLUSION: TSLP and IL-7 have an additive effect on the production of Th17-cytokines in a human in vitro model, and enhance arthritis in mice linked with enhanced inflammation and immunopathology. As both cytokines signal via the IL-7R, these data urge for IL-7R-targeting to prevent the activity of both cytokines in RA.
25982097 The exaggerated inflammatory response in Behçet's syndrome: identification of dysfunction 2015 Sep The mechanisms underlying the exaggerated inflammatory response in Behçet's syndrome (BS) remain poorly understood. We investigated the response of CD14(+) blood monocytes to interferon (IFN)-γ, focusing on the chemokine CXCL10. Chemokine synthesis and release were analysed at a protein and mRNA level following stimulation with IFN-γ. Findings in BS patients were compared with 25 healthy controls (HC), 15 rheumatoid arthritis (RA) and 15 systemic lupus erythematosus (SLE) disease control patients. BS monocytes produced significantly more CXCL10 protein than HC monocytes from 2 h following IFN-γ stimulation, despite equivalent quantities of mRNA, suggesting more efficient translation. This was significantly more pronounced in BS with high disease activity and in those with ocular and neurological clinical manifestations. The imbalance between CXCL10 protein and mRNA expression was not observed in either RA or SLE patients, and was not seen with other chemokines studied (CXCL9, CXCL11 and CCL2). Furthermore, BS monocytes treated with an alternative stimulant (LPS) did not show abnormal tumour necrosis factor (TNF)-α release. Sucrose density gradients to segregate monocyte CXCL10 mRNA into free RNA or polysome-associated RNA showed equal proportions in BS and HC samples, suggesting that the difference between BS and HC may be due to reduced negative control of CXCL10 translation in BS at a post-initiation level. We conclude that BS monocytes have dysfunctional post-transcriptional regulation of CXCL10 mRNA, resulting in over-expression of CXCL10 protein upon IFN-γ stimulation. As CXCL10 is a chemokine that recruits mononuclear cells, this abnormality may contribute to the exaggerated inflammatory responses that characterizes BS.
26103979 Step-down strategy of spacing TNF-blocker injections for established rheumatoid arthritis 2016 Jan Tumour necrosis factor (TNF)-blocker tapering has been proposed for patients with rheumatoid arthritis (RA) in remission. OBJECTIVE: The trial aims to compare the effect of progressive spacing of TNF-blocker injections (S-arm) to their maintenance (M-arm) for established patients with RA in remission. METHODS: The study was an 18-month equivalence trial which included patients receiving etanercept or adalimumab at stable dose for ≥1 year, patients in remission on 28-joint Disease Activity Score (DAS28) for ≥6 months and patients with stable joint damage. Patients were randomised into two arms: maintenance or injections spacing by 50% every 3 months up to complete stop. Spacing was reversed to the previous interval in case of relapse, and eventually reattempted after remission was reachieved. The primary outcome was the standardised difference of DAS28 slopes, based on a linear mixed-effects model (equivalence interval set at ±30%). RESULTS: 64 and 73 patients were included in the S-arm and M-arm, respectively, which was less than planned. In the S-arm, TNF blockers were stopped for 39.1%, only tapered for 35.9% and maintained full dose for 20.3%. The equivalence was not demonstrated with a standardised difference of 19% (95% CI -5% to 46%). Relapse was more common in the S-arm (76.6% vs 46.5%, p=0.0004). However, there was no difference in structural damage progression. CONCLUSIONS: Tapering was not equivalent to maintenance strategy, resulting in more relapses without impacting structural damage progression. Further studies are needed to identify patients who could benefit from such a strategy associated with substantial cost savings. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT00780793; EudraCT identifier: 2007-004483-41.
27852377 [Predictive value of dynamic enhanced MR synovial wash in rate in progression to rheumatoi 2016 Nov 8 Objective: To investigate the predictive value of dynamic enhanced MR synovial wash in rate (WASHIN) in progression to rheumatoid arthritis (RA) in patients with undifferentiated arthritis (UA). Methods: The data of dynamic enhanced MR synovial WASHIN and C- reactive protein (CRP) of 33 patients with UA were analyzed between October 2014 and January 2016 from Tianjin First Center Hospital, so as to evaluate the correlation between the two indicators. According to the value of CRP, the patients were divided into two groups, the CRP>8 mg/L for CRP positive group (18 cases), CRP≤8 mg/L for CRP negative group (15 cases). Ranked sum test was used to compare the difference of WASHIN between two groups. The ROC curve analysis was carried out to test the diagnostic power of WASHIN. Results: In 33 patients with UA, the correlation between WASHIN and CRP was positive, r=0.767, P<0.01; as for the WASHIN, there was significant difference between CRP positive group(49.51±19.79)/s and CRP negative group(19.90±14.51)/s (P<0.01). 9 cases were clinically diagnosed with RA during follow-up, of which 8 cases for CRP positive group and 1 case for CRP negative group. The biggest area under the ROC curve of synovial WASHIN was 0.944, the biggest Youden index was 0.85, sensitivity was 100.0%, specificity was 87.5%. 2 cases were clinically diagnosed with osteoarthrosis during follow-up, synovial WASHIN respectively of 18.42 and 21.48 /s. Conclusion: Synovial WASHIN can improve the sensitivity and specificity to predict the prognosis from UA to RA, and can provide certain guiding significance for clinical work.
25858640 Expression of chemokines CXCL4 and CXCL7 by synovial macrophages defines an early stage of 2016 Apr BACKGROUND AND OBJECTIVES: For our understanding of the pathogenesis of rheumatoid arthritis (RA), it is important to elucidate the mechanisms underlying early stages of synovitis. Here, synovial cytokine production was investigated in patients with very early arthritis. METHODS: Synovial biopsies were obtained from patients with at least one clinically swollen joint within 12 weeks of symptom onset. At an 18-month follow-up visit, patients who went on to develop RA, or whose arthritis spontaneously resolved, were identified. Biopsies were also obtained from patients with RA with longer symptom duration (>12 weeks) and individuals with no clinically apparent inflammation. Synovial mRNA expression of 117 cytokines was quantified using PCR techniques and analysed using standard and novel methods of data analysis. Synovial tissue sections were stained for CXCL4, CXCL7, CD41, CD68 and von Willebrand factor. RESULTS: A machine learning approach identified expression of mRNA for CXCL4 and CXCL7 as potentially important in the classification of early RA versus resolving arthritis. mRNA levels for these chemokines were significantly elevated in patients with early RA compared with uninflamed controls. Significantly increased CXCL4 and CXCL7 protein expression was observed in patients with early RA compared with those with resolving arthritis or longer established disease. CXCL4 and CXCL7 co-localised with blood vessels, platelets and CD68(+) macrophages. Extravascular CXCL7 expression was significantly higher in patients with very early RA compared with longer duration RA or resolving arthritis CONCLUSIONS: Taken together, these observations suggest a transient increase in synovial CXCL4 and CXCL7 levels in early RA.
24864075 Defining the role of Porphyromonas gingivalis peptidylarginine deiminase (PPAD) in rheumat 2015 Nov BACKGROUND: Antibodies to citrullinated proteins are a hallmark of rheumatoid arthritis (RA). Porphyromonas gingivalis peptidylarginine deiminase (PPAD) has been implicated in the initiation of RA by generating citrullinated neoantigens and due to its ability to autocitrullinate. OBJECTIVES: To define the citrullination status and biology of PPAD in P gingivalis and to characterise the anti-PPAD antibody response in RA and associated periodontal disease (PD). METHODS: PPAD in P gingivalis cells and culture supernatant were analysed by immunoblotting and mass spectrometry to detect citrullination. Recombinant PPAD (rPPAD), inactive mutant PPAD (rPPAD(C351S)), and N-terminal truncated PPAD (rPPAD(Ntx)) were cloned and expressed in Escherichia coli. Patients with RA and healthy controls were assayed for IgG antibodies to citrullinated rPPAD and unmodified rPPAD(C351S) by ELISA. Anti-PPAD antibodies were correlated with anti-cyclic citrullinated peptide (third-generation) antibody levels, RA disease activity and PD status. RESULTS: PPAD from P gingivalis is truncated at the N-terminal and C-terminal domains and not citrullinated. Only when artificially expressed in E coli, full-length rPPAD, but not truncated (fully active) rPPAD(Ntx), is autocitrullinated. Anti-PPAD antibodies show no heightened reactivity to citrullinated rPPAD, but are exclusively directed against the unmodified enzyme. Antibodies against PPAD do not correlate with anti-cyclic citrullinated peptide levels and disease activity in RA. By contrast, anti-PPAD antibody levels are significantly decreased in RA patients with PD. CONCLUSIONS: PPAD autocitrullination is not the underlying mechanism linking PD and RA. N-terminal processing protects PPAD from autocitrullination and enhances enzyme activity. Anti-PPAD antibodies may have a protective role for the development of PD in patients with RA.
27245864 High frequency of antidrug antibodies and association of random drug levels with efficacy 2017 Jan OBJECTIVES: To evaluate (i) the association between random certolizumab drug levels, antidrug antibodies (ADAbs) and treatment response in patients with rheumatoid arthritis (RA); (ii) longitudinal factors associated with ADAbs and certolizumab drug levels. METHODS: This prospective cohort included 115 patients with RA treated with certolizumab. Serum samples were collected at 3, 6 and 12 months following treatment initiation. Drug levels and ADAbs were measured using ELISA and radioimmunoassay, respectively, at 3, 6 and 12 months. Disease Activity Score in 28 joints (DAS28) were measured at each visit and 12 months European League Against Rheumatism (EULAR) response was calculated. Patient self-reported adherence was collected longitudinally. Ordinal logistic regression and generalised estimating equation were used to test the association: (i) between drug levels, from serum sampled and treatment response; (ii) between ADAbs and drug levels; (iii) patient-centred factors and drug levels. RESULTS: ADAbs were detected in 37% (42/112 patients by 12 months). The presence of ADAbs were significantly associated with lower drug levels over 12 months (β=-0.037, 95% CI -0.055 to 0.018, p<0.0001) but not independently with 12 months EULAR response (β=0.0013 (95% CI -0.0032 to 0.00061), p=0.18). Drug level was associated with 12 months EULAR response (β=0.032 (95% CI 0.0011 to 0.063), p=0.042). In the multivariate model, ADAb level and adherence were significantly associated with drug concentrations. CONCLUSIONS: This is the first study to demonstrate that higher certolizumab drug levels are associated with better 12 months EULAR response. ADAbs in certolizumab-treated patients with RA were detected at higher levels than previous studies and help determine the aetiology of a low drug level.
28041910 Necrotizing fasciitis in a patient receiving tocilizumab for rheumatoid arthritis - Case r 2018 May We present a case of necrotizing fasciitis in a 66-year-old Caucasian woman with rheumatoid arthritis receiving tocilizumab, and provide a review of published cases. The patient exhibited no systemic symptoms and discreet cutaneous inflammatory signals at presentation. She was successfully treated with broad-spectrum empiric antibiotic therapy and surgical debridement.
26708943 Time lag between the initiation of adalimumab after methotrexate correlates with the effic 2016 Sep OBJECTIVES: To evaluate the efficacy and safety of adalimumab (ADA) and methotrexate (MTX) in patients with rheumatoid arthritis (RA) and investigate critical factors associated with efficacy. METHODS: In this retrospective cohort study, patients received ADA at a single facility. Clinical outcome was retrospectively evaluated using the Disease Activity Score in 28 joints with Erythrocyte Sedimentation Rate (DAS28-ESR). RESULTS: Of the 122 patients undergoing treatment with ADA between July 2008 and April 2014, DAS28-ESR data after 6 months of treatment were available for 103 and 87 (84.5%) were treated with a combination of ADA and MTX. For combination therapy, time lag between MTX and the initiation of ADA significantly correlated with efficacy of ADA at 6 months, as well as prior use of biologics, but not disease duration. CONCLUSIONS: Clinical outcomes were correlated with the time lag between MTX and the initiation of ADA, not disease duration. Early initiation of ADA after MTX might improve clinical outcomes.
26353115 Constitutive STAT3 Phosphorylation in Circulating CD4+ T Lymphocytes Associates with Disea 2015 The aim of the present study was to examine constitutive signal transducer and activator of transcription 3 (STAT3) phosphorylation in circulating leukocytes as a candidate biomarker in rheumatoid arthritis (RA). 25 patients with recent-onset, untreated RA provided samples for whole blood flow cytometric determination of intracellular STAT3 phosphorylation, expressed as relative fluorescence units. The occurrence of constitutive STAT3 phosphorylation was evaluated by determining proportion of STAT3-phosphorylated cells among different leukocyte subtypes. Plasma levels of interleukin (IL)-6, IL-17 and IL-21 were measured by immunoassay, radiographs of hands and feet were examined and disease activity score (DAS28) was determined. Biomarkers were restudied and treatment response (according to European League Against Rheumatism) was determined after 12 months of treatment with disease-modifying antirheumatic drugs. At baseline, constitutive phosphorylation of STAT3 occurred in CD4+ T cells of 14 (56%) patients, CD8+ T cells of 13 (52%) patients, in CD19+ B cells of 7 (28%) patients, and in CD14+ monocytes of 12 (48%) patients. STAT3 phosphorylation levels of CD4+ T cells associated with DAS28, and those of all leukocyte subtypes studied associated with erosive disease. The presence of constitutive STAT3 phosphorylation in CD4+ T lymphocytes, pSTAT3 fluorescence intensity of CD4+ and CD8+ T cells and C-reactive protein (CRP) levels at baseline associated with good treatment response. In conclusion, constitutive STAT3 phosphorylation in circulating CD4+ T cells is common in recent-onset untreated RA and associates with good treatment response in patients characterized by high disease activity and the presence of systemic inflammation.